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Authors: Volkan Adsay, M.D., Diana Agostini-Vulaj, D.O., Beena Ahsan, M.D., Derek Allison, M.D., Ayşe Armutlu, M.D., Vidya Arole, M.D., Gokce Askan, M.D., Olca Basturk, M.D., Adam L. Booth, M.D., Pınar Bulutay, M.D., Wei Chen, M.D., Ph.D., Irene Y. Chen, M.D., David J. Escobar, M.D., Ph.D., Ashwini Kumar Esnakula, M.D., M.S., Raul S. Gonzalez, M.D., Jan Hrudka, M.D., Ph.D., Aaron R. Huber, D.O., Danielle Hutchings, M.D., Deepali Jain, M.D., Victoria M. Jones, M.D., Ryan Kendziora, M.D., Sarah Kisha, M.D., Amanda Kitson, M.D., Katrina Krogh, M.D., Enoch Kuo, M.D., Claudio Luchini, M.D., Ph.D., Maria Gaia Mastrosimini, M.D., Paola Mattiolo, M.D., Alexei Mikhailov, M.D., Ph.D., Pooja Navale, M.D., Kenechukwu Ojukwu, M.D., M.P.P., Hulya Sahin Ozkan, M.D., Gaetano Paolino, M.D., Nat Pernick, M.D., Maryam Kherad Pezhouh, M.D., M.Sc., Maria Luisa C. Policarpio-Nicolas, M.D., Jen Rytych, M.D., Olivia A. Sagan, M.D., Omid Savari, M.D., Jiaqi Shi, M.D., Ph.D., Susan Shyu, M.D., Aatur D. Singhi, M.D., Ph.D., Sabrina C. Sopha, M.D., Orhun Çiğ Taşkın, M.D., Joseph F. Tomashefski, Jr., M.D., Pierre Tran, B.A., Jennifer Vazzano, D.O., M.S., Monika Vyas, M.D., Rong Xia, M.D., Ph.D., Guang-Yu Yang, M.D., Ph.D., Aslihan Yavas, M.D., Lizhi Zhang, M.D., Jennifer Ziebell, M.D.

Editorial Board Members: Naziheh Assarzadegan, M.D., Wei Chen, M.D., Ph.D., Bonnie Choy, M.D., Raul S. Gonzalez, M.D., Catherine E. Hagen, M.D., Aaron R. Huber, D.O., Danielle Hutchings, M.D., Xiaoyan Liao, M.D., Ph.D., Maryam Kherad Pezhouh, M.D., M.Sc., Monika Vyas, M.D.

Deputy Editors-in-Chief: Raul S. Gonzalez, M.D., Catherine E. Hagen, M.D., Aaron R. Huber, D.O., Debra L. Zynger, M.D.

Editor-in-Chief: Debra L. Zynger, M.D.

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Editorial Board oversight: Wei Chen, M.D., Ph.D. (last reviewed December 2024)

Superpage Topics

Acinar cell carcinoma Acinar cystic transformation ACTH secreting tumors Acute pancreatitis Adenosquamous carcinoma Allograft rejection Anatomy & histology Autoimmune pancreatitis type 1 Autoimmune pancreatitis type 2 Chronic pancreatitis Clear cell pancreatic endocrine tumor Colloid carcinoma Cystic endocrine tumors Cystic fibrosis Cytology Diabetes mellitus Ductal adenocarcinoma, NOS Familial pancreatic neoplasms (pending) Features to report-pancreatectomy Frozen section Gastrinoma Glucagonoma (alpha cell tumors) Grossing Heterotopic pancreas Insulinoma (beta cell tumor) Intraductal oncocytic papillary neoplasm (IOPN) Intraductal papillary mucinous neoplasm (IPMN) Intraductal tubulopapillary neoplasm (ITPN) Lymphoepithelial cysts Medullary carcinoma MEN1 syndrome Mixed neuroendocrine nonneuroendocrine neoplasms (MiNENs) Molecular genetics of pancreatic ductal carcinoma Mucinous cystic neoplasm (MCN) Mucinous pancreatic tumor overview Nesidioblastosis Neuroendocrine neoplasms-general Neuroendocrine tumor with sarcomatous differentiation Pancreatic cystic fluid analysis (pending) Pancreatic polypeptide secreting tumors Pancreatoblastoma PanIN Poorly differentiated neuroendocrine carcinoma PRSS1 hereditary pancreatitis Pseudocysts Risk stratification of IPMNs (pending) Sclerosing epithelioid mesenchymal neoplasm Serous cystadenoma Simple mucinous cyst Solid pseudopapillary neoplasm Somatostatinoma Staging-exocrine Staging-neuroendocrine True cysts Undifferentiated carcinoma Undifferentiated carcinoma with osteoclast-like giant cells VIPoma Well differentiated neuroendocrine tumor WHO classification WHO reporting system for pancreaticobiliary cytopathology

Acinar cell carcinoma

Table of Contents

Definition / general

Malignant exocrine neoplasm of the pancreas composed of cells with morphological resemblance to acinar cells and with immunohistochemistry positive for acinar markers

Essential features

Epithelial neoplasm showing acinar differentiation
Immunohistochemical positivity for BCL10 and trypsin (Virchows Arch 2009;454:133, Cancer Cytopathol 2013;121:459, Pathologica 2020;112:210)

Terminology

Main category: acinar cell carcinoma
Subtypes: acinar cell cystoadenocarcinoma, mixed acinar neuroendocrine carcinoma, mixed acinar ductal adenocarcinoma

ICD coding

ICD-O: 8550/3 - acinar cell carcinoma
ICD-11: 2C10.0 & XH3PG9 - adenocarcinoma of the pancreas & acinar cell carcinoma

Epidemiology

M:F = 2.1:1 (Semin Diagn Pathol 2016;33:307, Am J Surg Pathol 2012;36:1782)
Average age: 60 years (Semin Diagn Pathol 2016;33:307)
1 - 2% of all pancreatic neoplasms in adults and 15% in children (Semin Diagn Pathol 2016;33:307)

Sites

Head of the pancreas is the most common site (Semin Diagn Pathol 2016;33:307)

Pathophysiology

Accumulation of genetic alteration, including chromosomal instability and frequent allelic copy number variation

Etiology

Tobacco smoking, defective DNA repair; presence of chromosomal instability and frequent allelic copy number variation (Nat Commun 2017;8:1323)
Most cases are sporadic but a minority (

Clinical features

Presenting symptoms include abdominal or back pain, weight loss, nausea, vomiting; jaundice is more rarely observed than in ductal adenocarcinoma (Am J Surg Pathol 1992;16:815)
In the case of extensive metastatic disease, patients may show symptoms related to lipase hypersecretion, including subcutaneous fat necrosis (Front Med (Lausanne) 2015;2:41)

Diagnosis

CT scan and MRI are the preferred imaging modality (J Belg Soc Radiol 2019;103:43)
Diagnosis is by biopsy or surgical resection

Laboratory

Rarely, patients can show increased levels of AFP, especially young patients (Hum Pathol 2000;31:938)
Patients with metastatic disease can show elevated levels of serum lipase (World J Clin Cases 2020;8:5304)

Radiology description

Typical CT and MRI features of pancreatic acinar cell carcinoma: relatively large mass with a well defined margin, exophytic growth and heterogeneous enhancement (J Belg Soc Radiol 2019;103:43)

Prognostic factors

The prognosis is poor, with an average survival time of about 19 months (Semin Diagn Pathol 2016;33:307)
To date, the TNM stage can be considered the only significant prognostic moderator (Am J Surg Pathol 2012;36:1782)
Tumors with intraductal growth display a better prognosis than conventional acinar cell carcinomas (Am J Surg Pathol 2007;31:363)

Case reports

41 and 77 year old men presenting with acinar cell carcinoma extensively involving the pancreas (Medicine (Baltimore) 2017;96:e7904)
52 year old man with acinar cell carcinoma of the pancreas harboring BRCA2 germline mutation (Cancer Biol Ther 2019;20:949)
69 year old man with acinar cell carcinoma of the pancreas mixed with ductal adenocarcinoma (World J Surg Oncol 2020;18:238)
71 year old man with acinar cell carcinoma of the pancreas, with extension into the main pancreatic duct (Surg Case Rep 2021;7:90)
81 year old man with acinar cell carcinoma of the pancreas harboring NTRK fusion gene, with exceptional response to molecularly based target therapy (J Natl Compr Canc Netw 2021;19:10)

Treatment

Surgical resection if possible, gemcitabine based chemotherapy / radiofrequency ablation, molecularly based target therapy in the case of actionable alterations (World J Clin Cases 2020;8:1241)

Gross description

Well circumscribed mass, at least partially encapsulated, solid and large, with fleshy consistency

Gross images

AFIP images

Cut surface displays large nodules

Frozen section description

Hypercellular neoplasm with acinar resembling cells

Microscopic (histologic) description

Unlike conventional ductal adenocarcinoma, this tumor is highly cellular and with scant fibrous stroma
Cells show moderate amounts of granular eosinophilic cytoplasm containing PAS positive diastase resistant zymogen granules
Nuclei are uniform with a typically present, single and prominent nucleolus (Semin Diagn Pathol 2016;33:307)
Perineural invasion and vascular invasion are very common
Can have different architectures and growth patterns, including cystic, acinar, glandular and intraductal
Nonneuroendocrine component of mixed neuroendocrine nonneuroendocrine neoplasms (MiNEN) in the pancreas can be represented by acinar cell carcinoma; MiNEN diagnosis should be based on both morphology and immunohistochemistry

Microscopic (histologic) images

Contributed by Claudio Luchini, M.D., Ph.D.

Typical histology

Intraductal growth

Cell detail

Association with neuroendocrine tumors

BCL10 expression pattern

Trypsin expression pattern

Cytology description

Hypercellular / moderately cellular neoplasm, monomorphic nuclei with prominent nucleoli (Diagn Cytopathol 2017;45:247)

Cytology images

Contributed by Claudio Luchini, M.D., Ph.D.

Cytological aspects

Positive stains

Keratins (particularly CK7 and CK8 / CK18 / CK19), BCL10 (particularly the clone 331.3) and trypsin (Virchows Arch 2009;454:133, Cancer Cytopathol 2013;121:459, Pathologica 2020;112:210)
Nuclear expression of beta catenin and CD200 expression is found in about 10% of cases (Am J Surg Pathol 2012;36:1782, Virchows Arch 2019;474:105)

Negative stains

Neoplastic cells are negative for chromogranin and synaptophysin (rarely, scattered positive cells may be present)

Molecular / cytogenetics description

Most common molecular alterations of pancreatic ductal adenocarcinoma (e.g. KRAS and SMAD4 mutations) are usually absent
Recurrent presence of BRAF, RAF1 and RET rearrangements (Cancer Discov 2014;4:1398, Mod Pathol 2020;33:1811, Mod Pathol 2020;33:657)
Wnt pathway alterations with APC / CTNNB1 mutations can be present in a subset of cases

Sample pathology report

Distal stomach, duodenum and pancreatic head, pancreaticoduodenectomy (Whipple resection):
- Acinar cell carcinoma of the pancreas, 2.2 cm
- Carcinoma involves distal bile duct
- All margins negative for carcinoma
- Positive for lymphovascular invasion and perineural invasion
- Metastatic carcinoma involving 1 of 27 lymph nodes
- Portion of benign stomach and duodenum with no significant pathologic change

Differential diagnosis

Neuroendocrine neoplasms:
- BCL10 negative, chromogranin and synaptophysin positive
- Salt and pepper chromatin
- No evident nucleoli
Pancreatoblastoma:
- Pancreatic neoplasm with acinar differentiation: the presence of squamoid nests is diagnostic for pancreatoblastoma
Intraductal tubulopapillary neoplasm (ITPN):
- In cases with intraductal growth
- BCL10 negative and MUC6 positive

Additional references

WHO Classification of Tumours Editorial Board: Digestive System Tumours, 5th Edition, 2019

Board review style question #1

A high magnification field of a tumor within the pancreas is shown above. Can the diagnosis of acinar cell carcinoma be based on morphology alone or are other analyses required?

No, morphology alone is always sufficient
Yes, electron microscopy is of great help to rule out a neuroendocrine tumor and is always required
Yes, in addition to morphology, the immunohistochemical demonstration of the acinar differentiation represents the diagnostic gold standard
Yes, molecular analysis is mandatory
Yes, the demonstration of a BRAF rearrangement is required for the diagnosis

Board review style answer #1

C. Yes, in addition to morphology, the immunohistochemical demonstration of the acinar differentiation represents the diagnostic gold standard. Morphology and immunohistochemistry represent the 2 most important tools for the diagnosis. The acinar differentiation seen at histology should be supported with BCL10 and trypsin positivity. Tumor cells are also positive for PASD.

Comment Here

Reference: Acinar cell carcinoma

Board review style question #2

Is it important to report the intraductal growth pattern of pancreatic acinar cell carcinoma?

No, it is only a descriptive finding
No, this pattern does not belong to the morphological spectrum of acinar cell carcinoma
Yes, this pattern is associated with a better prognosis
Yes, this pattern is associated with a very poor prognosis
Yes, this pattern is associated with intraductal papillary mucinous neoplasm

Board review style answer #2

C. Yes, this pattern is associated with a better prognosis. This pattern represents a potential diagnostic pitfall with intraductal neoplasms (above all, intraductal tubulopapillary neoplasm) and is associated with a better prognosis.

Comment Here

Reference: Acinar cell carcinoma

Acinar cystic transformation

Table of Contents

Definition / general

Rare, nonneoplastic cystic lesion of the pancreas lined by benign appearing acinar and ductal epithelium

Essential features

First described in 2002; recognized by WHO in 2010 (Am J Surg Pathol 2002;26:698)
Clinically indolent; no cases of metastasis have been reported
Most cases found incidentally; though may be symptomatic
Cyst epithelium of acinar cystic transformation (ACT) consists of bland acinar and ductal epithelium, without mitoses, atypia and necrosis

Terminology

Other names include acinar cell transformation and acinar cell cystadenoma

ICD coding

ICD-11: DC30.0 - cyst of pancreas

Epidemiology

Rare; so far < 130 cases reported in the literature (J Clin Pathol 2023;76:740)
Female predominance (65.3%) with no age predilection

Sites

Found in all sites of the pancreas; can diffusely involve the gland
More common in head of pancreas

Pathophysiology

Most studies report nonneoplastic dilatation of the acinar and ductal epithelium (Oncol Lett 2014;8:852, J Clin Pathol 2023;76:740)
May arise from a heterogeneous background (Am J Surg Pathol 2023;47:379)
- Evolving from acinar microcysts
- Secondary to underlying obstructive lesions
- Subset may possibly be neoplastic

Etiology

Unknown; some may occur due to obstruction
No longer thought to represent the benign counterpart to acinar cell cystadenocarcinoma

Clinical features

Often found incidentally on imaging
Abdominal pain (42.1%), weight loss (4.9%), pancreatitis (4.9%), palpable mass (3.3%), jaundice (2.5%) (J Clin Pathol 2023;76:740)

Diagnosis

Requires clinical, radiologic and pathologic correlation

Radiology description

Nonspecific but the presence of 5 or more cysts, clustered peripheral small cysts, presence of cyst calcifications and absence of communication with the main pancreatic duct are supportive (Eur Radiol 2014;24:2128)

Prognostic factors

Clinically benign; there is no evidence of recurrence, malignant transformation or association with acinar cell carcinoma
Minority of cases involve controversial / high risk histomolecular features, including intralesional pancreatic intraepithelial neoplasia (PanIN) (4%), chromosomal gains and somatic mutations of KRAS and SMO genes (J Clin Pathol 2023;76:740)

Case reports

22 year old woman with epigastric pain and 5 cm cystic lesion in tail of pancreas (Surg Case Rep 2016;2:39)
43 year old woman with recurrent attacks of acute pancreatitis found to have diffuse involvement of pancreas by small multiple cysts (< 1 cm in maximum diameter) (Int J Surg Pathol 2022;30:697)
52 year old man with a pancreatic tail mass found incidentally on routine imaging for renal cell carcinoma followup (Korean J Radiol 2011;12:129)
Largest systematic review of literature (J Clin Pathol 2023;76:740)

Treatment

Benign; no need of surgical resection (J Clin Pathol 2023;76:740)
Some are resected for symptomatic relief or to exclude other cystic neoplasms associated with malignancy

Gross description

Unifocal > multifocal, multilocular > unilocular
Average size ~5 cm (range: 2 - 20 cm)
Typically does not communicate with ductal system, though rare cases have been reported
Thin walled cyst containing clear white serous watery fluid
Solid areas or papillary excrescences on cyst wall are typically absent
References: J Clin Pathol 2023;76:740, Am J Surg Pathol 2023;47:379, Esposito: Pathology of the Pancreas, 1st Edition, 2022

Gross images

Contributed by Wei Chen, M.D., Ph.D.

Unilocular ACT

Images hosted on other servers:

Multiple cystic lesions

Raw specimen
and fixed and
cut specimen

Microscopic (histologic) description

Cysts of variable sizes lined by bland flattened cuboidal acinar cells with apical granular eosinophilic cytoplasm and dense basophilic basal cytoplasm
Ductal epithelium can be admixed with the acinar cells
May contain corpora amylacea-like dense eosinophilic lamellar concretions
Multilocular cyst often demonstrates incomplete septa and club-like pseudopapillae
Low Ki67 proliferation (≤ 3%) and nuclear atypia is minimal
Cyst lining may show focal mucinous or clear cell change
Negative for ovarian type stroma, necrosis or infiltrative growth
References: J Clin Pathol 2023;76:740, Am J Surg Pathol 2023;47:379, Esposito: Pathology of the Pancreas, 1st Edition, 2022

Microscopic (histologic) images

Contributed by Vidya Arole, M.D. and Wei Chen, M.D., Ph.D.

Incidental microscopic ACT

Multilocular cystic structure

Club-like pseudopapillae

Microscopic ACT CK19 immunostain

Microscopic ACT trypsin immunostain

Large unilocular ACT

ACT cyst epithelium

Large ACT CK7 immunostain

Large ACT trypsin immunostain

Cytology description

Lesional epithelium indistinguishable from normal acinar and ductal cells
Smears usually low cellularity, containing cells resembling benign acinar or ductal epithelial cells
Smears / FNA specimens often interpreted as benign or nondiagnostic
Eosinophilic concretions can mimic mucinous secretions

Positive stains

Trypsin, chymotrypsin, lipase, CAM 5.2, CK7, CK8, CK18
Apical cytoplasm with PAS positive, diastase resistant granules
CK19 will stain intervening patches of the ductal epithelium
References: J Clin Pathol 2023;76:740, Am J Surg Pathol 2023;47:379, Esposito: Pathology of the Pancreas, 1st Edition, 2022

Negative stains

Alpha amylase, synaptophysin, chromogranin

Molecular / cytogenetics description

Single report of array comparative genomic hybridization (CGH) reported the following chromosome gains: 1p, 3p, 5q, 6p, 7q, 8, 10q, 11, 14, 20 and X (Am J Surg Pathol 2012;36:1579)
Random X chromosome inactivation observed in 5/5 cases, favoring nonneoplastic origin (Am J Surg Pathol 2013;37:1329)
In molecular analysis of 4 ACT cases, all cases had wild type status for KRAS and CTNNB1 genes (Oncol Lett 2014;8:852)
Next generation sequencing (NGS) performed on 9 ACT cases demonstrated driver mutations in 2 cases: one case a likely pathogenic mutation in SMO gene and the other a pathogenic mutation in KRAS gene (Am J Surg Pathol 2023;47:379)

Sample pathology report

Distal pancreas and spleen, distal pancreatectomy and splenectomy:
- Acinar cystic transformation, 3.8 cm, pancreatic tail (see comment)
- Proximal pancreatic resection margin is uninvolved
- Benign spleen with no diagnostic abnormality
- Comment: Sections show a multilocular cyst lined by bland cuboidal cells with granular cytoplasm. Eosinophilic concretions are present in the cyst. On immunohistochemical staining, the cyst epithelium is positive for both trypsin and CK19. The findings support the diagnosis of acinar cystic transformation.

Differential diagnosis

Cystic variant of acinar cell carcinoma (acinar cell cystadenocarcinoma):
- May have similar histology but mitotic activity is conspicuous and there is clear atypia
Intraductal papillary mucinous neoplasms:
- Mucinous, papillary lining and connection to ductal systems favors IPMN
Mucinous cystic neoplasm:
- Ovarian type stroma is diagnostic; absent in cystic acinar cell lesions
- Cyst lining is typically mucinous but may be nonmucinous; does not contain acinar cells
Serous cystadenoma:
- Areas with attenuated cytoplasm may mimic ACT
- Serous cystadenoma contains rich subepithelial vascular network, which is typically absent in ACT
- Should be negative for trypsin
Squamoid cyst of pancreatic ducts:
- Cystically dilated ducts are lined by a squamous / transitional epithelium, not acinar cells
- May contain acidophilic concretions
Retention cyst:
- Cyst > 1 cm lined by flat (not papillary) epithelium and connected to pancreatic ductal system; secondary to obstruction (Am J Surg Pathol 2015;39:1730)
- Cyst epithelium may show mucinous change, negative for acinar cells / trypsin

Additional references

WHO Classification of Tumours Editorial Board: Digestive System Tumours, 5th Edition, 2019

Board review style question #1

This is an incidental cyst found in the distal pancreas. On immunohistochemical staining, the cyst epithelium is positive for both CK19 and trypsin. Ki67 proliferation is low (< 3%). What is the diagnosis?

Acinar cystic transformation
Cystic acinar cell carcinoma
Cystic solid pseudopapillary neoplasm
Intraductal papillary mucinous neoplasm

Board review style answer #1

A. Acinar cystic transformation. The photograph demonstrates a cystic lesion lined by bland nonmucinous epithelium and filled with eosinophilic concretions. The positive CK19 and trypsin indicate ductal and acinar differentiation. The overall histomorphology and immunoprofile support the diagnosis of acinar cystic transformation of the pancreas. Answer D is incorrect because the cyst epithelium is nonmucinous. Answer B is incorrect because acinar cell carcinoma would have a much higher proliferation rate than 3%. Answer C is incorrect because solid pseudopapillary neoplasm should be negative for trypsin.

Comment Here

Reference: Acinar cystic transformation

ACTH secreting tumors

Table of Contents

Definition / general

Rare pancreatic neuroendocrine neoplasm producing adrenocorticotrophic hormone (ACTH)
ACTH can also rarely be produced by acinar cell carcinoma or pancreatoblastoma (Am J Surg Pathol 2015;39:374)

Essential features

Rare lesion mostly described in case reports
Patients develop Cushing syndrome clinically
Aggressive, with poor prognosis

Terminology

Recognized by IARC as ACTH producing tumor with Cushing syndrome (Lloyd: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017)

ICD coding

ICD-10: E24.3 - ectopic ACTH syndrome

Epidemiology

Responsible for about 15% of cases of ectopic Cushing syndrome

Sites

May be more common in tail of pancreas

Clinical features

Mean age 42 years, with a female predominance (Am J Surg Pathol 2015;39:374)
Causes Cushing syndrome: central obesity, muscle weakness, glucose intolerance, hypertension
33% of patients also have Zollinger-Ellison syndrome
10 year survival is roughly 15% (Am J Surg Pathol 2015;39:374)

Diagnostic criteria

Determined clinically, not by immunohistochemical positivity for ACTH

Radiology images

Images hosted on other servers:

Pancreatic tail / body mass

Case reports

27 year old woman with ovarian and pelvic metastases (Int J Clin Exp Pathol 2015;8:15396)
40 year old woman with Cushing syndrome (Ann Hepatobiliary Pancreat Surg 2017;21:61)
41 year old woman with bilateral ovarian metastases (Int J Gynecol Pathol 2002;21:276)
48 year old woman with tumor secreting ACTH and possibly corticotropin releasing hormone (CRH) (Endocr Pathol 2015;26:239)
54 year old woman with ACTH secretion only at second relapse (J Clin Endocrinol Metab 2004;89:3731)

Treatment

Surgical excision

Gross description

Firm, gray-white, well circumscribed lesions that may measure up to 5 cm

Gross images

Images hosted on other servers:

Pancreatic tail mass

Microscopic (histologic) description

Appears similar to other well differentiated neuroendocrine tumors of the pancreas
Lymphovascular and perineural invasion often present
Focal necrosis is rare

Microscopic (histologic) images

AFIP images

ACTH producing tumor with Cushing syndrome

Images hosted on other servers:

Typical neuroendocrine tumor appearance

66 year old man with ultrasound guided biopsy: H&E and ACTH antibody

Cytology images

Images hosted on other servers:

Scattered neuroendocrine cells

Positive stains

ACTH (though this does not establish the diagnosis), beta endorphin, galectin3
Ki67 usually 3 - 20%, as these lesions are typically WHO grade 2

Electron microscopy description

Round cytoplasmic secretory granules, diameter of 100 - 300 nm, with an electron dense core (Int J Clin Exp Pathol 2015;8:15396)

Sample pathology report

Pancreas, tail, resection:
- Pancreatic neuroendocrine tumor, WHO grade 1 (see synoptic report and comment)
- Comment: The patient’s clinical history of Cushing syndrome is noted. This may be due to ACTH secretion by this tumor. Immunohistochemical stains for synaptophysin and chromogranin are positive and the Ki67 index is approximately 2.3%.

Differential diagnosis

Non-ACTH secreting pancreatic neuroendocrine tumor:
- Must be determined on clinical grounds, though ACTH positivity by immunohistochemistry is rare in these (Proc (Bayl Univ Med Cent) 2015;28:46)
Pancreatic acinar cell carcinoma
Pancreatoblastoma

Board review style question #1

ACTH
Cortisol
Gastrin
Glucagon

Board review style answer #1

A. ACTH. The patient is presenting with Cushing syndrome, secondary to ACTH production by her pancreas lesion (likely a neuroendocrine tumor), which leads to increased cortisol production by the adrenal glands. Pancreatic tumors do not themselves secrete cortisol.

Comment Here

Reference: ACTH secreting tumors

Board review style question #2

Abundant necrosis
Grade 3 mitotic rate
Lymphocytic infiltration
Perineural invasion

Board review style answer #2

D. Perineural invasion. These tumors, which are commonly WHO grade 2, often show lymphovascular and perineural invasion. Focal necrosis may sometimes be seen.

Comment Here

Reference: ACTH secreting tumors

Acute pancreatitis

Table of Contents

Definition / general

Inflammatory disease of the exocrine pancreas that causes acute onset of severe abdominal pain and might lead to pancreatic necrosis

Essential features

Reversible pancreatic parenchymal injury
Causes include gallstones, alcohol and hypertriglyceridemia
Main histological features include acute inflammatory cells with hemorrhage and necrosis
Treatment is supportive

Terminology

Interstitial edematous pancreatitis: often referred to simply as acute pancreatitis
Necrotizing pancreatitis
Other terminologies: bile pancreatitis, infected pancreatic necrosis and postoperative pancreatitis

ICD coding

ICD-10
- K85.9 - acute pancreatitis, unspecified
- K85.90 - acute pancreatitis without necrosis or infection, unspecified
- K85.91 - acute pancreatitis with uninfected necrosis, unspecified
- K85.92 - acute pancreatitis with infected necrosis, unspecified

Epidemiology

Incidence of acute pancreatitis is similar among men and women; male sex is associated with higher mortality
Peak incidence of acute pancreatitis is in the fifth and sixth decades
In the U.S., incidence has been cited as 600 - 700 per 100,000 people, with 200,000 - 250,000 discharges occurring yearly for acute pancreatitis
Gallstone disease is the leading cause and accounts for 20 - 70% of all cases in the West
Alcohol is the second most common cause of acute pancreatitis, accounting for up to 30% of cases
Hypertriglyceridemia accounts for ~9% of cases, making it the third most common cause
Mortality of acute pancreatitis ranges from 3% in patients with mild edematous pancreatitis to as high as 20% in patients with pancreatic necrosis
References: StatPearls: Acute Pancreatitis [Accessed 11 July 2023], United European Gastroenterol J 2018;6:649, J Clin Med 2021;10:300

Sites

Pancreas

Pathophysiology

Acute pancreatitis is triggered by various factors that disrupt normal intracellular calcium signaling in pancreas cells, which normally maintains stimulus secretion coupling
Increasing intracellular calcium leads to premature activation of the enzyme trypsinogen to trypsin within the acinar cell instead of the duct lumen
Intracellular calcium also overwhelms mitochondria leading to impaired production of adenosine triphosphate (ATP)
Diminished ATP affects cellular process leading cytokine release, cellular necrosis and inflammation
Proinflammatory cytokines mediate powerful immune response, leading to systemic inflammatory response syndrome, multiorgan dysfunction and higher susceptibility to infections
References: Drugs 2022;82:1251, StatPearls: Acute Pancreatitis [Accessed 11 July 2023], Int J Mol Sci 2020;21:4005

Etiology

Gallstone disease: the leading cause of acute pancreatitis worldwide; accounts for 20 - 70% of cases in the West and is more common in women
Alcohol: second most common cause of acute pancreatitis in North America and Europe, contributing to up to 33% of cases
Hypertriglyceridemia: elevated triglyceride levels in the blood can cause acute pancreatitis, accounting for ~9% of cases
Drugs such as antiretrovirals, chemotherapeutic agents, antibiotics, steroids and others
Infectious causes: most commonly mumps, cytomegalovirus (CMV), Epstein-Barr virus (EBV)
Genetic factors also play a role, such as hereditary pancreatitis associated with specific gene mutations in PRSS1, SPINK1, CFTR and CTRC
Other causes: there are various less common causes of acute pancreatitis, including trauma, hypercalcemia, tumors, anatomical variants, cardiac bypass surgery, scorpion bites and organophosphate poisoning
References: Drugs 2022;82:1251, World J Clin Pediatr 2022;11:27

Diagrams / tables

Images hosted on other servers:

Overview of pathogenesis

Clinical features

Symptoms: mild to severe epigastric pain, nausea and vomiting
Signs: high white blood count, diffuse fat necrosis, peripheral vascular collapse, acute tubular necrosis, shock (blood loss, electrolyte disturbances, endotoxemia, release of cytokines), hypocalcemia, hyperglycemia
Complications: pancreatic pseudocyst, walled off necrosis, peripancreatic fluid collection
Systemic complications include: acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), disseminated intravascular coagulation (DIC)
References: Drugs 2022;82:1251, World J Emerg Surg 2019;14:27

Diagnosis

Abdominal pain consistent with pancreatitis
Serum amylase or lipase 3 or more times the upper limit of normal
Findings consistent with pancreatitis on CT, MRI or in some cases transabdominal ultrasound (TUS)
References: Drugs 2022;82:1251

Laboratory

High amylase and lipase
High blood glucose

Radiology description

Abdominal ultrasound (US): first line modality
- Pancreatic enlargement and decreased parenchymal echogenicity due to interstitial edema
- Limitations of US is the inability to make distinction between interstitial and necrotizing pancreatitis
Computed tomography (CT): gold standard
- Enlargement of the pancreas
- Ill defined parenchymal contours and decreased density and inhomogeneity of the pancreatic parenchyma
- Fluid collections in the peripancreatic region and the inflammatory reaction can produce increased attenuation of the peripancreatic fat tissue commonly described as stranding
Reference: Diagn Interv Imaging 2015;96:151

Radiology images

Images hosted on other servers:

CT scan

Necrotizing pancreatitis

Prognostic factors

Bed side index of severity of acute pancreatitis (BISAP)
- Blood urea and nitrogen level > 8.9 mmol/L
- Systemic inflammatory response syndrome is present
- Age > 60
- Pleural effusion on radiology
Reference: World J Emerg Surg 2019;14:27

Case reports

35 year old man with acute pancreatitis due to over the counter calcium carbonate (J Investig Med High Impact Case Rep 2020;8:2324709620922724)
50 year old man with acute pancreatitis with normal lipase and amylase (Medicine (Baltimore) 2019;98:e15138)
57 year old woman with steroids induced acute pancreatitis (Cureus 2021;13:e19132)
71 year old woman with acute pancreatitis following COVID-19 vaccination (Medicine (Baltimore) 2022;101:e28471)
75 year old woman with acute pancreatitis due to cytomegalovirus infection (IDCases 2020;22:e00932)

Treatment

Oxygen supplementation
Intravenous fluid resuscitation to correct third space volume loss and tissue hypoperfusion
Pain management: NSAIDs or opioids, depending on the severity
Reference: Drugs 2022;82:1251

Clinical images

Images hosted on other servers:

Intraoperative findings of necrotizing pancreatitis

Gross description

Diffuse stippled necrosis of the pancreatic parenchyma and peripancreatic fat
Hemorrhagic, black-brown necrosis of the pancreatic parenchyma and peripancreatic fat

Gross images

Images hosted on other servers:

Acute pancreatitis with fat necrosis

Acute hemorrhagic pancreatitis

Microscopic (histologic) description

Acute interstitial or edematous: the interstitial fibrous tissue, adipose tissue and pancreatic parenchyma are edematous and contain acute inflammatory cells with limited fat necrosis
Acute necrotizing: marked hemorrhage, panlobular coagulative necrosis and extensive fat necrosis of peripancreatic tissues, presence of intravascular thrombi
Initially neutrophils are present, then macrophages and lymphocytes
Calcification occurs early and extensively
Fat necrosis, which is characterized by lipid laden macrophages and foreign body giant cells, can progress to fat saponification, which involves calcium deposition

Microscopic (histologic) images

Contributed by Beena Ashan, M.D. and Sarah Kisha, M.D.

Acute interstitial pancreatitis

Hemorrhagic pancreatitis

Fat necrosis with hemosiderin disposition

Virtual slides

Images hosted on other servers

Hemorrhagic pancreatitis with necrosis

Cytology description

Benign pancreatic acinar tissue and ducts
Fat necrosis, fibrotic stromal tissue
Acute and chronic inflammatory infiltrate

Cytology images

Contributed by Beena Ashan, M.D. and Sarah Kisha, M.D.

Dense inflammatory infiltrate

Molecular / cytogenetics description

Most common genes associated with acute pancreatitis include
- PRSS1 mutations: inhibits trypsin self destruction, mutations lead to pancreatic autodigestion and pancreatitis
- SPINK1 mutations: encodes a trypsin inhibitor and mutations lead to increased intrapancreatic trypsin activity
References: Diagnostics (Basel) 2020;11:31, Gastroenterology 2019;156:1951

Videos

Pancreas: acute pancreatitis, gross and microscopy

Sample pathology report

Pancreas, resection:
- Fragments of necrotic pancreatic and adipose tissues with fat necrosis, hemorrhage, bacterial colonies and fibrinopurulent exudate, consistent with acute hemorrhagic pancreatitis

Differential diagnosis

Acute cholecystitis:
- Severe abdominal pain with jaundice
- Imaging studies are utilized to make a definite diagnosis
Acute mesenteric ischemia:
- Severe, sudden abdominal pain in patients with history of atherosclerotic disease
- Angiography
Acute cholangitis:
- Clinical features include right upper quadrant pain, fever, malaise, chills and jaundice
- Imaging studies including US, CT scan and magnetic resonance cholangiopancreatography (MRCP)
Chronic pancreatitis:
- Less severe pain
- Malabsorption syndrome (fatty stool and weight loss)
- Histological features of chronic pancreatitis include loss of acinar cells, islet cell hyperplasia, presence of intralobular fibrosis and periductal chronic inflammation
Myocardial infarction:
- Chest and upper abdominal pain in patients with history of atherosclerotic disease
- ECG with characteristic changes of ischemic injury
Peptic ulcer disease:
- Bouts of mid epigastric pain associated with eating
- Upper gastrointestinal endoscopy

Board review style question #1

Which lab test result would indicate acute pancreatitis?

Elevated bilirubin levels
Elevated blood alcohol level
Elevated serum lipase and amylase levels
Low white blood cell count

Board review style answer #1

C. Elevated serum lipase and amylase levels. Amylase and lipase are digestive enzymes normally released from the acinar cells of the exocrine pancreas into the duodenum. Following injury to the pancreas, these enzymes are released into the circulation and the pancreas will continue to release these enzymes form injured cells even when the normal outflow of these enzymes is obstructed. This will result in elevated serum lipase and amylase levels in the blood. Answer A is incorrect because elevated bilirubin is associated with gall stones and acute cholecystitis. Answer B is incorrect because high blood alcohol levels have no immediate association with acute pancreatitis and only indicate recent drinking. Answer C is incorrect because acute pancreatitis is an inflammatory condition that leads to high white blood count.

Comment Here

Reference: Acute pancreatitis

Board review style question #2

Why is the body more susceptible to secondary infections during cases of pancreatitis?

Activation of leukocytes in response to proinflammatory cytokine production
Formation of pseudocysts
Production of anti-inflammatory cytokines and specific cytokine inhibitors
Release of cortisol in response to stress

Board review style answer #2

C. Production of anti-inflammatory cytokines and specific cytokine inhibitors. As a result of the systemic inflammatory response during acute pancreatitis, anti-inflammatory cytokines and specific cytokine inhibitors are produced, increasing the body's risk for infection. Answer A is incorrect because increased leucocytes lead to activation of the immune response and less susceptibility to infections. Answer B is incorrect because pseudocyst cyst formation is a result of the ongoing inflammation and has no relation with susceptibility to infections. Answer D is incorrect because cortisol is ordinarily anti-inflammatory and contains the immune response, so acute increase does not increase infection susceptibility.

Comment Here

Reference: Acute pancreatitis

Adenosquamous carcinoma

Table of Contents

Definition / general

Malignant tumor that consists of both squamous cell carcinoma and ductal adenocarcinoma components (Digestion 2005;72:104, Cancer 2003;99:372, Int J Pancreatol 1999;26:85, Arch Surg 1999;134:599)

Essential features

Malignant tumor consisting of both squamous cell carcinoma and ductal adenocarcinoma components (Digestion 2005;72:104, Cancer 2003;99:372, Int J Pancreatol 1999;26:85, Arch Surg 1999;134:599)
Closely related to and admixed with pancreatic ductal adenocarcinoma (PDAC); some require 30% squamous differentiation for the diagnosis of adenosquamous carcinoma
Cases with < 30% of squamous component also behave like adenosquamous carcinoma and can be acknowledged as PDAC with focal (< 30%) squamous differentiation
Metastatic tumor can be solely composed of the glandular component (Mod Pathol 2001;14:443)
Often has necrotic and cystic components (Arch Surg 1999;134:599)
Behaves even worse than ordinary PDAC

ICD coding

ICD-O: 8560/3 - adenosquamous carcinoma

Epidemiology

Accounts for about ~2% of exocrine pancreatic malignancies
M:F = 2:1
Mean age of 65 years (Arch Surg 1999;134:599)

Sites

Body and tail of the pancreas is more often affected than the head (J Surg Res 2012;174:12)

Etiology

Ionizing radiation of the pancreas may predispose to the occurrence of adenosquamous carcinoma (Mod Pathol 2001;14:443)

Diagnosis

Generally discovered with radiology and confirmed on fine needle aspiration biopsy (FNAB) or resection

Radiology description

Similar to pancreatic ductal adenocarcinoma but many cases present with more round, lobulated lesion with extensive central necrosis
Portal venous system may contain tumor thrombus (Abdom Radiol (NY) 2016;41:508)

Radiology images

Contributed by Orhun Çığ Taşkın, M.D.

Cystic and necrotic changes

Prognostic factors

Similar to PDAC, stage is the most important prognostic factor

Case reports

63 year old man and 69 year old woman with adenosquamous carcinoma of the pancreas (Annu Rev Pathol 2020;15:97)
66 year old woman with adenosquamous carcinoma of the pancreas (Clin Case Rep 2022;10:e6181)
80 year old Japanese woman with adenosquamous carcinoma coexisting with intraductal papillary mucinous neoplasm of the pancreas (J Med Case Rep 2023;17:72)

Treatment

Similar to pancreatic ductal adenocarcinoma
If the tumor is operable, complete surgical resection, followed by adjuvant chemotherapy; increasingly neoadjuvant therapy is utilized just as in PDAC (Hum Pathol 2010;41:113, J Gastrointest Oncol 2015;6:115)
Even more aggressive than ordinary PDAC with a median survival of < 1 year (Gastrointest Cancer Res 2013;6:75)
Based on the immunohistochemical results, 11% of patients are assumed to be potential candidates for therapy with antibodies against PD-1 / PDL1 (Pancreatology 2021;21:920)

Gross description

Large, firm mass of the pancreas, with ill defined borders, often with necrotic component, with or without cystic areas
Some cases are more demarcated
Reference: World J Gastrointest Oncol 2015;7:132

Microscopic (histologic) description

Adenocarcinoma component can bare all the characteristics of classic pancreatic ductal adenocarcinoma
Squamous component can show keratinization with intercellular bridges or sheets of squamous cells with keratohyaline granules or pearls
- Some are adenoacanthoma-like, with bland mature squamous elements, whereas others are more basal-like (with high N:C ratio and basophilic appearance)
Adenocarcinoma and squamous components can vary greatly in the amount and distribution
Sarcomatous component can also be encountered (Anticancer Res 2019;39:4575)

Microscopic (histologic) images

Contributed by Orhun Çığ Taşkın, M.D., Raul S. Gonzalez, M.D. and AFIP

Glandular and squamous components

p63

Adenocarcinoma and squamous carcinoma

Squamous components

Mucoepidermoid pattern

CAM5.2

CK13

Cytology description

Squamous component may be undersampled but malignant squamous cells are highly significant for the diagnosis (Acta Cytol 2013;57:139)
Glandular and squamous components can both be distinguished
Dense globules, silhouettes of squamous cells, anucleate squames, atypical cytoplasm and enlarged pyknotic nuclei are present in the prominent necrotic background
Sheets and clusters of atypical cells with nuclei of variable sizes and shapes (Cancer 2003;99:372)

Cytology images

Contributed by Orhun Çığ Taşkın, M.D.

Pap stain

Cell block

Cell block, p40

Positive stains

Immunoreactivity for AE1 / AE3 is identified
p63, p40, high molecular weight cytokeratin specifically highlights the squamous component (Mod Pathol 2005;18:1193, Mod Pathol 2009;22:651)

Negative stains

Loss of SMAD4 / DPC4 protein expression

Molecular / cytogenetics description

KRAS mutations occur in almost all cases (Mod Pathol 2001;14:443, Mod Pathol 2009;22:651)
TP53 mutations and 3p loss are commonly encountered
Recently discovered basal-like molecular subtype of PDAC is believed to also represent adenosquamous carcinoma (Nature 2016;531:47)
Both components are believed to originate from the same progenitor cell (J Pathol 2017;243:155)
Susceptibility genes including MAP3K1, PDE4DIP and BCR are frequently mutated in the germlines of patients (Cancer Biomark 2020;27:389)

Sample pathology report

Pancreas, resection:
- Adenosquamous carcinoma (see synoptic report)

Differential diagnosis

Pure squamous cell carcinoma:
- Extremely rare; most cases contain a small amount of glandular component, which is enough to call the tumor adenosquamous carcinoma
Metastasis of adenosquamous carcinoma of the lung:
- Needs to be carefully excluded (Virchows Arch 2004;444:527)

Board review style question #1

A 65 year old man presented with back pain and severe weight loss. Radiologic images showed a 4 cm relatively round, lobulated mass with extensive central necrosis in the pancreatic body. He underwent resection. Histologic sections demonstrate conventional ductal adenocarcinoma admixed with sheets of squamous cells with keratohyaline granules and intercellular bridges. Which of the following immunohistochemical stains would be positive in this case?

Beta catenin nuclear expression
Chromogranin A
p63
Synaptophysin

Board review style answer #1

C. p63. The histology described in this case is consistent with pancreatic adenosquamous carcinoma. The squamous components should be positive with p63 immunohistochemistry. Neuroendocrine neoplasms are positive for chromogranin and synaptophysin. Beta catenin nuclear expression is observed in solid pseudopapillary neoplasm.

Comment Here

Reference: Adenosquamous carcinoma

Board review style question #2

Which of the following is true for adenosquamous carcinoma of the pancreas?

It has a better prognosis than ordinary pancreatic ductal adenocarcinoma
It is the most common type of pancreatic malignancy
It usually affects pediatric patients
p63 specifically highlights the squamous component

Board review style answer #2

D. p63 specifically highlights the squamous component. The squamous components of the tumor should be positive with p63 immunohistochemistry. Answer A is incorrect as adenosquamous carcinomas behave worse than pancreatic ductal adenocarcinomas. Answer B is incorrect as pancreatic ductal adenocarcinoma is the most common pancreatic malignancy. Answer C is incorrect as adenosquamous carcinomas occur in elder patients (mean age of 65 years).

Comment Here

Reference: Adenosquamous carcinoma

Allograft rejection

Table of Contents

Definition / general

Pancreas transplant rejection is an immunological reaction directed by the host immune system against the allograft, leading to allograft damage and requiring immunosuppressive treatment to prevent permanent disruption of the allograft function

Essential features

Pancreas transplantation is the only method to achieve long term insulin independence and euglycemia (Transplant Proc 2022;54:1918, Am J Transplant 2011;11:1792, Am J Transplant 2024;24:362)
Although the serum level of pancreatic enzymes tends to increase in pancreas transplants undergoing rejection, a pancreas transplant biopsy is the gold standard in the diagnosis of pancreas rejection and the only method to differentiate between cell and antibody mediated rejection
Classification and grading of pancreas transplant rejection are performed according to the Banff guidelines, which take into consideration the type, location and numbers of inflammatory cells, involvement of the pancreatic structures, the presence of complement deposition and donor specific antibodies and chronic changes

Terminology

Histological definitions used in the diagnosis of pancreas rejection are listed in the 2008 Banff Schema for Grading Pancreas Allograft Rejection and updated in the Banff 2022 pancreas transplantation multidisciplinary report (Am J Transplant 2008;8:1237, Am J Transplant 2024;24:362)
Venulitis: circumferential cuffing of septal veins with subendothelial accumulation of inflammatory cells and endothelial injury, activation, swelling or lifting (Am J Transplant 2008;8:1237, Am J Transplant 2024;24:362)
Ductitis: infiltration of ductal epithelium by mononuclear cells or eosinophils and ductal epithelial cell injury, reactive features, disarray, sloughing (Am J Transplant 2008;8:1237, Am J Transplant 2024;24:362)
Activated lymphocyte: lymphocyte that is activated by antigen binding to its receptor; it shows more abundant cytoplasm and an enlarged nucleus with more open chromatin
Active inflammation: activated lymphocytes with or without eosinophils
Neural and perineural inflammation: septal inflammatory infiltrates in and around the nerve branches (Am J Transplant 2008;8:1237)
Acinar inflammatory focus: collection of ≥ 10 lymphocytes / eosinophils within an acinar area (Am J Transplant 2008;8:1237)
Focal acinar inflammation: ≤ 2 inflammatory foci per lobule with no evidence of acinar cell injury (Am J Transplant 2008;8:1237)
Multifocal acinar inflammation: ≥ 3 foci of inflammation per lobule with isolated cell injury / necrosis
Severe acinar inflammation: confluent diffuse acinar inflammation with focal or diffuse acinar cell injury or necrosis (Am J Transplant 2008;8:1237)
Acinar cell injury: cytoplasmic swelling and vacuolization or karyopiknosis, apoptotic bodies, cell dropout (Am J Transplant 2008;8:1237)
Active antibody mediated rejection components
1. Confirmed donor specific antibody
2. Morphologic evidence of active tissue injury (interacinar inflammation with neutrophilic infiltrates / capillaritis, acinar cell damage, vasculitis, thrombosis)
3. Complement component 4d (C4d) positivity in interacinar capillaries (Am J Transplant 2024;24:362)
Chronic rejection: progressive fibrosis resulting from persistent, repeated or untreated allograft rejection (Am J Transplant 2024;24:362)
- Chronic active cell mediated rejection: ongoing inflammation in acini or ducts or arteries with features of chronic injury, fibrosis or remodeling (Am J Transplant 2024;24:362)
- Chronic allograft arteriopathy: arterial intimal fibrosis with mononuclear cell infiltration in fibrosis, formation of neointima (Am J Transplant 2008;8:1237)
- Active allograft arteriopathy: narrowing of the arterial lumen by a subendothelial proliferation of fibroblasts, myofibroblasts and smooth muscle cells with infiltration of the subintimal fibrous proliferation by mononuclear cells (Am J Transplant 2008;8:1237)

ICD coding

ICD-10
- Z94.83 - pancreas transplant status
- T86.89 - complications of other transplanted tissue / transplant failure of rejection of pancreas
- T89.899 - unspecified complications of other transplanted tissue / complications of transplanted pancreas

Epidemiology

Pancreas transplantation is a surgical treatment for diabetes mellitus
Most transplant recipients have diabetes mellitus type 1 and 18.4% have diabetes mellitus type 2 (Transplant Proc 2022;54:1918)
Median age for pancreas transplant recipients is 42 (12 - 75) years; pancreas transplants in pediatric recipients are done rarely (Transplant Proc 2022;54:1918)
Between years 2015 and 2019, 5,369 pancreas transplants were performed in the United States and Canada and 3,923 in Europe (Transplant Proc 2022;54:1918)
Number of living donor transplants in the United States is very low to none (Transplant Proc 2022;54:1918)
Most pancreas transplants (73.4%) in the United States were simultaneous pancreas and kidney (SPK); 14.6% were pancreas after kidney (PAK) and 7.8% were pancreas transplant alone (PTA) (Transplant Proc 2022;54:1918)
59% of SPK transplants are a 5 or 6 HLA antigen mismatch (Transplant Proc 2022;54:1918)
Preferred duct management technique is enteric drainage (Transplant Proc 2022;54:1918)
Patient survival at 1 year is > 96%
Incidence of acute rejection by 1 year is 12.5% for PAK, 21.8% for PTA and 10.6% for SPK (Am J Transplant 2022;22:137)
Risk factors for acute rejection include a solitary pancreas transplant (PAK or PTA), race mismatch, HLA mismatch, transplantation involving a male donor and a female recipient and increasing donor age (UpToDate: Pancreas Allograft Rejection [Accessed 1 March 2024])

Sites

Pancreas

Pathophysiology

Both major and minor histocompatibility antigens activate the immune system against the allograft
Major histocompatibility complex (MHC) encodes the human leukocyte antigens
MHC molecules present foreign antigens to the T cells
MHC class I molecules are constitutively expressed on the surface of all nucleated cells
MHC class II molecules are constitutively expressed on the surface of professional antigen presenting cells but many cell types upon activation express MHC class II
T cells directly recognize intact nonself MHC molecules present on the surface of donor cells, eliciting the strongest of responses to allogeneic tissues (Pediatr Nephrol 2010;25:61)
Processed MHC peptides and minor histocompatibility antigens elicit a slower, less intense immune response (Pediatr Nephrol 2010;25:61)
T cell activation is central to graft rejection
Graft tissue destruction occurs due to direct T cell mediated lysis of graft cells, T cell activation of accessory cells (cell mediated rejection), alloantibody production and complement activation (Pediatr Nephrol 2010;25:61)
Arteries, ducts and acini are the preferred targets of cell mediated rejection
Islets of Langerhans are not immediately or directly affected (Am J Transplant 2008;8:1237)
Presence of allograft infiltrating B cells and plasma cells correlates with irreversible acute and chronic rejection (Pediatr Nephrol 2010;25:61)
B cells damage grafts by producing donor specific antibodies (antibody mediated rejection), which bind to HLA or non-HLA molecules on endothelial cells within the graft and activate complement dependent and independent mechanisms that recruit leukocytes and macrophages leading to interacinar capillaritis and acinar damage
Islets may be susceptible to microvascular injury in antibody mediated rejection (Am J Transplant 2008;8:1237)

Etiology

Solid organ allograft rejection is initiated when recipient T lymphocytes recognize donor derived antigens, resulting in T lymphocyte activation
Activated T cells undergo clonal expansion, differentiate into effector cells and migrate into the graft where they promote tissue destruction
Traditionally, acute rejection is classified as either cell mediated rejection or antibody mediated rejection
Activation and differentiation of CD4+ T helper cells (Th) into specific Th subsets plays a central role in the acute cell mediated rejection (Transplantation 2023;107:2341)
Th1 cells secrete interleukins IL2, IL12, IFNγ and TNFα, promoting leukocyte recruitment and cytotoxin T lymphocyte priming (Transplantation 2023;107:2341)
Th2 cells secrete cytokines IL4, IL5, IL6, IL9 and IL13, inducing macrophage activity and shaping T cell responses (Transplantation 2023;107:2341)
Tfh cells activate the alloantigen specific B cells, contributing to antibody responses (Transplantation 2023;107:2341)
After direct activation by MHC class I alloantigen, graft infiltrating CD8+ cells play a central role in allograft injury via, e.g., secretion of TNFα, IFNγ, perforin and granzyme secretion, natural killer (NK) cell activation (Transplantation 2023;107:2341)

Clinical features

Some patients with pancreas graft rejection occasionally present with mild graft tenderness or fever, whereas many patients are asymptomatic (UpToDate: Pancreas Allograft Rejection [Accessed 1 March 2024])

Diagnosis

Primary means of monitoring for pancreas allograft rejection is periodic laboratory testing (UpToDate: Pancreas Allograft Rejection [Accessed 1 March 2024])
Elevated serum amylase / lipase prompt CT or MRI abdomen and further testing (see Laboratory) and pancreas allograft biopsy (see Curr Transplant Rep 2015;2:169 and UpToDate: Pancreas Allograft Rejection [Accessed 1 March 2024] for the pancreas allograft diagnosis and treatment algorithm)
Pancreas allograft biopsy is the gold standard in the diagnosis of pancreas rejection
In SPK recipients, renal allograft rejection is a poor surrogate for pancreas allograft status due to high biopsy discordance rate (Transplantation 2010;90:75)
Likewise, sampling of the duodenal mucosa from the pancreaticoduodenal graft is not widely accepted due to potential for discordant findings (Curr Transplant Rep 2015;2:169)

Laboratory

Elevated pancreatic enzymes (amylase and lipase) is the most common presentation of pancreatic allograft rejection and correlates with the grade of acute rejection (Curr Transplant Rep 2015;2:169, Transplantation 1998;66:1741)
However, their lack of specificity precludes their use as sole markers of acute rejection (Transplantation 1998;66:1741)
Lipase is considered to be more specific than amylase (Curr Transplant Rep 2015;2:169)
If the pancreas allograft has received bladder drainage, a decrease in urinary amylase is observed
As early rejection usually does not affect the islets of Langerhans (see Etiology), fasting blood glucose is not a useful parameter in the early diagnosis of rejection (Transplantation 1998;66:1741)
Elevated fasting blood glucose, elevated hemoglobin A1C or decrease in fasting C peptide levels are a late finding in acute rejection and are usually associated with significant graft tissue damage (Transplantation 1998;66:1741, UpToDate: Pancreas Allograft Rejection [Accessed 1 March 2024])
Clinical parameters cannot discriminate between acute cell and antibody mediated rejection (Am J Transplant 2011;11:1792)
Patients may develop chronic rejection and graft failure without significant increases in the pancreatic enzymes (Curr Transplant Rep 2015;2:169)
In SPK transplant recipients, an elevated serum creatinine concentration may be a surrogate marker for pancreas allograft rejection; however, stable kidney function does not consistently guarantee the absence of pancreas allograft rejection (UpToDate: Pancreas Allograft Rejection [Accessed 1 March 2024], Curr Transplant Rep 2015;2:169)
De novo donor specific antibodies (DSA) or rising DSA levels in a patient with preexisting DSA have been associated with antibody mediated rejection and graft loss (UpToDate: Pancreas Allograft Rejection [Accessed 1 March 2024], Am J Transplant 2002;2:134)
Donor derived cell free DNA shows promise for rejection surveillance in SPK transplant recipients (Transplant Direct 2022;8:e1321)

Radiology description

Imaging findings are nonspecific and they may look similar to other complications, such as pancreatitis; contrast enhanced CT or MRI may show heterogeneous parenchymal enhancement, allograft swelling or stranding (Insights Imaging 2010;1:329, UpToDate: Pancreas Allograft Rejection [Accessed 1 March 2024])
In chronic rejection, the graft appears small on imaging studies (Curr Transplant Rep 2015;2:169)

Radiology images

Images hosted on other servers:

Ultrasound guided biopsy

Prognostic factors

Acute rejection episodes have a negative impact on the transplant pancreas and kidney survival in SPK recipients (Am J Transplant 2003;3:439)
Early diagnosis and successful treatment of pancreas allograft rejection results in preservation of graft endocrine function
Pancreatic enzyme levels frequently recover to the previous baseline level, although not always (UpToDate: Pancreas Allograft Rejection [Accessed 1 March 2024])

Case reports

31 year old man with a history of diabetes mellitus 1 received an SPK and underwent severe rejection, damaging the kidney only (J Am Soc Nephrol 1994;4:1841)
40 year old man with a history of diabetes mellitus 1 and HIV infection received an SPK (Transplant Proc 2010;42:3887)
45 year old man with a history of diabetes mellitus 1 received an SPK and developed thrombotic microangiopathy (Nephrology (Carlton) 2017;22:23)

Treatment

Induction therapy is the initial high dose bolus of immunosuppression given perioperatively to transplant patients (Transpl Int 2013;26:704)
In particular, high risk patients, such as sensitized patients, recipients of solitary pancreas transplants, repeat transplants, African American patients or patients receiving positive crossmatch organs, are thought to benefit from induction therapy (Transpl Int 2013;26:704)
Induction therapy involves the use of depleting (e.g., antithymocyte globulin, alemtuzumab) or nondepleting antibodies (daclizumab, basiliximab) ( Transplant Proc 2022;54:1918)
Most used combinations for maintenance therapy are cyclosporine A with azathioprine and later tacrolimus with mycophenolate mofetil with or without (due to their diabetogenicity) steroids (Transplant Proc 2022;54:1918)
For patients with acute cell mediated rejection grade 1, 2 or 3, treatment with rabbit antithymocyte globulin plus glucocorticoids is recommended; if high dose glucocorticoids alone are used, a follow up pancreas biopsy should be considered to confirm the resolution of rejection (UpToDate: Pancreas Allograft Rejection [Accessed 1 March 2024])
For patients with acute antibody mediated rejection, various combinations of plasmapheresis, intravenous immune globulin and rituximab are used (UpToDate: Pancreas Allograft Rejection [Accessed 1 March 2024])
Patients with mixed acute rejection are treated for both acute cell and antibody mediated rejection

Frozen section description

Pancreas transplant rejection cannot be diagnosed on frozen sections

Microscopic (histologic) description

Modern histological criteria and histological grading of pancreas allograft rejection were established by the multidisciplinary international consensus panel in the reports of 2008, 2011 and 2022
Adequate pancreas biopsy includes at least 3 lobular areas and their associated interlobular septa
Arteries should be present; their absence should be noted in the pathology report (Am J Transplant 2008;8:1237)
As a general guideline, histologic features favoring active cell mediated rejection are septal infiltrates, eosinophils, venulitis, mononuclear acinar inflammation (Am J Transplant 2024;24:362)
Histologic features favoring active antibody mediated rejection: neutrophilic acinar / septal infiltrates, capillaritis, necrotizing vasculitis, interstitial hemorrhage, hemorrhagic necrosis (Am J Transplant 2024;24:362)
6 diagnostic categories are defined as follows
1. Normal: absent or inactive septal inflammation not involving ducts, veins, arteries or acini; no graft sclerosis (fibrosis) (Am J Transplant 2024;24:362)
2. Indeterminate: septal inflammation that has focal features of activity but there is no ductitis, venulitis or acinar inflammation (Am J Transplant 2024;24:362)
3. Cell mediated rejection
  - Acute cell mediated rejection grade 1 / mild active cell mediated rejection: active septal inflammation with venulitis, ductitis, neural / perineural inflammation or focal acinar inflammation (Am J Transplant 2008;8:1237)
  - Acute cell mediated rejection grade 2 / moderate active cell mediated rejection: features of mild acute cell mediated rejection or multifocal acinar inflammation with spotty acinar cell injury / dropout or mild intimal arteritis with < 25% luminal compromise (Am J Transplant 2024;24:362)
  - Acute cell mediated rejection grade 3 / severe active cell mediated rejection: features of mild acute cell mediated rejection or severe acinar inflammation with focal or diffuse / confluent acinar cell necrosis or moderate or severe intimal arteritis (> 25% luminal compromise) with or without transmural inflammation - necrotizing arteritis (Am J Transplant 2008;8:1237, Am J Transplant 2024;24:362)
  - Chronic active cell mediated rejection: predominantly mononuclear inflammation in fragmented acini with ≥ stage 1 graft fibrosis; ductal inflammation with periductal fibrosis or degenerative atrophic or metaplastic epithelial changes; chronic transplant arteriopathy (Am J Transplant 2024;24:362)
  - Concurrent active cell mediated rejection should be graded separately (Am J Transplant 2024;24:362)
4. Antibody mediated rejection: active has all 3 diagnostic components (see Terminology) present and probably active has 2 of 3 components present (Am J Transplant 2024;24:362)
  - Chronic active antibody mediated rejection: active antibody mediated rejection and chronic tissue injury with ≥ stage 1 graft fibrosis or vascular changes (e.g., chronic transplant arteriopathy) (Am J Transplant 2024;24:362)
  - Probable chronic active antibody mediated rejection (see Am J Transplant 2024;24:362)
5. Graft fibrosis (sclerosis)
  - No graft fibrosis: the fibrous component is limited to normal septa and is proportional to the size of ducts and vessels (Am J Transplant 2008;8:1237)
  - Mild graft fibrosis / fibrosis stage 1: fibrosis involves < 30% of the core surface; expansion of the fibrous septa; acinar lobules have eroded at the periphery (atrophy) (Am J Transplant 2024;24:362)
  - Moderate graft fibrosis / fibrosis stage 2: fibrosis involves 30 - 60% of the core surface, the acinar atrophy affects the majority of the locules at the periphery and in the center, thin fibrous strands crisscross between individual acini (Am J Transplant 2024;24:362)
  - Severe graft fibrosis / fibrosis stage 3: fibrosis involves > 60% of the core surface with only isolated residual acinar tissue and islets present (Am J Transplant 2024;24:362)
6. Islet pathology
  - Islet injury due to parenchymal ischemia
  - β cell injury due to calcineurin inhibitor toxicity
  - Recurrence of autoimmune diabetes mellitus (insulitis, selective β cell loss)
  - Features of diabetes mellitus type 2 (islet amyloid deposition)
  - Nonspecific reactive / regenerative changes (nesidioblastosis, islet hyperplasia)
7. Other histologic diagnosis

Microscopic (histologic) images

Contributed by Alexei Mikhailov, M.D., Ph.D. and Cinthia Drachenberg, M.D.

Inactive lymphocytes

Active acinar inflammatory infiltrate

Ductitis, no duct damage

Ductitis with epithelial damage

Venulitis

Neural inflammation

Cellular rejection grade 1

Cellular rejection grade 2

Cellular rejection grade 3

Graft fibrosis stage 2

Graft fibrosis stage 3

Chronic active cellular rejection

Antibody mediated rejection

Irregular fibrosis in peripancreatitis

Cytology description

Cytology studies are not used in the diagnosis of pancreas transplant rejection

Positive stains

CD3 and CD68 immunohistochemical stains highlight the presence of T lymphocytes and macrophages in the lobules and facilitate the detection of lymphocytes in the venules and ducts
At present, however, the Banff pathology working group recommends that the diagnosis and grading of rejection remain based on the evaluation of routine stains (Am J Transplant 2024;24:362)
C4d immunohistochemical staining if positive in the interacinar capillaries (≥ 1% of the acinar lobular surface) becomes 1 of the 3 diagnostic components in the detection of active or chronic active antibody mediated rejection

Negative stains

Insulin and glucagon immunohistochemical stains demonstrate diminished secretion in both β and α cells in ischemic graft injury
Diagnosis of type 1 diabetes mellitus recurrence requires immunohistochemical demonstration of a lack of β cells in the islets (Am J Transplant 2024;24:362)

Electron microscopy description

Electron microscopy is not used in the diagnosis of pancreas transplant rejection

Sample pathology report

Pancreas, transplant, biopsy:
- Acute cell mediated rejection with ductitis, venulitis and foci of mild acinar inflammation, consistent with Banff grade 1
- Focal mild septal fibrosis stage 1
- Clinical information
  - The patient is a 34 year old man with a history of end stage renal disease secondary to diabetes mellitus type 1. He received a simultaneous pancreas kidney biopsy 1 year ago. Laboratory data: serum amylase 123 IU/mL, serum lipase 170 IU/mL, serum creatinine 1.4 mg/dL (baseline 0.9 mg/dL).
- Microscopic description
  - 6 lobules of pancreatic parenchyma are sampled. The septa show variable numbers of lymphocytes, including activated lymphocytes, with admixed eosinophils, from scattered cells to groups and clusters. Several ducts show intraepithelial lymphocytes with associated vacuolization and detachment of ductal epithelium. A few venules display circumferential cuffing, activated endothelium and subendothelial lymphocytes. Some lobules display small foci of lymphocytes with no appreciable acinar cell damage. There is mild fibrosis involving ~15% of the biopsy core surface, with peripheral acinar erosion. Unremarkable medium caliber arteries are present.
- Special stains
  - The C4d immunoperoxidase stain is negative
  - The immunoperoxidase stains for CD3 and CD68 demonstrate increased numbers of septal and acinar T lymphocytes and macrophages

Differential diagnosis

Ischemia reperfusion injury:
- Seen in the early postoperative period, significant inflammation is absent (Am J Transplant 2024;24:362)
Pancreatitis / peripancreatic fluid collection:
- Septa and periphery of lobules show mixed (lymphocytes, plasma cells, eosinophils, neutrophils) inflammation; center of lobules is preserved (Am J Transplant 2008;8:1237)
Peripancreatitis:
- Fibrosis may appear very pronounced in the superficial areas of the pancreas and it does not affect the deeper areas, which may lead to errors in determining the fibrosis stage
Cytomegalovirus pancreatitis:
- Cytomegalovirus cytopathic changes in acinar, stromal and endothelial cells (Am J Transplant 2008;8:1237)
Polyomavirus nephropathy:
- Develops in the kidney of the SPK transplants only; the pancreas is spared from clinical evidence of infection (Transplant Proc 2004;36:1097, Transplant Proc 2004;36:1095)
Posttransplant lymphoproliferative disorder:
- Infiltrates are nodular and expansile, containing a significant proportion of atypical plasmacytoid B cells
- In situ hybridization with Epstein-Barr encoded RNAs is positive (Hum Pathol 1998;29:569)
Bacterial or fungal infection:
- Purulent, necrotizing, granulomatous
- Systemic or localized infectious symptoms are seen (Am J Transplant 2008;8:1237)
Calcineurin inhibitor toxicity:
- Pathologic changes are limited to islet β cells, which demonstrate cytoplasmic clearing / vacuolization and weak insulin staining (Am J Transplant 2024;24:362)
- Findings of rejection are absent
Diabetes type 1 recurrence:
- Insulitis with progressive and selective loss of β cells (Am J Transplant 2024;24:362)
- Findings of rejection are absent
Diabetes type 2 development:
- Often associated with amyloid deposition and degenerative changes in islets (Am J Transplant 2024;24:362)
- Findings of rejection are absent

Board review style question #1

The representative image above is from the pancreas biopsy of a simultaneous pancreas kidney transplant recipient. Biopsy was performed due to elevated serum amylase and lipase. Based on this H&E stained section alone, how would you grade this biopsy?

Acute antibody mediated rejection
Acute cell mediated rejection, grade 1
Acute cell mediated rejection, grade 2
Acute cell mediated rejection, grade 3
Indeterminate for rejection

Board review style answer #1

B. Acute cell mediated rejection, grade 1. The interlobular septum is diffusely involved with a mononuclear infiltrate containing activated lymphocytes and eosinophils; there is ductitis with significant epithelial damage, defining this process as acute cell mediated rejection, grade 1. Answer E is incorrect because the septal infiltrate is active and shows features of acute cell mediated rejection. Answers C and D are incorrect because acute cell mediated rejection grades 2 and 3 require multifocal or severe acinar inflammation. Answer A is incorrect because there are no histological (interacinar capillaritis) or laboratory (donor specific antibodies) features of acute antibody mediated rejection.

Comment Here

Reference: Allograft rejection

Board review style question #2

A pancreas transplant recipient underwent an allograft biopsy. A representative image of the biopsy core stained with antibodies to CD3 is shown above. Based on this image alone, what is your diagnosis?

Acute cell mediated rejection, grade 1
Acute cell mediated rejection, grade 2
Acute cell mediated rejection, grade 3
Indeterminate for rejection
Normal pancreas

Board review style answer #2

A. Acute cell mediated rejection, grade 1. Most of the septum shown is occupied by an unremarkable artery and the remaining portion shows only scattered T cells. Focal acinar inflammation (≤ 2 foci of T cells with at least 10 cells in each focus), however, is present, defining this as acute cell mediated rejection, grade 1. Answers D and E are incorrect because the lobule clearly shows several foci of lymphocytic accumulation. Answers B and C are incorrect because ≥ 3 foci of lymphocytic inflammation with at least 10 cells in each focus are not seen.

Comment Here

Reference: Allograft rejection

Board review style question #3

A patient with diabetes mellitus 1 received a pancreas transplant. Maintenance therapy included tacrolimus; FK506 level was higher than expected. Serum amylase and lipase were normal but the blood glucose level became higher. An allograft biopsy demonstrated islet cell swelling, vacuolization, islet cell dropout and formation of empty spaces; no islet centered inflammation was found. What additional pathological changes were most likely seen on this biopsy?

Acinar cells with enlarged nuclei with viral cytopathic changes
Ductitis, venulitis and acinar inflammation
Endarteritis
Mixed septal and peripheral lobular inflammatory infiltrate containing polymorphonuclear neutrophils
Weak or absent insulin staining

Board review style answer #3

E. Weak or absent insulin staining. Isolated β cell damage in the absence of islet centered inflammation is characteristic for calcineurin inhibitor toxicity; note also the high FK506 (tacrolimus) level and high blood glucose in this patient. Answers B and C are incorrect because these are manifestations of acute cell mediated rejection. Selective islet cell damage is not characteristic for acute cell mediated rejection; note also high levels of immunosuppressant tacrolimus and normal pancreatic enzymes. Answer D is incorrect because it points to the histological features of pancreatitis and answer A is incorrect because it points to cytomegalovirus pancreatitis; again, selective islet cell damage is not seen under these conditions.

Comment Here

Reference: Allograft rejection

Anatomy & histology

Table of Contents

Definition / general

The pancreas is a mixed exocrine and endocrine gland located in the retroperitoneum behind the stomach, in front of the inferior vena cava and the aorta

Essential features

Retroperitoneal organ with exocrine and endocrine functions
Histology: serous ductal / acinar (exocrine cells) gland with tubuloalveolar arrangement with interspersed islets of Langerhans (endocrine cells)

Terminology

Anatomically, from right to left, the pancreas is divided into the caput (head), collum (neck), corpus (body) and cauda (tail)
Pancreatic secretion is drained by the main pancreatic duct (Wirsung duct), with orifice in major duodenal papilla (papilla of Vater), mostly together with the main bile duct
~5 - 10% of people have an accessory pancreatic duct (Santorini duct), with orifice in minor duodenal papilla
Pancreas is embedded in fibrous capsule passing in fibrous septa, separating pancreatic lobuli
Lobuli consist of multiple acini (the exocrine part) drained by intralobular ducts (leading the pancreatic juice into the small bowel)
Interlobular ducts originate from the confluence of many intralobular ducts
Interlobular ducts lead to the main pancreatic duct

Physiology

Exocrine function (99% of cells): pancreatic juice is produced by acinar cells
- Pancreatic juice contains bicarbonate and proteolytic enzymes (trypsinogen, chymotrypsinogen, carboxypeptidase, elastase), lipolytic enzymes (lipase, esterase, phospholipase), saccharide degrading enzyme (amylase), nucleic acid degrading enzymes (DNAse, RNAse)
- Enzymes are activated in the intestine; enterocyte glycocalyx enzymes (enterokinase) turns trypsinogen to trypsin
- Trypsin catalyzes activation of the other enzymes
Endocrine function (1% of cells): islets of Langerhans consist of several cell types producing various hormones, which are released into the blood
- A cells (20% of the islets): in the periphery of the islets, glucagon production - increase of blood glucose concentration
- B cells (70% of the islets): in the center of the islets, insulin production - decrease of blood glucose, glucose intake in adipocytes and muscle cells
- D cells (5% of the islets): somatostatin production - inhibition of smooth muscle motility, antagonist of several gastrointestinal hormones
- F cells (1% of the islets): pancreatic polypeptide production - regulation of pancreatic juice and bile release
- D1 cells (less than 1%): vasoactive intestinal polypeptide - glycogenolysis and hyperglycemia, stimulates GI fluid secretion and causes secretory diarrhea
- EC (enterochromaffin) cells (less than 1%): P substance, serotonin - stimulation of gastrointestinal motility
- G cells (less than 1%): gastrin - stimulation of gastric juice release
- PP cells: pancreatic polypeptide - stimulates secretion of gastric and intestinal enzymes and inhibits intestinal motility
- Ghrelin producing cells: ghrelin - regulation of hunger and energetic metabolism

Anatomy

15 cm long, 60 - 140 g
Shape is akin to letter J turned sideways, with loop of J around the duodenum
Divided into head (right of left border of superior mesenteric vein; contains uncinate process), body (between left border of superior mesenteric vein and left border of aorta) and tail
Retroperitoneal organ (except for tail), lies within duodenal curve, close to superior mesenteric artery and portal vein
Anterior body of pancreas touches posterior wall of stomach
Posterior of pancreas touches aorta, splenic vein and left kidney
Pancreatic tail extends to the splenic hilum
Pancreatic head has close anatomic relationship to the common bile duct (choledochus) - distal part (ca. 4 - 5 cm) passes through the pancreatic head into the small intestine
- Orifice of the bile duct is called ampulla of Vater (major papilla), which is equipped with circular smooth muscle (sphincter of Oddi) releasing bile and pancreatic juice into the duodenum
- Pathology of pancreatic head, common bile duct and papilla share clinical symptoms

Embryology

Forms from embryonic foregut, of endodermal origin (Wikipedia: Pancreas [Accessed 7 December 2017])
Pancreas forms from ventral and dorsal buds that rotate and fuse
Ventral bud (anlage) develops from hepatic duct, forms posterior / inferior head and uncinate process
Dorsal bud (anlage) develops from foregut and extends into dorsal mesentery; forms body, tail, anterior head
Fusion of ducts at week 7 creates main pancreatic duct (Wirsung), which extends to papilla of Vater, usually with common bile duct
Proximal portion of dorsal duct persists as accessory duct of Santorini, empties into minor duodenal papilla
Usually numerous anastomotic connections between ducts of Wirsung and Santorini; if not, result is pancreas divisum (10% of individuals), in which duct of Santorini is major drainage duct
Percentage of acinar cells decreases after birth
Anomalies:
- In 67% of adults, pancreatic duct empties into common bile duct, not into ampulla directly
- Abnormal fusion of ventral and dorsal buds causes annular pancreas or heterotopic pancreas

Exocrine pancreas

Acini comprise 80% of pancreas
Composed of columnar to pyramidal epithelial cells with minimal stroma
Basophilic due to prominent rough endoplasmic reticulum
Pancreas produces 2 liters/day of bicarbonate rich fluid containing digestive enzymes and proenzymes, regulated by neural stimulation (vagus nerve) and humoral factors (secretin, cholecystokinin)
- Cholecystokinin: released from duodenum in response to fatty acids, peptides and amino acids; promotes discharge of digestive enzymes by acinar cells
- Secretin: stimulates water and bicarbonate secretion by duct cells; is stimulated by acid from stomach and luminal fatty acids
Pancreatic self digestion is prevented by:
- Packaging of most proteins as inactive proenzymes, enzyme sequestration in zymogen granules
- Proenzymes activated only by trypsin, which is activated only by duodenal enterokinase
- Trypsin inhibitors are present in ductal and acinar secretions
- Intrapancreatic release of trypsin activates enzymes, which degrade other digestive enzymes before they can destroy pancreas
- Lysosomal hydrolases can degrade zymogen granules to prevent autodestruction if acinar secretion is impaired
- Acinar cells themselves are highly resistant to trypsin, chymotrypsin and phospholipase A2
- Pancreatic ductal epithelia secrete the bulk of secretagogue induced bicarbonate ions by moving HCO3 from the blood into the pancreatic fluid (Said: Physiology of the Gastrointestinal Tract, 6th Edition, 2018)
- Mucin producing cells are also found among pancreatic ductal epithelia - mucin lubricates, hydrates and protects epithelial cells (Johnson: Encyclopedia of Gastroenterology, 1st Edition, 2004)

Endocrine pancreas

Consists of islets of Langerhans; represents 1% of pancreas (percentage higher at birth)
Round, compact, highly vascularized with scant connective tissue
More irregular outline and trabecular arrangement in posterior head of pancreas, with cells producing pancreatic polypeptide
Size of islets usually 0.1 - 0.2 mm; endodermal origin; 1 million islets present in pancreas
Postgastrectomy, may get islet hypertrophy, then beta cell proliferation, then atrophy and amylin deposits (Hum Pathol 2000;31:1368)
Alpha cells: peripherally dense and round on electron microscopy
Beta cells: crystalline appearance on electron microscopy, with surrounding halo
Delta cells: large pale granules on electron microscopy
PP cells: also scattered in exocrine pancreas; more PP cells in posterior head of pancreas (from ventral bud)
Nesidioblastosis:
- Islets in intimate association with ducts, with formation of ductuloinsular complexes
Nesidiodysplasia (Hum Pathol 1988;19:1215):
- Loss of the usual centrilobular concentration of larger islets, with increased small irregularly distributed aggregates of islet cells
- Also increase in beta cell nuclear size and DNA content
- May be associated with endocrine neoplasms
Peliosis:
- Selective congestion and dilation of vessels of islets only, not seen in vessels elsewhere

Drawings / diagrams

AFIP images

Development of human pancreas

Anatomy of pancreas

Images hosted on other servers:

Development of pancreas

Embryology

Pancreas of human embryo

Stages of development

Microscopic (histologic) description

Vast majority of pancreas volume is composed of exocrine tissue (pancreatic acini)
- Acini show alveolar (round) shape and lobulated architecture
- Acini are packed closely together, drained by series of ductules and ducts
- Acinar cells stain blue by hematoxylin at their base because of high RNA content and presence of nuclei
- Luminal aspect stains pink due to high content of digestive enzymes (zymogen granula, staining with PAS)
- Ductules and ducts are lined by a single layer of cuboidal or cylindrical epithelia
- There is a significant amount of collagen within the wall of large ducts, including main pancreatic duct
Embedded within the pancreatic exocrine tissue are the islets of Langerhans
- Islets display rich vascularization and consist of endocrine cells
- Endocrine cells have polygonal to round shape, voluminous pale to slightly eosinophilic cytoplasm and monomorphic round nuclei with heterogenous (salt and pepper) chromatin

Microscopic (histologic) images

Contributed by Jan Hrudka, M.D., Ph.D.

Normal pancreas histology

Chromogranin A IHC

Glucagon IHC

Insulin IHC

Contributed by Grigory Demyashkin, M.D., Ph.D. and AFIP images

10 week old fetus

Islets in newborn

Adult pancreas: distribution of islet cell types

6 - 8 week embryo

Cytology description

Smear, cytospins or cytoblock from brushings or needle aspirates from ducts; eventually fine needle aspirations (FNAs) from solid tissue
FNA - predominant cell type is acinic: pyramidal or triangular cells with abundant granular cytoplasm and round eccentric or central nucleus with fine chromatin and often distinct nucleolus
Ductal cells = 2 dimensional flat sheets (honeycomb), picket fence appearance, tall or cuboidal cells with scant pale cytoplasm and basally located bland appearing nuclei
Contaminants = mesothelia or hepatocytes in transcutaneous biopsies, duodenal or gastric mucosa in endoscopic aspirations (more often)

Cytology images

AFIP images

Normal pancreatic acinar cells

Normal ductal cells in sheet arrangement

Positive stains

Exocrine cells: cytokeratin 8 / 18, trypsin, BCL10, PAS (zymogen granules)
Endocrine cells: chromogranin, synaptophysin, neuron specific enolase, neurofilament, CD56

Electron microscopy images

AFIP images

38 / 39 week old fetus

Adult pancreatic islet cells

2 centroacinar cells with electron lucent cytoplasm

Images hosted on other servers:

Zymogen granules

Board review style question #1

Elastase, trypsin and DNAse are placed in the

Basophilic basal part of acinic cells
Cytoplasmic vacuoles in the ductal cells
Eosinophilic cytoplasm of beta cells
Eosinophilic granula in the acinic cells

Board review style answer #1

D. Eosinophilic granula in the acinic cells. As basic substances, proteins are usually eosinophilic in H&E staining. The eosinophilic granula are called zymogenic in pancreas acinic cells. Answer A is incorrect because the basophilic part of the acinic cell cytoplasm contains ribosomes (rough endoplasmic reticulum). Answer B is incorrect because vacuoles in the ductal cells contain mucin. Answer C is incorrect because beta cells are a major part of Langerhans islets; eosinophilic cytoplasm contains endocrine granula (insulin).

Comment Here

Reference: Pancreas - Anatomy & histology

Autoimmune pancreatitis type 1

Table of Contents

Definition / general

1 of 2 types of autoimmune pancreatitis
Pancreatic manifestation of IgG4 related disease (IgG4 RD)

Essential features

Autoimmune pancreatitis is the pancreatic manifestation of IgG4 RD so patients typically have increased IgG4 on serology and other organ involvement by the disease
Diagnosis can be difficult due to rarity, vague presentation and being a mimic of pancreatic ductal adenocarcinoma
International Consensus Diagnostic Criteria (ICDC) for autoimmune pancreatitis has set a standard diagnostic approach and criteria for diagnosis, which includes imaging, serology and histology
Characteristic histologic findings are periductal lymphoplasmacytic infiltrate without granulocytic infiltration, obliterative phlebitis, storiform fibrosis and abundant IgG4 positive plasma cells

Terminology

Autoimmune pancreatitis (AIP) type 1 or IgG4 related pancreatitis (IgG4 RP)
Historically termed lymphoplasmacytic sclerosing pancreatitis (LPSP) or AIP without granulocyte epithelial lesions (GELs) (Pancreas 2011;40:352)

ICD coding

ICD-10: K86.1 - other chronic pancreatitis
ICD-11: DC33 - autoimmune pancreatitis

Epidemiology

Patients are generally male and older than 50 years old (Pathologica 2020;112:197, World J Gastroenterol 2022;28:6867)
Increased prevalence in Asia (Adv Med Sci 2020;65:403)
Rare; prevalence is < 1% (World J Gastroenterol 2022;28:6867)
Incidence has been increasing due to better description and recognition of the disease but overall numbers are most likely still underestimated due to the complexity of the disease (World J Gastroenterol 2022;28:6867)

Sites

Pancreatic manifestation of IgG4 RD
Extrapancreatic organ sites can be affected, including salivary and lacrimal glands, retroperitoneum, biliary tree, prostate and kidneys (Pathologica 2020;112:197, World J Gastroenterol 2022;28:6867, Adv Med Sci 2020;65:403)
- Other organ involvement is defined as the manifestation of IgG4 related systemic disease and may be diagnosed through imaging, clinical exam or histology (Pancreas 2011;40:352)

Pathophysiology

Currently unknown
Still unclear whether the IgG4 antibodies are a reflection of overexpression caused by an unknown inflammatory stimulus or whether they are self reactive autoantibodies
Has been linked to an increase in interferon type I (IFN I) produced by plasmacytoid dendritic cells but this is nonspecific to autoimmune pancreatitis
H. pylori infection may be the trigger mechanism for an autoimmune response against pancreatic acini via molecular mimicry but this hypothesis is not supported at this time
Reference: Adv Med Sci 2020;65:403

Etiology

Multifactorial, including genetic, environmental and immunological factors
- HLA region genes, HLA DRB1 and ABCF1, are associated with disease susceptibility
- Repeated exposure to certain antigens, including mineral oils, solvents and industrial or metal dusts, may contribute
Reference: Adv Med Sci 2020;65:403

Diagrams / tables

Images hosted on other servers:

AIP diagnostic algorithm

Diagnostic levels

Diagnostic criteria

Clinical features

Patients most commonly present with obstructive jaundice (Pathologica 2020;112:197, World J Gastroenterol 2022;28:6867)
Patients can also present with a pancreatic mass, weight loss or abdominal pain / discomfort but do not present with acute pancreatitis symptoms (Adv Med Sci 2020;65:403)
Diabetes commonly occurs with autoimmune pancreatitis (World J Gastroenterol 2022;28:6867)
Other manifestations and symptoms of IgG4 RD can be present, including enlargement of the lacrimal and salivary glands as well as retroperitoneal fibrosis and inflammation of the biliary tree (Adv Med Sci 2020;65:403)

Diagnosis

ICDC for autoimmune pancreatitis was published in 2011, which uses the following combination of categories for diagnosis (Pancreas 2011;40:352)
- Imaging
- Serology
- Other organ involvement (OOI)
- Histology
- Response to steroid therapy
Can be diagnosed without histology (Pancreas 2011;40:352)
Other diagnostic criteria can be used, including the HISORt criteria published by Mayo Clinic; however, the ICDC is the most widely used (Adv Med Sci 2020;65:403)
See Diagrams / tables

Laboratory

IgG4 > 2 times the upper limit of normal on serology (Pancreas 2011;40:352)
- Serum IgG4 elevation is the single best marker of autoimmune pancreatitis (Pancreas 2011;40:352)
- Elevated IgG4 can also be seen in pancreatic carcinoma patients (10%) and so elevation is not sufficient to make a diagnosis unless seen in the setting of typical imaging or histologic findings (Adv Med Sci 2020;65:403, Pancreas 2011;40:352)
Positive autoimmune markers are common, including antinuclear antibodies (ANA) (40%), anticarbonic anhydrase II antibodies (55%), antipancreatic secretory trypsin inhibitor (PSTI) antibodies (55%) and antilactoferrin antibodies (75%) (Adv Med Sci 2020;65:403)
May have elevated CA 19-9, which can raise suspicion of malignancy (Pathologica 2020;112:197)

Radiology description

Parenchymal imaging
- Typical: diffuse enlargement with delayed enhancement (sometimes associated with rim-like enhancement)
- Indeterminate (including atypical): segmental / focal enlargement with delayed enhancement
Ductal imaging (endoscopic retrograde cholangiopancreatography [ERCP])
- Level 1: long (> one - third length of the main pancreatic duct) or multiple strictures without marked upstream dilatation
- Level 2: segmental / focal narrowing without marked upstream dilatation (duct size
- Diffuse / non-mass forming autoimmune pancreatitis
  - Diffuse pancreas enlargement ("sausage" pancreas), often with low density edge (halo ring sign or capsule sign) on computed tomography (CT) (World J Clin Cases 2022;10:12458)
  - Contrast can highlight the capsule and shows mild enhancement during the venous or delayed phase (World J Clin Cases 2022;10:12458)
- Mass forming autoimmune pancreatitis
  - Often shows a low density or isodense mass in the head of the pancreas on CT (World J Clin Cases 2022;10:12458)
  - Contrast enhanced CT shows slight enhancement of the lesion in the arterial phase and obvious uniformity and delayed enhancement in the venous phase (World J Clin Cases 2022;10:12458)
- Ducts
  - Smooth stenosis at the lower end of the common bile duct can be shown in autoimmune pancreatitis patients with obstructive jaundice (World J Clin Cases 2022;10:12458)
  - Pancreatic duct is usually irregularly narrow and interrupted and often exceeds one - third of the total length of the main pancreatic duct or appears as a jumping stenosis (World J Clin Cases 2022;10:12458)
- Contrast enhanced CT and magnetic resonance imaging (MRI) show similar results; ultrasound can be variable in diagnostic quality (Adv Med Sci 2020;65:403)
- Other organ involvement can also be seen on imaging and help support the diagnosis of autoimmune pancreatitis

Radiology images

Images hosted on other servers:

PET

Endoscopic ultrasound

ERCP with stricture

Ultrasound

MRI

Mass forming autoimmune pancreatitis (CT)

Mass forming autoimmune pancreatitis (PET)

Prognostic factors

Patients commonly relapse (40%) despite remarkable responses to treatment (Pathologica 2020;112:197, Adv Med Sci 2020;65:403)

Case reports

49 year old woman with weight loss, abdominal pain and jaundice (Cureus 2023;15:e47471)
54 year old man with weight loss and abdominal pain status post-COVID vaccine (ACG Case Rep J 2023;10:e00950)
55 year old man with weight loss, jaundice and pruritus (Cureus 2023;15:e45970)
64 year old Japanese woman with new onset bleeding due to acquired hemophilia A with known longstanding disease (Int J Hematol 2018;108:335)

Treatment

Steroids are the main treatment strategy
- Steroid trial of prednisone 0.6 - 1 mg/kg for 2 weeks with improvement on repeat imaging and serology can be confirmatory in the appropriate context (Pancreas 2011;40:352)
- Steroid trial should not be done in isolation for diagnosis of autoimmune pancreatitis (Pancreas 2011;40:352)
Immunosuppressants or rituximab can be started if corticosteroids are not effective or cannot be tolerated
Patients with asymptomatic disease should be treated to prevent the progression of fibrotic changes and decrease the risk of developing pancreatic insufficiency or relapse
Follow up should consist of a combination of methods (symptoms, serology, imaging) and not IgG4 levels alone
Endoscopic procedures may be needed in cases of insufficient drug effect or obstructive jaundice
Surgery should be reserved for cases where malignancy cannot be excluded, extensive fibrosis is present or endoscopic biliary drainage cannot be performed
Reference: Adv Med Sci 2020;65:403

Gross description

Disease is localized mainly in the pancreatic head, less frequently in the body / tail
Diffuse enlargement or "sausage" pancreas may be observed without a discrete mass
Segmental stenosis of the main duct may be seen
References: Pathologica 2020;112:197, Abdom Radiol (NY) 2016;41:1003, World J Gastroenterol 2022;28:6867

Gross images

Contributed by Aaron R. Huber, D.O.

Ill defined fibrosis

Images hosted on other servers:

Nodular lesions

Ill defined pancreatic head mass

Microscopic (histologic) description

Characteristic findings (at least 3 for level 1 criteria) (Pancreas 2011;40:352)
- Periductal lymphoplasmacytic infiltrate without granulocytic infiltration
- Obliterative phlebitis
- Storiform fibrosis
- Abundant (> 10 cells/high power field) IgG4 positive plasma cells
Biopsy showing some but not all of the above features can be used as supportive evidence for the diagnosis of autoimmune pancreatitis (Pancreas 2011;40:352)
Inflammation is localized within the pancreatic parenchyma and is centered around / within medium to large interlobular ducts, which causes shrinkage of the ductal lumen (Pathologica 2020;112:197)
Inflammation can also be seen between the pancreatic parenchyma and peripancreatic adipose tissue (Pathologica 2020;112:197)
Inflammation of the venous wall can progress to obliterative phlebitis with fibrosis of the lumen (Pathologica 2020;112:197)
As the inflammation progresses, fibrosis becomes more diffuse, assuming a whorled or storiform pattern (Pathologica 2020;112:197)
Perineural inflammation can also be present (Pathologica 2020;112:197)
Involvement of the pancreatic neck margin or biliary resection margin should be clearly stated in the pathology report for therapeutic purposes (Pathologica 2020;112:197)

Microscopic (histologic) images

Contributed by Aaron R. Huber, D.O. and @RaulSGonzalezMD on Twitter

Fibrosis and inflammation

Inflammation

Fibrosis

Phlebitis

Autoimmune pancreatitis type 1

Elastic stain

IgG4

Cytology description

FNA has variable results with diagnosing autoimmune pancreatitis type 1 but can be used to rule out malignancy in mass forming lesions (Diagnostics (Basel) 2021;11:1653)
Lymphoplasmacytic infiltration, storiform fibrosis and obliterative phlebitis can be seen alone or in combination (Diagnostics (Basel) 2021;11:1653, World J Gastroenterol 2012;18:3883)

Cytology images

Images hosted on other servers:

Type 1 FNA

Positive stains

IgG and IgG4
- > 10 IgG4 positive cells per high power field in biopsy specimens (Pancreas 2011;40:352)
- > 50 IgG4 positive cells per high power field in resection specimens (Virchows Arch 2018;472:545)
- IgG4/IgG ratio > 40% (Virchows Arch 2018;472:545)
Elastic: highlights remnant veins in longstanding autoimmune pancreatitis
Masson trichrome: highlights storiform fibrosis
Normal / intact expression of DPC4 in entrapped ducts

Sample pathology report

Pancreas, mass, core needle biopsy:
- Chronic pancreatitis with storiform fibrosis and increased IgG4 positive plasma cells (see comment)
- Negative for malignancy
- Comment: H&E sections demonstrate pancreatic parenchyma with dense storiform fibrosis and numerous chronic inflammatory cells including abundant plasma cells. A partially obliterated vein is seen. Immunohistochemical stain for IgG4 shows increased IgG4 positive plasma cells (up to 20 - 25 per high power field). The combined findings are most consistent with autoimmune pancreatitis type 1.

Differential diagnosis

Pancreatic ductal adenocarcinoma:
- Can have similar presentation (vague abdominal symptoms, jaundice, pancreatic mass) with similar radiographic findings and serology (increased CA 19-9 with or without increased IgG4)
- Infiltrating well to poorly formed glandular / ductal structures surrounded by remarkably desmoplastic stroma
- Perineural or lymphovascular invasion
- Molecular alterations not present in AIP type 1 (World J Gastroenterol 2023;29:2241)
Autoimmune pancreatitis type 2:
- Younger patients with no sex predilection
- Associated with chronic inflammatory bowel disease
- Serum IgG4 antibody levels are within normal ranges
- Requires histological specimen to make definitive diagnosis (Pancreas 2011;40:352)
- Duct centric granulocytic abscesses and lobular (but not storiform) fibrosis
Follicular pancreatitis:
- Inflammation with numerous lymphoid follicles with or without prominent germinal centers
- Lacks storiform fibrosis, obliterative phlebitis and IgG4+ cells
Obstructive chronic pancreatitis:
- Groups of acini and tubules scattered in fibrous tissue

Board review style question #1

Which of the following clinical and histologic features would support a diagnosis of autoimmune pancreatitis (AIP) type 1 over AIP type 2?

25 year old patient
Abundant IgG4 positive plasma cells on histologic section
Female patient
Lobular fibrosis

Board review style answer #1

B. Abundant IgG4 positive plasma cells on histologic section is the most supportive of a diagnosis of AIP type 1. AIP type 1 is the pancreatic manifestation of IgG4 related disease (IgG4 RD) and so patients will typically have elevated IgG4 levels on serology as well as demonstrate abundant IgG4 positive plasma cells on histologic section. Answers A and C are incorrect because AIP type 1 patients are more commonly over 50 years old and male. Answer D is incorrect because AIP type 1 also shows characteristic storiform fibrosis, not lobular fibrosis, which can be seen in AIP type 2.

Comment Here

Reference: Autoimmune pancreatitis type 1

Board review style question #2

Which of the following would most likely accompany the features seen on the pancreas histologic section shown above?

Acute abdominal pain with elevated lipase on serology
Elevated CA 19-9 on serology
Elevated IgG4 on serology
Histology of inflammatory bowel disease
Pancreas mass on imaging

Board review style answer #2

C. Elevated IgG4 on serology. The histologic section shows the characteristic findings of autoimmune pancreatitis (AIP) type 1 (storiform fibrosis and a lymphoplasmacytic infiltrate). Most AIP type 1 patients have elevated IgG4 on serology. Answer A is incorrect because patients do not present with symptoms of acute pancreatitis (acute abdominal pain with elevated lipase on serology). Answer B is incorrect because AIP type 1 patients can present with elevated CA 19-9 on serology but this is not as common as elevated IgG4. Answer D is incorrect because inflammatory bowel disease is associated with AIP type 2, not type 1. Answer E is incorrect because a pancreas mass can be seen in AIP type 1 but this is variable.

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Reference: Autoimmune pancreatitis type 1

Autoimmune pancreatitis type 2

Table of Contents

Definition / general

1 of 2 types of autoimmune pancreatitis, characterized by clinical evidence of jaundice, with or without formation of a pancreatic mass on radiographic imaging, with excellent clinical response to steroid treatment
Unlike type 1 autoimmune pancreatitis, type 2 is IgG4 negative and does not show extra pancreatic organ involvement and is not associated with increased IgG4 in serum or IgG4 positive plasma cells
Diagnosis requires histologic confirmation of granulocytic epithelial lesions (Pancreas 2011;40(3):352, Am J Surg Pathol 2003;27:1119)

Essential features

Characterized by clinically nonspecific signs and symptoms, radiographic evidence of pancreas enlargement, histologic evidence of destructive duct centric inflammation with granulocytic epithelial lesions, with an excellent response to treatment with steroids

Terminology

Autoimmune pancreatitis type 2, idiopathic duct centric pancreatitis, autoimmune pancreatitis with granulocyte epithelial lesions, nonalcoholic duct destructive pancreatitis

Epidemiology

Incidence largely unknown; requirement of tissue for definitive histologic diagnosis limits estimates of true incidence; thought to be less common than type 1 autoimmune pancreatitis (< 1 per 100,000) (Int J Rheumatol 2012;2012:358371)
Age: mean 40 - 44 years (Gut 2013;62:1771, Pancreas 2011;40:809)
Sex: M = F

Sites

Pancreas
No significant extra pancreatic involvement

Pathophysiology

Largely unknown

Etiology

Largely unknown

Clinical features

Numerous, nonspecific signs and symptoms
Jaundice, weight loss, abdominal pain, diffuse enlargement or mass forming lesion on imaging
No biochemical evidence of pancreatitis, absent serum IgG4, no extra pancreatic organ involvement (Pancreas 2011;40:809)
An association with inflammatory bowel disease, especially ulcerative colitis, is observed in up to 15% of cases (Gastroenterology 2015;149:39)

Diagnostic criteria

Histologic examination of tissue is critical for diagnosis per International Consensus Diagnostic Criteria 2011 (Pancreas 2011;40(3):352)
Categorization as "definitive" or "probable" based on histologic criteria:
- Level 1
  - Granulocytic infiltration of duct wall [aka granulocytic epithelial lesion(s)] with or without granulocytic acinar inflammation
  - Absent or scant IgG4 positive cells (0 - 10 cells/high powered fields)
- Level 2
  - Granulocytic and lymphoplasmacytic acinar infiltrate
  - Absent or scant IgG4 positive cells (0 - 10 cells/high powered fields)
Definitive type 2 autoimmune pancreatitis:
- Level 1 histologic findings with supportive findings on imaging or level 2 histologic findings, supportive findings on imaging, clinical inflammatory bowel disease and response to steroid treatment
Probable type 2 autoimmune pancreatitis:
- Level 2 histologic findings, supportive findings on imaging, variable inflammatory bowel disease and response to steroid treatment

Laboratory

No serum biomarkers have been elucidated (Pancreas 2011;40:809)
No biochemical evidence of pancreatitis (normal serum amylase, lipase)

Radiology description

No specific radiologic features to distinguish type 2 from type 1
Contrast enhanced ultrasound (Endosc Ultrasound 2018;7:196):
- Noninvasive imaging study; dynamic contrast enhancement improved discrimination between autoimmune pancreatitis and pancreatic ductal adenocarcinoma
- Shows iso or hyperenhancement during the arterial and phases
CT (AJR Am J Roentgenol 2015;205:2):
- Important imaging modality for differentiation from pancreatic cancer
- Diffuse parenchymal involvement, sausage shaped
- Delayed enhancement studies
- Rim-like enhancement
Magnetic resonance (Pancreas 2018;47:1115, Radiology 2011;260:428)
- T1 weighted: hypointense
- T2: predominantly hyperintense
- Dynamic study shows the effect of fibrosis widening the extracellular and extravascular spaces, resulting in hypointensity during pancreatic phase and contrast retention / hyperintensity during the delayed phase
Magnetic resonance cholangiopancreatography (Pancreas 2018;47:1115)
- Stenosis of the main pancreatic duct, however with less upstream dilatation than seen in type 1 autoimmune pancreatitis
- Rare / absent common bile duct stenosis and rare / absent stenosis of intrahepatic bile ducts, consistent with no extra pancreatic organ involvement in type 2 autoimmune pancreatitis compared to type 1 autoimmune pancreatitis

Radiology images

Images hosted on other servers:

Diffuse pancreas enlargement

Prognostic factors

Excellent prognosis (up to 99% remission) with steroid treatment
Low risk of recurrence (10 - 15%) (Gut 2013;62:1771)

Case reports

9 year old girl with intrahepatic and extrahepatic biliary ductal dilatation (Clin J Gastroenterol 2015;8:421)
20 year old man with Crohn's disease (Intern Med. 2018 Oct 15;57(20):2957)
64 year old man with inflammatory bowel disease and dilated common bile duct (J Investig Med High Impact Case Rep 2017;5:2324709617734245)

Treatment

Steroids, up to 99% response (Gastrointest Endosc Clin N Am 2018;28:493)
Immune modulation (rituximab, methotrexate)
Surgical resection of pancreas in rare cases unresponsive to medical management

Microscopic (histologic) description

Confined to pancreas
Key histologic features:
- Lymphoplasmacytic inflammation, predominantly periductal, although acini are also involved
- Epithelium of medium and small sized duct walls infiltrated by neutrophils [(granulocytic epithelial lesion(s)] with or without granulocytic acinar inflammation
  - Often causes destruction of the pancreatic duct epithelium
Lobular fibrosis (but not storiform) and obliterative phlebitis, however less prominent than in type 1 autoimmune pancreatitis
Absent or scant IgG4 positive cells (plasma cells) (0 - 10 cells / high powered fields) (Gastroenterology 2015;149:39)

Microscopic (histologic) images

Contributed by David J. Escobar, M.D., Ph.D.

Granulocyte epithelial lesion

IgG4-

Positive stains

IHC not necessary for diagnosis
One study has suggested a role for evaluating IL8 expression in ductal epithelium (85% versus 0% in type 1 autoimmune pancreatitis) and infiltrating neutrophils (100% versus 0% in type 1 autoimmune pancreatitis) (Am J Surg Pathol 2017;41:1129)

Negative stains

Scant or absent IgG4

Differential diagnosis

Pancreatic ductal adenocarcinoma
- Most important entity to exclude when considering autoimmune pancreatitis
- May present as jaundice, with infiltrative mass on radiographic imaging, variable serum IgG4 levels, variable elevated serum CA 19-9 levels
- Radiographic findings may be similar with contrast enhancement
Autoimmune pancreatitis type 1
- Associated with an older age group
- Serum IgG4 levels may be elevated
- Histology shows dense lymphoplasmacytic infiltrate, storiform fibrosis and obliterative phlebitis
- IgG4 positive plasma cells may be present, considered IgG4 related if IgG4/IgG ratio > 40% (Virchows Arch 2018;472:545)
Alcoholic / gallstone pancreatitis
- Acute pancreatitis that occurs in any age group
- Elevated amylase and lipase
- Histology is not needed for diagnosis, shows acute interstitial inflammation with spotty peripancreatic fat necrosis (mild cases) or large areas of saponification, hemorrhage and spotty widened viable acinar lumens (severe cases)
Chronic pancreatitis
- Progressive inflammation and fibrosis of the pancreas, resulting in waxing and waning nausea, weight loss, fat malabsorption (steatorrhea) and diabetes
- May have elevated serum CA 19-9
- Histology reveals atrophy of acini and ducts with preservation of pancreatic lobular architecture, variable amount of fibrosis centered around ducts and between lobules and mild chronic inflammatory cell infiltrate (Mod Pathol 2007;20:S113)

Additional references

Pancreatology 2010;10:664, Virchows Arch 2004;445:552, Gastroenterol Clin North Am 2016;45:29

Board review style question #1

A 40 year old man presented with jaundice and abdominal imaging showed a pancreatic mass. Serum IgG4 levels were not elevated. Endoscopic ultrasound guided fine needle biopsy was performed and a representative photomicrograph is shown. Which of the following statements is true?

Although serum IgG4 levels are not elevated, will have IgG4 positive cells
Despite steroid therapy, the patient's symptoms will persist and this will support the most likely diagnosis
Histopathologic findings in the photomicrograph are required for definitive diagnosis
Most likely diagnosis is associated with systemic inflammation, with frequent involvement of extra pancreatic organs

Board review style answer #1

C. According to the International Consensus Diagnostic Criteria established in 2011, the definitive diagnosis autoimmune pancreatitis type 2 requires tissue biopsy of the pancreas demonstrating granulocytic infiltration of the pancreatic duct wall [(granulocytic epithelial lesion(s)].
Answer choice A: IgG4 positive cells are absent in autoimmune pancreatitis type 2. This finding is more characteristic of autoimmune pancreatitis type 1.
Answer choice B: Both autoimmune pancreatitis types 1 and 2 respond to the steroid therapy.
Answer choice D: Autoimmune pancreatitis type 2 is not associated with extra pancreatic organ manifestations. This finding is more characteristic of autoimmune pancreatitis type 1.

Comment Here

Reference: Autoimmune pancreatitis type 2

Board review style question #2

A 45 year old woman presented with abdominal pain and jaundice. Abdominal imaging showed a diffusely enlarged sausage shaped pancreas and stenosis of the main pancreatic duct. Serum amylase, lipase and IgG4 levels were not elevated. During the workup, endoscopic ultrasound guided fine needle biopsy was performed and histologic sections showed pancreatic duct centric inflammation including ductal epithelium with intra-epithelial neutrophils. Upon further gathering of past medical history, the patient was most likely found to have which of the following?

Ankylosing spondylitis
Inflammatory bowel disease
Salivary gland enlargement and thyroiditis
Systemic lupus erythematosus

Board review style answer #2

B. There is a known association between autoimmune pancreatitis type 2 and inflammatory bowel disease, especially ulcerative colitis, occurring in 15 - 20% of biopsy proven autoimmune pancreatitis type 2. The basis of this association is unclear.
Answer choice A: Ankylosing spondylitis is an inflammatory disease that is associated with HLA-B27 and is not known to be associated with autoimmune pancreatitis type 2.
Answer choice C: Autoimmune pancreatitis type 1 is an IgG4 related disease. Patients often present with extra pancreatic manifestations of systemic IgG4 related inflammation including enlarged salivary glands and Riedel thyroiditis or the sclerosing variant of Hashimoto thyroiditis.
Answer choice D: Systemic lupus erythematosus is not known to be associated with autoimmune pancreatitis type 2.

Comment Here

Reference: Autoimmune pancreatitis type 2

Chronic pancreatitis

Table of Contents

Definition / general

Pancreatic fibroinflammatory syndrome histologically characterized by parenchymal fibrosis, atrophy and duct changes and clinically by pain and symptoms of pancreatic insufficiency (Pancreatology 2020;20:586)

Essential features

Pancreatic fibroinflammatory disease with fibrosis, loss of acinar tissue and duct changes
Histology alone is not sufficient; clinical and radiological data are required for diagnosis (Pancreatology 2020;20:586)

Terminology

Main category: chronic pancreatitis
Subtypes: alcoholic pancreatitis, obstructive pancreatitis, hereditary pancreatitis, paraduodenal (groove) pancreatitis (PGP)

ICD coding

ICD-10:
- K86.0 - alcohol induced chronic pancreatitis
- K86.1 - other chronic pancreatitis
ICD-11: DC32 - chronic pancreatitis

Epidemiology

Alcoholic pancreatitis: young to middle aged males (Pathologica 2020;112:197)
Obstructive pancreatitis: M = F; wide age range (Pathologica 2020;112:197)
Hereditary pancreatitis: M = F; PRSS1 and CFTR related: very young patients (SPINK1 associated: adult patients (Nat Genet 1996;14:141, Gastroenterology 1981;81:1143, Nat Genet 2000;25:213)
Paraduodenal pancreatitis: middle aged males with a history of alcohol abuse and smoking (World J Surg 2009;33:2664)

Sites

Alcoholic and hereditary chronic pancreatitis affects the whole pancreas
Obstructive pancreatitis affects the gland distal to the site of obstruction
Paraduodenal pancreatitis is centered around the minor papilla, in the so called groove area between the common bile duct, the superior margin of the pancreatic head and the duodenal wall (Pathologica 2020;112:197)

Pathophysiology / etiology

Alcoholic pancreatitis: prolonged alcohol abuse and other cofactors such as smoking (Alcohol Health Res World 1997;21:13)
Obstructive pancreatitis: obstruction of main or secondary pancreatic ducts due to mass forming lesions or intraductal stones
Hereditary pancreatitis: germline mutations in the genes serine protease 1 (PRSS1) or serine peptidase inhibitor kazal type 1 (SPINK1); autosomal recessive mutations in cystic fibrosis transmembrane conductance regulator (CFTR)
Paraduodenal pancreatitis: chronic obstruction of the minor papilla (Pathologica 2020;112:197)

Clinical features

Severe abdominal pain, often radiated to the interscapular region
Signs and symptoms of exocrine and endocrine pancreatic dysfunction: steatorrhea, weight loss, bloating, diabetes (J Clin Gastroenterol 2022;56:e1)
Paraduodenal pancreatitis may be associated with signs and symptoms of duodenal stenosis such as postprandial vomit
Risk of developing pancreatic ductal adenocarcinoma is increased tenfold in patients with chronic pancreatitis

Diagnosis

Histology alone is not gold standard; clinical and radiological data are required for a definitive diagnosis of chronic pancreatitis (Pancreatology 2020;20:586)
Typical clinical picture
History of alcohol abuse or smoking
Pancreatic calcifications on CT scans
Morphological triad of fibrosis, loss of acinar tissue and duct changes

Laboratory

Lab tests alone are of limited utility in the diagnosis of chronic pancreatitis
Low plasma amylase levels, particularly in advanced cases (Alcohol Health Res World 1997;21:13)

Radiology description

Ultrasound: diffuse hyperechogenicity
CT: parenchymal atrophy, duct dilation, presence of calcification and pseudocysts
Paraduodenal pancreatitis may mimic cystic lesions or malignancy and may be associated with the so called double duct sign, due to dilation of the main pancreatic duct and the common bile duct (Alcohol Health Res World 1997;21:13)

Case reports

34 year old man with a mass forming chronic pancreatitis mimicking a cystic neoplasm (World J Gastroenterol 2018;24:297)
39 year old woman with hereditary pancreatitis who developed a pancreatic anaplastic carcinoma (Am J Case Rep 2021;22:e928993)
51 year old woman with paraduodenal pancreatitis mimicking undifferentiated carcinoma with osteoclastic giant cells (UCOCGC) (Cytopathology 2015;26:122)
57 year old man with chronic pancreatitis with ductal stones in the pancreatic head, successfully treated by surgery (J Surg Case Rep 2020;2020:rjaa352)

Treatment

Therapeutic strategies are mostly supportive
Paraduodenal pancreatitis may require pancreaticoduodenectomy
Mass forming / symptomatic cases may be amenable to surgical resection
Reference: Dis Mon 2021;67:101225

Gross description

Whitish parenchyma with extensive fibrosis, dilated ducts and calculi
Fibrotic parenchyma retains a lobulated appearance
In advanced stages, a reduction in the volume of the pancreatic gland may occur
Parenchymal and intraductal calcification are typical and often grossly appreciable
Pseudocysts are more common in alcoholic pancreatitis, whereas obstructive pancreatitis shows retention cysts (Pathologica 2020;112:197)
Paraduodenal pancreatitis may show cystic change near the minor ampulla and trabeculated fibrosis centered around the duodenal wall (Semin Diagn Pathol 2004;21:247)

Gross images

Contributed by Claudio Luchini, M.D., Ph.D. and Gaetano Paolino, M.D.

Head transverse section

Frozen section description

Frozen sections may show extensive fibrosis of the parenchyma and architectural distortion of pancreatic ducts
To identify invasive carcinoma on frozen sections with chronic pancreatitis, look for ruptured glands, high grade dysplasia, mitoses, perineural invasion, naked gland in peripancreatic adipose tissue
References: Arch Pathol Lab Med 2005;129:1610, Arch Pathol Lab Med 2022;146:84

Frozen section images

Contributed by Claudio Luchini, M.D., Ph.D. and Gaetano Paolino, M.D.

Distal pancreatectomy

Microscopic (histologic) description

Triad of cardinal features: fibrosis, loss of acinar tissue, duct changes (Pancreatology 2020;20:586)
No universally accepted and reproducible grading system (Pancreatology 2020;20:586)
No unique morphologic features to distinguish different etiologies of nonautoimmune chronic pancreatitis
Fibrosis is initially perilobular; during disease progression, it involves the pancreatic lobular units, eventually replacing the acinar parenchyma (so called intralobular fibrosis)
Acinar tissue may be replaced by fibrosis or fatty tissue; the latter process (lipomatous atrophy) is more frequently seen in hereditary pancreatitis (Pathologica 2020;112:197)
Loss of acinar tissue predates that of pancreatic islets, which are often seen isolated in fibrosis or fatty tissue in advanced cases
Ductal changes include distortion of ductal profiles, ectasia, presence of intraluminal concretions of amorphous material (so called protein plugs), squamous metaplasia, intraductal calcification
Foci of low and high grade pancreatic intraepithelial neoplasia (PanIN) may be encountered
Foci of periductal chronic inflammation and fat necrosis represent a common finding
Pseudocysts lined by granulation tissue are common in alcoholic chronic pancreatitis
Paraduodenal pancreatitis shows Brunner gland hyperplasia, myofibroblastic proliferation in the duodenal wall, cysts lined by cuboidal ductal epithelium, which may be replaced by granulation tissue; multinucleated giant cells may be found (Cytopathology 2015;26:122)

Microscopic (histologic) images

Contributed by Claudio Luchini, M.D., Ph.D. and Gaetano Paolino, M.D.

Cardinal triad

Duct dilation

Lipomatous atrophy

Chronic inflammation

Squamous metaplasia

Perivenulitis

Residual Langerhans islets

Paraduodenal (groove) pancreatitis

Cytology description

Clusters of acinar cells with mild atypia and no atypical mitotic figures
Chronic inflammatory elements: lymphocytes, macrophages
Clusters of activated fibroblasts may be found
Proteinaceous material may be present
Neutrophils may be present in case of associated acute inflammation
Multinucleated giant cells may be present in paraduodenal pancreatitis (Cytopathology 2015;26:122)

Cytology images

Contributed by Claudio Luchini, M.D., Ph.D. and Gaetano Paolino, M.D.

Fibrous stromal elements and inflammatory cells

Positive stains

Ductal epithelium is positive for keratins CK7 and CK19
Nuclear expression of SMAD4 is retained
Reference: World J Gastrointest Surg 2021;13:406

Negative stains

Staining for p53 does not show a mutated pattern of expression

Molecular / cytogenetics description

Most common mutations in PRSS1 related hereditary pancreatitis are R122H, R122C, N29I and A16V (Am J Physiol Gastrointest Liver Physiol 2014;306:G466)
SPINK1 related pancreatitis is associated with the presence of high risk SPINK1 N34S haplotype (PLoS One 2008;3:e2003)

Sample pathology report

Duodenum and pancreatic head, pancreaticoduodenectomy:
- Pancreatic head with diffuse fibrous replacement of acinar tissue, foci of chronic inflammation, pseudocysts lined by granulation tissue, duct ectasia with protein plugs and squamous metaplasia of the lining epithelium (see comment)
- No evidence of infiltrating carcinoma
- 12 lymph nodes and duodenal margins with no significant pathologic change
- Comment: Histologic picture is consistent with chronic pancreatitis.

Differential diagnosis

Pancreatic ductal adenocarcinoma:
- Ruptured glands, gland in peripancreatic adipose tissue without pancreatic islets, mitotic figures, perineural and vascular invasions are useful tips in the differential diagnosis
- Immunohistochemistry for p53 and SMAD4 may be of aid in the differential diagnosis between chronic pancreatitis and foci of ductal adenocarcinoma
Autoimmune pancreatitis type 1:
- Chronic inflammation centered around ducts and venules
- Presence of ≥ 10 IgG4 positive plasma cells/high power field (HPF), although a widely accepted and standardized threshold is still lacking
- Integration of clinical, laboratory and radiological data is required for differential diagnosis
Autoimmune pancreatitis type 2:
- Granulocytic epithelial lesions (GEL) with formation of neutrophil microabscesses within the duct lumen
- Integration of clinical, laboratory and radiological data is required for differential diagnosis

Additional references

van Krieken: Encyclopedia of Pathology, 2020

Board review style question #1

What are the cardinal features of chronic pancreatitis?

Fat necrosis, chronic inflammation and loss of Langerhans islets
Fibrosis, loss of acinar tissue and duct changes
Giant cell granulomas, perineural inflammation and plasma cell infiltrate
Intraductal proliferative lesions, lipomatous atrophy and perivenulitis
Necrosis, granulocytic epithelial lesions and pseudocysts

Board review style answer #1

B. Fibrosis, loss of acinar tissue and duct changes

Comment Here

Reference: Chronic pancreatitis

Board review style question #2

Is there a reproducible grading system for chronic pancreatitis?

No, there is no universally accepted grading system
Yes, grading is based on the degree of acinar tissue loss
Yes, grading is based on the entity of fibrosis
Yes, grading is based on the presence of pseudocysts
Yes, grading is based on the severity of chronic inflammation

Board review style answer #2

A. No, there is no universally accepted grading system. However, classification as mild, moderate or severe may be applied.

Comment Here

Reference: Chronic pancreatitis

Clear cell pancreatic endocrine tumor

Table of Contents

Definition / general

Uncommon morphologic variant of pancreatic well differentiated neuroendocrine tumor; associated with von Hippel-Lindau syndrome (VHL) and multiple endocrine neoplasia type I (MEN I) syndrome

Essential features

Clear, vacuolated cytoplasm due to accumulation of lipid, glycogen or mucin
Characteristic salt and pepper nuclear chromatin features
Can be easily misdiagnosed due to morphologic similarities with primary and metastatic tumors of the pancreas

Terminology

Also known as lipid rich variant

ICD coding

ICD-10: C25.4 - malignant neoplasm of endocrine pancreas

Epidemiology

Adults ages 40 - 60
No sex predilection
Syndromic patients may present at an earlier age (Pathol Res Pract 2016;212:747)

Sites

Most commonly in the head of the pancreas

Pathophysiology

In VHL, the disease results from deletions or mutations in the VHL tumor suppressor gene on chromosome 3p25.5 (Mod Pathol 2011;24:S66)
Mutations in MEN1 on chromosome 11q result in loss of function of tumor suppressor protein menin (Mod Pathol 2011;24:S66)
Sporadic tumors consistently result from allelic loss of chromosome 11q

Clinical features

Patients with VHL or MEN I may be screened following clinical suspicion
Patients may present for evaluation of abdominal symptoms or abnormal laboratory results
Some cases may be found incidentally on imaging (Mod Pathol 2011;24:S66)
Pancreatic neuroendocrine tumors in VHL or MEN I are typically nonfunctional (Arch Pathol Lab Med 2006;130:963)

Diagnosis

Imaging may identify a suspicious mass
Definitive diagnosis is made following endoscopic biopsy or surgical resection

Radiology description

Hyperintense, enhancing mass, well circumscribed with sharp borders on computed tomography (Radiographics 2010;30:1445)

Prognostic factors

Worse prognosis with high Ki67 proliferative index, tumor size > 2 cm, nonfunctioning tumors, tumor necrosis and poor response to chemotherapy (J Hepatobiliary Pancreat Sci 2015;22:586, Mod Pathol 2011;24:S66)

Case reports

29 year old man with liver and pancreatic lesions (Diagn Cytopathol 2009;37:365)
32 year old woman with abdominal pain and a pancreatic mass (Cytojournal 2016;13:7)
47 year old woman presenting with a mass in the pancreatic tail (Neuro Endocrinol Lett 2017;38:83)
60 year old woman with pancreatic cysts and octreotide avid lesions (Virchows Arch 2013;463:593)
64 year old man with a nodule in the head of the pancreas (Cytopathology 2013;24:197)

Treatment

Surgical resection and chemotherapy (Mod Pathol 2011;24:S66)

Gross description

Most often solid, solitary, homogenous, tan to yellow (Am J Surg Pathol 2001;25:602)
If extensive fibrosis present, may be gray and firm (J Hepatobiliary Pancreat Sci 2015;22:586)
Hereditary syndromes may present with multiple tumors
Rarely a cystic component can be seen (Neuro Endocrinol Lett 2017;38:83)

Microscopic (histologic) description

Solitary, well circumscribed
Widely variable architectural patterns: nested, trabecular, glandular, ribbon-like, tubuloacinar, mixed patterns are common; however, there is usually a dominant pattern (Arch Pathol Lab Med 2006;130:963)
Small / medium round, polygonal cells with clear, vacuolated cytoplasm due to lipid accumulation
Central nucleus with characteristic salt and pepper chromatin pattern and inconspicuous nucleoli (Arch Pathol Lab Med 2009;133:350)

Microscopic (histologic) images

Contributed by Aatur Singhi, M.D., Ph.D.

Nests of tumor cells

Clear, vacuolated cytoplasm

Salt and pepper chromatin

Synaptophysin positivity

Cytology description

Isolated or small clusters of round monomorphic tumor cells (Cytopathology 2013;24:197)
Numerous small cytoplasmic vacuoles imparting a foamy appearance
Eccentric nuclei with fine nuclear chromatin, without prominent nucleoli (J Hepatobiliary Pancreat Sci 2015;22:586)

Cytology images

Image hosted on other servers:

Papanicolaou stain of FNA

Positive stains

Synaptophysin, chromogranin A, CD56, AE1 / AE3, PAX8 (Laboratory Medicine 2009;40:417, Cytopathology 2013;24:197, Virchows Arch 2013;463:593, J Hepatobiliary Pancreat Sci 2015;22:586)

Negative stains

CK7, CK20, MelanA, CAIX, HMB45 (Mod Pathol 2008;21:1075, Cytopathology 2013;24:197, Arch Pathol Lab Med 2010;134:1080, J Hepatobiliary Pancreat Sci 2015;22:586)

Electron microscopy description

Variably sized cytoplasmic lipid globules and dense neurosecretory granules (Arch Pathol Lab Med 2009;133:350)

Molecular / cytogenetics description

Von Hippel-Lindau disease
- Autosomal dominant mutation in VHL tumor suppressor gene on chromosome 3p25.5 (Arch Pathol Lab Med 2010;134:1080)
Multiple endocrine neoplasia type I
- Autosomal dominant germline mutation in MEN1 tumor suppressor gene on chromosome 11q13
Sporadic tumors may arise from chromosomal alterations, epigenetic changes or functional genomic alterations

Videos

Pancreatic neuroendocrine neoplasms: overview

Sample pathology report

Pancreas and duodenum, Whipple procedure:
- Clear cell pancreatic neuroendocrine tumor, WHO grade 1 (see synoptic report and comment)
- Comment: The patient's clinical history of von Hippel-Lindau syndrome is noted. The clear cell variant of pancreatic neuroendocrine tumor is more common in this setting. Immunohistochemical stains for synaptophysin and chromogranin are positive and the Ki67 index is approximately 2.0%.

Differential diagnosis

Metastatic:
- Renal cell carcinoma, clear cell type:
  - Positive for AE1/AE3, CD10, PAX8, CAIX
  - Negative for neuroendocrine markers (Arch Pathol Lab Med 2010;134:1080)
Primary:
- Ductal adenocarcinoma with clear cell features:
  - Positive for AE1 / AE3
  - Negative for neuroendocrine markers
- Serous cystadenoma, solid variant:
  - Positive for PAS, AE1 / AE3, vimentin
  - Negative for synaptophysin
- Solid pseudopapillary neoplasm, clear cell variant:
  - Positive for beta catenin (nuclear and cytoplasmic), CD10, CD56, vimentin
  - Variable neuroendocrine markers
  - Loss of E-cadherin (J Hepatobiliary Pancreat Sci 2015;22:586)
- Clear cell sugar tumor / PEComa:
  - Positive for PAS, HMB45
Peripancreatic region:
- Adrenocortical tumors:
  - Positive for inhibin, MelanA
  - Weak with AE1 / AE3
  - Negative for chromogranin A (J Hepatobiliary Pancreat Sci 2015;22:586)
- Clear cell hepatocellular carcinoma:
  - Positive for Arginase1, HepPar1
  - Negative for neuroendocrine markers

Additional references

Am J Surg Pathol 2006;30:194, Adv Anat Pathol 2004;11:202

Board review style question #1

A diagnosis should not stimulate genetic evaluation for the VHL syndrome
Frequently immunoreactive for cytokeratins
Immunohistochemistry can distinguish from histologically similar metastatic clear cell renal cell carcinoma in VHL disease
Only seen in the setting of VHL disease
Tumors associated with VHL syndrome and MEN1 syndrome are often functional tumors

Board review style answer #1

C. Immunohistochemistry can distinguish clear cell pancreatic endocrine tumors from histologically similar metastatic clear cell renal cell carcinoma in VHL disease

Comment Here

Reference: Clear cell pancreatic endocrine tumor

Board review style question #2

Mutation in APC tumor suppressor gene on chromosome 5q21-22
Mutation in c-KIT proto-oncogene gene on chromosome 4q11-4q13
Mutation in CDH1 gene on chromosome 16q22.1
Mutation in MET proto-oncogene located on chromosome 17q31.1-34
Mutation in VHL tumor suppressor gene on chromosome 3p25.5

Board review style answer #2

E. Mutation in VHL tumor suppressor gene on chromosome 3p25.5

Comment Here

Reference: Clear cell pancreatic endocrine tumor

Colloid carcinoma

Table of Contents

Definition / general

Infiltrating ductal epithelial neoplasm of the pancreas characterized by the presence (in at least 80% of the neoplasm) of large extracellular stromal mucin pools containing suspended neoplastic cells (WHO)

Essential features

> 80% of the tumor volume is composed of mucin pools with scanty floating tumor cells
Associated with intraductal papillary mucinous neoplasm (almost always arises in an intestinal type IPMN), mucinous cystic neoplasm (MCN) and ampullary / duodenal tubulovillous adenomas
Thought to have more favorable prognosis than conventional pancreatic ductal adenocarcinoma (cPDAC) (World J Gastroenterol 2018;24:4846)

Terminology

Colloid carcinoma
Mucinous noncystic carcinoma
Gelatinous carcinoma

ICD coding

ICD-10: C25 - malignant neoplasm of pancreas

Epidemiology

1 - 3% of malignant neoplasms of the exocrine pancreas
27 - 70% of IPMNs with associated invasive adenocarcinoma have a colloid component (Pathology 2008;40:655)

Sites

Usually in the head of the pancreas

Pathophysiology

Inverse polarization of cells (mucin glycoproteins in stroma facing surfaces instead of luminal surface)
Expression of MUC2 (gel forming mucin, rare in cPDAC) and the absence of external lamina or basement membrane may lead to accumulation of extracellular mucin, which limits tumor spread and appears to have tumor suppressor activity (Am J Surg Pathol 2003;27:571, Mod Pathol 2002;15:1087)

Clinical features

Mean age: 61 years
M = F
Abdominal / epigastric pain (in contrast to back pain of cPDAC), pancreatitis (50% of patients), diarrhea, jaundice, weight loss
Larger (6.0 cm) compared with cPDAC, lower stage, better survival
Incisional biopsy may contribute to thromboembolic complications (Am J Surg Pathol 2001;25:26)
Pseudomyxoma peritonei can be a rare complication

Diagnosis

Based on extensively sampled resection specimen

Radiology description

Dilated ducts (sometimes filled with nodular lesions)

Radiology images

Images hosted on other servers:

CT scan

Prognostic factors

5 year survival is 57 - 72% (versus 12% for resectable cPDAC) (Am J Surg Pathol 2001;25:26, Dig Dis Sci 2011;56:1295)
Tumor diameter, presence of IPMN / MCN precursor lesion, surgical margin status, vascular or perineural invasion, lymph node status, KRAS mutation or TP53 mutation are not prognostic factors (Am J Surg Pathol 2001;25:26)

Case reports

52 year old woman with history of necrotizing pancreatitis (Arch Pathol Lab Med 2005;129:255)
58 year old man with recurrent pancreatitis and 72 year old woman with pancreatic exocrine and endocrine insufficiency (Case Rep Pancreat Cancer 2016;2:40)
64 year old man with 15 cm tumor (JOP 2012;13:219)
65 year old man with pancreatic head tumor (Oncol Lett 2015;10:3195)

Treatment

No specific treatment guidelines

Gross description

Large (mean 5 cm), well demarcated tumor
Solid, firm, gelatinous cut surface

Gross images

AFIP images

Whipple resection specimen

Microscopic (histologic) description

At least 80% of the neoplasm consists of large extracellular stromal mucin pools
Scanty carcinoma cells suspended within these mucin pools
- Usually cuboidal or columnar cells
- Cribriform or stellate clusters, strips of columnar cells, small tubules or signet ring cells
Incomplete lining of mucin lakes common
Mucin tends to be retained during histologic processing (in contrast to IPMN and MCN)
Muconodular invasive component of 1 cm or more
Usually arise in association with IPMN, MCN or tubular / tubulovillous adenoma
Perineural invasion and regional lymph node metastasis common
Reference: Am J Surg Pathol 2001;25:26

Microscopic (histologic) images

Contributed by Jennifer Vazzano, D.O., M.S. and Wei Chen, M.D., Ph.D.

Large mucin pools

Cytology description

Difficult to spread thinly on slides due to abundant mucus
Cellularity of malignant component may be low

Positive stains

Strong expression of CDX2 and MUC2 (indicating intestinal differentiation); cPDAC usually MUC2-
CEA shows accentuated staining in basal aspects of tumor cells (luminalization), in addition to luminal staining
May show focal reactivity for synaptophysin or chromogranin
Reference: Am J Surg Pathol 2001;25:26

Negative stains

Negative for HER2 and MUC1

Electron microscopy description

Mucigen granules on stromal surface, no basement membrane

Molecular / cytogenetics description

KRAS codon 12 mutation (33%); less frequent than cPDAC (> 90%)
TP53 mutation (22%)
High prevalence of somatic mutations in GNAS
Microsatellite stable, unlike mucinous carcinomas of colon (Mod Pathol 2003;16:537)

Sample pathology report

Distal stomach, duodenum and pancreatic head, pancreaticoduodenectomy:
- Colloid carcinoma of the pancreas, arising in a background of high grade intraductal papillary mucinous neoplasm (IPMN)
- Carcinoma involves the muscularis propria of the duodenum
- Positive for perineural invasion
- Negative for lymphovascular invasion
- All margins of resection, negative for carcinoma or high grade dysplasia
- Metastatic carcinoma involving one of seventeen lymph nodes (1/17)
- Portion of benign stomach with chronic inactive gastritis, negative for Helicobacter pylori on H&E stained sections

Differential diagnosis

Extravasated benign stromal mucin:
- Mucus lakes limited to periductal location, devoid of neoplastic cells
- Frequently inflamed
Intraductal papillary mucinous neoplasm:
- Smooth contours, complete epithelial lining, intraluminal mucin lost during processing
Mucinous cystic neoplasm:
- Ovarian type stroma
- Usually occurs in women
Conventional ductal adenocarcinoma:
- Intracytoplasmic and luminal mucin
- No or scant stromal mucin

Additional references

Curr Diagn Pathol 2004;10:61, Am J Surg Pathol 2002;26:56, WHO Classification of Tumours Editorial Board: Digestive System Tumours, 5th Edition, 2019

Board review style question #1

A 62 year old woman presented with a pancreatic head mass. Histologic sections demonstrate areas of irregular mucin pools with suspended clusters of malignant cells and also floating signet ring cells. However, no individual infiltrating signet ring cells are identified in the stroma. There is an intestinal type intraductal papillary mucinous neoplasm (IPMN) in the background; no conventional ductal adenocarcinoma component is seen. What is the diagnosis?

Colloid carcinoma
IPMN with rupture and extruded stromal mucin
Mucinous cystadenocarcinoma
Signet ring cell carcinoma

Board review style answer #1

A. Colloid carcinoma

Comment Here

Reference: Colloid carcinoma

Cystic endocrine tumors

Table of Contents

Definition / general

Distinctive subgroup of pancreatic neuroendocrine tumors that are well differentiated with a low mitotic rate and low Ki67 proliferative index as well as have a cystic component (Am J Surg Pathol 2012;36:1666)

Essential features

Histologically resembles typical pancreatic neuroendocrine tumor but with cystic component
Improved prognosis
Occurs more frequently in patients with MEN1

ICD coding

ICD-10: C25.4 - malignant neoplasm of endocrine pancreas

Epidemiology

Up to 17% of pancreatic neuroendocrine tumors are purely or partially cystic, due to cystic degeneration of originally solid tumor (J Am Coll Surg 2008;206:1154, Rev Esp Enferm Dig 2018;110:130)

Sites

More common in tail of pancreas

Pathophysiology

10 - 25% are associated with MEN1, occur in younger patients and are more often multiple and functional (Rev Esp Enferm Dig 2017;109:778)

Clinical features

Usually (85%) nonfunctional (Rev Esp Enferm Dig 2017;109:778)
If functional, usually insulinoma
Often (45%) diagnosed incidentally (Rev Esp Enferm Dig 2017;109:778)

Diagnosis

Can be confirmed by octreoscan scintigraphy

Radiology description

Cystic, making diagnosis difficult; may be confused with other pancreatic cystic lesions (including intraductal papillary mucinous neoplasm and mucinous cystic neoplasm)
Usually shows peripheral enhancement (AJR Am J Roentgenol 2013;200:W283)

Radiology images

Images hosted on other servers:

Cystic pancreas lesion on CT scan

Prognostic factors

Better prognosis than noncystic neuroendocrine tumors of pancreas
60% disease free survival at 10 years (Rev Esp Enferm Dig 2017;109:778)

Case reports

20 year old woman with incidental tumor (J Cancer Res Ther 2012;8:289)
42 year old woman with cystic mass and tumorlets (World J Gastroenterol 2017;23:6911)
51 year old woman with multicystic pancreas mass (Clin J Gastroenterol 2018;11:87)
66 year old woman with lesion mimicking mucinous cystic neoplasm (Clin J Gastroenterol 2018;11:333)
78 year old man with epigastric pain (BMC Res Notes 2014;7:510)

Treatment

Surgical excision

Gross description

Mean 5 cm
Generally unilocular cystic lesion filled with straw colored fluid

Gross images

AFIP images

Large cystic tumor

Images hosted on other servers:

Cystic pancreas mass

Large spherical lesion with multiple loculations arising from head of pancreas

Cystic pancreatic endocrine neoplasm

Microscopic (histologic) description

Typically appears as a thick fibrous wall with neuroendocrine cells lining the central cystic space and sometimes forming nests or vesicular structures within the fibrosis (Am J Surg Pathol 2001;25:752)
Necrosis and lymphovascular invasion are uncommon

Microscopic (histologic) images

Contributed by Raul S. Gonzalez, M.D.

Fibrous wall

Cyst lining

Unilocular lesion

Neuroendocrine cells within fibrosis

Images hosted on other servers:

Cystic pancreatic neuroendocrine tumor

Cytology description

Loosely cohesive aggregates and single cells
Cells are small and plasmacytoid with occasional cytoplasmic vacuoles; nuclei are round / oval and uniform with finely and evenly distributed chromatin (Cancer 2009;117:203)

Cytology images

Images hosted on other servers:

Plasmacytoid cells on FNA

Conventional smear

Positive stains (IHC and special stains)

Neuroendocrine markers (synaptophysin / chromogranin)
Often express glucagon but do not behave clinically as glucagonomas

Sample pathology report

Pancreas, tail, resection:
- Pancreatic neuroendocrine tumor with cystic degeneration, WHO grade 1 (see synoptic report and comment)
- Comment: Immunohistochemical stains for synaptophysin and chromogranin are positive and the Ki67 index is approximately 1.1%.

Differential diagnosis

Acinar cell cystadenoma / cystadenocarcinoma:
- Cysts are lined by acinar cells without associated acinar cell nests
- Negative for synaptophysin and chromogranin

Board review style question #1

Almost never incidental, despite this case
More common in patients with MEN1 syndrome
Probably arose in the head of the pancreas
Very poor prognosis

Board review style answer #1

B. More common in patients with MEN1 syndrome. This is a cystic pancreatic neuroendocrine tumor.

Comment Here

Reference: Cystic endocrine tumors

Board review style question #2

BCL10 and trypsin
Beta catenin (nuclear)
Chromogranin and synaptophysin
S100

Board review style answer #2

C. Chromogranin and synaptophysin. This is a cystic pancreatic neuroendocrine tumor.

Comment Here

Reference: Cystic endocrine tumors

Cystic fibrosis

Table of Contents

Definition / general

Autosomal recessive disorder affecting most critically the lungs; also pancreas, liver, intestines; characterized by abnormal transport of chloride and sodium across an epithelium, leading to thick, viscous secretions (Wikipedia: Cystic Fibrosis [Accessed 11 December 2017])
Incidence: 1 in 20 in U.S. are carriers
Most common mutation is #708 (seen in 70% with disease)
Mutations cause reduced chloride ion in secretions, thicker respiratory secretions, upper respiratory infections
Complications: pancreatic insufficiency late in disease course in 90%, diabetes, malabsorption, pancreatitis
Mutations also cause defective cilia and infertility; may cause meconium ileus (5 - 10%), intussusception
Cysts form secondary to ductal obstruction due to thick, tenacious secretions, variable numbers of cysts range from 1 to 3 mm, very rarely entire pancreas replaced by multiple macroscopic cysts, termed "pancreatic cystosis"

Gross images

Images hosted on other servers:

At autopsy, pancreas
is mucoid and
slightly smaller
than normal

Microscopic (histologic) description

Grade I: accumulation of secretion
Grade II: exocrine atrophy
Grade III: atrophy with lipomatosis
Grade IV: fibrosis with total obliteration of the exocrine glands and ducts with scattered islets of Langerhans
Pancreatic ducts diffusely dilated and filled with numerous lamellated concretions
Associated with fibrosis
Nondiabetic patients have fibrocystic changes with normal islets, prominent nesidioblastosis, some persisting exocrine tissue
Young adult diabetic patients have total loss of exocrine pancreas with fat replacement, no nesidioblastosis, reduced islets (Hum Pathol 1984;15:278)

Positive stains

PAS+ diastase resistant, CEA, alpha-1-antitrypsin (Arch Pathol Lab Med 1989;113:1142)

Videos

Histopathology pancreas: cystic fibrosis

Differential diagnosis

Kartagener syndrome:
- Defective cilia syndrome

Cytology

Table of Contents

Definition / general

Normal and nonneoplastic findings in pancreas cytology
Preparations:
- Conventional smears or touch preparation stained with Diff-Quik, Papanicolaou
- Liquid based (thin prep)
- Cytospin
- Cell block (for immunohistochemistry and molecular)
- Cyst fluid (chemistry, tumor markers, molecular)

Essential features

Normal cellular elements:
- Acinar
- Ductal
- Islet cells (rare)
Contaminants during procedure:
- Bile
- Gastric epithelium
- Duodenal epithelium
- Hepatocytes
- Mesothelial cells
Procedures:
- Pancreas image guided fine needle aspiration (FNA)
- Bile duct brushing
- Percutaneous interventional guided FNA

Sites

Head / uncinate, body and tail of pancreas

Clinical features

General settings: patients with suspected neoplasia of the pancreaticobiliary tract should receive the following (Diagn Cytopathol 2014;42:325)
- Clinical history and physical examination, including identifying risk factors for malignant causes and for benign explanations for a stricture or cyst (e.g. chronic pancreatitis, primary sclerosing cholangitis / inflammatory bowel disease, autoimmune disease, etc.)
- Laboratory studies (e.g. serum bilirubin and alkaline phosphatase)
- Selective use of serum tumor markers (CA19-9 and CEA)
- Imaging studies
- Serum IgG4 when autoimmune disease is suspected
Clinical indications for pancreas FNA
- Pancreatic mass / cyst on imaging (Diagn Cytopathol 2014;42:325)
- Unexplained acute pancreatitis in older patients
- Newly diagnosed late onset diabetes mellitus
- Jaundice, pruritus, cholestasis unexplained by underling hepatobiliary disease or choledocholithiasis
- Anorexia, weight loss, abdominal pain radiating to the back
Clinical indications for bile duct brushing
- Obstructive jaundice (Acta Cytol 2016;60:167)
- Distal common bile duct stricture
- Proximal / complex hilar stricture
- Screening patients with primary sclerosing cholangitis for biliary neoplasia (Endoscopy 2016;48:432)

Diagnosis

Common diagnostic procedures utilized in the procurement of pancreatic cytology samples:
- Endoscopic ultrasound (EUS) guided FNA for pancreatic mass / lesions
- Endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC) are used to obtain brushing or aspiration from the common bile duct and pancreatic duct stricture / mass

Cytology description

Normal

Bile duct
- Monolayered flat sheets arranged in honeycomb pattern
- Cuboidal to columnar cells
- Bland appearing basally located nuclei imparting a picket fence appearance
- Scant pale cytoplasm
Acinar cells
- Pyramidal to triangle shaped cells arranged singly, in clusters or grape-like appearance occasionally embedded in fibroconnective tissue
- Abundant granular cytoplasm
- Round central to eccentric nuclei
- Occasional nucleoli
Islet cells
- Infrequently seen in normal pancreas

Nonneoplastic contaminants

Bile: seen in biliary specimens
Duodenal epithelium: seen in EUS guided transduodenal FNA for lesions in pancreatic head and uncinate
- Flat sheets (honeycomb) arrangement, occasional singly scattered cells
- Uniformly round, bland appearing evenly spaced nuclei
- Scant pale cytoplasm
- Goblet cells present (Diagn Cytopathol 2005;33:381)
Gastric epithelium: present in transgastric EUS FNA for pancreatic lesions in the body and tail
- Flat sheets arranged in monolayered (honeycomb) pattern (Diagn Cytopathol 2005;33:381)
- Cells with uniformly round, evenly spaced bland appearing nuclei
- Pale cytoplasm with well defined cell border
- Surface epithelium lined by tall columnar cells with basally located nuclei and cytoplasm filled with abundant mucin
Hepatocytes: contaminant in procedures using percutaneous interventional guided FNA
- Polygonal cells with well defined cell borders and abundant granular cytoplasm
- May have intracytoplasmic pigment (bile, lipofuscin or iron)
- Centrally located nuclei, prominent nucleoli
- Occasional intranuclear inclusions
Mesothelial cells: contaminant in procedures using percutaneous interventional guided FNA
- Polygonal cells arranged in flat sheets
- Moderate amount of cytoplasm (dense in the center and pale in periphery)
- Clear spaces in between cells intercellular windows
- Single to occasionally binucleated to multinucleated round to oval nuclei

Cytology images

Contributed by Maria Luisa C. Policarpio-Nicolas, M.D.

Ductal cells with bland nuclei

Ductal cells with tubule formation

Ductal epithelium cell block

Clusters of acinar cells

Acini in grape-like arrangement

Acinar and ductal cells histology

Gastric epithelium

Duodenal epithelium with goblet cells

Hepatocytes with intracytoplasmic pigment

Hepatocytes with bile

Mesothelial cells in sheets

Mesothelial cells with intercellular windows

Sample pathology report

Pancreas, head, endoscopic ultrasound guided fine needle aspiration:
- Nondiagnostic
- Normal acinar and ductal epithelium. The biopsy does not explain the well defined pancreatic mass seen on imaging (Cytojournal 2014;11:3).

Differential diagnosis

Acinar carcinoma:
- Highly cellular, small to moderate sized loose groups, numerous single cells and stripped round nuclei, prominent acinar formation, little anisonucleosis, prominent nucleoli (Diagn Cytopathol 2006;34:367)
Ductal adenocarcinoma:
- 3 dimensional to glandular arrangement of tumor cells, loss of polarity, moderate to marked variation in nuclear size (4:1 ratio), small to large prominent nucleoli, singly scattered tumor cells, mitotic figures (few to many)
Low grade neoplastic mucinous cyst (intraductal papillary mucinous neoplasm, mucinous cystic neoplasm):
- On cytomorphology alone, it is extremely difficult to distinguish gastric contamination from a neoplastic mucinous cyst
- If background mucin is present, a note / comment can be added (see below)
  - Note / comment: Benign appearing mucinous epithelium is present from this transgastric FNA in a background of extracellular mucin. The morphology of the cells is nonspecific and may represent low grade dysplasia or gastric contamination. No high grade atypia is identified and no necrosis is present (Pitman: The Papanicolaou Society of Cytopathology System for Reporting Pancreaticobiliary Cytology, 2015).

Board review style question #1

The above image is an FNA sample from the pancreatic head. Which of the following choices represents the image in the sample?

Acinar cells
Ductal cells
Islet cells
Malignant cells

Board review style answer #1

B. Ductal cells

Comment Here

Reference: Pancreas - Cytology

Board review style question #2

Which is the method used to procure a cytology sample from a bile duct stricture?

Endoscopic ultrasound guided
CT guided
Endoscopic retrograde cholangiopancreatography
MRI guided

Board review style answer #2

C. Endoscopic retrograde cholangiopancreatography

Comment Here

Reference: Pancreas - Cytology

Diabetes mellitus

Table of Contents

Definition / general

Chronic disorder of carbohydrate, fat and protein metabolism due to defective or deficient insulin secretory response (Wikipedia: Diabetes Mellitus [Accessed 8 December 2017])

Epidemiology

3% of world population, 26 million in U.S. but only 75% are clinically diagnosed
#7 leading cause of death in 2007 (underlying cause on 71,382 death certificates) (American Diabetes Association: Statistics About Diabetes [Accessed 8 December 2017])
Lifetime risk of diabetes: type 1 - 0.5%, type 2 - 5%
Numerous variations, all with hyperglycemia

Etiology

Destruction of islets due to drugs (steroids, thiazides, pentamidine), hemochromatosis ("bronze diabetes" due to hemosiderin deposition in pancreas), hereditary ceruloplasmin deficiency (Hum Pathol 1997;28:499), infections (congenital rubella, CMV, coxsackievirus [Arch Pathol Lab Med 1980;104:438], enteroviruses [Diabetologia 2004;47:225]), pancreatitis, surgery, tumors, endocrinopathies (pituitary, adrenal, pregnancy) or idiopathic

Type 1

Chronic disease of carbohydrate, fat and protein metabolism due to reduction in beta cell mass causing severe, absolute lack of insulin (eMedicine: Type 1 Diabetes Mellitus [Accessed 8 December 2017])
10% of all cases
Without insulin, patients develop diabetic ketoacidosis (DKA), coma and death

Etiology

Presumed autoimmune cause for islet cell destruction but precise etiology unclear (Wikipedia: Diabetes Mellitus Type 1 [Accessed 8 December 2017])
Usually Northern European descent
70% concordance in identical twins, HLA-D linked
Genetic predisposition may affect immune responsiveness to a beta cell autoantigen or method of presentation to T cells

Viruses and IDDM:

Viruses may damage beta cells, exposing antigens which trigger an autoimmune response
May be due to molecular mimicry (immune response develops against shared amino acid sequences): GAD and Coxsackie B4 virus share a six amino acid sequence
Retrovirus may serve as a superantigen

Autoimmune aspects:

Islet cell autoantibodies present in 70%; also CD8+ T cell infiltrate in islets
Antigens are glutamic acid decarboxylase (GAD), islet autoantigen 2, insulin associated antibody, gangliosides
GAD antibodies precede clinical symptoms, present in most newly diagnosed patients and 80% of first degree relatives
GAD antibody also causes stiff man syndrome, whose patients often have a history of IDDM
Many IDDM patients also have antithyroid peroxidase, antiparietal cell and antiadrenocortical antibodies
Some NIDDM patients have autoantibodies but no other features of IDDM
Usually chronic (years)
Clinical disease when 90% of islet cells are destroyed

Clinical features

Onset at age < 20 years, normal weight (unlike most NIDDM)
Characterized by PPP (polyuria, polydipsia, polyphagia) and ketoacidosis (DKA)
Polyphagia combined with weight loss is specific for IDDM; type 2 patients rarely have either
Severe fasting hypoglycemia is due to cessation of glycogen storage in fat and muscle
Glycosemia causes glycosuria with depletion of water and electrolytes
Also: low / absent plasma insulin, high plasma glucagon, unstable glucose tolerance (very sensitive to changes in insulin, diet, exercise, infection, stress), presence of free fatty acids (due to breakdown of adipose stores), which produces ketone bodies (acetoacetic acid and beta hydroxybutyric acid)
May get hyperosmotic nonketotic coma - dehydration due to hyperglycemic diuresis with failure to drink enough fluids to compensate, often in an elderly person with diabetes and stroke / infection
"Dead in bed syndrome": sudden death in young people with type 1 diabetes, cause unknown (Hum Pathol 2010;41:392)

Type 2 (NIDDM)

Also called adult onset, non insulin dependent diabetes mellitus / NIDDM, type 2
80 - 90% of cases of diabetes (Wikipedia: Diabetes Mellitus Type 2 [Accessed 8 December 2017])
Usually > 30 years old, obese (80% of cases, abdominal obesity more important than subcutaneous obesity), normal or increased blood insulin, rare diabetic ketoacidosis, no anti-islet antibodies

Pathophysiology
Early:

Normal insulin secretion and plasma levels but loss of pulsatile, oscillating pattern of secretion
Also loss of rapid first phase of insulin secretion triggered by glucose
NO insulinitis is present

Later:

Mild / moderate insulin deficiency, may be due to beta cell damage
Beta cells may be "exhausted" due to chronic hyperglycemia and persistent beta cell stimulation

Amylin:

37 amino acid peptide, normally produced by beta cells, packaged and cosecreted with insulin
In NIDDM patients, tends to accumulate outside beta cells and resembles amyloid

Clinical features

90%+ concordance in twins, apparently due to multiple genetic polymorphisms (no HLA association)
Due to insulin resistance (associated with obesity and pregnancy) or derangement in beta cell secretion of insulin
Associated with amyloid deposits in islets (amyloid associated with basement membrane heparan sulfate proteoglycan) (Arch Pathol Lab Med 1992;116:951) and pituitary (Arch Pathol Lab Med 1995;119:1055)

Maturity onset diabetes of the young

1 - 2% of all cases of diabetes (Diabetes Metab Syndr Obes 2012;5:101)
Also called monogenic diabetes (Wikipedia: Maturity Onset Diabetes of the Young [Accessed 8 December 2017])
Type 2 diabetes-like condition which occurs in 2+ generations, with autosomal dominant inheritance (Diabetes Care 2011;34:1878)
Autosomal dominant but not a single entity - mutations in 9 genes identified to date (see Diagrams / tables below)
Common genes affected are hepatic nuclear factor 1 or 4 alpha, glucokinase
Onset before age 25, normal weight, mild hypoglycemia
No GAD antibodies, no insulin resistance, no beta cell loss but impaired beta cell function

Diagrams / tables

Images hosted on other servers:

Single gene mutations
resulting in monogenic
diabetes / MODY

Clinical complications

General

Main complications are microangiopathy, retinopathy, nephropathy, neuropathy - all due to hyperglycemia
Kidneys transplanted into diabetic patients develop nephropathy within 3 - 5 years but kidneys from diabetic patients transplanted into normal patients have remission of nephropathy
Strict control of diabetes delays progression of microvascular complications
Complications are due to nonenzymatic glycosylation and disturbances in polyol pathways

Nonenzymatic glycosylation

Glucose + protein => Schiff base (protein - NH = CH (CHOH)4-CH2OH) => Amadori product
(protein - NH-CH2-C = 0-(CHOH)3-CH2OH) => protein - protein cross linking via N-C-N bonding
Early reactions are reversible and related to HbA1c level
Advanced glycosylation end products (AGE) are not reversible
AGE traps LDL in blood vessels, enhances cholesterol deposition, accelerating atherosclerosis
AGE inhibition antagonizes diabetic complications in experimental models

Vascular complications

Relative risk is 100:1
Accelerated atherosclerosis in aorta and large / medium sized vessels
Myocardial infarction: most common cause of death, no gender preference
Gangrene of lower extremities
Micro description:
- Hyaline arteriolosclerosis, associated with hypertension, more common / severe in diabetes but not specific
- Amorphous hyaline thickening in arteriolar wall
- Related to severity of disease and hypertension
- Microangiopathy: diffuse basement membrane thickening with protein leakage in capillaries of skin, skeletal muscle, retina, renal glomeruli, renal medulla, renal tubules, Bowman capsule, peripheral nerves, placenta

Diabetic renal disease

See Diabetic kidney disease

Ocular

#4 cause of blindness in U.S.
Associated with retinopathy, cataracts, glaucoma
Polyol pathways: important in lens and other tissues (nerves, kidney, blood vessels) that don't require insulin for glucose transport
- High intracellular glucose plus aldose reductase produces sorbitol and later fructose, causing water influx and osmotic cell injury
- In lens, causes swelling and opacity
- Inhibition of sorbitol may reduce formation of cataracts and neuropathy

Neuropathy

Peripheral, symmetric neuropathy of lower extremity most common, sensory more common than motor

Diagnosis

High fasting glucose or impaired glucose tolerance (without diabetes, oral glucose loads cause only slight rise in blood glucose due to brisk insulin response; with diabetes, blood glucose rises markedly for a sustained period)

Case reports

Adult with acute onset, death within 3 days, T cell pancreatic infiltrate (Arch Pathol Lab Med 1994;118:84)
Islet inflammation with Coxsackie B5 infection (Hum Pathol 1982;13:661)

Treatment

Type 1: immunosuppressive therapy is effective in children with new onset disease
Type 2: diet, exercise and education (eMedicine: Type 2 Diabetes Mellitus [Accessed 8 December 2017])
- Lifestyle intervention and metformin delay onset of diabetes (N Engl J Med 2012;367:1177)

Microscopic (histologic) description

Type 1: inconsistent reduction in number and size of islets, uneven insulinitis (T lymphocytes)
Type 1: early insulinitis with marked islet atrophy and fibrosis and severe beta cell depletion (Islets 2011;3:131)
Type 2: subtle reduction in islet cell mass, amyloid replacement of islets due to amylin fibrils (also seen in aging nondiabetics); associated with marked fatty replacement
Type 2: amyloid in the islets of Langerhans is the uniform pathologic feature
Gestational diabetes: lower total insulin+ area due to smaller islets (Islets 2011;3:231)
Infants of diabetic mothers: islet cell hypertrophy / hyperplasia

Videos

Histopathology pancreas: type 2 diabetes mellitus

Ductal adenocarcinoma, NOS

Table of Contents

Definition / general

Pancreatic ductal adenocarcinoma (PDAC) is an invasive pancreatic epithelial neoplasm with glandular (ductal) differentiation, usually demonstrating luminal or intracellular mucin and without a substantial component of any other histological type

Essential features

Adenocarcinoma derived from pancreatic ductal epithelia, with randomly arranged epithelial elements, intense stromal desmoplasia and variable necrosis
Poor prognosis: 5 year survival rate of 6% (ranges from 2 - 9%) (Cancer Res 2014;74:2913, World J Gastroenterol 2016;22:9694)
Precursors of invasive ductal adenocarcinoma:

Terminology

Sometimes called tubular adenocarcinoma

ICD coding

ICD-11: 2C10.0 - adenocarcinoma of pancreas

Epidemiology

Fourth leading cause of cancer related deaths in the U.S. (predicted to rise to the second most common cause by 2030) (CA Cancer J Clin 2021;71:7, Cancer Res 2014;74:2913)
Globally, 495,773 new cases and 466,003 new deaths in 2020 (CA Cancer J Clin 2021;71:209)
M:F = 1.13:1 (CA Cancer J Clin 2021;71:209)

Sites

Head of the pancreas: 60 - 70%; body: 5 - 15%; tail: 10 - 15%
Head tumors: 50% have distention of biliary tree and progressive jaundice; 85% have extension beyond pancreas at diagnosis
Body / tail tumors: typically larger at diagnosis since these tumors do not cause symptoms until late; 25% have peripheral venous thrombi; metastases common
Rarely arises from heterotopic pancreatic tissue in the gastrointestinal tract
Reference: Surg Pathol Clin 2016;9:547

Pathophysiology

Invasive ductal adenocarcinoma arises in association with precursor lesions: PanIN, IPMN or MCN

Etiology

Risk factors: smoking, alcohol abuse, obesity, high intake of dietary saturated fat, chronic pancreatitis, diabetes
Hereditary syndromes: Peutz-Jeghers syndrome, hereditary pancreatitis, familial atypical multiple mole melanoma (FAMMM), familial pancreatic cancer, Lynch syndrome, familial breast cancer and other Fanconi anemia genes, familial adenomatous polyposis (FAP)
Reference: World J Gastroenterol 2018;24:4846

Clinical features

Back pain, weight loss, malaise, jaundice, diabetes mellitus
Trousseau sign: migratory thrombophlebitis in 10% due to tumor or tumor necrosis producing platelet aggregating factors and procoagulants; causes arterial and venous thrombi
Coexisting pancreatitis in 10%
Metastases:
- Local lymph nodes (microscopic metastases found in 75% with T1 / T2 disease)
- Liver, lung, peritoneum, adrenal, bone, distal nodes
- Supraclavicular node metastasis may be a presenting symptom
- Tumor may track along biopsy needle path
- Metastases to ovary may simulate primary mucinous ovarian tumors (Am J Surg Pathol 1989;13:748)

Diagnosis

Preoperative / pretreatment by endoscopic ultrasound guided fine needle aspiration (EUS-FNA)
Surgical resection specimen

Laboratory

Serum tests: CA19-9, CEA

Radiology description

Hypodense mass on CT imaging in 92% of cases
Double duct sign (dilation of both the biliary and pancreatic ducts) in pancreatic head mass
Reference: Gastroenterology 2014;146:291

Radiology images

Images hosted on other servers:

Axial CT pancreas

Prognostic factors

Dependent on stage and tumor size
Resectable and size < 4.5 cm are favorable factors
Perineural invasion and vascular invasion are adverse prognostic factors (Eur J Surg Oncol 2007;33:892)
High histologic grade unfavorable
Any squamous component indicates poorer prognosis (median survival: 7 - 11 months)

Case reports

Woman in her 50s with faint hypoechoic area in the body of the pancreas (J Med Ultrason 2018;45:617)
63 year old man with lobulated cystic lesion in the head of the pancreas with diffuse dilatation of the main pancreatic duct (Pancreas 2019;48:e24)
78 year old man with two solid tumors in the remnant pancreas after pancreaticoduodenectomy for acinar cell carcinoma (J Nippon Med Sch 2019;86:279)

Treatment

Most (85%) tumors are not amenable to curative surgery
For head / periampullary tumors: Whipple resection (subtotal pancreaticoduodenectomy); perioperative mortality: ~2%
For body / tail tumors: distal pancreatectomy
Resect retroperitoneal nerves and nodes if stage I / II to reduce local recurrence
Palliative treatment: bypass operations, chemotherapy and radiation therapy
Reference: World J Gastroenterol 2018;24:4846

Gross description

White gray, sclerotic, poorly defined mass
> 75% are solid tumors
25% of head tumors extend to duodenal wall
If advanced, may be difficult to determine site of origin between pancreas, ampulla and common bile duct
20% have multiple tumors
Reference: Surg Pathol Clin 2016;9:547

Gross images

Contributed by Wei Chen, M.D., Ph.D.

Arising in IPMN

Arising in high grade PanIN

Frozen section description

Frozen sections used to confirm diagnosis and determine vascular resectability, margin positivity and status of extraregional lymph nodes / other metastatic sites
Common margins evaluated: pancreatic neck / distal pancreatic parenchyma, bile duct and uncinate
Helpful features of PDAC: anisonucleosis in a single gland (at least 4:1), perineural invasion, tumor gland immediately next to large vessel, single infiltrating cells, low power evaluation for disorganized duct distribution with ill defined borders, necrosis and mitoses (Arch Pathol Lab Med 2021 Mar 26 [Epub ahead of print])

Microscopic (histologic) description

Infiltrating well to poorly formed glandular / ductal structures surrounded by remarkably desmoplastic stroma
Mucin production is specific for ductal origin versus acinar or neuroendocrine differentiation
Perineural invasion present in 90%, typically with better differentiated glands
Angiolymphatic invasion in 50%; vascular invasion may mimic PanIN (Am J Surg Pathol 2012;36:235)
Well differentiated: pink apical band composed of mucin granules, irregular shape and distribution; desmoplasia, marked nuclear pleomorphism with nucleoli, loss of polarity, mitotic figures
Moderately to poorly differentiated (most tumors); abortive tubular structures, deeply infiltrative growth pattern, frequent mitosis, irregular and abortive mucin production
TNM histologic grading system (College of American Pathologists), based on extent of glandular differentiation:
- G1 = well differentiated (> 95% tumor composed of glands)
- G2 = moderately differentiated (50 - 95% glands)
- G3 = poorly differentiated (< 50% glands)
Post neoadjuvant therapy (Hum Pathol 2021;109:1, Mod Pathol 2018;31:4, Arch Pathol Lab Med 2020;144:838):
- Variable amount of residual tumor in a densely fibrotic tumor bed
- Attention to perineural space and duodenal wall for residual tumor glands
- Blue-grey fibrosis is a useful clue to suggest the possibility of adjacent residual tumor (Hum Pathol 2021;109:1)
- May show vacuolated or eosinophilic tumor cell changes
WHO variants:
- Adenosquamous carcinoma and squamous cell carcinoma
- Colloid carcinoma
- Hepatoid carcinoma
- Medullary carcinoma
- Invasive micropapillary carcinoma
- Signet ring cell (poorly cohesive cell) carcinoma
- Undifferentiated carcinoma (anaplastic, sarcomatoid, carcinosarcoma)
- Undifferentiated carcinoma with osteoclast-like giant cells
Non-WHO variants / patterns:
- Clear cell:
  - Glandular, ductal or nested structures with single layer of polygonal cells, distinct cell borders and variable nuclear atypia
  - Not due to accumulation of glycogen or mucin
  - Overexpression of HNF1β by IHC (Mod Pathol 2008;21:1075)
- Foamy gland:
  - Deceptively benign appearing pattern
  - Well formed glands with bland cells but subtle infiltration
  - Cells have abundant microvesicular (white and crisply foamy) cytoplasm with distinct pink brush border-like zone at apical / luminal portion of the cell, nuclei are basal oriented, dense or wrinkled (raisinoid)
  - Foamy material due to evenly sized mucigen granules that are mucin negative
  - Foamy PanIN proposed to be the precursor lesion (Am J Surg Pathol 2000;24:493, Ann Diagn Pathol 2008;12:252)
- Large duct:
  - Seen in < 10% of PDAC
  - Clustered ducts with irregular jagged contours (diameter: 0.5 mm - 1 cm)
  - Desmoplastic and myxoid stroma, intraluminal neutrophils and granular debris
  - Focal microcystic appearance due to marked ectasia of infiltrating neoplastic glands, particularly near duodenal muscularis propria
  - May have papillary pattern (Mod Pathol 2012;25:439, Am J Surg Pathol 2012;36:696)
- Vacuolated:
  - High grade tumors, clusters of tumor cells containing large vacuoles imparting cribriform architecture (reminiscent of adipocytes or signet ring cells)
  - Microcysts contain cellular debris and mucin
  - Can resemble fat necrosis or lipogranulomas in lymph node
  - Recognizing the atypical, enlarged, hyperchromatic nuclei is key (Virchows Arch 2010;457:643)

Microscopic (histologic) images

Contributed by Wei Chen, M.D., Ph.D.

Anisonucleosis

Glands next to vessel

Perineural invasion

Gland in adipose tissue

Moderately differentiated

Poorly differentiated

Foamy gland pattern

Vacuolated pattern

Clear cell pattern

Large duct pattern

Post therapy tumor bed

Post therapy eosinophilic change

Post therapy dystrophic tumor glands

Perineural residual tumor glands

Post therapy vascular change

Virtual slides

Images hosted on other servers:

Pancreatic ductal adenocarcinoma

Cytology description

EUS-FNA has sensitivity and specificity of > 90% and 100%, increased sensitivity with ThinPrep, brushings are 50% sensitive (repeat if inconsistent with clinical or radiologic findings) (Arch Pathol Lab Med 2000;124:387)
Aspirates are cellular, without acinar cells, with atypical ductal cells in sheets (drunken honeycomb), clusters or singly; anisonucleosis (4:1 variation)
Signet ring cells and mitotic figures are helpful when present
Papanicolaou Society of Cytopathology's 6 tiered system for pancreatobiliary cytology: nondiagnostic, negative for malignancy, atypical, neoplastic, suspicious and positive / malignant (Cytojournal 2014;11:3)
Duodenal secretions are 80% sensitive in head tumors, 33% sensitive in tail tumors; endoscopic retrograde cholangiopancreatography (ERCP) juice is 50 - 85% sensitive

Cytology images

Contributed by Regina Plummer, D.O., Victoria Saksenberg, M.D. and AFIP images

Abundant inspissated mucin

Transition into drunken honeycomb

Anisonucleosis (4:1 variation)

Signet ring cells

Moderately
differentiated
ductal
adenocarcinoma

Positive stains

Maspin, placental S100 (S100P), IMP3 (all positive in > 90% PDACs) (Arch Pathol Lab Med 2012;136:601, Hum Pathol 2013;44:503)
p53 expressed in most cases
CK7, CK8, CK18, CK19, MUC1, MUC3, MUC4, MUC5AC, CEA, B72.3, CA19-9, CA125 (48%)

Negative stains

pVHL negative / loss seen in > 90% PDACs (Arch Pathol Lab Med 2012;136:601, Hum Pathol 2013;44:503)
Loss of SMAD4 / DPC4 seen in 55%; specific for malignancy (in situ or invasive) (Am J Clin Pathol 2001;116:831)
CK20, MUC2, vimentin, synaptophysin, chromogranin, trypsin, chymotrypsin, lipase

Electron microscopy description

Mucigen granules

Electron microscopy images

AFIP images

Well differentiated

Molecular / cytogenetics description

4 key driver gene mutations (Arch Pathol Lab Med 2011;135:716, Hum Pathol 2009;40:612, Cancer Cell 2017;32:185)
- KRAS: > 95%, early event during carcinogenesis (Cancer 2007;109:1561)
- CDKN2A (p16): 95%
- TP53: 50 - 80%
- SMAD4: 55%
50% overexpress HER2
Many core signaling pathways involved
~10% of pancreatic cancers have a familial basis

Sample pathology report

Distal stomach, duodenum and pancreatic head, pancreaticoduodenectomy:
- Moderately differentiated pancreatic ductal adenocarcinoma, 2.2 cm
- Adenocarcinoma involves distal bile duct
- All margins negative for carcinoma or high grade dysplasia
- Positive for lymphovascular invasion and perineural invasion
- Metastatic adenocarcinoma involving 2 of 23 lymph nodes (2/23)
- Portion of benign stomach with chronic inactive gastritis, negative for Helicobacter pylori on H&E
- Benign duodenum with no significant pathologic change

Differential diagnosis

Ampullary adenocarcinoma:
- Epicenter at ampulla, presence of preinvasive component at ampulla
Chronic pancreatitis:
- Lobular architecture at low power with central ectatic branched ductules and clusters of round ductules surrounded by cuff of stroma (Arch Pathol Lab Med 2009;133:382)
- Features of PDAC to differentiate from chronic pancreatitis (Arch Pathol Lab Med 2015;139:848):
  - Haphazard architecture and glands at abnormal locations in interlobular areas, next to vessels and naked glands in fat
  - Anisonucleosis (4:1 variation), loss of cell polarity, perineurial invasion, individual cell infiltration, budding into lumen; has p53 mutations and loss of SMAD4 / DPC4
Distal bile duct adenocarcinoma:
- Epicenter at bile duct, circumferential / symmetrical involvement of the bile duct, presence of in situ component (BilIN or biliary intraductal papillary neoplasm)

Additional references

WHO Classification of Tumours Editorial Board: Digestive System Tumours (Medicine), 5th Edition, 2019, Semin Diagn Pathol 2014;31:443, Arch Pathol Lab Med 2017;141:366

Board review style question #1

Among the entities below, which one is considered a precursor lesion for invasive ductal adenocarcinoma of pancreas?

Intraductal papillary mucinous neoplasm
Lymphoepithelial cyst
Serous cystadenoma
Solid pseudopapillary neoplasm

Board review style answer #1

A. Intraductal papillary mucinous neoplasm

Comment Here

Reference: Ductal adenocarcinoma, NOS

Board review style question #2

Intraductal papillary mucinous neoplasm
Pancreatic ductal adenocarcinoma
Pancreatic intraepithelial neoplasia, high grade
Pancreatic intraepithelial neoplasia, low grade

Board review style answer #2

B. Pancreatic ductal adenocarcinoma

Comment Here

Reference: Ductal adenocarcinoma, NOS

Familial pancreatic neoplasms (pending)

[Pending]

Features to report-pancreatectomy

Table of Contents

Definition / general

This topic describes which features to report for exocrine and endocrine pancreatic neoplasms obtained from pancreaticoduodenectomy, distal pancreatectomy and total pancreatectomy procedures
Essential clinical history: none

Essential features

Essential features for reporting the tumors of the exocrine pancreas:
- Core data elements by CAP: procedure, tumor site, histologic type, histologic grade, greatest dimension of the tumor (cm), site(s) involved by direct tumor extension (except for pancreatic surfaces), treatment effect, lymphovascular invasion, perineural invasion, margin status, margin(s) involved by tumor, regional lymph node status, number of lymph nodes with tumor, number of lymph nodes examined, distant metastasis, TNM descriptors, pT / pN / pM categories
- Optional data elements by CAP: additional dimensions of tumor (cm x cm), involvement of pancreatic surface(s), closest margins, distance to closest margin (cm), additional findings, special studies, comments
Essential features for reporting the tumors of the endocrine pancreas:
- Core data elements by CAP: procedure, tumor site, histologic type, histologic grade, mitotic rate (number of mitoses per 2 mm²), Ki67 index (%), greatest dimension of tumor (cm), tumor focality, site(s) involved by direct tumor extension, lymphovascular invasion, perineural invasion, margin status, margin(s) involved by tumor, regional lymph node status, number of lymph nodes with tumor, number of lymph nodes examined, distant metastasis, TNM descriptors, pT / pN / pM categories
- Optional data elements by CAP: clinical history, functional type, additional dimensions of the tumor (cm x cm), tumor necrosis, closest margins, distance to closest margin (cm), additional findings, comments

Features to report by organization

Features to report (including pancreatic neuroendocrine neoplasms)

Procedure
Tumor location
Histologic type
Histologic grade
Precursor preinvasive neoplastic lesions; including their location and histologic grade
Tumor size
- Document overall tumor size and size of the invasive component separately for the carcinomas associated with preinvasive neoplastic lesions: i.e., intraductal papillary mucinous neoplasm (IPMN), intraductal tubulopapillary neoplasm (ITPN), intraductal oncocytic papillary neoplasm (IOPN), mucinous cystic neoplasm (MCN)
Tumor focality (for pancreatic neuroendocrine neoplasms)
Microscopic direct tumor extension
Lymphovascular invasion
Perineural invasion
Mitotic index and Ki67 proliferation index (for pancreatic neuroendocrine neoplasms)
Surgical margin status
Free pancreatic surface status
Treatment effect, if applicable
Regional lymph node status
Distant metastasis status
TNM descriptors, if applicable
pT stage
pN stage
pM stage
Additional findings, including adjacent pancreas parenchyma and other organs
Special studies, if any
Notes, if needed

Tips

pT stage should be reported based on the size of the invasive component only for the carcinomas associated with preinvasive neoplastic lesions
For cases with more than one tumor, pT stage should be reported based on the largest tumor
- Additionally, localization and characteristics of the other (smaller) tumor(s) should be documented
Macroscopic tumor size should be confirmed by microscopic examination for the postneoadjuvant treatment pancreatectomy specimens
- The largest dimension of the entire area defined by viable neoplastic cells including intervening stroma and nonneoplastic pancreatic tissue should be measured microscopically (Am J Surg Pathol 2022;46:754)
There are several methods for Ki67 proliferation index assessment for pancreatic neuroendocrine tumors, including automated counting by image analyzer
- Manual counting of camera captured / printed image is encouraged since it is highly reliable and easily performed (Mod Pathol 2015;28:686)
For pancreaticoduodenectomy (Whipple) specimens, status of bile duct margin, pancreatic neck margin, uncinate (retroperitoneal) margin, proximal margin of the stomach / duodenum and distal margin of the duodenum should be reported
For distal pancreatectomy specimens, proximal pancreatic parenchyma margin should be reported

Additional references

CAP: Protocol for the Examination of Specimens from Patients with Carcinoma of the Pancreas [Accessed 2 December 2022], CAP: Protocol for the Examination of Specimens from Patients with Tumors of the Endocrine Pancreas [Accessed 2 December 2022], WHO Classification of Tumours Editorial Board: Digestive System Tumours, 5th Edition, 2019, WHO Classification of Tumours Editorial Board: Endocrine and Neuroendocrine Tumours, 5th Edition, 2022, Am J Surg Pathol 2005;29:724, Ann Surg 2016;263:162

Board review style question #1

Which of the following is a core (mandatory) data element when reporting the resection specimens with pancreatic neuroendocrine tumors according to CAP?

Distance of the tumor from all negative margins
Functional type of the tumor
Histologic grade of the tumor
Patient’s clinical history
Tumor necrosis

Board review style answer #1

C. Histologic grade of the tumor

Comment Here

Reference: Features to report - pancreatectomy

Frozen section

Table of Contents

Definition / general

Click here for the frozen section procedure topic
This topic describes frozen section (intraoperative consultation) procedures for pancreaticoduodenectomy and distal pancreatectomy specimens
Essential clinical history: none

Procedure

Frozen section for primary diagnosis:
- Preoperative diagnostic modalities have mostly replaced frozen section practice for primary diagnosis
- However, it is still performed on occasional cases when the preoperative cytology or biopsy was inconclusive or when there are unusual intraoperative findings (Arch Pathol Lab Med 2022;146:84)
Frozen section for distant metastasis:
- Since presence of any distant metastasis means unresectable disease for pancreatic ductal adenocarcinoma (PDAC) cases, surgeons may send suspected tissues (e.g., liver, peritoneum, distant lymph nodes, etc.) for frozen section examination
- If it reveals metastasis, the procedure will most likely be aborted (J Clin Pathol 2007;60:975)
Frozen section for margin status:
- Main purpose for this request is to evaluate the completeness of the resection (Ann Surg Oncol 2013;20:3626)
- If the margin (i.e., pancreatic parenchyma / duct, biliary duct) is positive, the surgeon will resect additional tissue to achieve a clear margin
- For the pathologist, the main question is whether there is an invasive carcinoma or high grade dysplasia in the margin or not
- Presence of low grade dysplasia does not require further resection
Frozen section for intraductal neoplasms:
- Sometimes surgeons may request intraoperative examination of an intraductal neoplasm to investigate if there is high grade dysplasia or invasive carcinoma
- However, both high grade dysplasia and invasive carcinoma are usually focal and an invasive carcinoma component may not be easy to identify grossly
- Therefore, it is not possible to fully exclude high grade dysplasia or invasive carcinoma during the frozen section and a discrepancy may occur between frozen section and permanent assessment (Ann Surg 2016;263:162)

Tips

It can be challenging to differentiate pancreatic ductal adenocarcinoma from PanIN or a reactive process (e.g., chronic pancreatitis) in frozen section
Findings in favor of pancreatic ductal adenocarcinoma include:
- Loss of normal lobular organization and haphazardly distributed ducts / glands (Semin Diagn Pathol 2004;21:268)
- Irregular shaped ducts with angular contours and incomplete lumen formation (Arch Pathol Lab Med 2002;126:1169, Semin Diagn Pathol 2004;21:268)
- Complex and atypical arrangement (e.g., cribriform, cord-like or single cell infiltration) (Arch Pathol Lab Med 2002;126:1169)
- Abnormal location of glands (i.e., adjacent to a thick walled, medium - small sized muscular artery) (Am J Surg Pathol 2004;28:613)
- Naked (solitary) duct in adipose tissue without an intervening stroma (Semin Diagn Pathol 2004;21:268)
- Perineural or vascular invasion
- Nuclear atypia, pleomorphism (i.e., variation in nuclear size of 4:1 or more within an individual gland), hyperchromatism, nuclear membrane irregularities, nuclear grooves, raisinoid / wrinkled nuclei (especially in the foamy gland pattern), mitotic figures, atypical mitosis, loss of polarity and large nucleoli (Arch Pathol Lab Med 2002;126:1169, Semin Diagn Pathol 2004;21:268)
- Cytoplasmic characteristics (e.g., foamy gland pattern pancreatic ductal adenocarcinoma is characterized by abundant foamy / microvesicular cytoplasm) (Am J Surg Pathol 2000;24:493)
- Intraluminal necrotic / cellular debris and plugs (Arch Pathol Lab Med 2002;126:1169, Semin Diagn Pathol 2004;21:268)
- Disorganized, basophilic and even myxoid stroma (Semin Diagn Pathol 2004;21:268)
Sometimes, low grade gastric-like mucinous epithelium may be identified in the pancreatic parenchyma margin
- For such cases, it is difficult (if not impossible) and unnecessary to distinguish pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) during the intraoperative consultation
- It is sufficient to document that there is no high grade dysplasia or invasive carcinoma in the margin; low grade mucinous epithelium is identified in the margin and differential diagnoses include low grade PanIN and low grade IPMN (Ann Surg Oncol 2013;20:3626)

Frozen section images

Contributed by Hulya Sahin Ozkan, M.D.

Cytological features of PDAC

Perineural invasion

Foamy gland pattern PDAC

Liver metastasis of PDAC

Lymph node metastasis of PDAC

Potential mimicker of PDAC

Additional references

Am J Surg Pathol 2015;39:1730

Board review style question #1

Which of the following is a typical reason for frozen section requests in the surgical management of pancreatic tumors?

To evaluate a suspicious liver lesion
To evaluate extranodal tumor extension in a metastatic peripancreatic lymph node
To evaluate neoadjuvant treatment response
To evaluate the histologic grade of the tumor
To evaluate the mitotic index of the tumor

Board review style answer #1

A. To evaluate a suspicious liver lesion

Comment Here

Reference: Pancreas - Frozen section

Gastrinoma

Table of Contents

Definition / general

Pancreatic well differentiated neuroendocrine tumor that causes clinical symptoms secondary to secretion of gastrin

Essential features

Functionally active and usually aggressive neuroendocrine tumor
Gastrin secretion causes Zollinger-Ellison syndrome
May occur sporadically or in the setting of MEN1

Terminology

Pathology diagnosis should be well differentiated neuroendocrine tumor, as gastrinoma is a clinical determination
Sometimes called G cell neoplasm

ICD coding

ICD-O: 8153/3 - gastrinoma, malignant
ICD-10: C25.4 - malignant neoplasm of endocrine pancreas

Epidemiology

Roughly 20% of functional pancreatic neuroendocrine tumors are gastrinomas, though only about 5% of overall pancreatic neuroendocrine tumors are gastrinomas (Surg Pathol Clin 2014;7:559, World J Gastroenterol 2006;12:5440)

Sites

Gastrinomas are more common in duodenum than in pancreas
Rare examples of so called primary lymph node gastrinoma can occur:
- Gastrin producing tumors in lymph nodes with no GI or pancreatic primary, generally in patients with MEN1 (Am J Surg Pathol 2008;32:1101)
- Occur in gastrinoma triangle: from cystic and common bile ducts to the second and third portion of the duodenum to neck and body of the pancreas
- May be due to gastrin secreting neuroendocrine cells within these nodes or due to occult duodenal microgastrinomas with lymph node metastasis (Arch Pathol Lab Med 2000;124:832, Am J Surg Pathol 2008;32:1101)

Pathophysiology / etiology

Hypersecretion of gastrin stimulates secretion of gastric acid by parietal cells, leading to ulcer formation

Etiology

80% of cases are sporadic; 20% are familial due to MEN1 (Hepatogastroenterology 2005;52:1668)

Clinical features

Associated with hypersecretion of gastric acid and severe peptic ulceration
90% have ulcers (85% in duodenum / jejunum, 15% in stomach)
33% of patients have diarrhea
May be metastatic at time of diagnosis

Diagnosis

Glucagon provocative test is useful (Surg Today 2013;43:1281)

Radiology description

Highly vascular and well circumscribed, as with other neuroendocrine tumors of pancreas
Imaging may detect positive lymph nodes within the gastrinoma triangle (Diagn Interv Imaging 2016;97:1241)
Octreotide scans have high sensitivity

Radiology images

Images hosted on other servers:

CT of pancreatic gastrinoma

Prognostic factors

Sporadic tumors are usually solitary, aggressive and located in pancreas
MEN1 cases are often multicentric, less aggressive and arise in duodenal wall (Gut 2007;56:606)

Case reports

25 year old woman with mass blocking the pancreatic duct (Surgery 2005;138:111)
37 year old woman with von Hippel-Lindau syndrome and 2 pancreas lesions (Rev Esp Enferm Dig 2017;109:154)
68 year old woman with abdominal pain and diarrhea (Oncol Lett 2016;11:3433)
73 year old man with pancreatic gastrinoma and endobronchial metastasis (Am J Respir Crit Care Med 2012;185:590)

Treatment

H2 blockers for symptom management
Surgical resection of tumor

Gross description

Single or multiple lesions, most commonly in head of pancreas
Firm, homogeneous, well circumscribed

Gross images

AFIP images

Lymph node gastrinoma

Microscopic (histologic) description

Nests of monotonous low grade neuroendocrine cells with salt and pepper nuclei and ample amphophilic cytoplasm, as with any other well differentiated neuroendocrine tumor
Associated with pancreatic polypeptide cell hyperplasia (Hum Pathol 1997;28:149)
Nonneoplastic pancreas may show large islets and nesidioblastosis

Microscopic (histologic) images

Contributed by Raul S. Gonzalez, M.D. and AFIP images

Nests and cords of cells

Malignant tumor has trabecular pattern

Lobular trabecular pattern

Positive stains

Gastrin (though this does not establish the diagnosis)
Synaptophysin, chromogranin
PDX1, INSM1 (Am J Surg Pathol 2012;36:737)

Negative stains

CK7 (8%) (Am J Surg Pathol 2012;36:737)
CDX2
BCL10 (Pathol Int 2013;63:176)
Nuclear beta catenin (World J Gastrointest Onc 2016;8:615)

Electron microscopy description

Tumor cells may contain small, electron dense granules

Electron microscopy images

AFIP images

Pancreatic gastrinoma

Sample pathology report

Pancreas and duodenum, Whipple procedure:
- Pancreatic neuroendocrine tumor, WHO grade 2 (see synoptic report and comment)
- Comment: The patient’s clinical history of Zollinger-Ellison syndrome is noted. This may be due to gastrin secretion by this tumor, which would make it a gastrinoma. Immunohistochemical stains for synaptophysin and chromogranin are positive and the Ki67 index is approximately 4.5%.

Differential diagnosis

Nongastrin secreting pancreatic neuroendocrine tumor:
- No histopathologic differences
- Must be determined on clinical grounds

Board review style question #1

Gastrinoma
Glucagonoma
Insulinoma
Somatostatinoma
VIPoma

Board review style answer #1

A. Gastrinoma

Comment Here

Reference: Gastrinoma

Board review style question #2

Benign clinically
Cystic
Located in the pancreas
Multifocal
WHO grade 1

Board review style answer #2

C. Located in the pancreas

Comment Here

Reference: Gastrinoma

Glucagonoma (alpha cell tumors)

Table of Contents

Definition / general

Rare, poorly characterized pancreatic neuroendocrine tumor that produces glucagon

Essential features

WHO recognized diagnosis
Produces glucagon, akin to alpha cells of the pancreas
Clinical glucagonoma symptoms include necrolytic migratory erythema, diabetes, weight loss and anemia

Terminology

Necrolytic migratory erythema: skin rash of legs, perineum, groin; rash becomes blisters with central clearing, heals with hyperpigmentation but without scarring in 7 - 14 days (Am J Surg Pathol 1986;10:445)

ICD coding

ICD-10: D37.8 - Neoplasm of uncertain behavior of pancreas

Epidemiology

Incidence rate of approximately 2.5/100,000,000 (Oncol Lett 2018;15:2749)
Mean age 54 years
More common in women

Sites

More common in tail of pancreas

Pathophysiology

Generally sporadic
Patients with multiple endocrine neoplasia type 1 may have multiple small glucagonomas (with better prognosis)

Clinical features

Causes glucagonoma syndrome (necrolytic migratory erythema, diabetes mellitus, weight loss, anemia, angular stomatitis)
Necrolytic migratory erythema may become infected
Roughly half of cases metastasize, often to liver

Diagnosis

Determined clinically, not by immunohistochemical positivity for glucagon

Laboratory

Elevated blood glucagon levels

Radiology description

MRI: low signal intensity on T1, slightly high signal intensity on T2

Radiology images

Images hosted on other servers:

MRI

Liver metastases

Case reports

50 year old woman with pruritic rash (Oncol Lett 2015;10:1113)
51 year old woman with heart failure (Endocrinol Diabetes Metab Case Rep 2014;2014:140061)
62 year old woman with ovarian mass and history of glucagonoma (JOP 2013;14:510)
64 year old woman with erythematous rash (Case Rep Surg 2016;2016:1484089)
68 year old man with anemia and diabetes (J Hepatobiliary Pancreat Surg 2003;10:101)

Treatment

Surgery is only curative option
Somatostatin analogues may relieve symptoms (Clin Endocrinol (Oxf) 2011;74:593)

Clinical images

AFIP images

Necrolytic migratory erythema

Images hosted on other servers:

Necrolytic migratory erythema

Gross description

Average gross tumor size is 5.0 cm

Microscopic (histologic) description

Nests of monotonous low grade neuroendocrine cells with salt and pepper nuclei and ample amphophilic cytoplasm

Microscopic (histologic) images

Images hosted on other servers:

H&E and immunostains

H&E and glucagon

Liver metastasis

Chromogranin

Positive stains

Glucagon (though this does not establish the diagnosis)
Synaptophysin and chromogranin

Electron microscopy description

Single type secretory granules similar to normal alpha cell granules (Ultrastruct Pathol 1989;13:15)

Sample pathology report

Pancreas and duodenum, Whipple procedure:
- Pancreatic neuroendocrine tumor, WHO grade 1 (see synoptic report and comment)
- Comment: The patient’s clinical history of necrolytic migratory erythema is noted. This may be due to glucagon secretion by this tumor, which would make it a glucagonoma. Immunohistochemical stains for synaptophysin and chromogranin are positive and the Ki67 index is approximately 1.2%.

Differential diagnosis

Nonglucagon secreting pancreatic neuroendocrine tumor:
- Must be determined on clinical grounds (Proc (Bayl Univ Med Cent) 2015;28:46)

Board review style question #1

Angular stomatitis
Hypochlorhydria
Hypoglycemia
Water diarrhea

Board review style answer #1

A. Angular stomatitis (though the most common finding is necrolytic migratory erythema). Hypochlorhydria is sometimes seen in somatostatinoma. Hypoglycemia is typical of insulinoma. Watery diarrhea is typical of VIPoma.

Comment Here

Reference: Glucagonoma (alpha cell tumors)

Board review style question #2

Classic radiologic findings
Clinical glucagonoma type symptoms
Immunohistochemical positivity for glucagon
Specific histologic findings

Board review style answer #2

B. Clinical glucagonoma type symptoms. The diagnosis of glucagonoma is made on clinical grounds in the setting of a pancreatic mass lesion.

Comment Here

Reference: Glucagonoma (alpha cell tumors)

Grossing

Table of Contents

Definition / general

This topic describes how to gross specimens obtained from pancreaticoduodenectomy, distal pancreatectomy and total pancreatectomy procedures
Essential clinical history: none

Procedure

Pancreaticoduodenectomy (Whipple) specimens:

Orientation and external examination
- Specimen consists of pancreatic head and duodenum and occasionally distal stomach and gallbladder
- Examine the specimen freshly
- Measure the overall specimen and each organ / structure
- Identify the trapezoid:
  - There is a trapezoid shaped area in the posteromedian aspect of the pancreatic head (Am J Surg Pathol 2014;38:480)
  - The center of the trapezoid is a concave, smooth and shiny surfaced firm area, on which the superior mesenteric vein / portal vein and superior mesenteric artery lie
  - This area is referred to as the vascular groove or vascular bed (see figure 1)
- Identify and ink the important structures and margins:
  - Trapezoid is formed by the pancreatic neck margin on the left, the uncinate margin on the right and the common bile duct (CBD) on the top (see figure 1)
  - Pancreatic duct (PD) is in the upper half of the pancreatic neck margin towards the vascular groove
  - Ink the pancreatic neck margin, uncinate margin and common bile duct margin with different colors (e.g., green, black and red, respectively) (see figure 2)
  - Although it is not a surgical margin, ink the vascular groove area (e.g., orange) as well, after checking if it includes a portion of the portal vein (Am J Surg Pathol 2014;38:480)
- Check if a portion of the portal vein is present in the vascular groove area: if present, ink the superior and inferior margins using different colors
- Identify and ink the anterior and posterior free peritoneal surfaces:
  - Anterior free surface is convex shaped and contains abundant fat tissue
  - Pancreatic head - duodenum transition is abrupt and easily identifiable on this surface (see figure 3)
  - However, the posterior free surface is flat and shiny in appearance while the pancreatic head - duodenum transition in this area is smoother and barely identifiable (see figure 4)
  - If not sutured or stapled, the common bile duct margin can be seen readily on this aspect
  - Although they are not surgical margins, it is encouraged to ink the anterior and posterior free surfaces in different colors (e.g., blue for anterior, black for posterior) (Am J Surg Pathol 2014;38:480)
Removing the margins
- Bile duct margin:
  - Shave and submit enface (see figure 5) (Am J Surg Pathol 2014;38:480)
  - Bile duct margin corresponds to the CBD margin in most of the specimens
  - However, if gallbladder is attached to the specimen, it corresponds to common hepatic duct (CHD) margin
  - If the specimen includes cystic duct (CD) without attached gallbladder, it corresponds to both CHD and CD margins
- Pancreatic neck margin (including PD): shave and submit enface (see figure 6) (Am J Surg Pathol 2014;38:480)
- Uncinate (retroperitoneal or posteroinferior or superior mesenteric artery) margin:
  - This margin is formed by blunt dissection of the pancreatic head from the retroperitoneal soft tissues in the posterior inferior aspect of the uncinate process, rather than a surgical cut
  - Shave and submit entirely as 3 - 4 mm thick bread loaf sections in 2 or 3 cassettes (see figure 7) (Am J Surg Pathol 2014;38:480)
- Portal vein margins (if present): superior and inferior margins of the vein can be shaved and submitted enface or can be submitted as a part of the main perpendicular sections of the vessel wall
- Vascular groove (vascular bed or superior mesenteric / portal vein bed) surface:
  - Submitting 1 perpendicular section that shows the area closest to the tumor is enough for most of the cases
  - However, shaving and submitting bread loaf sections just like the uncinate margin is another option
- Proximal (stomach / duodenum) and distal (duodenum) margins: submit 1 shaved section from each margin
Opening the duodenum and examining intraduodenal aspect
- Open through the antipancreatic (antiampullary) border (Am J Surg Pathol 2014;38:480)
- Inspect the ampullary region to identify and describe any lesions (e.g., intra / periampullary localization; mass forming, papillary or mucinous features, etc.)
- Inspect the minor (accessory) ampulla, if present:
  - It is located ~2 cm anterior and superior to the main ampulla and looks like a small bump / nodule / polyp (see figure 8)
  - In some cases, the PD might open into minor ampulla (Am J Surg Pathol 2014;38:480)
Bivalving and sectioning
- Although there are several approaches in sectioning the pancreatic head, bivalving is the most commonly used method as it allows for assessment of the relation of tumor with both the CBD and PD and for proper evaluation and documentation of ampullary tumors (Am J Surg Pathol 2014;38:480)
- Bivalve the pancreatic head by placing the probes in the CBD and PD to the ampulla; probe the CBD all the way to the ampulla and the PD at least as far as it can be traced
- Start sectioning using a long knife (e.g., 6 inches)
  - Knife needs to be angled as if cutting the probes themselves (see figure 9)
  - Carefully examine and re-angle after each stroke (Am J Surg Pathol 2014;38:480)
  - Finally, the pancreatic head should be separated into anterior and posterior halves (see figure 10)
Identifying the tumor(s)
- Inspect and describe the following features of the tumor(s): localization, size (measurements), characteristics (e.g., color, solid / cystic, necrotic / hemorrhagic / papillary areas, soft / firm, well circumscribed / ill defined), association with / distance from the CBD, PD, ampulla, margins and surfaces
- Harvest fresh tumor samples for the tumor bank as needed
Identifying variant anatomies (i.e., low union)
- Normal (most common) insertion of the CD into the CHD is at least 5 mm above the pancreatic parenchyma border
- Other levels of insertion (i.e., within the 5 mm of pancreatic parenchyma border or even intrapancreatic) are considered as low union, which have been shown to play a significant role in pancreatobiliary and periampullary carcinogenesis (HPB (Oxford) 2020;22:1675)
- Therefore, when present, it should be documented (see figure 11)
Lymph node dissection
- Peripancreatic lymph nodes are separated into 8 regions as peri-CBD, anterior pancreatic, anterior pancreatoduodenal, superior pancreatic, inferior pancreatic, posterior pancreatic, posterior pancreatoduodenal and uncinate margin lymph nodes; however, these regions currently do not play any role in pN staging
- Shave off all peripancreatic soft tissues using the orange peeling method (see figures 12 and 13) including the priorly inked anterior and posterior free surfaces (Am J Surg Pathol 2014;38:480, Mod Pathol 2009;22:107)
  - Submit entirely in subsequent cassettes
  - Make a note of sectioned lymph nodes to prevent overcounting
- Dissect and submit perigastric and periduodenal lymph nodes using conventional methods
Fixation and harvesting
- Let the specimen be properly fixed in formalin for 24 - 48 hours
- After fixation, submit at least 1 section per centimeter of the tumor for solid tumors
  - Increase the number of the sections or even submit it entirely if the tumor was treated (Am J Surg Pathol 2022;46:754)
  - Unless there is a grossly visible invasion, cystic / intraductal tumors should be submitted entirely to rule out invasion (Ann Surg 2016;263:162)
- Include proper sections to show any association between the tumor and important structures (i.e., ampulla, CBD, PD, vascular bed, duodenum, etc.)
- Include nontumoral tissue sections from the pancreas and the adjacent organs
Taking gross images
- Always take several images of the specimen in both fresh (before and after inking, bivalving and sectioning) and fixed states

Distal pancreatectomy specimens:

Orientation, external examination and removing the margin
- Specimen consists of body and tail of the pancreas with or without spleen attached
- Freshly examine the specimen
- Measure the overall specimen and each organ / structure
- Identify splenic artery on the superior and splenic vein on the posterior surface of the pancreas (see figures 14 and 15)
- Ink anterior and posterior surfaces in different colors (e.g., blue for anterior, black for posterior)
- Identify, ink and remove the pancreatic parenchymal (duct) margin; shave and submit enface
Sectioning
- One approach is serial sectioning of the entire pancreas and spleen at 0.5 - 1 cm intervals starting from the proximal edge of the pancreas (see figure 16)
- Alternatively, entire pancreas and spleen can be bivalved and sectioned with the guidance of a probe placed in the PD, starting from the proximal edge of the pancreas (see figure 17)
  - Then, perpendicular (to the surfaces) sections are submitted from each half
Identifying the tumor(s)
- Inspect and describe the following features of the tumor(s): localization, size (measurements), characteristics (e.g., color, solid / cystic, necrotic / hemorrhagic / papillary areas, soft / firm, well circumscribed / ill defined), association with / distance from the PD, pancreatic parenchymal margin, anterior and posterior surfaces and spleen
- Harvest fresh tumor samples for the tumor bank as needed
Lymph node dissection
- Dissect the peripancreatic and splenic hilar lymph nodes using conventional methods
Fixation and harvesting
- Let the specimen be properly fixed in formalin for 24 - 48 hours
- After fixation, submit at least 1 section per centimeter of the tumor for solid tumors
  - Increase the number of the sections or even submit it entirely if the tumor was treated (Am J Surg Pathol 2022;46:754)
  - Unless there is a grossly visible invasion, cystic / intraductal tumors should be submitted entirely to rule out invasion (Ann Surg 2016;263:162)
- Include proper sections to show any association between the tumor and important structures (i.e., PD, spleen, splenic hilum, etc.)
- Include nontumoral tissue sections from the pancreas and the spleen
Taking gross images
- Always take several images of the specimen in both fresh (before and after inking, bivalving and sectioning) and fixed states

Total pancreatectomy specimens:

Specimen consists of pancreatic head, neck, body and tail, in addition to duodenum, spleen and occasionally distal stomach and gallbladder (see figure 18)
Follow the steps for pancreaticoduodenectomy and distal pancreatectomy for the appropriate portions of the specimen (see above)

Sections to obtain

Tumor:
- Submit representative tumor sections for a total of 1 cassette per 1 cm of the largest tumor dimension; increase the number as needed (e.g., if the tumor is cystic / intraductal, if the patient had neoadjuvant therapy, etc.) (Am J Surg Pathol 2022;46:754, Ann Surg 2016;263:162)
- Include proper sections to show any association between the tumor and adjacent structures
Margins: submit the proper margins for pancreaticoduodenectomy, distal pancreatectomy and total pancreatomy specimens as described above
Lymph nodes: submit all dissected lymph nodes (and the entire peripancreatic soft tissue for pancreaticoduodenectomy specimens) properly (Am J Surg Pathol 2014;38:480)
Nontumoral adjacent organs: submit uninvolved tissue sections from the pancreas and adjacent organs in 1 cassette for each organ

Tips

Distinguishing CBD and PD:
- CBD is a large, tan to light yellow colored (bile stained) duct exhibiting numerous punctuate orifices of the peribiliary glands (see figure 10)
- PD is a narrow, tan-white colored duct with a smooth and glistening luminal surface (see figure 10)
Probing the PD:
- If the PD orifice is not easily identified in the pancreatic neck margin, squishing the pancreatic head and looking for the pancreatic fluid coming from the PD might be useful
  - However it needs to be done carefully, as the pancreatic fluid can only be seen in the first few attempts
- In some cases, probing of the PD is problematic, especially in the distal part, because of its narrow and kinked nature in contrast to the CBD which is always probe-patent
  - One option is retroprobing the PD from the ampulla
  - If it does not work, another option is to probe the PD as far as it can be traced and past that point using the guidance of the CBD alone
Cystic tumors:
- Examine the nature of cystic fluid (e.g., mucinous, clear, hemorrhagic, etc.)
- Assess the association of the cyst with main / branch pancreatic ducts
- Pay attention to the solid / granular / papillary / nodular areas of the cyst, if any, since they have value in evaluating the invasion
Ampullary tumors:
- Ampullary carcinoma is defined by the bulk of the tumor (> 75%) being located in the ampulla
- Classification of ampullary carcinomas (i.e., intra-ampullary, ampullary ductal, periampullary duodenal and ampullary, NOS) depends on a proper gross examination (Am J Surg Pathol 2012;36:1592)
- Sections should be taken perpendicularly to make measurement of the invasion depth possible; they should also include the ampulla, pancreas, periampullary duodenum and periampullary soft tissues
Nonampullary duodenal tumors:
- By definition, the epicenter of a nonampullary duodenal carcinoma is entirely located in the duodenum and the ampulla is uninvolved
Distal CBD tumors:
- Distal CBD carcinoma is defined by whether the bulk of the tumor is located circumferentially around the CBD or if an associated precursor intraductal neoplasm is identified in the CBD (Mod Pathol 2016;29:1358, J Gastrointest Surg 2016;20:953)
Taking gross images of the specimen in both fresh and fixed states is helpful for microscopic examination and reporting

Gross description

Pancreatic ductal adenocarcinoma (PDAC):
- Ill defined solid mass with irregular / infiltrating borders, gray-white-tan greenish in color, firm and scirrhous in consistency (Am J Surg Pathol 2014;38:480)
- Necrosis or cystic degeneration may be present
Pancreatic neuroendocrine carcinoma (NEC):
- Ill defined or vaguely nodular solid mass with relatively irregular / infiltrating borders, tan-white-brown-red or yellowish in color, usually fleshier than PDAC
- Necrosis and hemorrhage are often easily identified (Am J Surg Pathol 2014;38:437)
Pancreatic neuroendocrine tumor (PanNET):
- Well circumscribed solid mass with pushing borders, gray-tan pinkish in color, soft and fleshy in consistency (Endocr Pathol 2014;25:65)
- Cystic degeneration or accompanying fibrosis, calcification and ossification may be present
Acinar cell carcinoma (ACC):
- Well circumscribed and sometimes encapsulated, solid, bulky mass, gray-tan pinkish reddish in color, fleshy in consistency (Semin Diagn Pathol 2016;33:307)
Solid pseudopapillary tumor (SPN):
- Well circumscribed and encapsulated mass, which reveals solid and cystic areas, tan-brown pinkish in color, fleshy and friable in consistency
- Hemorrhage and necrosis are observed in most cases (Arch Pathol Lab Med 2009;133:423)
Intraductal papillary mucinous neoplasm (IPMN):
- Cystic mass in the main or branch pancreatic ducts, may reveal mucin or papillary structures (Am J Surg Pathol 2014;38:480, Semin Diagn Pathol 2014;31:452)
Intraductal oncocytic papillary neoplasm (IOPN):
- Multilocular or unilocular cystic mass in the main pancreatic duct with friable papillary / nodular projections (Mod Pathol 2016;29:1058, Am J Surg Pathol 2019;43:656)
Intraductal tubulopapillary neoplasm (ITPN):
- Multinodular / polypoid / solid mass in the main pancreatic duct, without a very distinct cyst formation and papillary projections (Semin Diagn Pathol 2014;31:452, Mod Pathol 2017;30:1760)
Mucinous cystic neoplasm (MCN):
- Well circumscribed and large cystic mass without any association with ductal system, may reveal papillary / trabecular / nodular / solid areas (Arch Pathol Lab Med 2009;133:423, J Gastrointest Surg 2008;12:401)
Serous cystadenoma (SCA):
- Well circumscribed and multicystic (sponge-like) tumor, usually with a central scar and without any association with ductal system (Am J Surg Pathol 2015;39:1597, Semin Diagn Pathol 2014;31:475)
- Rare cases may reveal oligocystic or even solid appearance

Gross images

Contributed by Olca Basturk, M.D.

Trapezoid and important structures

Inked margins and vascular groove

Anterior free surface

Posterior free surface

Common bile duct margin

Pancreatic neck / duct margin

Uncinate margin

Minor (accessory) ampulla

Bivalving and sectioning

Cut surface of the pancreatic head

Low union

Peripancreatic lymph nodes

Lymph node dissection (orange peeling)

Anterior surface of distal pancreatectomy

Posterior surface of distal pancreatectomy

Serially sectioned distal pancreatectomy

Bivalved distal pancreatectomy

Total pancreatectomy

Gross template samples

Pancreaticoduodenectomy (Whipple) specimens:
- The specimen is received (fresh), labeled as pancreatoduodenectomy and consists of pancreatic head, duodenum and (other organs). The pancreas measures ( ) x ( ) x ( ) cm, the duodenum measures ( ) cm in length and ( ) cm in circumference, (other organs) measures ( ) cm. External surface of the pancreas is ( ). The pancreatic neck / duct margin is inked (green), the bile duct margin is inked (red), the uncinate margin is inked (black), the vascular groove is inked (orange), posterior surface of the pancreas is inked (black) and anterior surface of the pancreas is inked (blue). The bile duct and pancreatic neck / duct margins are shaved and submitted enface. The uncinate margin is shaved, serially sectioned and entirely submitted.
- Proximal and distal margins of the duodenum are submitted. Duodenum is opened through the antipancreatic border. Ampulla reveals ( ). The bile duct and pancreatic duct are probed.
- Bivalving of the pancreas reveals that the pancreatic duct is ( ) cm in length with a luminal circumference of ( ) cm, the bile duct is ( ) cm in length with a luminal circumference of ( ) cm. Cystic duct is present / absent in the specimen. If cystic duct is present, it is ( ) cm in length, with a luminal circumference of ( ) cm and it adjoins the common hepatic duct at ( ). There is a ( ) x ( ) x ( ) cm solid / cystic mass, ( ) in color, with a firm / soft / fleshy cut surface, ill defined / well circumscribed borders, located at the ( ). The tumor is in association with ( ). ( ) are involved by the tumor. The tumor is in ( ) cm distance from the ( ). Representative sections of the tumor submitted. Ampulla is submitted. Entire peripancreatic soft tissues and dissected periduodenal lymph nodes are submitted. The remaining pancreatic cut surface reveals ( ) / unremarkable. The remaining duodenal mucosal surface reveals ( ) / unremarkable. Other organs on the specimen reveal ( ) / unremarkable. Representative sections of the remaining pancreas and adjacent organs are submitted.
Distal pancreatectomy specimens:
- The specimen is received (fresh), labeled as distal pancreatectomy and splenectomy, and consists of distal pancreas and spleen. The distal pancreas measures ( ) x ( ) x ( ) cm. Spleen is () gr and measures ( ) x ( ) x ( ) cm. The pancreatic parenchymal margin is shaved and submitted enface. The anterior surface of the pancreas is inked (blue) and the posterior surface is inked (black). Serially sectioning (or bivalving) of the specimen reveals a ( ) x ( ) x ( ) cm solid / cystic mass, ( ) in color, with a firm / soft / fleshy cut surface, ill defined / well circumscribed borders, located at the ( ). The tumor is in association with ( ). ( ) are involved by the tumor. The tumor is in ( ) cm distance from the ( ). Representative sections of the tumor submitted. Peripancreatic and perihilar lymph nodes are dissected and submitted. The remaining pancreatic cut surface reveals ( ) / unremarkable. Sections of the spleen reveal ( ) / unremarkable. Representative sections of the remaining pancreas and spleen are submitted.
Total pancreatectomy specimens:
- See the gross template samples for pancreaticoduodenectomy and distal pancreatectomy specimens

Additional references

Diagnostics (Basel) 2019;9:132, Am J Surg Pathol 2015;39:1730

Board review style question #1

Gross examination of a pancreaticoduodenectomy (Whipple) specimen reveals a white-tan colored, firm, solid mass with ill defined borders, located in the pancreatic head. Which of the following would be included in the initial differential diagnosis?

Acinar cell carcinoma
Pancreatic ductal adenocarcinoma
Solid pseudopapillary tumor
Well differentiated pancreatic neuroendocrine tumor, grade 1
Well differentiated pancreatic neuroendocrine tumor, grade 3

Board review style answer #1

B. Pancreatic ductal adenocarcinoma

Comment Here

Reference: Pancreas - Grossing

Heterotopic pancreas

Table of Contents

Definition / general

Pancreatic tissue that is anatomically separate from the main pancreatic gland and has no vascular or ductal connection to it

Essential features

Pancreatic tissue that is anatomically separate from the main pancreatic gland and has no ductal or vascular connections to it the main pancreatic gland
Composed of a variable mixture of pancreatic acini, ducts and islets
Most common in stomach but may occur throughout GI tract; and rarely in extragastrointestinal sites
Often incidental finding
May develop the same diseases as the main pancreatic gland (e.g., pancreatitis or pancreatic neoplasms)
May be asymptomatic or depending on size and location, may present with symptoms such as abdominal pain, GI bleed or obstruction
Surgical management if symptomatic or if diagnosis is unknown

Terminology

Ectopic pancreas, heterotopic pancreas, pancreatic rest, accessory pancreas, aberrant pancreas, pancreatic choristoma

ICD coding

ICD-10: Q45.3 - other congenital malformations of pancreas and duct

Epidemiology

M:F = 3:1
Most commonly identified in fifth to sixth decades of life
Incidence of 0.5 - 13% in autopsy studies
Incidental finding in 0.2 - 0.9% of upper abdominal surgeries and gastrectomies, respectively
Reference: Gastroenterology Res 2021;14:45

Sites

Can occur anywhere in the gastrointestinal tract (GI)
Most common in upper GI tract (stomach, duodenum and proximal jejunum) (Gastroenterology Res 2021;14:45)
Less common in Meckel diverticulum, esophagus, ileum, colon, biliary tree, mesentery, spleen and lung (Gastroenterology Res 2021;14:45, Saudi Med J 2018;39:834)

Pathophysiology

Exact embryologic mechanism unknown
Misplacement theory: portion(s) of pancreas become separated during rotation of foregut and develop into mature pancreatic tissue (Radiographics 2017;37:484, Arch Pathol Lab Med 1999;123:707)
Metaplasia theory: pancreatic metaplasia of endodermal tissue that has migrated to submucosa (Radiographics 2017;37:484, Arch Pathol Lab Med 1999;123:707)
Totipotent cell theory: endodermal cells in GI tract differentiate into pancreatic tissue (Radiographics 2017;37:484)

Clinical features

Often asymptomatic (Gastroenterology Res 2021;14:45, Radiographics 2017;37:484)
Depending on location and size, can present with symptoms of abdominal pain, melena, obstruction or intussusception (Gastroenterology Res 2021;14:45, Radiographics 2017;37:484)
May develop the same diseases as the main pancreas, including acute or chronic pancreatitis and neoplasms (Radiographics 2017;37:484)

Diagnosis

Frequently is an incidental finding
Radiographically, typically appears as ovoid intramural mass (Radiographics 2017;37:484)
Endoscopically presents as a solid submucosal mass (Radiographics 2017;37:484)
Definitive diagnosis requires histologic examination

Laboratory

Most cases lack specific lab abnormalities
Rare cases may show lab abnormalities associated with disease of the heterotopic pancreatic tissue:
- Microcytic anemia related to GI bleed caused by heterotopic tissue (BMC Gastroenterol 2019;19:57)
- Elevated serum amylase in heterotopic pancreas with acute pancreatitis (Case Rep Gastrointest Med 2018;2018:5640379)
- Elevated CA 19-9 in adenocarcinoma arising in heterotopic pancreas (Int Surg 2012;97:351)

Radiology description

Endoscopically appears as a round, subepithelial lesion, often with a central depression that represents the opening of the duct (Insights Imaging 2021;12:144, Gastroenterol Rep (Oxf) 2017;5:237)
Endoscopic ultrasound (EUS) shows solid, submucosal mass that is hypoechoic relative to the hyperechoic submucosa and isoechoic relative to the muscularis propria (Insights Imaging 2021;12:144)
Typical computed tomography (CT) findings include small (< 3 cm), oval, intramural mass with microlobulated margins and an endoluminal growth pattern (Insights Imaging 2021;12:144, Radiographics 2017;37:484)
- Acinus dominant lesions show avid homogenous enhancement with intravenous contrast
- Duct dominant lesions are hypovascular and heterogenous
By magnetic resonance imaging (MRI), heterotopic pancreatic tissue will show similar characteristics to the native gland (Insights Imaging 2021;12:144, Radiographics 2017;37:484)
Magnetic resonance cholangiopancreatography (MRCP) can show ectopic duct sign (i.e., a dilated ectopic pancreatic duct) (Clin Radiol 2010;65:403)

Radiology images

Images hosted on other servers:

Gastric submucosal mass

Duodenal and gastric lesions

MRI lesion in duodenum

Prognostic factors

Overall good prognosis but with potential to vary, depending on disease state of heterotopic tissue
Patients with adenocarcinoma arising in pancreatic heterotopia may do better, compared to those with tumors arising in the main gland (BMC Surg 2017;17:53)

Case reports

9 month old girl with pancreatic heterotopia in omphalomesenteric duct remnant (Diagn Pathol 2017;12:49)
9 year old boy with inflamed Meckel diverticulum with elevated serum amylase mimicking acute pancreatitis (Indian J Crit Care Med 2017;21:789)
27 year old woman with large pancreatic heterotopia presenting with gastric outlet obstruction (Gastroenterol Rep (Oxf) 2017;5:237)
48 year old man with pancreatic heterotopia in jejunum and elevated serum chromogranin A (Cureus 2021;13:e15409)
71 year old woman with gastric pancreatic heterotopia with intraductal papillary mucinous neoplasm (IPMN) with GNAS mutation (World J Surg Oncol 2021;19:309)

Treatment

Surgery, if symptomatic

Clinical images

Contributed by Kenechukwu Ojukwu, M.D., M.P.P. and Stephanie Dreikorn, M.D.

Endoscopy, subtle ectopic pancreas

Images hosted on other servers:

Single balloon
enteroscopy
showing
submucosal lesion

Gross description

Usually is a submucosal based lesion but may involve other layers of GI tract (Hum Pathol 2016;55:135)
Well demarcated borders with vaguely lobular appearance (Hum Pathol 2016;55:135)
On cut surface, typically appears pale yellowish white in color with solid and firm consistency (Hum Pathol 2016;55:135)
Central mucosal dimple (opening of pancreatic ducts) may be visible

Gross images

Contributed by Kenechukwu Ojukwu, M.D., M.P.P. and Danielle Hutchings, M.D.

Heterotopic pancreas in Meckel diverticulum

Heterotopic pancreas in stomach

Microscopic (histologic) description

In GI tract, typically centered in submucosa but may involve other layers
Rarely may involve extragastrointestinal sites
Variable mixture of pancreatic acini, ducts, islets
May contain hypertrophic smooth muscle bundles
4 types of pancreatic heterotopia, originally described by Heinrich in 1909 and modified in 1973 by Gasper-Fuentes (Radiographics 2017;37:484):
- Type 1:
  - Contains all elements of normal pancreatic tissue (acini, ducts and islets)
- Type 2:
  - Acini and ducts (no islets) in Heinrich classification
  - Ducts only in Gasper-Fuentes classification
- Type 3:
  - Ducts only in Heinrich classification
  - Acini only in Gasper-Fuentes classification
- Type 4:
  - Does not exist in Heinrich classification
  - Islet cells only in Gasper-Fuentes classification (very rare) (Arch Pathol Lab Med 2002;126:464)
May show the same pathologic changes as the main gland, including acute or chronic pancreatitis, pseudocyst formation or neoplasia

Microscopic (histologic) images

Contributed by Kenechukwu Ojukwu, M.D., M.P.P. and Danielle Hutchings, M.D.

Pancreatic heterotopia in the stomach

Submucosal lesion, lobular architecture

Pancreatic acini and ducts

Heterotopic pancreas predominantly ducts

Branching ectopic pancreatic ducts

Ducts, acini and islets

Intraductal papillary mucinous neoplasm (IPMN)

Gastric type IPMN

IPMN, low grade dysplasia

Meckel diverticulum with heterotopia

Virtual slides

Images hosted on other servers:

Heterotopic pancreas presenting as gastric polyp

Cytology description

Predominantly pancreatic acini: polygonal cells with abundant granular cytoplasm and eccentric nuclei
Ductal structures: cuboidal to columnar cells, honeycomb sheets
Islet cells usually not seen
Reference: World J Gastroenterol 2015;21:2367

Cytology images

Images hosted on other servers:

Cell block with normal pancreatic acini

Benign pancreatic
acinar cells and
ductal epithelium
(Diff-Quik)

Positive stains

Heterotopic pancreas shows staining similar to the native gland
- Acinar cells: positive for trypsin, chymotrypsin, PAS and BCL10 (Virchows Arch 2009;454:133)
- Ductal epithelial cells: positive for CK7, CK8 / CK18
- Islet cells: positive for synaptophysin, chromogranin A and INSM1 (Am J Clin Pathol 2015;144:579)

Sample pathology report

Gastric antrum, endoscopic mucosal resection:
- Pancreatic heterotopia involving submucosa and focally mucosa
- Overlying unremarkable antral mucosa

Differential diagnosis

Pancreatic metaplasia:
- Involves mucosa
- Acinar cells only, no ducts or islet cells present
Adenocarcinoma:
- Duct predominant heterotopia may show branching pattern and be mistaken at low power for adenocarcinoma
- Adenocarcinoma shows infiltrative growth, irregular glands, desmoplasia and cytologic atypia

Additional references

Mills: Histology for Pathologists, 5th Edition, 2019, Wang: Practical Gastrointestinal Pathology - Frequently Asked Questions, 1st Edition, 2021, Noffsinger: Fenoglio-Preiser's Gastrointestinal Pathology, 4th Edition, 2017

Board review style question #1

A 22 year old woman presents with abdominal pain and is found to have an ileal lesion on imaging. A small bowel resection is performed and shows the image above. What is the most likely diagnosis?

Acute appendicitis
Endometriosis
Meckel diverticulum
Well differentiated neuroendocrine tumor

Board review style answer #1

C. Meckel diverticulum with pancreatic and gastric heterotopia

Comment Here

Reference: Heterotopic pancreas

Board review style question #2

A 55 year old man presents with persistent anemia, abdominal pain and intermittent melena. Endoscopy reveals a subepithelial gastric antral mass with overlying umbilicated mucosa. Endoscopic mucosal resection shows the images above. What is the most likely diagnosis?

Gastric adenocarcinoma
Heterotopic pancreas
Metastatic adenocarcinoma
Pancreatic metaplasia

Board review style answer #2

B. Heterotopic pancreas

Comment Here

Reference: Heterotopic pancreas

Insulinoma (beta cell tumor)

Table of Contents

Definition / general

Rare neuroendocrine neoplasm of pancreas with functional production of insulin

Essential features

Tumor secretes insulin (analogous to beta cell production in normal pancreatic islets) and thus clinical hyperinsulinemic hypoglycemia is required for this diagnosis
Majority of insulinomas are small (< 2 cm) and benign
Multiple insulinomas associated with multiple endocrine neoplasia type 1 (MEN1) syndrome

Terminology

Beta cell tumor

ICD coding

ICD-O: 8151/3 - insulinoma, malignant
ICD-10:
- C25.4 - malignant neoplasm of endocrine pancreas
- D13.7 - benign neoplasm of endocrine pancreas
- D37.8 - neoplasm of uncertain behavior of other specified digestive organs
ICD-11: 2C10.1 & XH3UK0 - neuroendocrine neoplasms of pancreas & insulinoma, malignant

Epidemiology

Usually seen in older adults
More common in females (Ann Surg 2008;247:165)
Overall most common functioning pancreatic neuroendocrine neoplasm (J Gastroenterol 2015;50:58)
Majority are benign; 5 - 10% are malignant (Best Pract Res Clin Gastroenterol 2005;19:783)

Sites

Pancreas, evenly distributed (Pancreas 2014;43:675, J Hepatobiliary Pancreat Sci 2019;26:383)
Extrapancreatic sites, such as duodenum or hilum of the spleen, are exceedingly rare (J Hepatobiliary Pancreat Sci 2019;26:383)

Pathophysiology

Unknown

Etiology

Mostly sporadic; familial cases are associated with MEN1 or MAFA germline mutations (Endocr J 2012;59:859, Proc Natl Acad Sci U S A 2018;115:1027)

Clinical features

Whipple triad: symptoms of hypoglycemia (stupor, confusion, loss of consciousness), glucose < 45 mg/dL, symptoms relieved by glucose or symptoms caused by fasting or exercise
10 - 15% associated with MEN1 syndrome; age < 20 years is suggestive of MEN1 (usually multiple tumors are seen) (Endocr J 2012;59:859, Best Pract Res Clin Gastroenterol 2005;19:783)

Diagnosis

Clinical diagnosis with demonstration of hyperinsulinemic hypoglycemia
72 hour fast is the gold standard for diagnosis (Endocrinol Metab Clin North Am 1999;28:519)
Imaging based modalities such as CT, ultrasound, MRI, PET or radiolabeled scintigraphy (Neuroendocrinology 2009;90:167, Best Pract Res Clin Endocrinol Metab 2005;19:311, J Clin Endocrinol Metab 2009;94:4398)
Arteriography was once the gold standard but has been obviated by other, less invasive, modalities and generally is restricted for difficult cases; transhepatic portal venous sampling and selective arterial calcium stimulation with venous sampling are additional more invasive methods (PLoS One 2019;14:e0224928)

Laboratory

Demonstration of hyperinsulinemic hypoglycemia
Blood glucose ≤ 45 mg/dL, insulin ≥ 43 pmol/L, C peptide ≥ 200 pmol/L, no sulfonylurea in plasma (Best Pract Res Clin Gastroenterol 2005;19:783)

Radiology description

CT shows higher attenuation within the lesion than surrounding uninvolved pancreas in venous contrast enhancement phase
On ultrasound, the lesion is characterized by low echogenicity and hypervascularity
MRI and radiolabeled glucagon-like peptide 1 receptor (GLP-1R) scintigraphy has been used to localize small insulinomas (J Clin Endocrinol Metab 2009;94:4398)
Reference: Neuroendocrinology 2009;90:167

Radiology images

Contributed by Irene Y. Chen, M.D.

CT abdomen

MRI abdomen

Prognostic factors

Stage and grade are important prognostic factors (Neoplasma 2015;62:484)
Increased risk for metastasis and reduced survival in the following:
- Tumor ≥ 2 cm (Neoplasma 2015;62:484, Endocr Pathol 2020;31:108)
- ARX immunohistochemical (IHC) protein expression (Endocr Pathol 2020;31:108)
- Loss of DAXX or ATRX by IHC stain and alternative lengthening of telomeres (ALT) (Gastroenterology 2014;146:453, Endocr Pathol 2020;31:108)
High Ki67 labeling index and high mitotic count are unfavorable prognostic factors (see well differentiated neuroendocrine tumor for additional details on grading)
Insulinomas generally have a more favorable prognosis compared with nonfunctional tumors, as well as other functioning tumors (Surg Pathol Clin 2016;9:595, Front Med 2016;10:444)
Proteomic study revealed low tumor protein D52 expression as a strong independent prognostic factor for both recurrence free and overall disease related survival (Mod Pathol 2015;28:69)

Case reports

20 year old slender, lean man complained of increased hunger, tremor and frequent seizures with worsening symptoms for 4 months (Cureus 2022;14:e23414)
32 year old woman with long history of prolactinoma and secondary amenorrhea presented with hypoglycemia (BMC Endocr Disord 2022;22:108)
50 year old man transiently lost consciousness while piloting a helicopter rescue (Med Lav 2022;113:e2022007)
83 year old woman with recurrent episodes of delirium occurring overnight, associated with hypoglycemia (Age Ageing 2022;51:afac055)
84 year old nondiabetic woman presented with recurrent falls and hypoglycemic episodes (Clin Med (Lond) 2022;22:90)

Treatment

Definitive surgical resection, enucleation is preferred if possible (J Laparoendosc Adv Surg Tech A 2022 Apr 19 [Epub ahead of print])
Symptomatic control with somatostatin analogs (octreotide) (Neoplasma 2015;62:484)

Gross description

Most commonly a solitary, well delineated lesion with tan-yellow homogenous cut surface, with or without hemorrhage (Surg Pathol Clin 2016;9:595)

Gross images

Contributed by Irene Y. Chen, M.D. and Dennis R. Dening, PA (ASCP)

Pancreatic head tumor

Pancreatic tail tumor

Microscopic (histologic) description

Trabecular, nested, gyriform or solid architecture
Monotonous cells demonstrating round nuclei with salt and pepper-like chromatin and abundant cytoplasm
Amyloid stromal deposition may be seen (nonspecific) (Arch Pathol Lab Med 1978;102:227, Endocr Pathol 2021;32:318)

Microscopic (histologic) images

Contributed by Diana Agostini-Vulaj, D.O.

Nested pattern

Synaptophysin

Insulin

Cytology description

See well differentiated neuroendocrine tumor and neuroendocrine neoplasms - general

Positive stains

Synaptophysin, chromogranin, ISL1, INSM1 (Am J Surg Pathol 2013;37:399)
Insulin (positivity is not required for diagnosis), proinsulin (50%), amylin, islet amyloid polypeptide (Am J Surg Pathol 2013;37:399)
PDX1 (beta cell marker) (Endocr Pathol 2020;31:108):
- Positive in indolent insulinoma; variable staining pattern in aggressive insulinoma
ARX (alpha cell marker) (Endocr Pathol 2020;31:108):
- Negative in indolent insulinoma; positive in aggressive insulinoma

Negative stains

Beta catenin (normal membranous expression)
PDX1 (beta cell marker) (Endocr Pathol 2020;31:108):
- Positive in indolent insulinoma; variable staining pattern in aggressive insulinoma
ARX (alpha cell marker) (Endocr Pathol 2020;31:108):
- Negative in indolent insulinoma; positive in aggressive insulinoma

Electron microscopy description

Round secretory granules with paracrystalline content (similar to granules seen in beta cells of normal pancreatic islets) (Nouv Presse Med 1977;6:3713)

Molecular / cytogenetics description

MEN1, DAXX, ATRX, PTEN and TSC2 mutations as those seen in PanNET, are rare in insulinoma (J Hepatobiliary Pancreat Sci 2019;26:383)
A subset (30%) showed recurrent p.T372R mutation in YY1 gene (Nat Commun 2013;4:2810, J Clin Endocrinol Metab 2015;100:E776)
A subset showed alternative lengthening of telomere phenotype, loss of DAXX / ATRX and loss of CDKN2A, which is associated with metastatic disease and closely related to PanNET (Endocr Pathol 2020;31:108)

Sample pathology report

Pancreas, distal pancreatectomy:
- Well differentiated neuroendocrine tumor, WHO grade __, functional, clinically consistent with insulinoma

Differential diagnosis

Noninsulin secreting pancreatic neuroendocrine tumor (see well differentiated neuroendocrine tumor and neuroendocrine neoplasms - general):
- Does not demonstrate clinical hyperinsulinemic hypoglycemia (i.e., are nonfunctional)
- Histologic features are essentially identical
Solid pseudopapillary neoplasm:
- Usually seen in young females
- No associated clinical syndrome of hyperinsulinemic hypoglycemia
- Pseudopapillae formation
- Positive nuclear beta catenin

Additional references

WHO Classification of Tumours Editorial Board: Digestive System Tumours, 5th Edition, 2019, WHO Classification of Tumours Editorial Board: Endocrine and Neuroendocrine Tumours, 5th Edition, 2022

Board review style question #1

Which syndrome is associated with multiple insulinomas?

MEN1
MEN2A
MEN2B
NF2
Peutz-Jeghers

Board review style answer #1

A. MEN1

Comment Here

Reference: Insulinoma

Board review style question #2

A midbody pancreatic enucleation is performed (see image above). Histologically, the neoplasm is positive for insulin, chromogranin and synaptophysin, with a Ki67 of < 2%. The patient has no clinical syndrome of hyperinsulinemic hypoglycemia. What is the most appropriate diagnosis?

Glucagonoma
Insulinoma
VIPoma
Well differentiated neuroendocrine tumor, G1
Well differentiated neuroendocrine tumor, G2

Board review style answer #2

D. Well differentiated neuroendocrine tumor, G1. In the absence of a clinical syndrome, the term insulinoma should not be used; the Ki67 of < 2% classifies this as a grade 1 neuroendocrine tumor.

Comment Here

Reference: Insulinoma

Intraductal oncocytic papillary neoplasm (IOPN)

Table of Contents

Definition / general

Intraductal pancreatic lesion with papillary architecture and characteristic oncocytic epithelium
First described in 1996 by Adsay et al (Am J Surg Pathol 1996;20:980)
2019 WHO recognizes as a distinct type of intraductal neoplasm
Accounts for 4.5% of intraductal neoplasms of the pancreas (Pancreas 2016;45:1233); also occurs in bile ducts (Surg Today 2012;42:1240)

Essential features

A rare and distinct type of intraductal neoplasm of pancreas
Distinctive cytologic features are oncocytic cells with large prominent nucleoli
Less mucin production than intraductal papillary mucinous neoplasms (IPMNs)
Lack genetic alterations commonly seen in IPMN
Indolent behavior even if associated with invasive carcinoma

Terminology

Intraductal oncocytic papillary neoplasm
Older term is oncocytic type of intraductal papillary mucinous neoplasm (WHO 2010)

ICD coding

8455/2 - Intraductal oncocytic papillary neoplasm NOS
8455/3 - Intraductal oncocytic papillary neoplasm with associated invasive carcinoma

Epidemiology

Mean age 59 years
F > M (Am J Surg Pathol 2019;43:656)
Accounts for 4.5% of intraductal neoplasms of the pancreas (Pancreas 2016;45:1233)

Sites

70% occur in the head, 10% involve whole gland (Am J Surg Pathol 1996;20:980)
Also occurs in bile ducts (Surg Today 2012;42:1240)

Etiology

No known etiological factors

Clinical features

Some are incidentally discovered (Pancreas 2016;45:1233)
Others present with abdominal pain and jaundice (Am J Surg Pathol 1996;20:980, J Am Coll Surg 2015;220:839)

Radiology description

Complex mass with both solid and cystic components that may lead to misdiagnosis of pancreatic ductal adenocarcinoma (Cancer Cytopathol 2016;124:122)

Prognostic factors

Exhibits indolent behavior even if associated with invasive carcinoma (Am J Surg Pathol 2019;43:656, J Am Coll Surg 2015;220:839)

Case reports

45 year old woman with intermittent nausea and vomiting (Can J Gastroenterol 2013;27:387)
53 year old woman with vague abdominal pain (JOP 2013;14:77)
69 year old woman presented with chest pain (J Pancreat Cancer 2017;3:5)

Treatment

Treated primarily by surgical resection

Gross description

Cystic with friable papillary or exophytic nodular projections often within the main pancreatic duct
Median size 4.5 cm (Am J Surg Pathol 2019;43:656)

Gross images

Contributed by @liverwei on Twitter

Contributed by @liverwei on Twitter (see original post here)">

Intraductal oncocytic papillary neoplasm

Microscopic (histologic) description

Multilocular or unilocular cysts containing complex and arborizing papillae with delicate ﬁbrovascular cores (Virchows Arch 2016;469:523)
Papillae are lined by multiple layers of neoplastic cells with voluminous granular oncocytic cytoplasm and prominent, large, eccentric nucleoli (Cancer Cytopathol 2016;124:122)
Cribriform structure and intraluminal mucin formation are not uncommon
Papillae may fuse and form solid growth pattern
Invasive carcinoma is seen in about 30% of cases (Am J Surg Pathol 2019;43:656)
True invasion seen in different patterns: small infiltrative tubules, mucinous and solid nests of oncocytic cells (Am J Surg Pathol 2019;43:656)
Tangential sectioning may mimic true invasion (Am J Surg Pathol 2019;43:656)
Abrupt transition from a normal epithelium to oncocytic epithelium, within the same duct, favors pseudoinvasion

Microscopic (histologic) images

Contributed by Gokce Askan, M.D. and Olca Basturk, M.D.

Unilocular or multilocular cystic lesion

Papillae lined by oncocytic epithelium

Intracytoplasmic vacuoles

MUC6

Pseudoinvasion

Tubular invasion pattern

Mucinous invasion pattern

Contributed by @liverwei on Twitter

Contributed by @liverwei on Twitter (see original post here)">

Intraductal oncocytic papillary neoplasm

Cytology description

Oncocytic cells with abundant granular cytoplasm, well defined cell borders, large central nuclei, prominent eccentric nucleoli and focal intercellular punched out spaces (Mod Pathol 2016;29:1058, Cancer Cytopathol 2016;124:122)

Cytology images

Images hosted on other servers:

Oncocytic cell sheets with prominent nucleoli

Punched out spaces, intracytoplasmic mucin

Positive stains

MUC1 and MUC6 (diffuse) (Virchows Arch 2016;469:523, Am J Surg Pathol 2010;34:364)
MUC2 and MUC5AC (restricted to goblet cells) (Virchows Arch 2016;469:523)
HepPar1, CDX2 (Virchows Arch 2016;469:523)

Negative stains

Trypsin, chymotrypsin and neuroendocrine markers (Virchows Arch 2016;469:523, Am J Surg Pathol 2010;34:364, Am J Surg Pathol 2001;25:942, J Pathol 2002;197:632)

Electron microscopy description

Cells frequently packed with mitochondria (Am J Surg Pathol 1996;20:980)

Molecular / cytogenetics description

IOPNs lack KRAS, GNAS and RNF43 mutations (Mod Pathol 2016;29:1058)
ARHGAP26, ASXL1, EPHA8 and ERBB4 are recurrently mutated in some IOPNs (Mod Pathol 2016;29:1058)
Recently it has been shown that a subset of IOPNs harbors DNAJB1-PRKACA fusions proving DNAJB1-PRKACA fusion is no longer specific for fibrolamellar hepatocellular carcinoma (Mod Pathol 2020;33:648, Gastroenterology 2020;158:573)

Sample pathology report

Pancreas and duodenum, pancreaticoduodenectomy:
- Intraductal oncocytic papillary neoplasm of pancreass (IOPN) (see comment)
- Comment: The pancreas was submitted entirely for microscopic evaluation and no associated invasive carcinoma is identified. The neoplasm involves the main pancreatic duct. The neoplasm measures 3.5 cm in greatest dimension. Adjacent pancreas reveals atrophy. Surgical margins are free of neoplasm. Twelve benign lymph nodes are identified (0/12).

Differential diagnosis

Intraductal papillary mucinous neoplasms (IPMNs), pancreatobiliary type
- More delicate papillae that are lined with highly atypical cuboidal cells
- No intraepithelial lumina
- Positive for MUC1
- KRAS mutations are common
Acinar cell carcinoma
- No intracellular mucin or cytoplasmic vacuoles
- Mitotically very active
- Positive for trypsin and chymotrypsin
Neuroendocrine neoplasms
- Salt and pepper chromatin pattern
- Positive for synaptophysin, chromogranin and CD56

Additional references

WHO Classification of Tumours Editorial Board: Digestive System Tumours (Medicine), 5th Edition, 2019

Board review style answer #1

Cribriform structure is one of the most common histologic features
They commonly occur in the tail of the pancreas
They exhibit indolent behavior even if associated with invasive carcinoma
They have mucin production as much as seen in intraductal papillary mucinous neoplasms (IPMNs)
They have same genetic alterations that commonly seen in intraductal papillary mucinous neoplasms (IPMNs)

Board review style answer #1

C. They exhibit indolent behavior even if associated with invasive carcinoma

Comment Here

Reference: Intraductal oncocytic papillary neoplasm (IOPN)

Board review style question #2

Chromogranin
Chymotrypsin
MUC6
Synaptophysin
Trypsin

Board review style answer #2

C. MUC6

Comment Here

Reference: Intraductal oncocytic papillary neoplasm (IOPN)

Intraductal papillary mucinous neoplasm (IPMN)

Table of Contents

Definition / general

Grossly visible noninvasive mucinous epithelial neoplasm arising from main pancreatic duct or branch ducts, usually > 5 mm, composed of various cell types with various cytologic and architectural atypia (Virchows Arch 2005;447:794, Pancreatology 2017;17:738)
- Further classified as:
  - Low grade (encompasses low or intermediate grade dysplasia) (Am J Surg Pathol 2015;39:1730)
  - High grade (Am J Surg Pathol 2015;39:1730)
  - With an associated invasive carcinoma (Am J Surg Pathol 2015;39:1730)
1 of 3 precursor lesions of pancreatic adenocarcinoma (see also mucinous cystic neoplasm)

Essential features

Grossly visible (> 5 mm) cystic pancreatic neoplasm, usually in head of pancreas
> 90% 5 year survival with complete resection
Roughly 33% of cases have an associated invasive carcinoma
Further subtyped into gastric, intestinal and pancreaticobiliary types based on epithelium (note: intraductal oncocytic papillary neoplasm (IOPN) is now considered a distinct and separate entity)

Terminology

Low grade to intermediate grade dysplasia previously termed: intraductal papillary mucinous adenoma
High grade dysplasia previously termed: intraductal papillary mucinous carcinoma, noninvasive
With an associated invasive carcinoma previously termed: intraductal papillary mucinous carcinoma, invasive
Other previous terms include: mucin producing tumor, mucinous duct ectasia, ductectatic mucinous cystadenoma / cystadenocarcinoma, villous adenoma or papillary adenoma / carcinoma

ICD coding

ICD-10: D13.6 - benign neoplasm of pancreas

Epidemiology

Rising incidence likely secondary to better characterization of this entity along with use of radiologic imaging studies (Clin Gastroenterol Hepatol 2010;8:213)
More common in men, usually ages 60 - 70 years (Hum Pathol 2012;43:1)

Sites

Main duct intraductal papillary mucinous neoplasm (IPMN) mostly involves head of pancreas, 33% in body and tail (Hum Pathol 2012;43:1)
Branch duct IPMN mostly involves head of pancreas or uncinate process, with multiple distinct lesions seen in ~33% of cases (Hum Pathol 2012;43:1)

Pathophysiology

See Molecular / cytogenetics description

Etiology

No well established factors; cigarette smoking implicated in one series (Adv Anat Pathol 1999;6:65)
Reported in Peutz-Jeghers syndrome and familial adenomatous polyposis (Gut 2002;51:446, Am J Pathol 1999;154:1835)

Diagrams / tables

Images hosted on other servers:

Indications for surgery

Clinical features

Clinically divided into main duct IPMN, branch duct IPMN and mixed IPMN (most mixed type IPMN present and behave as main duct IPMN) (Hum Pathol 2012;43:1)
Main duct IPMN tends to be symptomatic, with symptoms related to duct obstruction (pancreatitis) (Hum Pathol 2012;43:1)
- Signs and symptoms include epigastric pain, weight loss, jaundice, diabetes, pancreatitis (Arch Pathol Lab Med 1996;120:981)
Branch duct IPMN tends to be asymptomatic and is generally discovered incidentally on imaging (Hum Pathol 2012;43:1)
Peutz-Jeghers syndrome (autosomal dominant inherited syndrome, mutations in STK11 / LKB1I) is also associated with IPMN (Hum Pathol 2012;43:1)

Diagnosis

Radiographic / endoscopic findings
Fine needle aspiration
Surgical specimen

Laboratory

Pancreatic cyst fluid analysis can assist in determining type of cyst (Am J Gastroenterol 2008;103:2871, Gastrointest Endosc 2009;69:1095, Gastrointest Endosc 2016;83:140)
- Elevated CEA and identification of KRAS / GNAS mutations supports diagnosis of mucinous cyst

Radiology description

CT:
- Main duct IPMN causes distention of main pancreatic duct
- Branch duct IPMN produces multilocular grape-like cystic appearance
ERCP (endoscopic retrograde cholangiopancreatography): pancreatic ductal filling defects may be seen / ductal dilation
MRCP (magnetic resonance cholangiopancreatography): additional imaging option which does not produce radiation
EUS (endoscopic ultrasound): can also allow FNA and cyst fluid analysis
References: Diagn Interv Imaging 2016;97:1275, World J Gastroenterol 2016;22:9562

Radiology images

Images hosted on other servers:

MRCP demonstrating various types of IPMN

MRCP demonstrating side branch IPMNs

Differing radiologic
modalities demonstrating
various types of
IPMN and MCN

Prognostic factors

Without an invasive carcinoma, has > 90% 5 year survival; those associated with an invasive carcinoma carry a worse prognosis (about half die of the disease) (Ann Surg 2016;263:162)
Main duct IPMN: 60% have high grade dysplasia and 45% are associated with an invasive carcinoma (Hum Pathol 2012;43:1)
Branch duct IPMN: most are low grade, 25% have high grade dysplasia and 20% are associated with an invasive carcinoma (Hum Pathol 2012;43:1)
Invasive carcinoma associated with IPMN includes:
- Tubular (ductal) adenocarcinoma: seen in about half of cases, with slightly better prognosis than non IPMN associated pancreatic ductal adenocarcinoma
- Colloid carcinoma: seen in half of cases, with much better prognosis than pancreatic ductal adenocarcinoma (Ann Surg 2016;263:162)

Case reports

52 year old man with recurrent upper abdominal pain (Int J Clin Exp Med 2015;8:3332)
53 year old man with multiple pancreatic cystic lesions (World J Gastroenterol 2013;19:3358)
55 year old woman with abdominal pain and anemia; pancreatic masses are found on CT (World J Surg Oncol 2018;16:83)
68 year old man with cystic pancreatic mass with mural nodule (Int J Surg Case Rep 2017;40:69)
74 year old man with cystic pancreatic lesion on ultrasound (Intern Med 2018;57:1093)

Treatment

Main duct IPMN: surgical resection indicated if main pancreatic duct > 10 mm, jaundice or presence of mural nodules (Pancreatology 2017;17:738)
- Branch duct IPMN: surgical resection indicated if symptomatic, presence of mural nodule ≥ 5 mm, suspicious / positive cytology, obstructive jaundice or main pancreatic duct ≥ 10 mm (Pancreatology 2017;17:738)
- See Diagrams / tables

Clinical images

Images hosted on other servers:

Mucin extrusion from duodenal papilla

Gross description

Main duct involvement:
- Usually diffusely dilated, tortuous and irregular, filled with mucin
- Typically arises in head and progresses along path of main duct, may involve entire pancreas; may involve major or minor papillae leading to mucin extrusion from ampulla
- Uninvolved pancreas is often pale and firm, reflecting extensive chronic obstructive pancreatitis
Branch duct involvement:
- Often in uncinate process
- Forms multicystic, grape-like structures; cystically dilated ducts, filled with tenacious mucin; cyst walls are usually thin with flat or papillary lining
- Cysts separated by normal pancreas, suggesting that cysts are separate on cut sections
Multicentricity seen in up to 40% of cases (Am J Gastroenterol 2007;102:1759)
Extensive sampling / complete submission of cyst for microscopic evaluation important to rule out an associated invasive carcinoma (Am J Surg Pathol 2014;38:480, Ann Surg 2016;263:162)
Greater than 5 mm in diameter
- Incipient IPMN is a term that can be used for lesions 0.5 - 1.0 cm in size

Gross images

Contributed by Dennis R. Dening, PA (ASCP)

Main duct IPMN

Frozen section description

Typically pancreatic resection margin status will be evaluated to exclude IPMN; additional margins will be submitted if invasive carcinoma is present or possibly for the presence of high grade dysplasia (Am J Surg Pathol 2015;39:1730, Pancreatology 2017;17:738)
If low grade dysplasia is seen, typically no additional resection done; this may represent pancreatic intraepithelial neoplasia (PanIN) versus IPMN (Am J Surg Pathol 2015;39:1730, Pancreatology 2017;17:738)

Frozen section images

Images hosted on other servers:

Normal pancreatic duct

Pancreatic duct with low grade dysplasia

Microscopic (histologic) description

Mucin producing epithelial cells with varied degrees of dysplasia (Am J Surg Pathol 2015;39:1730)
- Low grade dysplasia is characterized by a flat epithelial lining with basal located nuclei without significant pleomorphism, while intermediate dysplasia has features between those of low and high grade dysplasia (note: low and intermediate dysplasia are now both grouped as low grade dysplasia) (Am J Surg Pathol 2015;39:1730)
- High grade dysplasia is characterized by complex architectural features (i.e. irregular branching, cribiforming) with loss of nuclear polarity along with increased nuclear hyperchromasia and nuclear irregularities (Am J Surg Pathol 2015;39:1730)
Epithelial cells show variable differentiation and can be subclassified into: intestinal, gastric and pancreaticobiliary subtypes (oncocytic lining suggests intraductal oncocytic papillary neoplasm)
Associated with pancreatic intraepithelial neoplasia (PanIN), chronic pancreatitis (Am J Surg Pathol 2004;28:1184)
No ovarian type stroma
Assess presence or absence of invasive carcinoma (most important prognostic factor) (Hum Pathol 2012;43:1)
Type of invasion is associated with MUC1 / MUC2 pattern; see below (Mod Pathol 2002;15:1087)
Gastric type IPMN:
- Cells resemble gastric foveolae
- Intestinal metaplasia may be seen, usually with low grade dysplasia and branch duct IPMN
- If associated invasive carcinoma present, typically ductal (tubular) adenocarcinoma (Ann Surg 2016;263:162, Virchows Arch 2005;447:794)
Intestinal type IPMN:
- Cells with tall columnar epithelium (resembling intestinal villous adenomas)
- Usually low or high grade dysplasia and main duct IPMN
- If associated invasive carcinoma present, typically mucinous (colloid) carcinoma
Pancreaticobiliary type IPMN:
- Complex, thin branching papillae resembling cholangiopapillary neoplasms
- Cuboidal cells with prominent nucleoli
- Usually high grade dysplasia and main duct IPMN
- If associated invasive carcinoma present, typically ductal (tubular) adenocarcinoma

Microscopic (histologic) images

Contributed by Diana Agostini-Vulaj, D.O.

IPMN intestinal subtype with low grade dysplasia

IPMN gastric subtype with low grade dysplasia

IPMN with high grade dysplasia

MUC1

MUC2

Virtual slides

Images hosted on other servers:

IPMN, low grade, intestinal type

Cytology description

Cannot distinguish IPMN from mucinous cystic neoplasm on cytology (neoplastic mucinous cyst)
Disordered mucinous epithelial clusters with nuclear overlap and variable cytologic atypia
Distinguishing a low grade mucinous neoplasm from gastrointestinal tract contaminant (particularly gastric mucosa) can be challenging

Cytology images

Images hosted on other servers:

Low grade epithelial atypia

High grade epithelial atypia with necrotic debris

Positive stains

General ductal markers are positive, including CK7, CK19, CA 19-9, B72.3 and CEA
Subtypes show various mucin glycoprotein (MUC) expression (as below):
- Gastric type IPMN: MUC5AC+, MUC6 variable (Am J Surg Pathol 2006;30:1561, Mod Pathol 2016;29:977)
- Intestinal type IPMN: MUC2+, CDX2+, MUC5AC+; similar staining pattern for associated invasive colloid carcinoma (Mod Pathol 2016;29:977)
- Pancreaticobiliary type IPMN: MUC1+, MUC6+, MUC5AC+; similar staining pattern for associated invasive ductal adenocarcinoma (Am J Surg Pathol 2006;30:1561, Mod Pathol 2016;29:977)

Negative stains

Gastric type IPMN: MUC1-, MUC2- (Am J Surg Pathol 2006;30:1561, Mod Pathol 2016;29:977)
Intestinal type IPMN: MUC1-; similar staining pattern for associated invasive colloid carcinoma (Mod Pathol 2016;29:977)
Pancreaticobiliary type IPMN: MUC2-; similar staining pattern for associated invasive ductal adenocarcinoma (Am J Surg Pathol 2010;34:364, Mod Pathol 2016;29:977)

Molecular / cytogenetics description

KRAS, GNAS and RNF43 mutations seen in decreasing frequency in noninvasive IPMNs and IPMNs with an associated invasive carcinoma (J Am Coll Surg 2015;220:845)
GNAS mutations more commonly associated with IPMNs, which harbor an invasive colloid carcinoma
KRAS mutations more commonly associated with IPMNs, which harbor an invasive tubular (ductal) adenocarcinoma
With increasing grades of dysplasia, increased mutations in KRAS, TP53, CDKN2A (p16); also hypermethylation and reduced BRG1 protein (Hum Pathol 2012;43:585)
Loss of programmed cell death 4 (PDCD4) and CD24 expression associated with tumor progression and proliferation (Hum Pathol 2010;41:1507, Hum Pathol 2010;41:1466)
Cyst fluid shows mutations in KRAS2 and GNAS

Sample pathology report

Pancreas, small bowel and stomach, pancreaticoduodenectomy (Whipple resection):
- Intraductal papillary mucinous neoplasm (IPMN), low grade, gastric phenotype, branch duct type, 3.0 cm (see comment)
- Negative for high grade dysplasia or malignancy.
- Margins are negative for IPMN.
- 23 lymph nodes with no significant histologic abnormality.
- Comment: The entire cyst is submitted for histologic examination.

Differential diagnosis

Intraductal oncocytic papillary neoplasm:
- Lined by oncocytic cells with complex growth patterns and arborizing papillae
- Distinct molecular pathway with ARHGAP26, ASXL1, EPHA8 and ERBB4 genetic alterations (Mod Pathol 2016;29:1058)
- DNAJB1-PRKACA fusions (Mod Pathol 2020;33:648)
- MUC1+, MUC6+
Intraductal tubulopapillary neoplasm:
- Recently recognized subtype with potential origin from peribiliary cysts (Am J Surg Pathol 2009;33:1164)
- Confluent epithelial cells with tubular and papillary architectural patterns and usually high grade dysplasia
- Necrotic foci, more solid growth without visible mucin or scanty cytoplasmic mucin, no KRAS2 gene mutations
- MUC1+, MUC2-, MUC6+
Mucinous cystic neoplasm:
- Epithelial mucinous lining with ovarian type stroma
- No communication to pancreatic ductal system
Pancreatic intraepithelial neoplasia (PanIN):
- Only detectable microscopically
- No mass lesion, unlike IPMN
- Almost always has gastric foveolar differentiation
Simple mucinous cyst:
- Cyst > 1 cm with flat (not papillary) gastric mucinous lining and no significant atypia (Am J Surg Pathol 2015;39:1730, Am J Surg Pathol 2017;41:121)
Retention cyst:
- Cyst > 1 cm with flat (not papillary) ductal lining and no significant atypia in a background of obstruction (Am J Surg Pathol 2015;39:1730)

Additional references

Bosman: WHO Classification of Tumours of the Digestive System, 4th Edition, 2010, WHO Classification of Tumours Editorial Board: Digestive System Tumours, 5th Edition, 2019

Board review style question #1

Which morphologic type of intraductal papillary mucinous neoplasm is depicted in the above photo, seen arising from a branch of the main pancreatic duct?

Gastric
Intestinal
Invasive
Oncocytic
Pancreaticobiliary

Board review style answer #1

A. Gastric. The histologic features are typical of the gastric type of IPMN, no features of intestinal or pancreatobiliary differentiation are seen (choices B and E); choice D is not a morphologic type of IPMN; rather, intraductal oncocytic papillary neoplams are a distinct separate entity.

Comment Here

Reference: Intraductal papillary mucinous neoplasm (IPMN)

Board review style question #2

Which of the following clinical scenarios would most likely represent an intraductal papillary mucinous neoplasm (IPMN)?

29 year old woman with 8 cm solid and cystic pancreatic tail mass
45 year old woman with 3 cm cystic pancreatic tail mass
58 year old man with 3 cm solid pancreatic head mass
66 year old man with 2 cm cystic pancreatic head mass

Board review style answer #2

D. 66 year old man with 2 cm cystic pancreatic head mass. IPMNs are more often seen in older men and are cystic; thus choices A - C are incorrect (choice A would be more typical of a solid pseudopapillary neoplasm; choice B would more typical of a mucinous cystic neoplasm; choice C would be more typical of pancreatic ductal adenocarcinoma or a pancreatic neuroendocrine tumor).

Comment Here

Reference: Intraductal papillary mucinous neoplasm (IPMN)

Intraductal tubulopapillary neoplasm (ITPN)

Table of Contents

Definition / general

Intraductal, grossly solid and cystic, tubule forming, epithelial neoplasm with high grade dysplasia and no overt mucin production (Am J Surg Pathol 2017;41:313)
First described in 2004 by Tajiri et al. under the name of intraductal tubular carcinoma (Pancreas 2005;30:115)
Renamed in 2009 by Jamaguchi et al. as intraductal tubulopapillary neoplasm (Am J Surg Pathol 2009;33:1164)
Previous (2010) and current (2019) WHO classify as a distinct intraductal neoplasm of the pancreas
Accounts for 3% of intraductal neoplasms of the pancreas (Am J Surg Pathol 2011;35:1812)

Essential features

A rare and distinct type of pancreatic intraductal neoplasm
Highly cellular, complex tubular or cribriform growth pattern
Focal papillary growth may be seen
Intracellular mucin is typically not detectable or is very minimal
Positive for MUC1 and MUC6; negative for MUC5AC
Lacks genetic alterations commonly seen in intraductal papillary mucinous neoplasms (IPMNs)
Favorable overall outcome even if associated with invasive carcinoma (Am J Surg Pathol 2017;41:313)

Terminology

Older term is intraductal tubular carcinoma (not recommended)

ICD coding

ICD-O:
- 8503/2 - intraductal tubulopapillary neoplasm
- 8503/3 - intraductal tubulopapillary neoplasm with associated invasive carcinoma

Epidemiology

Mean age: 55 years (Am J Surg Pathol 2017;41:313)
F:M = 17:14 (Am J Surg Pathol 2017;41:313)
Accounts for 3% of intraductal neoplasms of the pancreas (Am J Surg Pathol 2011;35:1812)

Sites

50% occur in head, 15% occur in tail and 30% involve entire gland of the pancreas (Am J Surg Pathol 2017;41:313, Int J Clin Exp Pathol 2015;8:9672)
Also occurs in bile ducts (Mod Pathol 2015;28:1249)

Etiology

No known etiological factors

Clinical features

Nonspecific symptoms: abdominal pain, weight loss, nausea, vomiting, steatorrhea
Jaundice is not common

Radiology description

2 tone duct sign on CT image and cork of wine bottle sign on MRCP examination as characteristic imaging findings that represent their intraductal growth (J Comput Assist Tomogr 2012;36:710, Medicine (Baltimore) 2019;98:e14426)
Intraductal solid tumor within dilated main pancreatic duct mimicking IPMN (Diagn Interv Radiol 2019;25:251)
Irregular main pancreatic duct dilatation may lead to misdiagnosis of chronic pancreatitis (Diagn Interv Radiol 2019;25:251)

Prognostic factors

Exhibits relatively indolent behavior even if associated with invasive carcinoma (Am J Surg Pathol 2017;41:313)

Case reports

23 year old woman with incidental asymptomatic retroperitoneal cystic lesion (Int J Clin Exp Pathol 2019;12:1041)
43 year old woman with epigastric pain (Diagn Pathol 2014;9:11)
62 year old man with epigastric pain, nausea and vomiting (J Clin Diagn Res 2017;11:PD14)
72 year old man with recurrent pancreatitis (Int J Surg Case Rep 2018;48:122)
73 year old man with nausea and persistent abdominal pain (World J Surg Oncol 2017;15:203)

Treatment

Treated primarily by surgical resection

Gross description

Multinodular, polypoid, solid or fleshy mass within dilated main pancreatic duct (Am J Surg Pathol 2017;41:313)
Cyst formation is less common
Median size: 4.5 cm (Am J Surg Pathol 2017;41:313)
Multifocality may be seen (Int J Clin Exp Pathol 2015;8:9672)

Gross images

Images hosted on other servers:

Polypoid mass within dilated main pancreatic duct

Microscopic (histologic) description

Circumscribed nodules of back to back tubular glands surrounded by fibrotic stroma; however, the intraductal location of at least some of the nodules is evidenced by continuity of the neoplastic epithelium with nonneoplastic ductal epithelium
Tubules are lined by cuboidal or columnar epithelium with a modest amount of eosinophilic or amphophilic cytoplasm
Nuclei are small, round to oval and moderately to markedly atypical with readily identifiable mitotic figures
Intracellular mucin production is typically not detectable or is very minimal
Intraluminal secretions and necrosis, often with comedo-like pattern, are present
Clear cell changes, cartilaginous or osseous metaplasia may be seen (Diagn Pathol 2014;9:11, Pathol Int 2012;62:339, Am J Surg Pathol 2017;41:313, Pathol Int 2015;65:501)
Associated invasive carcinoma is seen in about 70% of cases as individual cells or small angulated nonmucinous glands surrounded by usually desmoplastic stroma (Am J Surg Pathol 2017;41:313)

Microscopic (histologic) images

Contributed by Gokce Askan, M.D. and Olca Basturk, M.D.

Nodules of back to back tubular glands

Intraductal growth pattern

Sharply circumscribed nest formation

Tightly packed tubules lined by atypical cuboidal epithelium

Comedo-like necrosis

Clear cell changes

Osseous metaplasia

Invasion

MUC1 expression

MUC6 expression

Cytology description

Large cribriform and tubular clusters with luminal spaces and scanty intracytoplasmic mucin (Diagn Cytopathol 2014;42:314, Arch Pathol Lab Med 2017;141:366)

Positive stains

CK7 and CK19 (Pancreas 2004;29:116, Am J Surg Pathol 2017;41:313, Pancreas 2005;30:115, Am J Surg Pathol 2009;33:1164)
MUC1 and MUC6 (Pancreas 2004;29:116, Am J Surg Pathol 2017;41:313, Pancreas 2005;30:115, Am J Surg Pathol 2009;33:1164)
HepPar1 (rare and focal) (Am J Surg Pathol 2017;41:313)

Negative stains

MUC2 and MUC5AC (Pancreas 2004;29:116, Am J Surg Pathol 2017;41:313, Pancreas 2005;30:115, Am J Surg Pathol 2009;33:1164)
Acinar markers (trypsin, chymotrypsin) (Am J Surg Pathol 2017;41:313)
Neuroendocrine markers (a few scattered cells may be positive for chromogranin or synaptophysin) (Am J Surg Pathol 2017;41:313)

Molecular / cytogenetics description

In general, ITPNs lack KRAS, GNAS and BRAF mutation (Mod Pathol 2017;30:1760, Am J Surg Pathol 2009;33:1164, Am J Surg Pathol 2011;35:1812, J Pathol 2013;231:335)
PIK3CA, PIK3CB, INPP4A, PTEN may be mutated in ITPNs (Mod Pathol 2017;30:1760, Am J Surg Pathol 2009;33:1164, Am J Surg Pathol 2011;35:1812, J Pathol 2013;231:335)
Recently, it has been shown that certain chromatin remodeling genes (MLL1, MLL2, MLL3, BAP1, etc.) may be mutated in ITPNs and a subset of the cases harbors FGFR2 and STRN-ALK fusions (Mod Pathol 2017;30:1760)

Sample pathology report

Pancreas and duodenum, pancreaticoduodenectomy:
- Intraductal tubulopapillary neoplasm of pancreas (ITPN) (see comment)
- Comment: The pancreas was submitted entirely for microscopic evaluation and no associated invasive carcinoma is identified. The neoplasm involves the main pancreatic duct and measures 4 cm in greatest dimension. Adjacent pancreas reveals atrophy. Surgical margins are free of neoplasm. 15 benign lymph nodes are identified (0/15).
Pancreas and duodenum, pancreaticoduodenectomy:
- Intraductal tubulopapillary neoplasm of pancreas (ITPN) associated with an invasive ductal carcinoma (see comment)
- Comment: ITPN involves the main pancreatic duct. The entire tumor measures 5 cm in greatest dimension; the invasive carcinoma component measures 0.7 cm in greatest dimension (suggestion for if multifocal invasion is present: the invasive carcinoma accounts for 25% of entire tumor and is estimated to measure 1.25 cm in greatest dimension). Adjacent pancreas reveals atrophy. Surgical margins are free of ITPN and invasive carcinoma. 14 benign lymph nodes are identified (0/14).
Reference: Ann Surg 2016;263:162

Differential diagnosis

Intraductal papillary mucinous neoplasm, pancreatobiliary type:
- More delicate papillae that are lined with highly atypical cuboidal cells
- Positive for MUC5AC
- KRAS mutations are common
Acinar cell carcinoma intraductal variant:
- Eosinophilic zymogen granule containing cytoplasm and single prominent central nucleolus
- Mitotically very active
- Positive for trypsin, chymotrypsin and BCL10
Neuroendocrine neoplasm, with intraductal growth pattern:
- Salt and pepper chromatin pattern
- Positive for chromogranin and synaptophysin

Additional references

WHO Classification of Tumours Editorial Board: Digestive System Tumours (Medicine), 5th Edition, 2019

Board review style question #1

Which of the following is true about intraductal tubulopapillary neoplasm of the pancreas?

Jaundice is one of the most common symptoms
Papilla and mucin formation are common histologic features
They are positive for MUC5AC
They commonly have KRAS, GNAS and BRAF mutations
They have relatively indolent prognosis even when associated with invasive carcinoma

Board review style answer #1

E. They have relatively indolent prognosis even when associated with invasive carcinoma

Comment Here

Reference: Intraductal tubulopapillary neoplasm (ITPN)

Board review style question #2

Which one of the following stains is negative in intraductal tubulopapillary neoplasm of the pancreas?

CK7
CK19
MUC5AC
MUC1
MUC6

Board review style answer #2

C. MUC5AC

Comment Here

Reference: Intraductal tubulopapillary neoplasm (ITPN)

Lymphoepithelial cysts

Table of Contents

Definition / general

Rare, nonneoplastic, true cysts lined by squamous epithelium surrounded by abundant, reactive lymphoid tissue
Histologically similar to branchial cleft cysts arising in the neck
First described in 1985 (Pathologe 1985;6:217)
No association with salivary gland lymphoepithelial cysts

Essential features

Consists of a squamous, epithelial lined cyst with surrounding reactive lymphoid tissue

ICD coding

ICD-10: K86.2 - cyst of pancreas

Epidemiology

Mean age: 56 years
Range: 20 - 82 years
80% male
0.5% of resected pancreatic cysts (Diagnostics (Basel) 2022;13:65)

Sites

Occurs anywhere in pancreas (head, body or tail) or extrapancreatic location

Pathophysiology

May occasionally develop from epithelial remnants in lymph nodes or from accessory spleen in pancreas (Hum Pathol 1991;22:924, Mod Pathol 1998;11:1171)

Etiology

Several proposed hypotheses (Case Rep Gastrointest Med 2016;2016:5492824)
- May originate from epithelial remnants within a lymph node
- Arise via cystic transformation and squamous metaplasia of pancreatic ducts
- May derive from a misplaced branchial cleft cyst that fused with the pancreas during embryogenesis

Clinical features

Most common symptom is abdominal pain (~48%), particularly with larger cysts
Significant portion are asymptomatic (~43%)
Can occasionally present with fatigue or weight loss, mimicking malignancy (Case Rep Gastroenterol 2016;10:181)
Not associated with immunosuppression or autoimmune diseases

Diagnosis

Can be difficult to differentiate preoperatively from other pancreatic cystic lesions
Cyst fluid chemistry may show elevated CA 19-9 or elevated carcinoembryonic antigen (CEA)
Cytology / histology examination for final confirmation of diagnosis
Reference: Arch Pathol Lab Med 2020;144:47

Laboratory

Cyst fluid may have elevated CA 19-9 levels (50% of cases) and elevated CEA levels (up to 32% of cases) (diagnostic pitfall) (Case Rep Gastrointest Med 2016;2016:5492824)

Radiology description

Imaging varies and is similar to other pancreatic cystic lesions but more likely to be extrapancreatic or exophytic
CT: multilocular or unilocular cyst with possible solid component and slight hyperintensity of keratinized material (Case Rep Gastrointest Med 2016;2016:5492824)
MRI: multilocular or unilocular cyst with possible solid component, hyperintensity on T1 weighted images, hypointensity on T2 weighted images and water restriction in diffusion weighted images (Jpn J Radiol 2021;39:118)

Radiology images

Images hosted on other servers:

Large cystic mass

Mimicking serous / mucinous cystadenoma

Prognostic factors

Benign; does not recur or progress

Case reports

41 year old woman who presented with abdominal discomfort, bloating and dyspepsia (Acta Chir Belg 2022 Mar 17 [Epub ahead of print])
43 year old man with a lymphoepithelial cyst occurring in a pancreatic accessory spleen (Clin Case Rep 2021;9:e04241)
49 year old man with diarrhea and weight loss (Int J Surg Case Rep 2019;55:192)
62 year old man with abdominal pain and a pancreatic mass (Case Rep Med 2020;2020:4590758)
65 year old man with prior pancreatoduodenectomy for carcinoma arising from the ampulla of Vater and a new pancreatic mass in the remnant pancreatic tail (Surg Case Rep 2021;7:108)

Treatment

Asymptomatic patients with a confirmed diagnosis by FNA may be followed by serial imaging
Symptomatic patients with a confirmed diagnosis by FNA may be treated with enucleation or drainage (Indian J Surg 2010;72:427)
Resection is curative

Clinical images

Images hosted on other servers:

Intraoperative view

Gross description

Mean size: 5 cm (range: 1 - 17 cm) (Mod Pathol 2002;15:492)
Often round and well demarcated from surrounding pancreas
Either multilocular (60%) or unilocular (40%)
Cysts contain clear serous fluid or caseous / cheese-like material (Diagnostics (Basel) 2022;13:65)

Gross images

Contributed by Jen Rytych, M.D.

Sections of lymphoepithelial cyst

Images hosted on other servers:

Well demarcated cysts

Pancreas tail

Microscopic (histologic) description

Unilocular or multilocular cyst lined by squamous epithelium (nucleated or anucleated), with cyst wall containing lymphocyte rich cuff with germinal centers
Combinations of squamous lining with other epithelial types (i.e., simple columnar) have been reported
Lymphoid tissue, often a dense band
With or without keratinous debris
Occasional solid lymphoepithelial islands, rarely mucinous goblet cells
Rare sebaceous differentiation, keratin granulomas, cholesterol clefts, multinucleated giant cells and foamy histiocytes may be present
Reference: Diagnostics (Basel) 2022;13:65

Microscopic (histologic) images

Contributed by Jen Rytych, M.D. and Katrina Krogh, M.D.

Squamous lined cyst

Cyst with lymphoid cuff

Abundant keratin debris

Simple columnar and stratified squamous linings

Squamous lined lymphoid tissue

Cytology description

Predominantly mature squamous cells, anucleated squamous cells and keratin debris
Lymphocytes, macrophages and cholesterol crystals are occasionally seen (Arch Pathol Lab Med 2020;144:47)
May have mildly atypical mucinous glandular and parakeratotic epithelium

Cytology images

Contributed by Jen Rytych, M.D.

Degenerated squamous epithelial cells

Images hosted on other servers:

Squamous epithelium,
keratinaceous debris
and lymphocytes

Keratinaceous debris

Positive stains

Squamous epithelial lining is positive for CK7, p63, MUC1 and MUC4 (100%)
Squamous epithelial lining also frequently positive for CEA (89%), CA 19-9 (89%), PASD (78%) and MUC5AC (67%) (Mod Pathol 2010;23:1467)
Lymphoid tissue is composed of CD3+ T cells and CD20+ B cells (J Clin Pathol 1997;50:794)

Negative stains

Squamous epithelial lining is negative for MUC2 and MUC6 (100%) (Mod Pathol 2010;23:1467)

Molecular / cytogenetics description

No recurrent molecular / cytogenetic abnormalities identified

Sample pathology report

Pancreas, cyst, excision:
- Lymphoepithelial cyst

Differential diagnosis

Dermoid cyst (cystic teratoma):
- Requires the presence of microscopic elements such as dermal appendages, cartilage, respiratory mucosa or neural tissue
- Younger mean age
Epidermoid cyst in intrapancreatic spleen:
- Lined by squamous epithelium and surrounded by splenic tissue (Acta Pathol Jpn 1991;41:916)
Squamoid cysts:
- Smaller (median size: 1.5 cm)
- Lined exclusively by nonkeratinizing squamous epithelium without lymphoid tissue (Am J Surg Pathol 2007;31:291)
Lymphangioma:
- Lined by a single flat or cuboidal epithelium that will be positive for endothelial and lymphatic markers (such as CD31 and D2-40)
- Typically contains small aggregates of lymphoid tissue rather than a dense band (Arch Pathol Lab Med 2020;144:47)
Pseudocyst:
- No epithelial lining or lymphoid stroma
- Presence of granulation tissue and fibrosis
Of note, while the imaging or clinical differential diagnosis may include mucinous cystic neoplasm, intraductal papillary mucinous neoplasm (IPMN) and intraductal oncocytic papillary neoplasm (IOPN), these neoplasms are not similar appearing on histologic examination and are not on the histologic differential diagnosis

Board review style question #1

Which of the following statements about the pancreatic lesion shown above is true?

Carcinoembryonic antigen (CEA) is never elevated in cyst fluid
This lesion does not undergo malignant transformation
This lesion is more common than mucinous cystic neoplasm
This lesion is more commonly found in women

Board review style answer #1

B. This lesion does not undergo malignant transformation. Lymphoepithelial cysts are benign and there have been no reported incidences of malignant transformation. Answer C is incorrect because lymphoepithelial cysts of the pancreas are rare (0.5% of resected pancreatic cysts) and are much less common than pancreatic mucinous cystic neoplasms (~8% of resected pancreatic cysts). Answer D is incorrect because lymphoepithelial cysts are more common in men than women (80% men). Answer A is incorrect because CEA levels (as well as CA 19-9) are commonly elevated in lymphoepithelial cysts. This is a diagnostic pitfall that increases the clinical concern for malignancy.

Comment Here

Reference: Lymphoepithelial cysts

Board review style question #2

Which of the following statements about the pancreatic lesion shown above is true?

Foamy histiocytes and multinucleated giant cells can be present
This lesion is associated with immunosuppression or autoimmune dysfunction
This lesion is associated with ovarian type stroma
This lesion is the most common cystic lesion of the pancreas

Board review style answer #2

A. Foamy histiocytes and multinucleated giant cells can be present. Lymphoepithelial cysts are composed of squamous epithelium and reactive lymphoid tissue but may rarely show sebaceous differentiation, keratin granulomas, cholesterol clefts, multinucleated giant cells and foamy histiocytes. Answer D is incorrect because lymphoepithelial cysts of the pancreas are rare (0.5% of resected pancreatic cysts). The most common cystic lesion of the pancreas is intraductal papillary mucinous neoplasm (IPMN). Answer B is incorrect because while the etiology of lymphoepithelial cysts is not fully understood, it may originate from epithelial remnants within a lymph node, arise through cystic transformation of pancreatic ducts or be derived from a misplaced branchial cleft cyst that fused with the pancreas during embryogenesis. No association with immunosuppression or autoimmune dysfunction has been identified. Answer C is incorrect because lymphoepithelial cysts are composed of a squamous epithelial lined cyst with surrounding reactive lymphoid tissue. Mucinous cystic neoplasms (MCN) contain ovarian stroma.

Comment Here

Reference: Lymphoepithelial cysts

Medullary carcinoma

Table of Contents

Definition / general

Rare histologic variant of pancreatic ductal adenocarcinoma (PDAC) characterized by poor differentiation, pushing borders and a syncytial growth pattern

Essential features

Main histologic features are poor differentiation with limited gland formation, syncytial growth pattern and pushing borders
Prominent tumor infiltrating lymphocytes (TILs) are common
Associated with microsatellite instability (MSI) and wild type KRAS status
Represents < ~4% of PDAC cases
26 reported cases in the literature
References: Am J Pathol 1998;152:1501, Front Oncol 2023;12:1082927

Terminology

Pancreatic medullary carcinoma
Medullary pancreatic carcinoma

ICD coding

ICD-10: C25.9 - malignant neoplasm of pancreas
ICD-11: 2C10.0 - adenocarcinoma of pancreas

Epidemiology

Cancer screening in the patient's immediate family following diagnosis of medullary pancreatic carcinoma has been suggested (Am J Pathol 2000;156:1641)
Accumulated risk of pancreatic cancer in Lynch syndrome patients is 3.7% and tumors often have characteristic medullary morphology (J Cancer 2017;8:3667)
No known associations with race, gender, age, alcohol use or tobacco use

Pathophysiology

Possible association with PanIN as the precursor lesion (Am J Pathol 2000;156:1641)

Etiology

Hereditary syndromes: Lynch syndrome

Clinical features

Epigastric pain, back pain, jaundice, weight loss, diabetes mellitus

Diagnosis

Abdominal CT scan or MRI
Endoscopic ultrasound guided fine needle aspiration (EUS FNA)
Histologic evaluation of surgical resection specimen

Laboratory

Serum elevation of CA19-9 or CEA

Radiology description

PDAC typically appears as a hypoattenuating mass compared to normal pancreatic parenchyma (Insights Imaging 2020;11:58)

Prognostic factors

Poor prognosis (overall survival: 29% at 2 years, 13% at 5 years) (Am J Pathol 2000;156:1641)
15 out of 20 reported cases died of disease (Surg Case Rep 2018;4:80)
Tumor with certain genetic mutations may show improved survival (Surg Case Rep 2018;4:80, Pancreas 2020;49:999)
Limited data is available to draw meaningful conclusion about prognosis

Case reports

Woman in her 60s with head of the pancreas mass with POLE mutation (Pancreas 2020;49:999)
64 year old man with medullary pancreatic cancer and the first patient derived cell line (Front Oncol 2023;12:1082927)
73 year old woman with pancreatic mass with loss of MSH2 and MSH6 expression (Diagn Pathol 2021;16:117)
73 year old man with asymptomatic pancreatic duct cyst (Surg Case Rep 2018;4:80)

Treatment

Neoadjuvant chemotherapy (World J Gastroenterol 2022;28:3297)
Whipple resection or distal pancreatectomy depending on tumor location in the pancreas (World J Gastroenterol 2022;28:3297)
Due to the presence of MSI, may be responsive to treatment with immunotherapy (Front Oncol 2023;12:1082927)
Due to its rarity, data regarding drug response and treatment outcome is limited (Front Oncol 2023;12:1082927)

Gross description

There are no definitive diagnostic criteria to grossly distinguish medullary carcinoma from conventional PDAC; it may show circumscribed borders as compared to infiltrative borders of conventional PDAC (Pathologica 2020;112:210)

Microscopic (histologic) description

Well circumscribed tumor with pushing / expansile borders
Syncytial growth pattern with poorly defined cell borders
Solid pattern of growth (sheets and nests) with limited gland formation
Tumor cells with pleomorphic nuclei, prominent nucleoli and abundant amphophilic cytoplasm
Large areas of necrosis may be present
Abundant lymphocytes within and around tumor
Focal clear cells and squamoid differentiation have also been reported (Am J Pathol 2000;156:1641)

Microscopic (histologic) images

Contributed by Rong Xia, M.D., Ph.D. and Beena Ahsan, M.D.

Circumscribed borders

Sheet-like growth pattern

Syncytial growth pattern

Positive p63 immunostain

Positive stains

Similar to nonmedullary PDAC: CK AE1 / AE3, CK7, CK8, CK18, CK19, MUC1 (Pathologica 2020;112:210)
Loss of mismatch repair (MMR) proteins (~22%): MLH1, PMS2, MSH2, MSH6

Negative stains

Similar to nonmedullary PDAC: CK20, MUC2, trypsin, chymotrypsin, lipase
Neuroendocrine markers: chromogranin A, synaptophysin, CD56
Acinar cell marker: BCL10
Reference: Pathologica 2020;112:210

Molecular / cytogenetics description

Association with MSI (22%) and wild type KRAS (67%)
Most commonly associated with loss of MLH1 (Am J Pathol 2000;156:1641)
Possible genetic associations with KRAS mutation and somatic POLE mutation (Surg Case Rep 2018;4:80, Pancreas 2020;49:999)

Sample pathology report

Pancreas, Whipple resection:
- Poorly differentiated carcinoma, consistent with medullary carcinoma (x cm in maximum dimension)
- Resection margins are negative for carcinoma (mention the positive margin, if any)
- Negative / positive for perineural and lymphovascular invasion
- All lymph nodes are negative for carcinoma

Differential diagnosis

Poorly differentiated PDAC:
- Infiltrative growth pattern, well to poorly formed glands and desmoplastic stroma, KRAS mutated, microsatellite stable
EBV associated lymphoepithelioma-like carcinoma:
- EBV encoded RNA (EBER) in situ hybridization positive

Board review style question #1

Which of the following is characteristic of medullary carcinoma in the pancreas?

EBV encoded RNA (EBER) in situ hybridization positive
Infiltrative growth pattern with well to poorly formed glands
KRAS mutations
MSS (microsatellite stable)
Pushing borders with syncytial growth pattern, limited to no gland formation and tumor infiltrating lymphocytes

Board review style answer #1

E. Pushing borders with syncytial growth pattern, limited to no gland formation and tumor infiltrating lymphocytes. Expansile invasion (pushing borders), poorly defined cell borders (syncytial growth) and little to no glandular formation (poor differentiation) are the 3 main characteristics of medullary carcinoma in the pancreas. Abundant tumor infiltrating lymphocytes are also present. Answer D is incorrect because medullary carcinoma of the pancreas is associated with microsatellite instability (MSI), which may aid in the diagnosis. Answer C is incorrect because unlike conventional PDAC, medullary carcinoma of the pancreas is associated with wild type KRAS status. Answer A is incorrect because EBV encoded RNA (EBER) in situ hybridization positivity describes EBV associated lymphoepithelioma-like carcinoma. Answer B is incorrect because medullary carcinoma of the pancreas lacks well formed glands and is defined by syncytial growth pattern. 

Comment Here

Reference: Medullary carcinoma

MEN1 syndrome

Table of Contents

Definition / general

Syndrome characterized by mutations in MEN1 gene and development of multiple endocrine tumors (and other tumor types)
Formerly known as Wermer syndrome
Autosomal dominant inheritance

Essential features

Defined by MEN1 mutation (chromosome 11q13, menin, tumor suppressor gene, 100% penetrance)
Classic constellation of pituitary, parathyroid and pancreatic tumors (the 3 P's)
Variety of nonendocrine tumors are also part of MEN1 (meningioma, ependymoma, angiofibroma)

Epidemiology

Prevalence of MEN1 is 1:30,000 to 1:500,000 (geographic variability due to familial clustering) (F1000Res 2017;6:73)
MEN1 cases are 90% familial and 10% sporadic (F1000Res 2017;6:73)
100% penetrance (100% with parathyroid adenomas by age 50) (F1000Res 2017;6:73)
Most frequent cause of MEN1 related death is complications secondary to pancreatic / gastrointestinal neuroendocrine tumors (J Pediatr Genet 2016;5:89)

Sites

Variety of neuroendocrine and nonneuroendocrine tumors (J Pediatr Genet 2016;5:89, Cancer Genet 2016;209:36, Endocr Relat Cancer 2017;24:T119)

Endocrine tumors found in:

Parathyroid (90% of patients)
Anterior pituitary (30 - 40% of patients)
Pancreas / gastrointestinal tract (30 - 70% of patients)
Adrenal cortex
Thymus

Nonendocrine tumors found in:

Facial skin (angiofibromas, collagenomas)
Testis (epididymomas)
Meninges (meningiomas)

MEN1

Endocr Relat Cancer 2017;24:T119

Glucagonoma 60%
VIPoma 57%
Nonfunctioning PanNETs 44%
Gastrinoma 38%
Bronchial carcinoid 35%
Parathyroid adenoma 35%
Lipoma 28%
Insulinoma 2 - 19%
Angiofibroma 10%
Anterior pituitary tumor 3.5%
Adrenocortical tumor 2%

Pathophysiology

MEN1 gene first identified in 1997, found on chromosome 11q13 (Science 1997;276:404)
Menin, the protein product of MEN1, is a tumor suppressor gene
Twelve mutations were initially identified and more than 1,800 mutations have been identified to date
Most of these are private (family specific)
Seventy five percent are inactivating (F1000Res 2017;6:73)
5 - 20% may not harbor mutations in the MEN1 gene coding region (F1000Res 2017;6:73, Cancer Genet 2016;209:36)
There is no genotype phenotype correlation with the type of MEN1 mutation and the type of tumors which develop (F1000Res 2017;6:73)
Menin does not show homology with any other known protein but is conserved across species from Drosophila to humans (F1000Res 2017;6:73, Cancer Genet 2016;209:36)
Normal functions of menin: cell proliferation, apoptosis and genome integrity (F1000Res 2017;6:73)
Mechanism by which a nonfunctional menin protein causes tumor development remains unknown

Diagrams / tables

Images hosted on other servers:

Location of tumors in patients with MEN1

Clinical features

Endocrine tumors found in parathyroid, anterior pituitary, pancreas / gastrointestinal tract, adrenal cortex and thymus
Non endocrine tumors: angiofibromas, collagenomas, epididymomas, meningiomas
Increased frequency of renal stones compared with the general population
Penetrance is 100%, with all patients developing parathyroid adenomas by age 50
Patients with gastrinomas, typically found in the duodenum, may have Zollinger-Ellison syndrome
Primary gastrinomas may be microadenomas but the lymph node metastases can be much larger than the primary (J Pediatr Genet 2016;5:89)
Patients with parathyroid adenomas have hypersecretion of parathyroid hormone (PTH) with resultant symptoms of hypercalcemia (GI pain, renal stones, clouded mental functioning)
Cushing disease, Nelson syndrome, acromegaly or hyperprolactinemia in cases of functional pituitary adenomas
Pituitary adenomas can also cause a number of visual field defects due to compression of the optic chiasm or extraocular muscle compression
Syndromes of other functioning pancreatic and gastrointestinal neuroendocrine neoplasms can be found on Neuroendocrine Neoplasms - General

Diagnosis

Identification of a MEN1 mutation by PCR amplification of exons and splicing sites
- Notably, this fails to identify the subset of MEN1 patients that do not have the mutation within the coding region (World J Exp Med 2015;5:124)
- Next generation sequencing would bypass these limitations
Mutational analysis should be offered to:
- Asymptomatic first degree relatives of a known MEN1 patient
- Patients with at least two typical MEN1 tumors or one MEN1 tumor and a positive family history
- Patients with early onset (MEN1 manifestation (hyperparathyroidism, Zollinger-Ellison syndrome) (Endocr Relat Cancer 2017;24:T209)

Laboratory

Relevant to the type of tumor present and only functional tumors

Radiology description

Osteoporosis, terminal tuft erosion (distal phalanges) and nephrolithiasis in patients with parathyroid adenomas and hypercalcemia
Calvarial thickening, frontal bossing, enlarged sinuses (especially frontal sinuses), enlarged sella turcica, prognathic mandible and increased vertebral fractures in patients with acromegaly due to pituitary adenoma

Prognostic factors

As described for pancreatic and gastrointestinal tumors in the WHO classification

Case reports

18 year old woman with hyperprolactinemia and hypercalcemia since age 13 (Clinical Chemistry 2015;61:1328)
36 year old man with pancreatic neuroendocrine tumor, pituitary adenoma and acromegaly (W V Med J 2012;108:26)
51 year old man with urolithiasis and 2 jejunal perforations 9 months apart (Korean J Gastroenterol 2013;61:333)

Treatment

Surgical resection of neuroendocrine tumors
Minimally invasive trans sphenoidal approach for pituitary adenomas
Increased screening and surveillance in known kindreds: insulinoma starting age 5, pituitary adenoma starting age 5, parathyroid adenoma starting age 8, gastrinoma starting age 20, adrenal gland starting before age 10, thymic tumors starting before age 15 (World J Exp Med 2015;5:124)

Gross images

AFIP images

Intramucosal tumor nodules

Zollinger-Ellison syndrome

Microscopic (histologic) images

AFIP images

Pancreatic microadenomas in patients with MEN1

Duodenal gastrinoma in the mucosa and submucosa

Hypertrophic and eroded mucosa

Molecular / cytogenetics description

MEN1 mutation (chromosome 11q13)

Board review style question #1

MEN1

A patient with facial angiofibromas, trichodiscomas and achrochordons
A patient with MEN1 mutation and no tumor development at time of evaluation
A patient with parathyroid adenoma and nephrolithiasis
A patient with parathyroid adenoma, meningioma and epididymoma
A patient with parathyroid adenoma, pituitary adenoma and pancreatic neuroendocrine tumor

Board review style answer #1

A. The patient NOT representative of a patient with MEN1 syndrome is the patient with angiofibromas, trichodiscomas and achrochordons. Angiofibromas are a part of MEN1 syndrome but trichodiscomas and achrochordons are not (they are part of Birt-Hogg-Dubé syndrome).

Comment Here

Reference: MEN1 syndrome

Mixed neuroendocrine nonneuroendocrine neoplasms (MiNENs)

Table of Contents

Definition / general

Pancreatic mixed neuroendocrine nonneuroendocrine neoplasms (MiNENs) are rare and heterogeneous malignancies characterized by histologically recognizable neuroendocrine (i.e., carcinoma and rarely, a well differentiated neuroendocrine tumor) and exocrine (usually ductal carcinoma, acinar carcinoma or both) components, each composing ≥ 30% of the neoplasm volume (Endocr Pathol 2016;27:284)

Essential features

Histologically recognizable neuroendocrine and nonneuroendocrine components each comprise ≥ 30% of the neoplasm
Neuroendocrine component is mostly a poorly differentiated neuroendocrine carcinoma (NEC); rarely a well differentiated neuroendocrine tumor (NET)
Exocrine component can either be pancreatic ductal adenocarcinoma (PDAC) or acinar cell carcinoma (ACC); very rarely, both acinar and ductal carcinoma
Neuroendocrine and nonneuroendocrine components are confirmed with immunohistochemistry (IHC)
Poor prognosis

Terminology

Subtypes: mixed ductal neuroendocrine carcinoma, mixed acinar neuroendocrine carcinoma, mixed acinar neuroendocrine ductal carcinoma
Not recommended: composite carcinoid, mucin producing carcinoid, argentaffin cell adenocarcinoma, goblet cell carcinoid, adenocarcinoid, small cell undifferentiated carcinoma (Cancers (Basel) 2012;4:11)

ICD coding

ICD-O: 8154/3 - mixed pancreatic endocrine and exocrine tumor, malignant
ICD-10:
- C25.9 - malignant neoplasm of pancreas, unspecified
- C7A.8 - other malignant neuroendocrine tumors
- C25 - malignant neoplasm of pancreas
ICD-11: 2C10.0 & XH8E54 - mixed neuroendocrine nonneuroendocrine neoplasm (MiNEN)

Epidemiology

M = F
Average age at presentation is 68 years (ranges from 21 - 84 years) (Am J Surg Pathol 1994;18:765)
Mixed ductal neuroendocrine carcinomas comprise 0.5 - 2% of all ductal adenocarcinomas (Virchows Arch 2003;442:258)
Mixed acinar neuroendocrine carcinomas comprise 15 - 20% of all acinar carcinomas (Am J Surg Pathol 2012;36:1782)

Sites

Anywhere in the pancreas
Mixed ductal neuroendocrine carcinomas are more common in the head of the pancreas

Pathophysiology

Unclear
May arise as the combination of 2 neoplastic clones or as the proliferation of 1 precursor cell with divergent differentiation; however, molecular and genetic studies point towards a monoclonal origin of both components (Endocr Pathol 2016;27:284, J Clin Med 2020;9:273)
Behavior is thought to be driven by the neuroendocrine component (J Clin Med 2020;9:273)

Etiology

Unknown

Clinical features

Presentation is nonspecific and depends on the tumor size and degree of metastatic disease

Diagnosis

Histomorphology and IHC on surgical resection specimens
Biopsy may be used but is vulnerable to limited sampling and inadequate quantification of tumor components (Int J Surg Pathol 2017;25:585)

Laboratory

Similar to pancreatic adenocarcinomas
Increase in biliary and pancreatic enzymes may occur with obstruction of the common bile duct or main pancreatic duct (BMJ Case Rep 2020;13:e234855, Int J Surg Pathol 2017;25:585)

Radiology description

Radiologic features of MiNENs can resemble either pancreatic adenocarcinoma or pancreatic neuroendocrine neoplasms on abdominal CT scan with contrast (Pancreatology 2021;21:224)
Imaging findings similar to pancreatic adenocarcinomas (including hypodense hypoenhancing mass with ill defined border) are commonly seen with mixed ductal neuroendocrine carcinomas
Imaging findings similar to pancreatic neuroendocrine neoplasms (including heterogeneously enhancing mass with or without cystic component and well defined margins) are commonly seen with mixed acinar neuroendocrine carcinomas

Radiology images

Images hosted on other servers:

MiNEN in the head of the pancreas on CT

MiNEN in pancreas head with portal vein narrowing on CT

Prognostic factors

Tumor size and resectability are the most important prognostic factors
Mixed ductal neuroendocrine carcinoma: 5 year survival rates are similar to PDAC and NEC
Mixed acinar neuroendocrine carcinoma: similar to 5 year survival rate (36 - 72%) of pure acinar cell carcinoma (Am J Surg Pathol 2012;36:1782)
- Recent study demonstrated that acinar MiNEN patients have a worse prognosis than ACC and NEC (Pancreatology 2021;21:224)
A poorly differentiated neuroendocrine carcinoma component comprising > 50% of the tumor is associated with distant metastasis and poor prognosis (J Chin Med Assoc 2015;78:454)

Case reports

33 year old man with uncinate mass and a 66 year old man with pancreatic tail mass (Diagn Cytopathol 2018;46:971)
49 year old Indian man presented with constant, dull, aching epigastric pain (Int J Surg Case Rep 2021;88:106524)
61 year old man was admitted to the hospital with incidental pancreatitis (Asian J Surg 2022;45:520)
63 year old man presented with hyperglycemia (Surg Case Rep 2016;2:133)
70 year old man who was asymptomatic underwent a FNA after an incidental pancreatic mass was found on ultrasound (Clin J Gastroenterol 2022;15:244)
81 year old man presented with painful progressive jaundice for 1 month (BMJ Case Rep 2020;13:e234855)

Treatment

No clear treatment guidelines due to rarity of tumors
Some recommend treatment based on the neuroendocrine component since it seems to be the most aggressive (Neuroendocrinology 2016;103:186, J Clin Med 2020;9:273)
- Radical surgical resection with or without adjuvant chemotherapy for localized cases
- Chemotherapy (platinum based) for extensively metastatic cases

Gross description

Mixed ductal neuroendocrine carcinomas are solid tumors with infiltrative margins similar to ductal adenocarcinomas
Mixed acinar neuroendocrine carcinomas are usually nodular, fleshy, hemorrhagic and necrotic, similar to neuroendocrine carcinoma and acinar cell carcinoma (Am J Surg Pathol 1994;18:765)

Gross images

Images hosted on other servers:

Mixed ductal neuroendocrine carcinoma

Microscopic (histologic) description

Neuroendocrine and nonneuroendocrine components are intimately intermixed and sometimes can only be differentiated with IHC (Int J Surg Pathol 2017;25:585)
Both components must comprise ≥ 30% of the neoplasm (Endocr Pathol 2016;27:284)
Neuroendocrine component can either be poorly differentiated neuroendocrine carcinoma or well differentiated neuroendocrine tumor (Surg Pathol Clin 2020;13:377)
- Poorly differentiated neuroendocrine carcinoma (90% of MiNENs) (J Clin Med 2020;9:273):
  - Poorly formed trabeculae and nests or diffuse sheets of cells
  - Can be large cell types (moderate to abundant eosinophilic cytoplasm, fine to vesicular chromatin and prominent nucleoli) or small cell types (high nuclear to cytoplasmic ratio, hyperchromatic nuclei with fine chromatin, inconspicuous nucleoli)
  - Multiple foci of necrosis or geographic necrosis and numerous apoptotic bodies
  - Mitoses are frequent
  - Perineural and vascular invasion is common
- Well differentiated neuroendocrine tumor:
  - Nested, lobular or trabecular architecture composed of monomorphic, regularly arranged cells
  - Nuclei with stippled (salt and pepper) chromatin
  - Inconspicuous nucleoli
Ductal adenocarcinoma component:
- Identical to conventional pancreatic ductal adenocarcinoma
- Grade ranges from well differentiated to poorly differentiated adenocarcinoma
- Infiltrating, well to poorly formed glandular, cribriform, solid or trabecular structures surrounded by desmoplastic stroma
- Mucin production
- Perineural and vascular invasion are common
Acinar cell carcinoma component:
- Identical to acinar cell carcinoma
- Highly cellular
- Cystic, acinar or glandular architecture
- Abundant eosinophilic granular cytoplasm
- Monomorphic nuclei with a single prominent nucleolus
- Perineural and vascular invasion are common

Microscopic (histologic) images

Contributed by Jennifer Ziebell, M.D. and Ashwini Esnakula, M.D., M.S.

Mixed ductal neuroendocrine carcinoma

Neuroendocrine carcinoma component

Ductal adenocarcinoma component

Chromogranin A

Ki67 neuroendocrine carcinoma component

Cytology description

Diagnosis of MiNENs on FNA is exceedingly challenging due to cytomorphologic variability, sampling bias and the often minimal quantity of tissue available for cell block and (IHC (Diagn Cytopathol 2013;41:164, Acta Cytol 2013;57:296, Diagn Cytopathol 2018;46:971)
Mixed cytologic features of neuroendocrine and exocrine component (adenocarcinoma or acinar) should raise suspicion of MiNEN
IHC is helpful to demonstrate the endocrine and exocrine components

Positive stains

IHC expression is similar to the respective component of MiNENs (Endocr Pathol 2016;27:284)
Neuroendocrine component (Pathology 2020;52:336):
- Positive stains:
  - Synaptophysin (diffusely and strongly positive)
  - Chromogranin A (may be reduced in poorly differentiated neuroendocrine components)
  - INSM1 (Am J Clin Pathol 2015;144:579)
  - Cytokeratins CAM5.2, AE1 / AE3, CK8/18
  - Ki67: proliferation index is typically high in poorly differentiated NEC (> 50%); required for grading of well differentiated NET component, grade 1 ( 20%)
- Panel to differentiate poorly differentiated neuroendocrine carcinoma from well differentiated neuroendocrine tumor components (Arch Pathol Lab Med 2019;143:1317)
  - Poorly differentiated NEC: abnormal expression of p53, loss of Rb1
  - Well differentiated NET: loss of DAXX or ATRX in a subset of cases
Ductal adenocarcinoma component:
- Common expression of CEA, CAM5.2, AE1 / AE3, CK7, CK8/18, CK19, EMA (MUC1), MUC3, MUC4, MUC5AC, CA 19-9, CA125
- Maspin, placental S100 (S100P), IMP3 (Arch Pathol Lab Med 2012;136:601, Hum Pathol 2013;44:503)
Acinar cell carcinoma component (Pathology 2020;52:336):
- Chymotrypsin
- Trypsin
- BCL10

Negative stains

Neuroendocrine component:
- Trypsin (Am J Surg Pathol 2002;26:893)
- Chymotrypsin, BCL10 (Arch Pathol Lab Med 2019;143:1317)
Ductal adenocarcinoma component:
- CK20, synaptophysin, chromogranin, trypsin, chymotrypsin, lipase
- pVHL (Hum Pathol 2013;44:503)
- Loss of SMAD4 / DPC4 (Am J Clin Pathol 2001;116:831)
Acinar cell carcinoma component:
- Chromogranin and synaptophysin (synaptophysin can be focally positive)

Electron microscopy description

Electron microscopy diagnostic findings (Am J Surg Pathol 1994;18:765, Pathol Int 2021;71:485):
- Secretory zymogen granules in acinar cell component; usually > 500 nm in size
- Neuroendocrine granules in neuroendocrine component; usually 100 - 200 nm in size
- Mucinous granules in ductal adenocarcinoma component

Molecular / cytogenetics description

Not well understood but may show molecular alterations similar to conventional neuroendocrine neoplasms, ductal adenocarcinomas and acinar carcinomas, as highlighted below (Endocr Pathol 2016;27:284)
- Neuroendocrine carcinoma component:
  - TP53 and RB1 (Am J Surg Pathol 2012;36:173)
- Ductal adenocarcinoma component:
  - KRAS, CDKN2A (P16), TP53 and SMAD4 (DPC4) (J Clin Med 2020;9:273, Cancer Cell 2017;32:185, Hum Pathol 2009;40:612)
- Acinar carcinoma component:
  - APC / beta catenin alterations, BRAF fusions (Virchows Arch 2014;464:553, Cancer Discov 2014;4:1398, J Clin Med 2020;9:273)
No known association with genetic syndromes

Videos

MiNEN basics

Sample pathology report

Pancreas tail and spleen, distal pancreatectomy:
- Mixed neuroendocrine and nonneuroendocrine neoplasm (MiNEN) of pancreas composed of ductal adenocarcinoma and neuroendocrine carcinoma, 3.5 cm (see comment and synoptic report)
  - Tumor infiltrates the peripancreatic soft tissue
  - Prominent lymphovascular and perineural invasion is identified
  - Pancreatic parenchymal resection margin is negative for tumor
  - Metastatic neuroendocrine carcinoma is identified in 8 of 21 lymph nodes
  - Pathology stage: pT3 / N2
- Spleen with no significant diagnostic alterations
- Comment: The sections of the pancreatic tail mass show a biphasic appearance with histologically distinct ductal and neuroendocrine carcinoma components. The neuroendocrine component comprises approximately 60% of the tumor and is characterized by infiltrating sheets and nests of high grade tumor cells with moderate eosinophilic cytoplasm, vesicular chromatin and viably prominent nucleoli. Frequent mitoses are noted (up to 25/HPF). Areas of tumor necrosis are identified. A well differentiated ductal adenocarcinoma component, characterized by infiltrating well formed tubules, is seen intricately associated with the neuroendocrine carcinoma component. Neuroendocrine carcinoma shows diffuse and strong expression for neuroendocrine markers chromogranin and synaptophysin. The ductal carcinoma component is negative for neuroendocrine markers. Neuroendocrine carcinoma shows a Ki67 proliferative index of approximately 90%. Overall, the findings are consistent with mixed ductal neuroendocrine carcinoma of the pancreas.

Differential diagnosis

Amphicrine carcinoma (Pathol Int 2021;71:485):
- May represent a variant of MiNEN but does not fit under the current definition of MiNEN
- Rare tumor where each neoplastic cell displays exocrine and endocrine differentiation confirmed with IHC
Mixed intraductal papillary mucinous neoplasm (IPMN) neuroendocrine tumor (Virchows Arch 2021;478:1215):
- Rare tumor characterized by low or high grade IPMN associated with a well differentiated neuroendocrine tumor in the papillae
- Recent evidence suggests common clonal origin with shared molecular abnormalities in both components
- May represent a variant of MiNEN
Ductal adenocarcinoma with neuroendocrine component:
- Neuroendocrine component
- Pancreatic neuroendocrine tumor with entrapped ductules (Am J Surg Pathol 2004;28:813):
  - Entrapment of preexisting nonneoplastic ductules by neuroendocrine tumor
- Acinar cell carcinoma with a neuroendocrine component:
  - Neuroendocrine cells comprises May be focally positive for synaptophysin but should be negative for chromogranin; in contrast, in acinar MiNEN, immunohistochemistry for acinar and neuroendocrine cell markers demonstrates distinct compartments in the tumor tissue
- Collision tumors:
  - Neuroendocrine and nonneuroendocrine components are distinct from each other and not intimately intermixed
- Pancreatoblastoma:
  - Commonly a childhood malignant pancreatic neoplasm with predominantly acinar differentiation and squamoid nests
  - Can have neuroendocrine component
  - Squamoid nests are critical for diagnosis

Additional references

WHO Classification of Tumours Editorial Board: Digestive System Tumours, 5th Edition, 2019

Board review style question #1

A 55 year old man presented with a 4 cm large pancreatic head mass. The sections from the resected tumor showed a mixed neoplasm with varied histologic findings, as highlighted in the image above. What is the most common component of such neoplasms?

Acinar carcinoma
Ductal adenocarcinoma
Poorly differentiated neuroendocrine carcinoma
Squamous cell carcinoma
Well differentiated neuroendocrine tumor

Board review style answer #1

C. Poorly differentiated neuroendocrine carcinoma. The tumor is likely pancreatic mixed neuroendocrine nonneuroendocrine neoplasms (MiNENs) with ductal adenocarcinoma and poorly differentiated neuroendocrine carcinoma components. Poorly differentiated neuroendocrine carcinoma is the most common component seen in around 90% of MiNENs.

Comment Here

Reference: Mixed neuroendocrine nonneuroendocrine neoplasms pancreas (MiNENs)

Board review style question #2

In a mixed neuroendocrine nonneuroendocrine neoplasm (MiNEN), what is the lowest percentage of the neoplasm the neuroendocrine component can comprise in order to classify as a MiNEN?

Board review style answer #2

B. 30%

Comment Here

Reference: Mixed neuroendocrine nonneuroendocrine neoplasms pancreas (MiNENs)

Molecular genetics of pancreatic ductal carcinoma

Table of Contents

Definition / general

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, representing > 90% of all pancreatic malignancies
From a genetic point of view, PDAC is a complex disease with several genes altered through different mechanisms, which include point mutations, chromosomal aberrations and epigenetic changes

Essential features

Somatic mutations affect, above all, four genes: KRAS, which is an oncogene and TP53, CDKN2A and SMAD4, which are tumor suppressor genes (Lancet 2016;388:73)
A subset of pancreatic cancer arises in the background of genetic syndromes with germline mutations affecting different genes, such as CDKN2A, TP53, STK11, BRCA1 / 2, ATM and MMR (J Clin Oncol 2017;35:3382)
Transcriptomic profile divides pancreatic cancer into different groups; among them, the most important distinction involves the identification of the so called squamous subtype, which has the worst prognosis (Nature 2016;531:47)
Only a few molecular alterations have a predictive value in pancreatic cancer
BRCA mutated tumors show a good response to platinum based therapy and to poly ADP ribose polymerase (PARP) inhibitors; tumors with microsatellite instability can be treated with immunotherapy (N Engl J Med 2019;381:317, J Clin Oncol 2020;38:1)

Somatic mutations

Four genes are the most commonly mutated in PDAC: KRAS, which is an oncogene and TP53, CDKN2A and SMAD4, which are tumor suppressor genes (Lancet 2016;388:73)
- KRAS
  - Most frequently mutated gene in PDAC (90 - 92% of cases)
  - Oncogene
  - Located on chromosome 12
  - Downstream pathways: MAPK and PI3K
- TP53
  - Mutated in 50 - 60% of PDAC
  - Tumor suppressor gene
  - Located on chromosome 17
  - Encodes for P53, a crucial protein that controls cell growth, metabolism, senescence, DNA repair and apoptosis
- CDKN2A
  - Mutated in > 60% of PDAC
  - Tumor suppressor gene
  - Located on chromosome 9
  - Encodes for P16, a protein encoded that acts as a mediator of the retinoblastoma signaling pathway
- SMAD4
  - Mutated in 30 - 55% of PDAC
  - Tumor suppressor gene
  - Located on chromosome 18
  - Protein encoded by SMAD4 is an effector of the transforming growth factor (TGF) β signaling pathway
In addition to these four main genetic drivers, other important genes can be altered by somatic mutations in PDAC with a lower but significant prevalence (Lancet 2016;388:73, Gastroenterology 2019;156:2242):
- ARID1A (AT rich interaction domain 1A, 5 - 10% of cases), a tumor suppressor located on chromosome 3 involved in chromatin remodeling
- BRCA1 (breast cancer gene-1, up to 2% of cases) and BRCA2 (breast cancer gene-2, up to 7% of cases) are tumor suppressor genes located on chromosome 17 and 13, respectively, involved in the process of homologous recombination repair pathway
- BRAF (B-Raf proto-oncogene, up to 2% of cases), an oncogene located on chromosome 7, involved in MAPK pathway and with mutations that are almost always mutually exclusive with those affecting KRAS
- GNAS (guanine nucleotide binding protein, alpha stimulating activity polypeptide) is an oncogene located on chromosome 20; is typically mutated in the case of a cancer derived from an intraductal papillary mucinous neoplasm (IPMN)

Germline mutations / genetic syndromes

A subset of pancreatic cancer arises in the background of genetic syndromes with germline mutations most commonly affecting the following genes (J Clin Oncol 2017;35:3382, Ann Gastroenterol Surg 2020;4:229):
- CDKN2A: germline mutations of this gene characterize the familial atypical multiple mole melanoma (FAMMM) syndrome, an autosomal dominant syndrome in which the cumulative risk for PDAC development is up to 15%
- TP53: germline mutations of this gene characterize the Li-Fraumeni syndrome, an autosomal dominant syndrome in which the cumulative risk for PDAC development is up to 5%
- BRCA1 / 2 and PALB2: germline mutations of these genes characterize the hereditary breast and ovarian cancer syndrome, an autosomal dominant syndrome in which the cumulative risk for PDAC development is up to 7%
- ATM: germline mutations of this gene characterize the ataxia telangiectasia, familial breast cancer syndrome, an autosomal recessive syndrome in which the cumulative risk for PDAC development is up to 5%
- MMR genes: germline mutations of these genes characterize Lynch syndrome, an autosomal dominant syndrome in which the cumulative risk for PDAC development is up to 9%
- STK11: germline mutations of this gene characterize the Peutz-Jeghers syndrome, an autosomal dominant syndrome in which the cumulative risk for PDAC development is up to 30%
- PRSS1 and SPINK1: germline mutations of these gene characterize the hereditary pancreatitis syndrome through an autosomal dominant (PRSS1) or recessive (SPINK1) inheritance, in which the cumulative risk for PDAC development is up to 50%
- CFTR: germline mutations of this gene characterize the cystic fibrosis syndrome, an autosomal recessive syndrome in which the cumulative risk for PDAC development is up to 5%

Transcriptomic subtypes

Different studies have tried to address transcriptomic profiles and, along this line, the most reliable classification indicates the following four categories (Nat Med 2011;17:500, Nature 2016;531:47):
- Squamous subtype: characterized by a strong upregulation of TP63 and downregulation of GATA6; such tumors show the worst prognosis
- Pancreatic progenitor subtype: expresses transcriptional networks involving PDX1, FOXA2 and FOXA3, crucial for pancreatic cell fate determination
- Aberrantly differentiated endocrine exocrine (ADEX) subtype: expresses transcriptional networks crucial for more advanced stage of normal pancreatic differentiation
- Immunogenic subtype: correlates with a marked immune infiltrate, mainly B and T cells, with upregulation of immune checkpoints CTLA4 and PD1, suggesting a possible role for immunotherapy drugs in this tumor subtype

Other relevant genetic alterations

Microsatellite instability (MSI): a genetic condition due to mutations of the mismatch repair (MMR) genes, leading to a hypermutated phenotype with mutations clustered in specific regions known as microsatellites (Ann Oncol 2019;30:1232)
POLE mutation: a rare occurrence in pancreatic cancer associated with an ultra hypermutated phenotype due to mutations affecting polymerase ε; associated with prolonged survival (Pancreas 2020;49:999)
Kinase fusion genes: genetic alterations present in KRAS wild type pancreatic cancer; the genes most commonly involved are FGFR2, RAF, ALK, RET, MET and NTRK1 (Gastroenterology 2019;156:2242)

Clinical features

Some genetic alterations have been recently associated with specific clinical features (Gastroenterology 2019;156:2242):
- Mutations in KRAS, SMAD4 are more frequent in older patients (≥ 50 years)
- Alterations in BRCA1 / 2 are more frequent in younger patients (Mutations in KRAS, SMAD4 and CDKN2A are more frequent in female patients
- Mutations in GNAS and ATM are more frequent in male patients

Prognostic factors

SMAD4 mutations are associated with more aggressive behavior and with a widespread metastasis pattern (J Clin Oncol 2009;27:1806)
MSI tumors do not always have a more favorable prognosis, as in colorectal or gastric cancer (Gut 2020 Apr 29 [Epub ahead of print])

Treatment

Tumors with germline BRCA mutations can be treated with platinum based therapy and with PARP inhibitors (N Engl J Med 2019;381:317)
MSI tumors may be susceptible to immune checkpoint blockade (J Clin Oncol 2020;38:1)
Cancer with ALK fusion may be treated with ALK inhibitors (J Natl Compr Canc Netw 2017;15:555)

Microscopic (histologic) description

MSI tumors more often show a medullary or colloid morphology (Gut 2020 Apr 29 [Epub ahead of print])
Germline mutated ATM tumors more often show a mucinous / colloid histology (Mod Pathol 2019;32:1806)
Tumors with squamous features show a very poor prognosis (Nat Med 2011;17:500, Nature 2016;531:47)

Microscopic (histologic) images

Contributed by Claudio Luchini, M.D., Ph.D.

Medullary histology

Mucinous colloid histology

Adenosquamous histology

Board review style question #1

What is an important histologic characteristic associated with the genetic alteration of microsatellite instability in pancreatic cancer?

Adenosquamous histology
Hepatoid features
Mucinous colloid histology
Squamous histology
Undifferentiated anaplastic histology

Board review style answer #1

C. Mucinous colloid histology is a classic histology encountered in MSI pancreatic cancer.

Comment Here

Reference: Molecular genetics of pancreatic ductal carcinoma

Board review style question #2

Which is the most important and frequently mutated gene in pancreatic ductal adenocarcinoma?

ARID1A
CDKN2A
KRAS
SMAD4
TP53

Board review style answer #2

C. KRAS is the most important and frequent mutated gene in pancreatic ductal adenocarcinoma.

Comment Here

Reference: Molecular genetics of pancreatic ductal carcinoma

Mucinous cystic neoplasm (MCN)

Table of Contents

Definition / general

Benign or potentially low grade malignant cystic epithelial neoplasm composed of cells which contain intracytoplasmic mucin (ICD-O: 8470/0 [Accessed 18 February 2021])
WHO classification:
- MCN with low grade dysplasia (adenoma)
- MCN with high grade dysplasia (carcinoma in situ)
- MCN with invasive carcinoma

Essential features

Cystic neoplastic lesion that is a precursor to pancreatic adenocarcinoma
May harbor invasive carcinoma
Presence of associated ovarian type stroma

ICD coding

ICD-10: C25 - Malignant neoplasm of pancreas (if malignant)
ICD-10: D13.6 - Benign neoplasm of pancreas (if benign)

Epidemiology

Almost always women (> 95%); mean age of 45 years (Ann Surg 2008;247:571)

Sites

Distal pancreas (> 95%) (Ann Surg 2008;247:571)
Can also occur in the liver and gallbladder
Metastases usually restricted to abdominal cavity; metastases to ovary may simulate primary ovarian tumors

Pathophysiology

Ectopic ovarian stroma is thought to be seeded from primordial ovarian cells at early stages of embryonic development
Cysts are later formed by hormones and growth factors released by the ovarian stroma (Am J Surg Pathol 1999;23:410)

Etiology

No known etiology

Clinical features

Usually a single lesion (Gut Liver 2015;9:571)
May present as abdominal pain or acute pancreatitis (Ann Surg 2008;247:571)
Majority are slow growing and asymptomatic (Gastroenterology Res 2014;7:44)

Diagnosis

Cytology and lab analysis of pancreatic cyst fluid from endoscopic ultrasound guided FNA
Histology of pancreatic resection

Laboratory

Elevated carcinoembryonic antigen (CEA) and presence of KRAS mutation in cyst fluid supports a mucinous cyst (includes MCN and intraductal papillary mucinous neoplasm) (Ann Gastroenterol;26:122)

Radiology description

Thick walled, single, septated cyst in the body or tail of the pancreas (Gut Liver 2015;9:571)
May have nodules or calcifications

Prognostic factors

Prognosis is excellent unless there is invasive carcinoma with extracapsular or diffuse intracapsular infiltration (Am J Surg Pathol 2015;39:179, Ann Surg 2008;247:571)
Features associated with invasive carcinoma include increased cyst size (> 5 cm), intracystic papillary nodules > 1 cm in size and elevated serum CA19-9 (Am J Surg Pathol 2015;39:179)
Less than 20% of cases have invasive carcinoma (Gut Liver 2015;9:571, Ann Surg 2008;247:571)

Case reports

38 year old woman with anaplastic carcinoma and mucinous cystic neoplasm of the pancreas during pregnancy (World J Gastroenterol 2008;14:132)
46 year old man with pancreatic mucinous cystic neoplasm with sarcomatous stroma metastasizing to liver (World J Surg Oncol 2013;11:100)
52 year old Japanese woman with anaplastic carcinoma combined with mucinous cystadenocarcinoma of the pancreas (Arch Pathol Lab Med 1997;121:1104)
65 year old man (JOP 2012;13:687)

Treatment

Surgical resection is indicated for all MCNs (Gut Liver 2015;9:571, Gastroenterology Res 2014;7:44)

Gross description

Large (mean 10 cm)
Typically unilocular megacysts that do not communicate with ductal system, though up to 15% communicate with main pancreatic duct (Gut Liver 2015;9:571)
Cyst wall is papillary, trabecular or thickened
Has mucoid / watery cyst contents
Must sample solid areas within the cyst

Gross images

Contributed by Diana Agostini-Vulaj, D.O. and AFIP images

MCN with no connection to main duct

Unilocular cyst

Conspicuous, irregular, solid protuberances

Multiloculated cystic lesion

36 year old
woman: large
cyst with
solid tumor

Images hosted on other servers:

39 year old man with multilocular cyst with thick mucin

Microscopic (histologic) description

Large cyst lined by intestinal, pseudopyloric or gastric foveolar type epithelium that often form papillae, surrounded by characteristic dense ovarian type stroma (Gut Liver 2015;9:571)
Epithelial lining has variable atypia (none, low grade, high grade); scattered neuroendocrine cells may be present
Invasive adenocarcinoma may or may not be present; must sample extensively to rule out an invasive component (Gut Liver 2015;9:571, Am J Surg Pathol 1999;23:1320)
Calcifications are common
May have mural nodules with features of giant cell tumor, malignant fibrous histiocytoma or anaplastic carcinoma

Microscopic (histologic) images

Contributed by Raul S. Gonzalez, M.D. and Matthew W. Rosenbaum, M.D.

Spindled ovarian type stroma

Focal minute papillation

Foveolar mucinous epithelium

Classic ovarian type stroma

MCN with invasion

Estrogen receptor

Cytology description

Cyst aspirates are usually acellular with thick, gelatinous mucus
Clusters of 3 dimensional atypical glandular cells with hyperchromasia predict at least moderate dysplasia (Arch Pathol Lab Med 2009;133:388)

Cytology images

Contributed by Matthew W. Rosenbaum, M.D.

Cytology of mucinous cystic neoplasm

Positive stains

Ovarian type stroma: CD10, ER, inhibin, PR, smooth muscle actin (SMA) and vimentin (Gut Liver 2015;9:571)
Epithelium stains carcinoembryonic antigen (CEA), CK7, CK8, CK18 and CK19 (Gut Liver 2015;9:571)
Gastric type epithelium stains MUC5AC (Gut Liver 2015;9:571)
DPC4 (MADH4, SMAD4), MUC5AC present in situ areas (usually lost in invasive disease) (Am J Surg Pathol 2000;24:1544, Gut Liver 2015;9:571, Arch Pathol Lab Med 2015;139:24)
Invasive component stains MUC1
Cyst fluid may stain positive for Alcian blue and mucicarmine
S100P in epithelium (Arch Pathol Lab Med 2015;139:24)
SF1 in stroma (Pathol Int 2016;66:281)

Negative stains

MUC1 (except in invasive components) (Am J Surg Pathol 2002;26:466, Gut Liver 2015;9:571)
MUC2 (except for faint staining of goblet cells)
DPC4 (MADH4, SMAD4) staining is lost in invasive MCNs (Gut Liver 2015;9:571)
pVHL (Arch Pathol Lab Med 2015;139:24)

Molecular / cytogenetics description

KRAS mutations noted in in situ or invasive areas, inactivating SMAD4 and TP53 mutations in more advanced MCNs (Gut Liver 2015;9:571)
Negative for GNAS mutations

Sample pathology report

Pancreas and duodenum, Whipple resection:
- Mucinous cystic neoplasm with low grade intraepithelial neoplasia (8.3 cm) (see comment)
- Negative for high grade intraepithelial neoplasia or malignancy.
- Focal background chronic pancreatitis
- Margins of resection unremarkable.
- Seven benign lymph nodes.
- Comment: The gross cystic lesion was entirely submitted for microscopic analysis.
Pancreas and duodenum, Whipple resection:
- Focal adenocarcinoma arising from a mucinous cystic neoplasm (see synoptic report)

Differential diagnosis

Intraductal papillary mucinous neoplasm:
- Usually at the head of pancreas and communicates with the duct system (MCNs usually do not communicate with the main pancreatic duct)
- IPMNs may be positive for GNAS mutations while MCNs will be negative (Gut Liver 2015;9:571)
- Both have elevated CEA and KRAS mutation in cyst fluid
Ovarian mucinous tumors:
- Similar clinical and histologic appearance
Pancreatic ductal adenocarcinoma, large duct variant:
- Will have smaller cysts, clustering of ducts and myxoid stroma (Arch Pathol Lab Med 2009;133:423)
Pancreatic ductal adenocarcinoma:
- Usually not cystic, shows irregular infiltrative glands with nuclear atypia, no ovarian type stroma
Pancreatic pseudocyst:
- Mimics MCN when MCN has denuded cyst lining
- MCN cystic fluid has high CEA content and viscosity, high expression of microRNAs, lower amylase (< 250 U/L) and elastase I than pseudocyst, although values may vary within different loculi of same neoplasm (Am J Clin Pathol 1993;100:425, Ann Gastroenterol 2013;26:122, Gastroenterology Res 2014;7:44)
Serous cystadenoma:
- Has low levels of CEA

Board review style question #1

Which of the following findings on fine needle aspiration of a pancreatic cyst are most consistent with a mucinous cystic neoplasm?

Decreased CEA, decreased amylase, no KRAS mutation, no GNAS mutation
Elevated CEA, elevated amylase, KRAS mutation, GNAS mutated
Elevated CEA, highly elevated amylase, no KRAS mutation, no GNAS mutation
Elevated CEA, variable amylase, KRAS mutation, no GNAS mutation

Board review style answer #1

D. Mucinous cystic neoplasms have elevated CEA, variable amylase, KRAS mutation and no GNAS mutation. If a GNAS mutation is present, then the findings will favor an IPMN (answer B). Decreased CEA and amylase with no KRAS or GNAS mutations favor a serous cystadenoma (answer A). An elevated CEA and amylase without KRAS or GNAS mutations will favor a pancreatic pseudocyst (answer C).

Comment Here

Reference: Mucinous cystic neoplasm (MCN)

Mucinous pancreatic tumor overview

Table of Contents

Definition / general

Neoplasms within the pancreas characterized by predominant mucin production by the tumor cells
Mucus: a substance that is 95 - 98% water and 2 - 5% solids, with > 60% of the solid component consisting of mucin (World J Gastroenterol 2011;17:4757)
Mucin: a glycoprotein consisting of a polypeptide backbone with attached oligosaccharide conjugates

Essential features

General term for benign, low or high grade dysplastic or malignant mucin producing epithelium within the pancreas
4 most prevalent types
MCN and IPMN may harbor or develop into pancreatic ductal adenocarcinoma (small percentage); MCN may undergo transformation to cystadenocarcinoma as well (Pancreas 2017;46:745)

Comparison of essential features of the 4 types of pancreatic mucinous tumors
	Simple mucinous cyst / MNC	MCN	IPMN	Pancreatic ductal adenocarcinoma
Age, decade	Sixth - seventh	Fourth - fifth	Sixth - seventh	Sixth - eighth
Location	Head = body = tail	Body / tail > head	Head > body / tail	Head > body / tail
Sex predilection	F > M	F >>> M	Main duct: M > F Branch duct: F > M	M > F
CEA	↑	↑	↑	N / A
Amylase	↓	↓	↑	N / A
Pancreatic duct communication	Rare	No	Yes	Yes
Precursor for invasive carcinoma	No	Yes	Yes	N / A
Cytologic atypia	No	Low grade / high grade	Low grade / high grade	N / A
Epithelium type	Flat	Flat or papillary	Papillary	Flat or papillary
Ovarian stroma	No	Yes	No	N / A
Molecular mutations	KMT2C, KRAS, BRAF, RNF43, CDKN2A, TP53, SMAD4	KRAS, RNF43 (low grade); SMAD4, TP53 (high grade)	GNAS, KRAS, RNF43, TP53	KRAS, TP53, CDKN2A, SMAD4, BRCA1/2

Terminology

Simple mucinous cyst / mucinous nonneoplastic cyst
Mucinous cystic neoplasm / mucinous cystadenoma
Intraductal papillary mucinous neoplasm / carcinoma in situ
Pancreatic ductal adenocarcinoma / duct cell adenocarcinoma / infiltrating duct carcinoma / tubular adenocarcinoma

ICD coding

See individual topics

Epidemiology

Simple mucinous cyst / mucinous nonneoplastic cyst (MNC)
- 2 - 7% of pancreatic cyst resections and 8 - 10% of mucinous cysts of the pancreas
- More common in women (F:M = 2.8:1), mean age of 64 years old (Arch Pathol Lab Med 2017;141:1330)
Mucinous cystic neoplasm (MCN)
- Comprises ~25% of resected pancreatic cystic neoplasms
- Almost exclusively in women (> 95%)
- Rare; 2 - 5% exocrine pancreatic tumors
- Most common in fourth through fifth decade (Arch Pathol Lab Med 2017;141:1330, Gut Liver 2015;9:571)
Intraductal papillary mucinous neoplasm (IPMN)
- May account for between 18 and 50% of resected cystic pancreatic lesions (Arch Surg 2009;144:448, Pancreas 2008;37:254, Pancreas 2011;40:779)
- Main duct IPMN is slightly more common in men (M:F = 1.1:1), while branch duct IPMN is more common in women (M:F = 0.76:1) (Diagnostics (Basel) 2022;13:65)
- Most common in sixth through seventh decade (Arch Pathol Lab Med 2017;141:1330)
Pancreatic ductal adenocarcinoma
- Most common pancreatic tumor (~90% of pancreatic cancer diagnoses)
- 80% occur in patients 60 - 80 years old
- Slightly more common in men (CA Cancer J Clin 2018;68:394)
- Colloid carcinoma / mucinous carcinoma is an uncommon variant with > 50% extracellular mucus production, accounting for 1 - 3%

Sites

Simple mucinous cyst / mucinous nonneoplastic cyst (MNC)
- Occur equally in head / neck / uncinate and body / tail (Arch Pathol Lab Med 2017;141:1330)
Mucinous cystic neoplasm (MCN)
- > 95% arise in the distal pancreas as a single lesion (Gut Liver 2015;9:571)
Intraductal papillary mucinous neoplasm (IPMN)
- Can occur anywhere in the pancreas, most common in the head (~58%) (Am J Clin Pathol 2020;154:559)
Pancreatic ductal adenocarcinoma
- 60 - 70% occur in pancreatic head
- Usually solitary, occasionally multifocal (Surg Pathol Clin 2016;9:547)

Pathophysiology

Simple mucinous cyst / mucinous nonneoplastic cyst (MNC)
- Unknown pathogenesis but may develop from acinar ductal mucinous metaplasia (Hum Pathol 2010;41:513, Arch Pathol Lab Med 2017;141:1330)
Mucinous cystic neoplasm (MCN)
- Stromal component possibly derived from ovarian primordium / Müllerian type stroma or primary yolk cells implanted in the pancreas during embryogenesis (Am J Surg Pathol 1999;23:410, Dig Surg 2006;23:186)
Intraductal papillary mucinous neoplasm (IPMN)
- Histologically arising in the pancreatic main duct, branch duct or combined (Clin Gastroenterol Hepatol 2010;8:213)
Pancreatic ductal adenocarcinoma
- Arises from pancreatic duct epithelia
- Precursor lesions include intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN) and pancreatic intraepithelial neoplasia (PanIN)

Etiology

Simple mucinous cyst / mucinous nonneoplastic cyst (MNC)
- Unclear etiology
Mucinous cystic neoplasm (MCN)
- No known etiology
Intraductal papillary mucinous neoplasm (IPMN)
- In one study, most patients with IPMN were cigarette smokers (Adv Anat Pathol 1999;6:65)
- Patients with Peutz-Jeghers syndrome, familial adenomatous polyposis and McCune-Albright syndrome are at increased risk (Adv Anat Pathol 1999;6:65, Gut 2002;51:446, Virchows Arch 2017;470:391)
Pancreatic ductal adenocarcinoma
- Strongly associated with cigarette smoking (2 - 3x increased risk)
- History of pancreatitis (2 - 10 fold increased risk)
- Obesity / diet (risk increases with increasing body mass index [BMI])
- Hereditary pancreatic cancer syndrome (due to an underlying germline mutation)
- Familial pancreatic cancer syndrome (defined as pancreatic cancer in at least 2 first degree relatives without an underlying germline mutation)
- Other possible factors: high alcohol consumption, previous gastric surgery and diabetes (Lancet Gastroenterol Hepatol 2016;1:298, Lancet Gastroenterol Hepatol 2016;1:226, Medicine (Baltimore) 2017;96:e5908)

Clinical features

Simple mucinous cyst / mucinous nonneoplastic cyst (MNC)
- Half of patients are asymptomatic; others report abdominal pain or jaundice (Arch Pathol Lab Med 2017;141:1330)
Mucinous cystic neoplasm (MCN)
- More than half of patients are asymptomatic
- Causes compression of adjacent structures
- Symptoms include a palpable mass in the epigastric region and nonspecific abdominal pain or distension (World J Gastrointest Oncol 2020;12:642)
Intraductal papillary mucinous neoplasm (IPMN)
- Majority are asymptomatic; often incidental
- Symptoms present in 2 - 20% of patients and include epigastric pain, weight loss, diabetes and jaundice (Gut Liver 2015;9:571, Arch Pathol Lab Med 2022;146:298)
Pancreatic ductal adenocarcinoma
- Most commonly reported symptoms: loss of appetite (~45%), jaundice (~41%) and abdominal pain (40%)
- Other symptoms include weight loss, back pain, new onset diabetes, depression, migratory thrombophlebitis and acute pancreatitis (Clin Gastroenterol Hepatol 2004;2:510)

Diagnosis

Overall, diagnosis of mucinous cysts and neoplasms of the pancreas relies on
- Cyst fluid analysis obtained from endoscopic ultrasound guided fine needle aspiration (EUS FNA)
- Cytology analysis (EUS FNA)
- Histologic analysis of surgical resection
Reference: Front Physiol 2022;13:856803

Laboratory

Simple mucinous cyst / mucinous nonneoplastic cyst (MNC)
- Cyst fluid often shows variably elevated carcinoembryonic antigen (CEA) and amylase
Mucinous cystic neoplasm (MCN)
- Serum tumor markers include CEA, CA 19-9, TAG-72, CA 15-3 or MCA and low levels of amylase
- Cyst fluid often shows elevated CEA, CA 19-9 and low amylase
Intraductal papillary mucinous neoplasm (IPMN)
- Serum amylase and lipase are elevated
- Cyst fluid shows elevated CEA and amylase
Pancreatic ductal adenocarcinoma
- Serum tumor markers include CA 19-9, CEA
- Cyst fluid has high levels of CA 19-9, DUPAN-2, CEA, Span-1 (Arch Pathol Lab Med 2017;141:1330, Front Physiol 2022;13:856803)

Radiology description

Simple mucinous cyst / mucinous nonneoplastic cyst (MNC)
- Single unilocular or multilocular cyst (Front Physiol 2022;13:856803)
Mucinous cystic neoplasm (MCN)
- Well defined multilocular or unilocular thick walled cyst
- No connection with the main pancreatic duct (Front Physiol 2022;13:856803)
Intraductal papillary mucinous neoplasm (IPMN)
- Dilated main pancreatic duct in main duct type IPMN
- Branch duct IPMN typically produces a grape-like cyst
- Mural nodules may correspond to high grade dysplasia (Front Physiol 2022;13:856803)
Pancreatic ductal adenocarcinoma
- Irregular, solid hypodense mass
- Double duct sign (dilation of both the biliary and pancreatic ducts) is pathognomonic (Radiology 2011;260:446)

Prognostic factors

Simple mucinous cyst / mucinous nonneoplastic cyst (MNC)
- Not associated with progression or invasive carcinoma (Arch Pathol Lab Med 2017;141:1330)
Mucinous cystic neoplasm (MCN)
- 5 year survival rate of 96 - 100% after surgical resection (Am J Surg Pathol 2015;39:179, World J Surg Oncol 2020;18:287)
- No survival difference between MCNs with low grade or high grade dysplasia (Am J Surg Pathol 2018;42:578)
- Invasion limited to the ovarian type stroma, cystic septa or capsule has a favorable outcome (5 year survival 100%), while extracapsular invasion is associated with poor survival (J Pathol Clin Res 2021;7:507)
Intraductal papillary mucinous neoplasm (IPMN)
- Absence of invasive carcinoma is the most important prognostic factor (Hum Pathol 2012;43:1)
- Main duct type shows highest incidence of invasive adenocarcinoma (30 - 50%)
- Branch type without mural nodules are more commonly found with low grade dysplasia (~24% with invasion) (Dig Liver Dis 2012;44:257, Am J Surg Pathol 2000;24:1372, Arch Pathol Lab Med 2022;146:298)
Pancreatic ductal adenocarcinoma
- Most ductal adenocarcinomas are fatal (5 year survival ~5%)
- Survival time is longer in patients with tumors confined to the pancreas or Tumors in the body or tail tend to present at a more advanced stage (Cancer Res 2014;74:2913, J Gastrointest Surg 2000;4:567)
- Colloid carcinomas have a better prognosis than conventional adenocarcinomas with a 5 year survival rate of > 55% (Am J Surg Pathol 2003;27:571)

Case reports

32 year old woman with a large mucinous cystic neoplasm of the pancreas arising during pregnancy (J Surg Case Rep 2020;2020:rjaa085)
63 year old man with a 2 year history of abdominal pain without weight loss and a simple mucinous cyst (Virchows Arch 2021;479:179)
72 year old woman with pancreatic ductal carcinoma arising in pancreatic remnant 13 years after resected IPMN (Mol Clin Oncol 2018;8:417)
78 year old woman with a bowel obstruction and an intraductal papillary mucinous neoplasm (Radiol Case Rep 2023;18:1103)
91 year old woman with new onset diabetes mellitus and a pancreatic ductal adenocarcinoma (Cureus 2022;14:e31608)

Treatment

Simple mucinous cyst / mucinous nonneoplastic cyst (MNC)
- Typically resected, may be treated conservatively with continued imaging follow up
Mucinous cystic neoplasm (MCN)
- Surgical resection is typical
- Can follow with close imaging surveillance for poor surgical candidates with MCN without high risk imaging findings (Gut Liver 2015;9:571)
Intraductal papillary mucinous neoplasm (IPMN)
- Surgical resection for main duct IPMNs
- Can follow with close imaging surveillance for branch duct IPMN < 3 cm without high risk imaging findings (Arch Pathol Lab Med 2022;146:298)
Pancreatic ductal adenocarcinoma
- Radical resection with or without chemotherapy

Gross description

Simple mucinous cyst / mucinous nonneoplastic cyst (MNC)
- Macroscopic cyst > 1 cm, usually 3 - 12 cm
- Unilocular or multilocular
- May contain clear, serous or mucinous fluid (Arch Pathol Lab Med 2017;141:1330)
Mucinous cystic neoplasm (MCN)
- 2 - 35 cm in greatest dimension
- Unilocular or multilocular, thick walls
- Round mass with smooth surface and fibrous pseudocapsule, can have papillary projections in higher grade lesions
- Calcifications may be present
- May contain thick mucin, hemorrhage or necrotic debris (Am J Surg Pathol 2015;39:179)
Intraductal papillary mucinous neoplasm (IPMN)
- 1 - 8 cm in greatest dimension
- Cystic, multiloculated
- Grape-like clusters in branch type
Pancreatic ductal adenocarcinoma
- Firm, poorly defined mass, with yellow to white cut surface
- Can be difficult to differentiate from background pancreatitis (HPB (Oxford) 2014;16:83)

Gross images

Contributed by Katrina Krogh, M.D.

PDA: ill defined white lesion

MCN: unilocular cyst with thick wall

IPMN: small cysts with smooth linings

MNC: unilocular
simple cyst with
smooth thin lining

Microscopic (histologic) description

Simple mucinous cyst / mucinous nonneoplastic cyst (MNC)
- Cyst lined by monolayer of cuboidal to columnar mucinous epithelium
- Usually has gastric phenotype
- No ovarian type stroma present
- Little to no cytologic atypia and no / minimal papillary excrescences in epithelial lining
- No malignant potential
- Rare cases of focal high grade dysplasia reported (Arch Pathol Lab Med 2017;141:1330)
Mucinous cystic neoplasm (MCN)
- Cyst lined by 2 components
  - Inner epithelial layer composed predominantly of mucin producing cells
  - Outer densely cellular Müllerian / ovarian type stroma
- No connection to ducts
- Stroma can undergo luteinization, can have hilar-like cells and immunophenotypic sex cord stromal differentiation
- 2 tiered grading system
  - Low grade: mild moderate atypia, mitoses and papillary projections uncommon
  - High grade: severe atypia, papillae formation with irregular branching, loss of nuclear polarity, frequent mitoses
- Invasion seen in ~16% of MCN (Arch Pathol Lab Med 2022;146:298)
Intraductal papillary mucinous neoplasm (IPMN)
- Cyst lined by neoplastic columnar / mucinous epithelium that can be flat or form papillae
- 3 types of epithelium
  - Intestinal type (~20%): resembles villous adenomas of the gastrointestinal tract; often contains high grade dysplasia
  - Gastric type (~70%): resembles gastric foveolar epithelium; often low grade dysplasia
  - Pancreatobiliary type (~10%): frequently involves the main duct, shows complex branching of papillae and often contains high grade dysplasia
- 2 tiered grading system
  - Low grade: mild moderate atypia, mitoses are uncommon
  - High grade: severe atypia, irregular branching and budding of papillae, loss of nuclear polarity, frequent mitoses (Arch Pathol Lab Med 2022;146:298)
Pancreatic ductal adenocarcinoma
- Classically shows well developed neoplastic glands that imitate normal pancreatic ducts in the background of desmoplastic stroma
- Neoplastic glands show an irregular and haphazard distribution with irregular contours and frequently contain neutrophils and necrotic debris
- Nuclear pleomorphism, prominent nucleoli and mitoses are typically frequent
- Mucin containing glands may be ruptured or poorly formed
- Most are well to moderately differentiated
- Grade (College of American Pathologists) based on extent of glandular differentiation
  - Well differentiated (> 95% of tumor composed of glands)
  - Moderately differentiated (50 - 95% of tumor composed of glands)
  - Poorly differentiated (≤ 49% of tumor composed of glands)
- Colloid carcinoma is a subtype that contains ≥ 80% of neoplastic cells suspended in pools of mucin

Microscopic (histologic) images

Contributed by Jen Rytych, M.D. and Katrina Krogh, M.D.

Mucinous pancreatic adenocarcinoma

Pancreatic adenocarcinoma, grade 2

MCN: ovarian type stroma

IPMN, gastric type

IPMN, intestinal type

Simple mucinous cyst / mucinous nonneoplastic cyst (MNC)

MNC

Cytology description

Simple mucinous cyst / mucinous nonneoplastic cyst (MNC)
- Cuboidal or columnar cells in strips or honeycomb sheets without significant atypia
- Background mucin and macrophages are frequently present (Pancreas 2013;42:27)
Mucinous cystic neoplasm (MCN)
- Cannot be distinguished from IPMN on cytology
- Low grade MCN will have low cellularity with a variable amount of mucin with histiocytes and bland epithelial cells
- High grade MCN will have low to moderate cellularity, variable amount of mucin, pleomorphic, atypical cells with a high nuclear to cytoplasmic ratio and frequent necrosis
- Ovarian type stroma is not typically present (Cancer Cytopathol 2017;125:169)
Intraductal papillary mucinous neoplasm (IPMN)
- Cannot be distinguished from MCN on cytology
- Low grade IPMN will have low cellularity with minimal nuclear atypia in epithelial cells and no background necrosis
- High grade IPMN will be more cellular with small epithelial cells with hyperchromatic, irregular nuclei and prominent background inflammation and necrosis in most cases (Cancer Cytopathol 2014;122:40)
Pancreatic ductal adenocarcinoma
- Typically highly cellular, often with background necrosis
- Tissue fragments are composed of cells with irregular nuclear spacing (drunken honeycomb), hyperchromatic nuclei with irregular contours and occasional atypical mitotic figures (Cancer 2003;99:44)

Positive stains

Simple mucinous cyst / mucinous nonneoplastic cyst (MNC)
- Cytokeratins (7, 8, 18, 19, 20), CA 19-9, MUC5AC (90%), MUC6 (74%) (Arch Pathol Lab Med 2017;141:1330)
Mucinous cystic neoplasm (MCN)
- Epithelial component: CEA, cytokeratins (7, 8, 18 and 19) (Gut Liver 2015;9:571)
- Stromal component: vimentin, alpha SMA, desmin, inhibin, ER, PR and CD10 (Gut Liver 2015;9:571)
Intraductal papillary mucinous neoplasm (IPMN)
- Cytokeratins (AE1 / AE3, CK7, CK19, CAM 5.2), CEA, B72.3 and MUC5AC are positive in all types
- MUC2, CDX2 and CK20 are positive in intestinal type
- MUC1 is typically positive in pancreatobilliary type (Arch Pathol Lab Med 2017;141:1330)
Pancreatic ductal adenocarcinoma
- Cytokeratins (CK7, CK8, CK18 and CK19) are consistently expressed
- Cancer markers CEA, CA 19-9, CA-125, B72.3, DUPAN-2 are common
- EMA (MUC1), MUC3 and MUC5AC are typically positive
- TP53 is typically positive (Semin Diagn Pathol 2014;31:443)

Negative stains

Simple mucinous cyst / mucinous nonneoplastic cyst (MNC)
- Trypsin, CEA, synaptophysin, chromogranin A, calretinin, alpha inhibin, MUC1 (35% positive), MUC2 (1% positive), PR (8% positive)
- CDX2 (can be focally positive) (Arch Pathol Lab Med 2017;141:1330, Am J Surg Pathol 2017;41:121, Virchows Arch 2021;479:179)
Mucinous cystic neoplasm (MCN)
- MUC1 (can be aberrantly expressed in invasion), MUC2, pVHL (Arch Pathol Lab Med 2015;139:24)
Intraductal papillary mucinous neoplasm (IPMN)
- MUC2 (in biliary and gastric types)
- MUC1 (in gastric and intestinal types) (Front Physiol 2022;13:856803)
Pancreatic ductal adenocarcinoma
- CK20, vimentin, synaptophysin, chromogranin, MUC2
- pVHL (positive in reactive ducts) (Arch Pathol Lab Med 2012;136:601, Hum Pathol 2013;44:503)
- SMAD4 / DPC4 loss seen in 55%; specific for malignancy (Am J Clin Pathol 2001;116:831)

Molecular / cytogenetics description

Simple mucinous cyst / mucinous nonneoplastic cyst (MNC)
- KMT2C (62%), KRAS (15%), TP53 (15%), BRAF (8%), RNF43 (8%), CDKN2A (8%), SMAD4 (8%)
- No mutations detected in 31% of cases (Hum Pathol 2020;101:1)
Mucinous cystic neoplasm (MCN)
- KRAS (21 - 46%) and RNF43 (~50%) mutations in low grade lesions
- Inactivating and TP53 mutations in more advanced MCN
- No GNAS mutations (Gut Liver 2015;9:571, Proc Natl Acad Sci U S A 2011;108:21188, J Gastrointest Surg 2020;24:1201, Virchows Arch 2022;480:1189)
Intraductal papillary mucinous neoplasm (IPMN)
- Commonly mutated: KRAS (90%), GNAS (40 - 60%), RNF43 (25%), TP53 (10%)
- Lower frequency: CDKN2A, CTNNB1, IDH1, STK11, PTEN (World J Gastroenterol 2021;27:2710)
Pancreatic ductal adenocarcinoma
- Key drivers
  - TP53 is inactivated in 50 - 75%
  - KRAS: 70 - 95%, early event
  - CDKN2A (p16): > 95%
  - SMAD4: ~50 - 55%
  - BRCA1 / BRCA2: 5 - 10%
- Other less common alterations: microsatellite instability (MSI), BRAF mutations, MGMT promotor hypermethylation (Cancer Cell 2017;32:185, World J Gastroenterol 2021;27:2710)

Sample pathology report

Distal pancreas and spleen, distal pancreatectomy and splenectomy:
- Intraductal papillary mucinous neoplasm (IPMN) (3.0 cm), low grade, involving branch ducts (see comment)
- Comment: Pancreatic resection margin, negative for dysplasia. No high grade dysplasia or invasive component was identified. 13 lymph nodes with reactive changes (0/13).

Differential diagnosis

See individual topics
Also see table in Essential features

Additional references

JAMA Surg 2022;157:723, WHO Classification of Tumours Editorial Board: Digestive System Tumours, 5th Edition, 2019

Board review style question #1

A 55 year old woman presents with a pancreatic cyst incidentally detected on abdominal imaging. The cyst is located in the head of the pancreas and measures ~3 cm in size. Endoscopic ultrasound guided fine needle aspiration (EUS FNA) is performed and analysis of the cyst fluid reveals the following laboratory values: high CEA level, elevated amylase and low viscosity. A picture of the resection specimen is shown above. Which of the following statements is true about the most likely diagnosis?

This lesion can display multiple histologic subtypes that resemble gastric, intestinal or pancreatobiliary epithelium
This lesion does not commonly connect with the pancreatic duct system
This lesion is not a precursor for invasive ductal adenocarcinoma
VHL is the most commonly mutated gene in this lesion

Board review style answer #1

A. This lesion can display multiple histologic subtypes that resemble gastric, intestinal or pancreatobiliary epithelium. This lesion in the head of the pancreas with elevated CEA and amylase levels in the cyst fluid is an intraductal papillary mucinous neoplasm (IPMN). The epithelium in IPMNs most commonly resembles gastric epithelium, with intestinal and pancreatobiliary types being less common. Answer B is incorrect because IPMNs connect with the pancreatic duct system, which causes an increase in amylase levels in the cyst fluid. Other pancreatic cysts such as mucinous cystic neoplasm (MCN) and simple mucinous cysts do not typically connect with the pancreatic duct system. Answer C is incorrect because invasive carcinomas are found in ~30 - 50% of main duct IPMNs and ~24% of branch duct IPMNs. Answer D is incorrect because VHL is commonly mutated in serous cystadenomas, not IPMNs.

Comment Here

Reference: Mucinous pancreatic tumor overview

Board review style question #2

A 45 year old woman presents with abdominal discomfort and a large cystic lesion in the tail of the pancreas on abdominal imaging. Endoscopic ultrasound guided fine needle aspiration (EUS FNA) is performed and analysis of the cyst fluid reveals elevated levels of CEA, CA 19-9 and low amylase. A picture of the resection specimen is shown above. Which of the following statements about this pancreatic lesion is true?

This lesion contains ovarian type stroma and is most commonly seen in females
This lesion is most commonly seen in older men with a history of chronic pancreatitis
This lesion is typically a benign cystic tumor that contains serous fluid
These lesions are typically associated with elevated levels of amylase and CEA in the cyst fluid

Board review style answer #2

A. This lesion contains ovarian type stroma and is most commonly seen in females. This female patient with a cystic lesion in the tail of the pancreas with elevated CEA, CA 19-9 and low amylase has a mucinous cystic neoplasm (MCN). MCNs are characterized by the presence of ovarian type stroma and are seen almost exclusively in females (> 95%). Answer B is incorrect because pancreatic ductal adenocarcinomas are more commonly associated with older men with a history of chronic pancreatitis. MCNs are seen in female patients and are not associated with chronic pancreatitis. Answer C is incorrect because serous cystadenomas are benign cystic tumors that contain serous fluid. MCNs contain mucin and are characterized as low grade or high grade lesions with ~16% associated with invasive carcinoma. Answer D is incorrect because the cyst fluid of MCNs typically has elevated CEA and CA 19-9 but has low amylase levels because they do not connect to the pancreatic duct system. The presence of elevated amylase and CEA levels in pancreatic cyst fluid is most often associated with an intraductal papillary mucinous neoplasm (IPMN).

Comment Here

Reference: Mucinous pancreatic tumor overview

Nesidioblastosis

Table of Contents

Definition / general

Islets in intimate association with ducts, with formation of ductuloinsular complexes
Also called congenital islet hyperplasia
Indicates active formation of endocrine cells by multipotential cells in basal layer of ducts

Clinical features

Normal in infants, exaggerated in neonatal hyperglycemia (infants of diabetic mothers)
In adults, is rare cause of persistent hyperinsulinemic hypoglycemia
Associated with Beckwith-Weidemann syndrome, chronic pancreatitis, cystic fibrosis, endocrine neoplasms, gastric bypass patients (Mod Pathol 2009;22:239), Zollinger-Ellison syndrome
May be due to increase in expression of growth factors IGF2, IGF1Ra and TGFBR3 in islets (Mod Pathol 2009;22:239)
Must rule out mutation in HADH gene (J Clin Endocrinol Metab 2011;96:E498)
Either focal or diffuse (Am J Surg Pathol 1989;13:766):
- Focal: nodular hyperplasia of islet-like cell clusters, including ductuloinsular complexes and hypertrophied insulin cells with giant nuclei
- Diffuse: involves entire pancreas; irregularly sized islets and ductuloinsular complexes present, both contain hypertrophied insulin cells, peliosis type vascular ectasia

Case reports

44 year old man with symptomatic hypoglycemia and localized nesidioblastosis (Hum Pathol 2010;41:447)

Treatment

Focal nesidioblastosis: partial pancreatectomy with excision of diseased areas; diffuse: near total pancreatectomy

Microscopic (histologic) description

Islets in intimate association with ducts, with formation of ductuloinsular complexes
Beta cell hypertrophy (Am J Surg Pathol 2005;29:524)

Microscopic (histologic) images

Images hosted on other servers:

20 day old girl with persistent hypoglycemia and seizures

23 year old man with hypoglycemia mimicking an insulinoma

Neuroendocrine neoplasms-general

Table of Contents

Definition / general

Includes well differentiated neuroendocrine tumors (WDNET) and poorly differentiated neuroendocrine carcinomas (PDNEC)
Express neuroendocrine markers (synaptophysin and chromogranin A) (see Positive stains)
Mixed neuroendocrine nonneuroendocrine neoplasms (MiNEN) includes both neuroendocrine and nonneuroendocrine component (e.g., adenocarcinoma, acinar carcinoma), each ≥ 30%
Functional tumors are associated with elevated serum hormone levels and a clinical hormonal syndrome (see Clinical features)
Nonfunctional tumors are more common and are not associated with a clinical hormonal syndrome
- May still be associated with elevated serum hormone levels or tissue hormone expression on immunohistochemistry
- Nonfunctional tumors < 0.5 cm are termed pancreatic neuroendocrine microadenomas

Essential features

Well differentiated neuroendocrine tumors (WDNET):
- Clumped chromatin (salt and pepper) nuclei
- Cellular uniformity, central ovoid nucleus
- Organoid architecture: ribbons / trabeculae, nesting, glandular, gyriform, pseudoacinar
- Necrosis is rare
- Amyloid deposition in insulinomas
- Psammoma bodies in somatostatinomas (also associated with NF1)
- Background of microadenomas in multiple endocrine neoplasia type 1 (MEN1) and von Hippel-Lindau (VHL) syndromes
- Clear cell morphology in von Hippel-Lindau syndrome
Poorly differentiated neuroendocrine carcinomas (PDNEC):
- Diffuse sheets or solid nests of markedly atypical malignant cells with small cell or large cell morphology
- Abundant mitoses and apoptotic bodies
- Necrosis is frequent

Terminology

Antiquated terms: islet cell tumor / carcinoma, carcinoid, APUDoma
Classification based on WHO system:
- Per WHO 2019, neuroendocrine neoplasms with Ki67 > 20% are now regarded in 2 distinct groups, WDNET grade 3 or PDNEC, based on the morphologic characteristics
- Well differentiated neuroendocrine tumor grading:
  - WHO grade 1: < 2 mitoses/2 mm² or Ki67 index < 3%
  - WHO grade 2: 2 - 20 mitoses/2 mm² or Ki67 index 3 - 20%
  - WHO grade 3: > 20 mitoses/2 mm² or Ki67 > 20%
- Ki67 count should be done on a minimum of 500 cells in hot spot areas
- Both mitotic count and Ki67 should be performed and grade is assigned based on largest value; usually Ki67 is higher than mitotic count (Am J Surg Pathol 2013;37:1671)

Epidemiology

1 - 5% of all pancreatic neoplasms; increasing incidence due to improved imaging techniques (Arch Pathol Lab Med 2019;143:1317, Cancer 2015;121:589)
Incidence of 1 per 100,000 persons (Cancer 2015;121:589)
Wide age range but most common in third to sixth decades (Arch Pathol Lab Med 2019;143:1317)
M = F (Arch Pathol Lab Med 2019;143:1317)
Most are sporadic
10 - 20% associated with syndrome (Arch Pathol Lab Med 2019;143:1317):
- 20 - 70% of multiple endocrine neoplasia 1 (MEN1) patients
- 20% von Hippel-Lindau (VHL) patients
- 10% neurofibromatosis type 1 (NF1) patients
- 1% of tuberous sclerosis complex (TSC) patients

Sites

WDNET is more common in tail and body (Arch Pathol Lab Med 2019;143:1317)
PDNEC is more common in head (Arch Pathol Lab Med 2019;143:1317)
See Clinical hormonal syndromes

Pathophysiology

Varies with clinical syndrome (see Clinical features)

Etiology

Risk factors include smoking, diabetes and first degree relative with history of cancer (Sci Rep 2016;6:36073)
Subset associated with MEN1 (MEN1 gene on 11q13), von Hippel-Lindau (VHL tumor suppressor gene on 3p25), neurofibromatosis 1 (microdeletion in neurofibromin gene on 17q11.2) and tuberous sclerosis complex (TSC1 tumor suppressor gene on 9q34 or TSC2 tumor suppressor gene on 16p13.3) (Arch Pathol Lab Med 2019;143:1317)

Clinical features

Nonfunctional tumors are encountered incidentally and are usually larger at time of diagnosis
Local obstruction / mass effect, if located in the pancreatic head
Other clinical features of MEN1, VHL, NF1 or TSC (if applicable)
Clinical hormonal syndromes in functioning tumors, 10 - 30% of tumors (Arch Pathol Lab Med 2009;133:350)

Insulinoma:
- Most common
- Insulin secretion
- Whipple triad: symptoms of hypoglycemia, low plasma glucose, relief of symptoms with glucose administration
- Solitary tumor < 2 cm
- 5 - 10% MEN1 and are usually multiple
- Generally indolent
Gastrinoma:
- Second most common functioning pancreatic neuroendocrine tumor
- Gastrin secretion
- Zollinger-Ellison syndrome (peptic / duodenal ulcers, gastroesophageal reflux, diarrhea)
- Located in gastrinoma triangle (common bile duct, duodenum, pancreatic head)
- More commonly found in duodenum than pancreas
- 20 - 30% associated with MEN1
Glucagonoma:
- 4 Ds: diabetes, dermatitis (necrolytic migratory erythema), deep vein thrombosis, depression
- Solitary, large
- Tail > head
- > 50% have metastasis at presentation
VIPoma:
- Verner-Morrison syndrome: watery diarrhea, hypokalemia, achlorhydria / hypochlorhydria
- Solitary, large
- Tail > head
Somatostatinoma:
- Diabetes mellitus, diarrhea or steatorrhea, anemia, malabsorption, cholelithiasis
- Very rare
- Solitary, large
- > 50% have metastasis at presentation
Ectopic hormone producing neuroendocrine tumor:
- ACTH (Cushing syndrome), serotonin (atypical carcinoid syndrome), growth hormone
- Solitary, large

Laboratory

Elevated serum hormone in functional tumors (see Clinical features)
Elevated serum chromogranin A in 50 - 100%; correlates with tumor burden and metastasis but has limited utility due to low specificity and sensitivity (Arch Pathol Lab Med 2019;143:1317)

Radiology description

Round, solid, hypervascular
Subset may be cystic
Well circumscribed
Contrast enhanced computed tomography (CT) has decreased sensitivity in smaller (< 2 cm) tumors (Clin Endosc 2017;50:537)
Magnetic resonance imaging (MRI) has better sensitivity, especially for small tumors compared with CT (Clin Endosc 2017;50:537)
Gallium 68 dotatate positron emission tomography (PET) (Clin Endosc 2017;50:537):
- Uses radiolabeled somatostatin analog
- Useful for WDNETs, most of which express somatostatin receptor
- High sensitivity and specificity for somatostatin receptor expressing tumors

Radiology images

Images hosted on other servers:

MRI demonstrating small WDNET

CT and Gallium 68 Dotatate PET showing WDNET

Prognostic factors

WDNETs are usually slow growing with prolonged clinical course
PDNECs are usually aggressive and rapidly progressive
Ki67 index and mitotic count, as described for WHO grading
Prognostic immunohistochemical markers (not widely used in routine clinical practice):
- Expression of COX2, p27, CD99 and PR immunostains (Pathol Int 2001;51:770, Am J Clin Pathol 2003;120:685, Am J Surg Pathol 2006;30:1588, Cancer 1992;70:2268)
- Expression of CK19 is associated with aggressive behavior (Am J Surg Pathol 2006;30:1588, Histopathology 2007;50:597, Am J Surg Pathol 2004;28:1145)

Case reports

45 year old woman with possible VHL syndrome with mixed serous neuroendocrine neoplasm (World J Clin Cases 2019;7:4119)
48 year old man with cystic pancreatic WDNET radiographically mimicking cystic mucinous neoplasm (Autops Case Rep 2020;10:e2020171)
53 year old man with pancreatic WDNET with rhabdoid features (Virchows Arch 2018;473:247)
58 year old woman with systemic mastocytosis incidentally found to have pancreatic WDNET (Int J Surg Case Rep 2020;77:397)
73 year old woman with breast carcinoma with unrecognized neuroendocrine differentiation metastasizing to the pancreas (Int J Surg Pathol 2016;24:463)

Treatment

Surgical resection is the mainstay for WDNET, with resolution of both mass effect symptoms and symptoms associated with hormone secretion (Surg Clin North Am 2019;99:793)
- Benefit for both localized and metastatic disease
Other therapies for metastatic WDNET (Surg Clin North Am 2019;99:793):
- Somatostatin analog therapy
- Molecular therapies: tyrosine kinase inhibitor, sunitinib; mTOR inhibitor, everolimus
- Chemotherapy (capecitabine and temozolomide [CAPTEM])
- Peptide receptor radionuclide therapy (PRRT)
- Liver directed therapy: ablation or hepatic artery embolization of liver metastasis
PDNECs usually treated with platinum based chemotherapy (Surg Clin North Am 2019;99:793)

Gross description

Usually well circumscribed, homogeneous
May have cystic change
Color and consistency varies according to degree of vascularity and stroma, ranges from white to pink to tan to brown; may be yellow if necrosis present (Arch Pathol Lab Med 2009;133:350)
Pigmented black pancreatic neuroendocrine tumor contains intracytoplasmic lipfuscin and mimics metastatic melanoma (Arch Pathol Lab Med 2009;133:350)
Lipid rich pancreatic neuroendocrine tumor appears yellow and may mimic adrenal cortical neoplasia (Arch Pathol Lab Med 2009;133:350)
Large tumors may appear lobulated and infiltrative
Can invade adjacent fibroadipose tissue, other organs and large vessels

Gross images

Contributed by Danielle Hutchings, M.D.

Well circumscribed, solid tumor in pancreatic tail

Tumor with hemorrhage

Invasion into spleen

Large vessel invasion

Pancreatic duct obstruction

Cystic degeneration

Microscopic (histologic) description

Well differentiated neuroendocrine tumors:
- Organoid architecture: solid nests, trabeculae, gyri, cords, festoons, ribbons, glandular, tubuloacinar
- Small to medium cells with eosinophilic to amphophilic and finely granular cytoplasm; nuclei are uniform, central, round / oval, with salt and pepper (finely stippled) chromatin; no or inconspicuous nucleoli
- Rich vascular network
- Amyloid deposition in insulinomas
- Psammoma bodies in somatostatinomas
- May have hyaline globules (Am J Surg Pathol 2011;35:981)
- Variants include clear cell, lipid rich, oncocytic, rhabdoid and pigmented black neuroendocrine neoplasm (Arch Pathol Lab Med 2019;143:1317, Virchows Arch 2018;473:247, Cancer 2001;92:1984)
Poorly differentiated neuroendocrine carcinomas:
- Diffuse sheets or solid nests of markedly atypical malignant cells
- Salt and pepper chromatin is lost
- Abundant mitoses and apoptotic bodies
- Necrosis is frequent
- May be small cell (high N/C ratio, nuclear hyperchromasia and molding) or large cell (moderate to abundant amphophilic cytoplasm, may have prominent nucleoli) morphology

Microscopic (histologic) images

Contributed by Danielle Hutchings, M.D. and Sabrina Sopha, M.D.

Amyloid deposition

Poorly differentiated neuroendocrine carcinoma, small cell type

Poorly differentiated
neuroendocrine
carcinoma, large
cell type

Calcification

Cribriform pattern

Pseudoacinar pattern

Organoid pattern

Ki67 staining

INSM1 immunostain

Spread to duodenum (H&E and synaptophysin)

Synaptophysin staining

Chromogranin staining

Well differentiated pancreatic neuroendocrine tumor
(cell block, synaptophysin, chromogranin)

Cytology description

Well differentiated neuroendocrine tumors (Diagn Cytopathol 2006;34:649):
- Cellular specimen with clean background
- Clusters and individual cells
- Uniform round oval, small / medium sized cells
- Frequently plasmacytoid
- Amphophilic, finely granular cytoplasm (neurosecretory capability)
Poorly differentiated neuroendocrine carcinomas (Diagn Cytopathol 2006;34:649):
- Overtly malignant cells with small cell or large cell morphology
- Necrosis

Cytology images

Contributed by Sabrina Sopha, M.D. and AFIP images

Well differentiated pancreatic neuroendocrine tumor
(pap stained smears)

Round nuclei and scanty cytoplasm

Positive stains

Epithelial markers: CK8 / CK18, CAM 5.2, OSCAR, AE1 / AE3 (labels 50% of tumors) (Virchows Arch A Pathol Anat Histopathol 1986;409:609)
Neuroendocrine markers:
- Synaptophysin: strong and diffuse in WDNET; may be weak, patchy or negative in PDNEC (Hum Pathol 2020;96:8)
- Chromogranin A: may be more focal and 10 - 20% of WDNET may be negative; may be focal or negative in PDNEC (Hum Pathol 2020;96:8)
- INSM1: newer marker with high sensitivity and specificity (Am J Clin Pathol 2015;144:579)
- CD56, neuron specific enolase (NSE), CD57: less specific, limited utility (Hum Pathol 2020;96:8)
Panel to determine pancreatic origin for WDNET: Islet1+, PAX6+, TTF1-, CDX2 usually negative, SATB2-
- Panel is nonspecific in the setting of PDNEC
- TTF1 is positive in 40% of extrapulmonary PDNEC (Hum Pathol 2020;96:8)
Panel to differentiate WDNET, grade 3 from PDNEC (Arch Pathol Lab Med 2019;143:1317)
- WDNET: somatostatin receptor+, loss of DAXX / ATRX
- PDNEC: abnormal expression of p53, loss of RB1, loss of SMAD4 / DPC4
Hormone expression (insulin, glucagon, gastrin, somatostatin, VIP, pancreatic polypeptide): may be seen but does not indicate functional tumor
Trypsin: scattered positive cells may be seen but if > 25%, the tumor is classified as mixed (Am J Surg Pathol 1994;18:765, Am J Surg Pathol 2002;26:893, Dig Dis Sci 2002;47:2254)

Negative stains

Beta catenin (labels cell membrane only) (Arch Pathol Lab Med 2019;143:1317)
Trypsin (negative or only few positive cells) (Am J Surg Pathol 1994;18:765, Am J Surg Pathol 2002;26:893, Dig Dis Sci 2002;47:2254)
Chymotrypsin (Arch Pathol Lab Med 2019;143:1317)
BCL10 (Arch Pathol Lab Med 2019;143:1317)

Electron microscopy images

AFIP images

Enterochromaffin cell tumor: irregularly shaped

Molecular / cytogenetics description

WDNETs:
- MEN1 inactivation 44% (Arch Pathol Lab Med 2019;143:1317)
- DAXX / ATRX mutation or loss 43% (Arch Pathol Lab Med 2019;143:1317)
- mTOR pathway alterations (PTEN, TSC2, PIK3CA) 14% (Arch Pathol Lab Med 2019;143:1317)
- VHL small subset (Semin Diagn Pathol 2014;31:498)
Poorly differentiated neuroendocrine carcinomas and mixed neuroendocrine nonneuroendocrine neoplasms:
- TP53, RB, KRAS, APC, BRAF, SMAD4 / DPC4 (more like adenocarcinomas) (Arch Pathol Lab Med 2019;143:1317, Am J Surg Pathol 2012;36:173)

Videos

Solid tumors of the pancreas

Sample pathology report

Pancreas, distal pancreatectomy:
- Well differentiated neuroendocrine tumor, WHO grade 1 of 3 (3 cm) (see comment)
  - Ki67 proliferation index: 2%
  - 1 mitosis per 2 mm²
  - Tumor confined to the pancreas
- Lymphovascular and perineural invasion identified
- Proximal pancreatic parenchyma margin is uninvolved
- Metastatic tumor in 2/17 lymph nodes
- Comment: The tumor cells are positive for synaptophysin and chromogranin A.

Differential diagnosis

Solid pancreatic tumors:
- Acinar cell carcinoma:
  - Adults, high mitotic rate, labeling with BCL10, trypsin, chymotrypsin
  - May have focal positivity with synaptophysin but chromogranin is negative
- Pancreatoblastoma:
  - Children, squamoid nests
- Solid pseudopapillary neoplasm:
  - Women, degenerated pseudopapillae, hyaline globules
  - Nuclear labeling with beta catenin
  - May have focal positivity with synaptophysin but chromogranin is negative
- Usual ductal adenocarcinoma:
  - Desmoplastic stroma
  - Invasive mucin producing glands
- Paraganglioma:
  - Very rare, nested zellballlen architecture
  - Cytokeratin negative, S100 highlights sustentacular cells, GATA3 positive (Mod Pathol 2013;26:1365)
Clear cell tumors:
- Clear cell sarcoma:
  - Labels with melanoma markers and has t(12;22)
- Metastatic renal cell carcinoma:
  - PAX8+
- PEComa:
  - Labels with melanoma markers, inhibin, cathepsin K and TFE3, melanoma and other clear cell tumors
- Solid variant of serous cystadenoma:
  - Labels with inhibin (Am J Surg Pathol 2004;28:339)

Additional references

J Gastrointest Oncol 2020;11:548, Histopathology 2018;72:168, Am J Surg Pathol 2021;45:25, Clin Cancer Res 2016;22:1011, WHO Classification of Digestive System Tumours, 5th Edition, 2019

Board review style question #1

A 58 year old man presents with a 2.8 cm solid mass in the tail of the pancreas. Based on the morphology below, you suspect a well differentiated neuroendocrine tumor (WDNET). Which of the following immunoprofiles would be most characteristic of pancreatic WDNET?

Synatophysin-, chromogranin-, BCL10+, trypsin+, beta catenin cytoplasmic
Synatophysin-, chromogranin-, BCL10-, trypsin-, beta catenin nuclear
Synatophysin+, chromogranin+, BCL10-, trypsin-, beta catenin cytoplasmic
Synatophysin+, chromogranin-, BCL10-, trypsin-, cytokeratin-

Board review style answer #1

C. Synatophysin+, chromogranin+, BCL10-, trypsin-, beta catenin cytoplasmic

Comment Here

Reference: Neuroendocrine neoplasms-general

Board review style question #2

A 45 year old woman presents recurrent episodes of dizziness, palpitations and sweating, which she reports usually resolve with drinking orange juice. She is found to have a 2.0 cm solid mass in the body of the pancreas. Resection specimen is shown in the image above. What is the most likely diagnosis based on H&E and congo red stains?

Acinar cell carcinoma
Gastrinoma
Insulinoma
Pancreatic ductal adenocarcinoma
Well differentiated pancreatic neuroendocrine tumor, nonfunctional

Board review style answer #2

C. Insulinoma

Comment Here

Reference: Neuroendocrine neoplasms-general

Neuroendocrine tumor with sarcomatous differentiation

Table of Contents

Definition / general

Well differentiated neuroendocrine tumor with poorly differentiated myosarcomatous component

Essential features

Extremely rare lesion (two cases reported in English literature)
Lesion may transition from neuroendocrine to sarcomatous component or may have two discrete admixed components

Terminology

Both reported cases use outdated term islet cell tumor, as they were published in 1989 and 2001

ICD coding

ICD-10: C25.4 - malignant neoplasm of endocrine pancreas

Radiology images

Images hosted on other servers:

CT scan

Case reports

61 year old woman with 11 cm pancreas mass (Mod Pathol 2001;14:1187)
Patient with widely metastatic lesion with rhabdomyosarcomatous component (Am J Surg Pathol 1989;13:422)

Microscopic (histologic) description

Lesion is primarily composed of typical well differentiated neuroendocrine tumor
Sarcomatous component may have rhabdomyosarcomatous features or may show spindled cells with enlarged nuclei arranged in bundles
Sarcomatous component is admixed with neuroendocrine component but transition may be gradual or abrupt (with sarcomatous component appearing as discrete nodules)

Microscopic (histologic) images

Images hosted on other servers:

Nests of small, uniform polygonal cells

Pushing margin

Spindle cell component

Chromogranin

Desmin

Topoisomerase II alpha

Positive stains

Neuroendocrine markers (synaptophysin, chromogranin) in neuroendocrine component
Desmin in sarcomatous component

Electron microscopy description

Z lines and thick filaments (if rhabdomyosarcomatous component)

Sample pathology report

Pancreas and duodenum, Whipple procedure:
- Pancreatic neuroendocrine tumor with focal sarcomatous differentiation (see synoptic report and comment)
- Comment: Sarcomatous differentiation is extremely rare in pancreatic neuroendocrine tumors. Immunohistochemical stains for synaptophysin and chromogranin are positive in the typical neuroendocrine component and the Ki67 index in that component is approximately 2.7% (WHO grade 1).

Differential diagnosis

Leiomyosarcoma:
- Most common sarcoma of pancreas
- Would not demonstrate neuroendocrine component

Board review style question #1

A neuroendocrine tumor of the pancreas with a sarcomatous component would be most likely to show what sort of differentiation within that component?

Angiosarcomatous
Leiomyosarcomatous
Liposarcomatous
Osteosarcomatous

Board review style answer #1

B. Leiomyosarcomatous. Additionally, leiomyosarcoma is the most common primary sarcoma of the pancreas.

Comment Here

Reference: Neuroendocrine tumor with sarcomatous differentiation

Pancreatic cystic fluid analysis (pending)

[Pending]

Pancreatic polypeptide secreting tumors

Table of Contents

Definition / general

Neuroendocrine tumor with high proportion of pancreatic polypeptide (PP) cells
Not a WHO diagnosis

Essential features

Pancreatic neuroendocrine tumor that sometimes causes watery diarrhea, hypokalemia, achlorhydria (WDHA) syndrome (due to PP secretion)
May metastasize to liver

Terminology

Sometimes called PPoma

ICD coding

ICD-10: C25.4 - malignant neoplasm of endocrine pancreas

Sites

May arise anywhere within pancreas

Pathophysiology

Pancreatic polypeptide regulates endocrine and exocrine secretion by the pancreas
Vasoactive intestinal polypeptide (VIP) and PP are derived from a common precursor and thus pancreatic polypeptide secreting tumors can also cause watery diarrhea, hypokalemia, achlorhydria (WDHA) syndrome
It has been proposed that most / all nonfunctioning pancreatic neuroendocrine tumors represent pancreatic polypeptide secreting tumors (Best Pract Res Clin Gastroenterol 2012;26:737)

Clinical features

Can cause nonspecific abdominal pain or watery diarrhea, hypokalemia, achlorhydria (WDHA) syndrome
Patients may have multiple endocrine neoplasia 1 syndrome (MEN1) (Arch Surg 1984;119:508)

Diagnostic criteria

Pancreas mass and elevated levels of fasting pancreatic polypeptide hormone

Radiology images

Images hosted on other servers:

CT and ultrasound
with pancreatic
head mass

Case reports

46 year old woman with WDHA syndrome (Case Rep Gastroenterol 2008;2:238)
46 year old woman with MEN1 (Int J Gastrointest Cancer 2002;32:153)

Treatment

Surgery is generally curative (World J Surg 2008;32:1815)

Microscopic (histologic) description

Resembles all other well differentiated neuroendocrine tumors of the pancreas

Microscopic (histologic) images

AFIP images

Trabecular growth

Pancreatic endocrine tumor with PP expression

Images hosted on other servers:

Chromogranin and PP

Positive stains

Synaptophysin, chromogranin, PP

Electron microscopy images

Images hosted on other servers:

Abundant basal accumulation of secretory granules

Sample pathology report

Pancreas, tail, resection:
- Pancreatic neuroendocrine tumor, WHO grade 2 (see synoptic report and comment)
- Comment: The patient’s clinical history of watery diarrhea, hypokalemia and achlorhydria is noted. This may be due to pancreatic polypeptide secretion by this tumor. Immunohistochemical stains for synaptophysin and chromogranin are positive and the Ki67 index is approximately 3.2%.

Differential diagnosis

Nonfunctional well differentiated neuroendocrine tumor:
- Same microscopic appearance
- Some PP secretion may be seen by immunohistochemistry
- Distinction is based on serum PP levels
VIPoma:
- Same microscopic appearance
- Can also cause watery diarrhea, hypokalemia, achlorhydria (WDHA) syndrome
- Distinction is based on serum PP levels
Pancreatic polypeptide cell hyperplasia:
- Neuroendocrine hyperplasia admixed with elements of normal pancreas (J Clin Pathol 2006;59:1087)

Board review style question #1

Which of the following pancreatic neuroendocrine tumors can cause watery diarrhea, hypokalemia and achlorhydria?

Glucagonoma
Insulinoma
Pancreatic polypeptide secreting tumor (PPoma)
Somatostatinoma

Board review style answer #1

C. Pancreatic polypeptide secreting tumor (PPoma). Watery diarrhea, hypokalemia, achlorhydria (WDHA) syndrome can also be caused by VIPomas.

Comment Here

Reference: Pancreatic polypeptide secreting tumors

Pancreatoblastoma

Table of Contents

Definition / general

Rare pancreatic malignancy that is seen most often in children and displays multiple lines of differentiation

Essential features

Displays at least 2 pancreatic lines of differentiation, including acinar, ductal and neuroendocrine elements
Presence of squamoid nests is a defining diagnostic feature
Tumors are aggressive, with complete surgical resection being the most important prognostic factor

Terminology

Infantile pancreatic carcinoma
Pancreatic carcinoma in childhood (Cancer Cytopathol 2019;127:708)

ICD coding

ICD-O: 8971/3 - pancreatoblastoma
ICD-11:
- 2C10.Y - other specified malignant neoplasm of pancreas
- XH27L5 - pancreatoblastoma

Epidemiology

Children > adults
- Most common pancreatic tumor of children < 10 years old
  - Median age in this group is 4 - 5 years (Pediatr Surg Int 2019;35:1231)
- Mean age of presentation of adult tumors is 41 years
- M = F (Gland Surg 2015;4:322)
Only about 200 cases reported in the literature

Sites

About 50% occur in pancreatic head, with the rest relatively equally split between tail and body (Gland Surg 2015;4:322)
1 reported case found in ampulla of Vater (Arch Pathol Lab Med 2003;127:1501)

Pathophysiology

Unknown
Loss of chromosome 11p or mutations in APC / B catenin pathway possibly implicated in pathogenesis (Gland Surg 2015;4:322)

Etiology

Unknown
Some cases associated with Beckwith-Wiedemann syndrome, familial adenomatous polyposis (Gland Surg 2015;4:322)

Clinical features

Generally nonspecific presentation; most common symptom is abdominal pain (Sci Rep 2020;10:11285)
Commonly advanced at presentation with local extension and metastases
- Commonly metastasizes to liver > lymph nodes > lung
Associated with Beckwith-Wiedemann syndrome, familial adenomatous polyposis (Gland Surg 2015;4:322)

Diagnosis

Can be identified on CT or MRI
Difficult to diagnose by FNA due to variety of cell lines expressed (Gland Surg 2015;4:322)

Laboratory

Up to 50% of pediatric patients can show elevations in carcinoembryonic antigen (CEA) and alpha fetoprotein (AFP); less helpful in adults (Gland Surg 2015;4:322)
- 66% of children will have AFP > 1000 μg/L
Some tumors reported to secrete adrenocorticotropic hormone (ACTH), resulting in Cushing syndrome (J Cancer Res Ther 2015;11:1027)

Radiology description

Generally solid, irregular lesion but can be cystic or degenerative
Can grow outward, as branches growing from a tree trunk (Sci Rep 2020;10:11285)

Radiology images

Images hosted on other servers:

Pancreatoblastoma,
CT scan

Prognostic factors

Prognosis largely dependent on resectability of tumor (Pancreatology 2004;4:441)
- 5 year survival for resectable tumors: 65%
- 5 year survival for nonresectable tumors: 0%
Presence of distant metastases portends poorer prognosis
Prognosis worse in adults, as children tend to have well encapsulated tumors without metastases

Case reports

4 year old boy with multiple pancreatic and liver masses (Ecancermedicalscience 2018;12:861)
27 year old woman with a 3.6 cm pancreatic mass and metastasis to the liver and lungs (JOP 2012;13:301)
69 year old man with a pancreatic head mass (BMJ Case Rep 2020;13:e233884)

Treatment

Complete surgical resection is critical to prognosis
- Chemotherapy or radiotherapy may be used to ensure complete resection

Gross description

Large (average size is 10 cm), lobulated, fleshy mass
Can have cystic components or soft areas of necrosis
- Predominantly cystic tumors can be seen in Beckwith-Wiedemann syndrome (Gland Surg 2015;4:322)

Gross images

Images hosted on other servers:

Pancreatoblastoma,
body / tail mass

Microscopic (histologic) description

Multilineage components resembling embryologic pancreas
Geographic hypercellular solid tumor lobules separated by fibrous bands
Acinar differentiation is the predominant pattern, mimicking acinar cell carcinoma:
- Acinar appearances resembling normal acini, with small lumen and luminal secretion
- Focal solid, trabecular or pseudoglandular patterns
- Cells with eosinophilic or amphophilic granular cytoplasm, mild atypical nuclei and small nucleoli
Squamoid nests:
- Defining feature, present in every case
- Plump to spindle shaped cells with abundant eosinophilic / clear cytoplasm arranged in whorls or nests
- Typically bland cytology
- May show keratinization
Neuroendocrine component:
- More than 50% of cases show focal neuroendocrine differentiation
- Neuroendocrine cells diffusely intermix with acinar component, being highlighted by immunostains or form focal organoid or trabecular growth
Ductal component:
- Very focal glandular formation
- May be highlighted by a mucicarmine stain
Primitive component:
- Solid sheets of immature small round cells
Stroma:
- Variable cellularity
- Sometimes showing heterologous elements (e.g. bone, cartilage)
Reference: Am J Surg Pathol 1995;19:1371

Microscopic (histologic) images

Contributed by Lizhi Zhang, M.D.

Geographic tumor lobules

Lobulated tumor nests

Acinar differentiation

Squamoid nests

Squamoid nests with keratinization

Neuroendocrine component

Ductal component

Primitive component

Stroma

Keratin immunostain

Trypsin immunostain

Beta catenin immunostain

CK5 immunostain

Synaptophysin immunostain

Cytology description

Loosely cohesive, blast-like tumor cells are small, with fine chromatin, granular cytoplasm and atypia with nucleoli (Cancer Cytopathol 2019;127:708)
- Mimic acinar cell carcinoma
Squamoid nest cells can be well defined, whorled clusters or syncytial appearing groups (Cancer Cytopathol 2019;127:708)
- Better appreciated on cell block preparations

Positive stains

Pancytokeratin
Squamoid nests positive for beta catenin (nuclear staining), CK5 and EMA
Acinar markers (Gland Surg 2015;4:322):
- Trypsin
- Chymotrypsin
- Lipase
- BCL10
- PASD positive cytoplasmic granules
Ductal markers (positive in up to 65% of cases) (Gland Surg 2015;4:322):
- CEA
- B72.3
- DUPAN-2
- CK19
- Mucicarmine
Neuroendocrine markers (if present) (Gland Surg 2015;4:322):
- Synaptophysin
- Chromogranin
- INSM1
- AFP, if serum levels are elevated

Negative stains

Germ cell markers
p53
Rare cases loss of DPC4 expression (Am J Pathol 2001;159:1619)

Electron microscopy description

All showing zymogen granules (400 - 800 nm) for acinar differentiation (Am J Surg Pathol 1995;19:1371)
Some with neuroendocrine granules (125 - 250 nm) and mucigen granules (500 - 900 nm)

Molecular / cytogenetics description

Loss of chromosome 11p (Gland Surg 2015;4:322)
Alterations in the APC / beta catenin pathway (Am J Pathol 2001;159:1619)

Sample pathology report

Pancreas, duodenum and gallbladder, Whipple procedure:
- Pancreatoblastoma, forming an 8 x 6 x 4 cm mass in the pancreatic head (see comment)
- Tumor is confined within the pancreas without extension to peripancreatic soft tissue, common bile duct and duodenum
- Tumor necrosis is present
- Angiolymphatic and perineural invasion are present
- All surgical margins are negative for tumor
- Background pancreatic parenchyma is unremarkable
- Multiple (3 of 14) regional lymph nodes are positive for metastatic tumor
- Gallbladder is without diagnostic abnormality
- Comment: Immunoperoxidase stains show the tumor cells are positive for trypsin with beta catenin nuclear staining in the scattered squamoid nests, confirming the diagnosis. Focal area is also positive for synaptophysin and chromogranin, representing a minor component of neuroendocrine tumor. No convincing component of ductal adenocarcinoma is seen.

Differential diagnosis

Acinar cell carcinoma:
- No squamoid nests or other lines of differentiation
- No nuclear beta catenin staining
Neuroendocrine tumor / carcinoma:
- May have focal acinar appearance but no squamoid nests
- Nested or trabecular growth patterns
- Diffuse positive staining of neuroendocrine markers (synaptophysin, chromogranin, INSM1)
- No nuclear beta catenin staining
Solid pseudopapillary neoplasm:
- No acinar differentiation
- No squamoid nests
- Pseudopapillary structures
- Diffuse nuclear beta catenin staining
Undifferentiated carcinoma or anaplastic carcinoma:
- No acinar differentiation
- No squamoid nests
- Highly atypical and pleomorphic tumor cells
- May have multinucleated giant tumor cells or osteoclast-like giant cells

Additional references

WHO Classification of Tumours Editorial Board: Digestive System Tumours, 5th Edition, 2019

Board review style question #1

A 40 year old man presents with abdominal pain and unintentional weight loss. Subsequent imaging reveals an 8 cm mass in the pancreatic head invading into the duodenum and a likely metastasis in the liver. The patient undergoes neoadjuvant chemoradiation and a pancreaticoduodenectomy. A representative histology section is shown above. The cell population that most definitively identifies this diagnosis would be most specifically highlighted by which of the following immunohistochemical stains?

Alpha fetoprotein
Beta catenin
Chromogranin
Trypsin

Board review style answer #1

B. Beta catenin. Nuclear staining of beta catenin is a marker of alterations in the APC / beta catenin pathway, which commonly occurs in pancreatoblastoma associated with loss of chromosome 11p.

Comment Here

Reference: Pancreatoblastoma

Board review style question #2

A 5 year old boy presents with weight loss, abdominal pain and distention and hepatomegaly. An abdominal ultrasound reveals a pancreatic mass and multiple liver masses. A pancreas biopsy is performed. Based on the findings in the image shown above, what is the most likely diagnosis?

Acinar cell carcinoma
Malignant germ cell tumor
Pancreatic neuroendocrine tumor
Pancreatoblastoma

Board review style answer #2

D. Pancreatoblastoma. The characteristic squamoid nest shown in the image is a defining feature of pancreatoblastoma, present in every case.

Comment Here

Reference: Pancreatoblastoma

PanIN

Table of Contents

Definition / general

Pancreatic intraepithelial neoplasia (PanIN) is a microscopic neoplastic lesion of the pancreas that can progress to invasive ductal adenocarcinoma (Arch Pathol Lab Med 2017;141:1606)
Regarded as the main precursor lesion to invasive pancreatic carcinoma
Small, papillary or flat, noninvasive epithelial neoplasm characterized by variable mucin production and a spectrum / variable degrees of cytologic and architectural atypia (Am J Surg Pathol 2015;39:1730)
By definition, it is a nontumoral form of dysplasia (intraepithelial neoplasia) (see intraductal papillary mucinous neoplasm for the tumoral version of intraepithelial neoplasia)
As such, almost by default, it doesn't have any clinical manifestation
Other noninvasive precursors of pancreatic ductal adenocarcinoma such as intraductal papillary mucinous neoplasms (and similar intraductal neoplams) and mucinous cystic neoplasms, all of which are defined as grossly visible (tumoral) forms of intraepithelial neoplasia, are classified separately (Am J Surg Pathol 2015;39:1730, Am J Surg Pathol 2004;28:977)

Essential features

Usually < 0.5 cm (very small to be seen grossly or by radiologic imaging)
2 tiered classification, low grade versus high grade, was recommended to replace the former 3 tiered classification for PanIN, intraductal papillary mucinous neoplasm and mucinous cystic neoplasm at the Baltimore consensus meeting (2014) (Am J Surg Pathol 2015;39:1730)
Only carcinoma in situ type lesions are regarded high grade and warrant clinical attention

ICD coding

ICD-O: 8148/2 (for high grade only)

Epidemiology

Increase in frequency by age
Low grade lesion is a very common incidental finding (found in over half of the population > 50 years) (Ann Surg Oncol 2013;20:3643, Mod Pathol 2003;16:996)
In contrast, high grade is rarely seen without invasive ductal adenocarcinoma (Mod Pathol 2003;16:996)
- It can occasionally be seen incidentally in pancreatectomy performed for other lesions

Sites

Anywhere in the pancreas, mostly in cases with resected pancreatic ductal adenocarcinoma
It is more common in branch ducts rather than in main pancreatic duct
Can be present in heterotopic pancreas (Am J Surg Pathol 2017;41:833)

Diagrams / tables

Images hosted on other servers:

Classification

Clinical features

Does not manifest clinically
PanINs are very common adjacent to resected pancreatic ductal adenocarcinoma (Ann Surg Treat Res 2018;94:247)

Prognostic factors

Low grade is inconsequential
High grade believed to have a high frequency of progression into pancreatic ductal adenocarcinoma and therefore needs careful evaluation
PanIN of any grade at a margin of a resected pancreas that already has invasive carcinoma doesn't seem to have any prognostic implications; however, if PanIN 3 (carcinoma in situ) is encountered at a margin in a pancreas without carcinoma, it needs to be carefully evaluated (Am J Surg Pathol 2015;39:1730)

Case reports

47 year old woman with PanIN in heterotopic pancreas that was incidentally diagnosed on endoscopic mucosal resection of a duodenal polyp (BMJ Case Rep 2018 Jun 23;2018)
58 year old man with PanIN 2 in heterotopic pancreas (J Gastrointestin Liver Dis 2017;26:199)
63 year old man and 77 year old man with high grade PanIN over long time periods (Oncology 2017;93:81)
82 year old man with concurrent PanIN and type 1 autoimmune pancreatitis with marked pancreatic duct dilatation (Clin J Gastroenterol 2016;9:266)

Gross description

Not detectable grossly
Occasionally obstructs a duct and lead to subtle fibrosis of upstream pancreatic tissue

Frozen section images

Images hosted on other servers:

Margins with PanIN 1, 2 and 3

Microscopic (histologic) description

Usually < 0.5 cm
2 tiered classification, low grade versus high grade, was recommended to replace the former 3 tiered classification for PanIN, intraductal papillary mucinous neoplasm and mucinous cystic neoplasm at the Baltimore consensus meeting (2014) (Am J Surg Pathol 2015;39:1730)
PanIN 1A / low grade:
- Earliest precursor lesion
- Flat epithelium composed of tall columnar mucin producing cells with basally located small round to oval nuclei
- Cells show essentially no cytologic atypia
PanIN 1B / low grade:
- Identical to PanIN 1A but epithelium shows papillary, micropapillary or basally pseudostratified architecture
PanIN 2 / low grade:
- Flat to papillary mucinous epithelial proliferations with focal or mild nuclear abnormalities, such as loss of polarity, nuclear enlargement, nuclear crowding, hyperchromatism and pseudostratification
- Rare mitoses but not apical or atypical
PanIN 3 / high grade / carcinoma in situ:
- Predominantly papillary or micropapillary architecture, rarely flat
- Cribriforming, tufting pattern and luminal necrosis suggests PanIN 3
- Cytologically, these lesions have loss of polarity, dystrophic mucinous cells, enlarged irregular nuclei and prominent (macro) nucleoli
- Increased mitotic figures, including atypical forms
- Only carcinoma in situ type lesions are regarded as PanIN 3 / high grade (Am J Surg Pathol 2015;39:1730)

Pancreatic intraepithelial neoplasia classification
Oldest terminology	WHO 2010 classification	Baltimore consensus meeting 2014
Mucinous (goblet cell) metaplasia, flat duct lesion without atypia, mucinous ductal hyperplasia, simple hyperplasia, mucinous cell hyperplasia, flat duct hyperplasia, nonpapillary epithelial hypertrophy	PanIN 1A	Low grade PanIN
Papillary hyperplasia, papillary duct lesion without atypia, ductal hyperplasia, adenomatoid hyperplasia	PanIN 1B
Atypical hyperplasia, papillary duct lesion with atypia, low grade dysplasia, moderate dysplasia	PanIN 2
Carcinoma in situ, intraductal carcinoma, high grade dysplasia, severe dysplasia	PanIN 3	High grade PanIN

Microscopic (histologic) images

Contributed by Ayşe Armutlu, M.D.

Normal

Low grade / PanIN 1A

Low grade / PanIN 1B

Low grade / PanIN 2

High grade / PanIN 3

Cytology description

PanINs are, by definition, microscopic incidental lesions, not visible clinically or radiologically and therefore are not amenable to targeting by fine needle aspiration biopsy
On rare occasions that they come to aspiration material, they would appear as mucinous glandular epithelium with atypical changes but their nature as PanIN cannot be affirmed
The diagnosis of a PanIN should not be rendered on cytologic preparations

Positive stains

MUC5AC, MUC6, HER2 nonbreast and fascin
MUC1 (luminal membranous; cytoplasmic in high grade) and cyclin D1
Ki67 labeling increases with PanIN grade
In high grade lesions, a subset with p53 overexpression or SMAD4 / DPC4 loss

Negative stains

p63, p40

Molecular / cytogenetics description

Early molecular changes: telomere shortening, KRAS oncogene activation (can be seen in PanIN 1 / low grade), p21 upregulation
Intermediate steps: inactivation of tumor suppressor gene p16 CDKN2A
Late stages: BRCA2, SMAD4 (DPC4) and TP53 tumor suppressor gene inactivation (Am J Clin Pathol 2014;141:168, Arch Pathol Lab Med 2017;141:366)

Sample pathology report

Pancreas, tail, distal pancreatectomy:
- Incidental low grade pancreatic intraepithelial neoplasm (see comment)
- Comment: Incidental pancreatic intraepithelial neoplasms that are low grade are of no known clinical significance to an extent that consensus is that it may not even have to be reported. They are very common in general population.
Pancreas, tail, distal pancreatectomy:
- High grade pancreatic intraepithelial neoplasm (carcinoma in situ) (see comment)
- Comment: High grade pancreatic intraepithelial neoplasms are seldom detected in isolation. Invariably they represent carcinoma elsewhere in the gland. In fact, this finding may represent pagetoid spread of invasive carcinoma from somewhere else in the pancreas which is now showing intraductal spread ("cancerization") and creating the image of high grade pancreatic intraepithelial neoplasm. This possibility needs to be excluded with careful evaluation of the patient before this is accepted as a mere precursor lesion.

Differential diagnosis

Normal mucosal elements and peribiliary glands in ampulla and bile ducts:
- In the vicinity of the ampulla and bile ducts, normal mucosal elements often show cytologic findings that would otherwise qualify as low grade PanIN if they occur in the pancreatic ducts
Transitional / squamous metaplasia:
- Shows stratified cells with high N/C ratio and this can closely mimic high grade PanIN
Cancerization of ducts:
- Invasive carcinomas may re-enter and grow within the pancreatic ducts in a pagetoid spreading pattern, mimicking PanIN 3
- Invasive carcinoma near a duct lesion transitioning from high grade atypia to normal duct epithelium suggests cancerization but it can sometimes be impossible to make this determination
- In a case with invasive carcinoma, high grade lesion in a duct may have to be considered cancerization of ducts, especially if it is spatially close to invasive glands (Am J Surg Pathol 2015;39:1730)
Tumoral intraepithelial neoplasia:
- Defined as clinically and grossly visible intramucosal / intraepithelial tumors that are generally > 1 cm
- These include the branch duct spread of tumors like intraductal papillary mucinous neoplasm
- If taken in isolation at microscopic level, especially when they have more gastric / endocervical-like morphology, these tumors can be indistinguishable from PanINs
- Gastric type intraductal papillary mucinous neoplasms have significant morphologic overlap with PanINs at a microscopic level (Ann Surg 2016;263:162)
  - Though not widely employed, for cysts > 0.5 cm and < 1 cm lined by gastric-like mucinous epithelium, the term incipient intraductal papillary mucinous neoplasm has been proposed (Am J Surg Pathol 2014;38:360)
  - In indeterminate cases, should be classified as PanIN, not intraductal papillary mucinous neoplasm
Simple mucinous cysts with flat mucinous lining:
- Cysts with usually flat, gastric phenotype, lack ovarian stroma and are > 1 cm (Am J Surg Pathol 2017;41:121)
- Can show dysplastic changes of variable degrees and sometimes are diagnosed as simple mucinous cyst with PanIN
Vascular invasion in pancreatic ductal adenocarcinoma:
- If the invasive neoplastic cells form complete luminal structures inside of the blood vessels, classify the case as having PanIN-like vascular invasion (Am J Surg Pathol 2012;36:235)

Board review style question #1

A 60 year old man, who is an alcoholic, presented with back pain, weight loss and jaundice. Gross sections showed firm, white-beige appearance in the head of the pancreas. Initial histologic sections demonstrated chronic pancreatitis and this lesion in a focal area. Which of the following statements concerning this case and this pancreatic lesion is true?

p63 / p40 often labels this lesion
This does not need to be reported
This is low grade pancreatic intraepithelial neoplasia (PanIN 1)
This is probably accompanied by carcinoma and warrants a thorough examination of the remaining pancreas
This lesion is a very common incidental lesion in the general population

Board review style answer #1

D. This is probably accompanied by carcinoma and warrants a thorough examination of the remaining pancreas

Comment Here

Reference: PanIN (pancreatic intraepithelial neoplasia)

Board review style question #2

Which of the following statements concerning pancreatic intraepithelial neoplasia is true?

High grade PanIN (PanIN 3) is usually seen in pancreas without invasive ductal adenocarcinoma
PanIN 2 is a high grade pancreatic intraepithelial neoplasia by new classification
PanIN of any grade (including low grade) at a margin of a resected pancreas has very important prognostic implications
PanINs are large lesions that can be seen grossly or by radiologic imaging
Recommended latest terminology from Baltimore consensus meeting is a 2 tiered system: low grade and high grade PanIN

Board review style answer #2

E. Recommended latest terminology from Baltimore consensus meeting is a 2 tiered system: low grade and high grade PanIN

Comment Here

Reference: PanIN (pancreatic intraepithelial neoplasia)

Poorly differentiated neuroendocrine carcinoma

Table of Contents

Definition / general

Poorly differentiated, high grade, malignant epithelial neoplasm with neuroendocrine differentiation
Poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs) are divided into small cell type (SC PanNEC) and large cell type (LC PanNEC)

Essential features

Poorly differentiated neuroendocrine carcinomas represent a distinct entity from well differentiated (G1, G2, G3) neuroendocrine tumors (Am J Surg Pathol 2012;36:173)
By morphology, PanNECs can be divided into small cell or large cell subtypes
At the immunohistochemical level, the expression of neuroendocrine markers can be partial or weak (chromogranin A expression can even be absent)
Tumor necrosis and high grade cytology
Ki67 proliferation index > 20% (usually uniform and > 60%) (Ann Oncol 2013;24:152)
- Mitotic rate of > 20 mitoses/2 mm²

Terminology

Neuroendocrine carcinoma refers to poorly differentiated neuroendocrine neoplasms, high grade by definition
- Neuroendocrine tumor is now reserved for well differentiated neoplasms with typical pathologic features of neuroendocrine lineage, truly resembling their nonneoplastic counterpart (cells of pancreatic islet), regardless of grade
The current WHO (2019) classification groups pancreatic neuroendocrine neoplasms as follows:
1. Pancreatic neuroendocrine microtumor (< 5 mm); previously known as neuroendocrine microadenoma
2. Well differentiated pancreatic neuroendocrine tumor (WD PanNETs), including nonfunctional PanNETs and functional PanNETs (with clinical evidence of hormone release, such as insulinoma, glucagonoma, gastrinoma, VIPoma)
3. Poorly differentiated pancreatic neuroendocrine carcinomas (PD PanNECs), including SC PanNECs and LC PanNECs
Mixed neuroendocrine nonneuroendocrine neoplasm (MiNEN)
- Mixed neoplasm with a neuroendocrine component combined with a nonneuroendocrine component (typically ductal adenocarcinoma or acinar cell carcinoma)
- Each component must account for ≥ 30% of the tumor cell population and both components should be morphologically recognizable
- Neuroendocrine component may be a tumor (less frequently) or a carcinoma (more frequently)

ICD coding

ICD-O:
- 8246/3 - neuroendocrine carcinoma, NOS
ICD-11:
- 2C10.1 & XH0U20 - neuroendocrine neoplasms of pancreas & neuroendocrine carcinoma, NOS
- XH9SY0 - small cell neuroendocrine carcinoma
- XH0NL5 - large cell neuroendocrine carcinoma

Epidemiology

Rare (accounting for < 1% of all pancreatic tumors and no more than 2 - 3% of pancreatic neuroendocrine neoplasms)
Mean patient age is 59 years (patients are usually aged 50 - 60 years but can occur in younger patients as well)
M:F = 1.4:1
Large cell variant is more commonly encountered (60%) (Am J Surg Pathol 2012;36:173)

Sites

Pancreatic gland (head, neck, body, tail)
Head of the pancreas is the most common site (Am J Surg Pathol 2012;36:173)

Pathophysiology / etiology

Largely unknown
Tobacco smoking

Diagrams / tables

Images hosted on other servers:

Survival curves for
well differentiated
tumors and
carcinomas

Clinical features

Back pain, jaundice (for PanNECs of pancreatic head) or nonspecific abdominal symptoms, likewise pancreatic ductal adenocarcinomas
Neoplastic syndromes secondary to ectopic hormone production, such as ACTH (rare)
Vast majority (> 90%) of patients present with metastasis at the time of diagnosis (Am J Surg Pathol 2012;36:173)

Diagnosis

CT scan, MRI and ultrasonography are the preferred imaging modality
FDG PET scans present high standardized uptake value
Somatostatin receptor scintigraphy (SSRS) is often negative (or focal avidity) due to lack of expression of SSTR2 and SSTR5 (Arch Pathol Lab Med 2020;144:816)
Diagnosis is by cytology / fine needle biopsy or on surgical specimens (Am J Surg Pathol 2016;40:1192)

Laboratory

Serum hormone activity (such as chromogranin A) is very unusual (Cancer 1973;31:1523)
Serum carcinoma associated markers (e.g., CEA, CA19-9, CA125) levels may be elevated (Am J Surg Pathol 2016;40:1192)

Radiology description

CT and MRI features: irregular margins and frequent presence of necrotic foci within tumor mass

Grading

PanNECs are, by WHO definition high grade, based on Ki67 (MIB1) index > 20% and mitotic rate > 20 mitoses/2 mm²
WD PanNETs are graded from G1 to G3; but G3 PanNETs represent a distinct entity from PanNECs (Endocr Pathol 2022;33:115, Pathologica 2021;113:28)

Prognostic factors

Very poor prognosis, compared to WD PanNETs
Metastatic spread is present in most patients at the time of diagnosis
MiNEN including a NEC component show an aggressive behavior: in these tumors, the Ki67 index of the NEC component is the most important prognostic driver (Endocr Relat Cancer 2018;25:583)
Even in cases amenable to surgical resection and treated with adjuvant platinum based therapy, the median survival time is very short (< 1 year) and < 25% of patients survive beyond 2 years (Am J Surg Pathol 2012;36:173)

Case reports

27 year old woman with ACTH secreting PanNEC causing Cushing syndrome with pelvic and bilateral ovarian metastases (Int J Clin Exp Pathol 2015;8:15396)
56 year old man presenting with pure, alpha fetoprotein producing PanNEC without another coexisting malignant component, such as adenocarcinoma or hepatoid carcinoma (BMC Gastroenterol 2015;15:16)
65 year old man with SC PanNEC with similar genetic alterations to invasive ductal adenocarcinoma (KRAS mutation, altered expressions of TP53 and SMAD4 / DPC4) (Clin J Gastroenterol 2016;9:261)
67 year old woman with cutaneous metastases of a PanNEC with CK20 positivity (G Ital Dermatol Venereol 2018;153:722)

Treatment

Surgical resection
Chemotherapy (no established protocol): platinum based regimen (Pancreas 2021;50:138)

Gross description

Large neoplasms with infiltrative borders
Brownish to whitish color, fleshy or hard consistency and typically with grossly visible necrotic areas (Endocr Pathol 2022;33:115, Pathologica 2021;113:28)

Gross images

Images hosted on other servers:

Small cell carcinoma

Frozen section description

High grade and hypercellular neoplasm, with necrotic areas
Diagnosis should be postponed to definitive examination after formalin fixation and also supported by ancillary methods (Endocr Pathol 2022;33:115, Pathologica 2021;113:28)

Microscopic (histologic) description

Hypercellular neoplasm, with large and irregular nests, infiltrative growth pattern with randomly oriented large vascular structures and desmoplastic type fibrosis
Necrosis with geographic pattern and comedo-like appearance
High rate of cellular turnover (high mitotic rate and high apoptotic rate) (Front Oncol 2013;3:2)
SC PanNEC: diffuse sheets of relatively small cells with round or elongated hyperchromatic nuclei, finely granular chromatin and lacking nucleoli; typical feature of nuclear molding (sharing with the pulmonary counterpart) (Front Oncol 2013;3:2)
LC PanNEC: nesting / trabecular pattern, with round to polygonal medium to large sized cells, with amphiphilic cytoplasm and atypical nuclei with either coarse chromatin or conspicuous nucleoli; the nuclear to cytoplasmic (N/C) ratio of LCNECs is lower than that of SCNECs

Microscopic (histologic) images

Contributed by Claudio Luchini, M.D., Ph.D. and AFIP images

General morphological appearance

Tumor necrosis

Large cell PanNEC

Small cell PanNEC

Nodal metastasis of PanNEC

Synaptophysin positivity

Chromogranin A positivity

Typical p53 expression

Rb loss

Focal necrosis

Intense immunostaining for NSE

Solid diffuse pattern

Scattered somatostatin immunoreactive cells

Cytology description

Scant cytoplasm, slightly granular and high N/C ratio
SC PanNEC: small cells with large nuclei, nuclear molding, finely speckled and dark chromatin with inconspicuous nucleoli, prominent background degeneration and typical crush artifact with nuclear streaming (Am J Surg Pathol 2012;36:173)
LC PanNEC: large undifferentiated cells with bizarre forms or syncytial aggregates, irregular overlapping nuclei with prominent nucleoli, vesicular chromatin and abundant cytoplasm (delicate, dense or granular) (Am J Surg Pathol 2012;36:173)

Cytology images

Images hosted on other servers:

Overlapping pancreatic cells

Positive stains

Cytokeratins (CK8 / CK18, CK AE1 / AE3)
Synaptophysin: usually positive, may be rarely weak or focal (Am J Surg Pathol 2012;36:173)
Chromogranin A: usually positive or weakly positive; can be also almost absent; SC PanNEC can also show a paranuclear dot-like immunoreactivity (Endocr Pathol 2018;29:150)
CD56, neuron specific enolase (NSE), protein gene product 9.5 (PGP9.5) / ubiquitin C terminal hydrolase 1 protein (UCHL1): general neuroendocrine markers, less specific, limited utility
Insulinoma associated protein 1 (INSM1) has emerged as an additional general neuroendocrine marker (Am J Clin Pathol 2015;144:579)
Achaete-scute homolog 1 (ASH1) (Hum Pathol 2013;44:1391)
p53: abnormal expression pattern / nuclear accumulation (Pathologica 2021;113:28)
Useful (but neither ideal nor absolute) panel for determining pancreatic origin is PDX1+, ISL1+, PAX8+, CDX2+, TTF1- (Pathologica 2021;113:28)

Negative stains

Rb (classic loss of Rb protein) (Am J Surg Pathol 2012;36:173)
SMAD4 (Am J Surg Pathol 2016;40:1192)
BCL10 (helping in excluding an acinar cell carcinoma or the presence of a focal acinar differentiation)
Beta catenin (no nuclear staining; normal positivity of cell membrane)

Molecular / cytogenetics description

Alterations of TP53 and Rb represent the most typical molecular events in PanNEC (Cancer Treat Rev 2017;56:28, Cancer Discov 2022;12:692)
KRAS is also mutated in a significant proportion of cases (up to 30%) (Am J Surg Pathol 2012;36:173)
Inactivation of SMAD4 / DPC4 is also reported (5%) (Am J Surg Pathol 2012;36:173)
Microsatellite instability can be present in up to 5 - 8% of cases and should be assessed at the time of diagnosis (Hum Pathol 2022 Jun 14 [Epub ahead of print])

Sample pathology report

Duodenum and pancreatic head, pancreaticoduodenectomy:
- Pancreatic neuroendocrine carcinoma, large cell type (see comment)
- Pancreatic head with the presence of a high grade neuroendocrine neoplasm
- Ki67 (MIB1) index 70%; mitotic rate: 50 mitoses/2 mm²
- Presence of tumor necrosis
- The neoplasm infiltrates distal choledochus, adipose tissue and duodenum
- Metastasis in 3/12 lymph nodes
- Surgical margins without tumor involvement
- Comment: The integration of morphology with the immunohistochemical profile (and in particular, CK AE1 / AE3 and CK8 / CK18 positive, synaptophysin positive, chromogranin A weakly positive, TP53: aberrant pattern; Rb: negative) is consistent with the diagnosis of pancreatic neuroendocrine carcinoma.

Differential diagnosis

Well differentiated G3 neuroendocrine tumor (WD PanNET):
- Nonfunctional PanNETs are identified incidentally and have no symptoms
- PanNETs G3 show avidity on SSRS imaging (Octreoscan and Gallium 68 Dotatate PET / CT)
- Cytology: PanNETs G3 show abundant granular cytoplasm, low N/C and stippled chromatin
- Resection specimens: in PanNETs G3, the G3 component is usually not homogenous and mixed with a lower grade counterpart and the same for Ki67, which is heterogeneous
- Positive stains: in PanNETs, there are diffuse and strong chromogranin A (more specific) and synaptophysin (more sensitive) staining
- Molecular profile: in PanNETs, TP53 and Rb are usually wild type; there are recurrent and mutually exclusive mutations of DAXX (death domain associated protein, 25%) and ATRX (alpha thalassemia / intellectual disability syndrome X linked, 17.6%), usually wild type in PanNECs (Science 2011;331:1199)
High grade neuroendocrine carcinomas of other sites (pancreatic metastasis):
- NKX3.1+ in prostate
- CDX2+ / SATB2+ in lower GI tract
- CDX2- / SATB2+ in upper GI tract
- Both pancreas and small bowel primaries can be PAX8+
Other pancreatic primaries:
- Acinar cell carcinoma:
  - Positive for BCL10 and trypsin
  - Usually negative for neuroendocrine markers (scattered positive cells can be observed)
- Mixed neuroendocrine nonneuroendocrine neoplasms:
  - Different components should be identified by morphology and not only by immunohistochemistry
- Medullary carcinoma:
  - Syncytial growth pattern, intratumor inflammatory cells
  - Negative for neuroendocrine markers
Lymphoma:
- Most important markers are CD3, CD20, CD45, CD79a
- Negative for neuroendocrine markers
Melanoma:
- Positive for MART1, HMB45, SOX10
- Negative for neuroendocrine markers
Small blue cell tumors in young adults:
- Desmoplastic small cell tumor (Am J Surg Pathol 2004;28:808):
  - Large nests and broad bands of small blue cells, separated by fibrous stroma
  - Positive stains: cytokeratins (AE1 / AE3 and CAM5.2), NSE, desmin and WT1
  - Negative stains: chromogranin A, S100 and CD99
- Primitive neuroectodermal tumors (Am J Surg Pathol 2002;26:1040):
  - Sheets and lobules of small cells with round to oval nuclei, nuclear molding and scant cytoplasm; no Homer-Wright rosettes
  - Positive stains: CD99, cytokeratins (AE1 / AE3 and CAM5.2), NSE, chromogranin A or synaptophysin (may be focal or diffuse)
  - Negative stans: desmin, actin, S100 protein, insulin, glucagon or somatostatin

Additional references

WHO Classification of Tumours Editorial Board: Digestive System Tumours, 5th Edition, 2019

Board review style question #1

Which are the molecular hallmarks of PanNEC?

CCND1 amplification
DAXX and ATRX mutation
EGFR alteration
KRAS mutation
TP53 and Rb alteration

Board review style answer #1

E. TP53 and Rb alteration. Indeed, the most typical molecular events in PanNEC are TP53 and Rb alteration. Immunohistochemistry is a good surrogate of their molecular status and in PanNEC it generally shows an aberrant expression pattern (usually a hyperaccumulation) for p53 and Rb loss.

Comment Here

Reference: Neuroendocrine carcinoma

Board review style question #2

This photograph shows a primary pancreatic neoplasm. Which of the following histological features, present in the picture above, support the diagnosis of PanNEC?

Acinar-like appearance
Focal tumor necrosis and nuclear features
Glandular formation
Perineural invasion
Vascular invasion

Board review style answer #2

B. Focal tumor necrosis and nuclear features. Tumor necrosis is a very important morphological feature for supporting the diagnosis of PanNEC but the immunohistochemical confirmation of the neuroendocrine nature is also very important.

Comment Here

Reference: Neuroendocrine carcinoma

PRSS1 hereditary pancreatitis

Table of Contents

Definition / general

Autosomal dominant disorder caused by mutations of serine protease 1 (PRSS1), also known as the cationic trypsinogen gene, characterized by progressive irreversible lipomatous atrophy of the pancreatic parenchyma leading to pancreatic insufficiency (Am J Surg Pathol 2014;38:346)
Most common subtype of familial hereditary pancreatitis (80%); other gene mutations associated with chronic pancreatitis include SPINK1, CFTR and CTRC
Incomplete penetrance; 40 - 93% of mutation carriers develop chronic pancreatitis
Patients may develop pancreatic intraepithelial neoplasia (PanIN) and have an increased lifetime risk of pancreatic cancer

Essential features

Autosomal dominant mutation of PRSS1 with incomplete penetrance
Recurrent episodes of acute pancreatitis that progress to chronic pancreatitis and lipomatous atrophy of the pancreas
Increased risk of pancreatic cancer

Terminology

Familial pancreatitis, hereditary chronic pancreatitis, autosomal dominant hereditary pancreatitis, recurrent or relapsing acute or chronic pancreatitis

ICD coding

ICD-10: K86.1 - other chronic pancreatitis

Epidemiology

Age of onset ranges from infancy to sixth decade of life
Highest prevalence in the mid and southeastern regions of the United States, as well as parts of France, England and Germany (Clin Gastroenterol Hepatol 2004;2:252, Pancreatology 2001;1:439)

Pathophysiology

R122H and N29I mutations in PRSS1 result in an increased propensity for trypsin-mediated trypsinogen activation, referred to as autoactivation, resulting in increased inappropriate intrapancreatic trypsin activity and digestion of the pancreatic parenchyma (Clin Exp Gastroenterol 2016;9:197)
R122H mutation is a dual gain of function mutation that also prevents the autodegradation of active trypsin (Biochem Biophys Res Commun 2000;278:286)
Obstruction from intraductal calculi may be responsible for lipomatous atrophy; exact mechanism unclear

Clinical features

Recurrent episodes of acute pancreatitis, typically starting in childhood, with progression to chronic pancreatitis over time
Presentation of acute and chronic pancreatitis is clinically indistinguishable from other etiologies for pancreatitis

Diagnosis

Patients should be suspected of PRSS1 associated hereditary pancreatitis with the following: acute pancreatitis occurring in childhood; recurrent acute pancreatitis of unknown etiology; chronic pancreatitis of unknown cause (especially among individuals before age 25); a family history of recurrent acute pancreatitis and chronic pancreatitis following an autosomal dominant pattern of inheritance; and a family history of pancreatitis and pancreatic cancer
Considering the aforementioned suspected clinical findings, a diagnosis is established by the identification of a heterozygous pathologic mutation in PRSS1
Rare cases of PRSS1 R122H and A16V mutations have been reported in nonhereditary pancreatitis; therefore, family history prior to genetic testing is important to avoid misclassification and unnecessary testing (Clin Genet 2001;59:189, Pancreas 2001;22:18)

Prognostic factors

R122H mutation may be associated with a more aggressive course, with earlier onset and increased severity of disease (Br J Surg 2000;87:170)

Case reports

38 month old boy with pancreaticopleural fistula (Pediatr Gastroenterol Hepatol Nutr 2019;22:601)
12 year old boy with recurrent abdominal pain (Tohoku J Exp Med 2001;195:191)
15 year old girl with painless, progressive abdominal distention (Postgrad Med J 1986;62:873)
11 family members with chronic pancreatitis (Arch Dis Child 1999;80:473)

Treatment

Management is the same as for sporadic disease
Total pancreatectomy may be considered in older patients due to the increased risk of cancer (World J Gastroenterol 2003;9:1)
Relatives should undergo genetic counseling

Gross description

Pediatric specimens are typically unremarkable
Adult specimens are soft and shrunken with marked atrophy and fat replacement, ductal dilatation and multiple intraductal calcifications

Gross images

Contributed by Aatur D. Singhi, M.D., Ph.D.

Gross parenchymal atrophy

Microscopic (histologic) description

Childhood (early) changes
- Patchy loss of acinar and ductal tissue
- Loose perilobular and interlobular fibrosis
- Relative preservation and aggregation of islets of Langerhans (resulting in a hyperplastic appearance)
Young adult (second to third decade of life) changes
- Progressive loss of acinar cell mass and ductal epithelium and increased fibrosis over time
- Fibrosis is increasingly intermingled with adipocytes
- Islets of Langerhans are still preserved
Older adult (fourth to sixth decade of life) changes
- Near complete replacement of pancreatic parenchyma by mature adipose tissue with scattered islets of Langerhans and nerves
- Primarily periductal fibrosis
- Main pancreatic duct and larger interlobular ducts are more likely to be dilated, while smaller ducts are reduced or scarred
- Amyloid deposition may be seen
Nonspecific ductal changes such as atrophy, dilatation, squamous metaplasia and intraductal calcifications
Can be associated with pancreatic intraepithelial neoplasia at any age (Am J Surg Pathol 2014;38:346, Dig Liver Dis 2012;44:8)

Microscopic (histologic) images

Contributed by Aatur D. Singhi, M.D., Ph.D.

Early microscopic changes

Residual islets of Langerhans

Progressive replacement by fibrosis and fat

Near complete replacement

Low grade PanIN

Molecular / cytogenetics description

2 most common PRSS1 mutations are the R122H and N29I missense mutations
> 30 mutations within PRSS1 have been identified; other less common mutations include A16V, R122C, N29T, D22G and K23R (Clin Gastroenterol Hepatol 2004;2:252)

Sample pathology report

Pancreas, biopsy:
- Pancreatic parenchyma with intralobular and interlobular fibrosis (history of hereditary pancreatitis)
Pancreas, total pancreatectomy:
- Pancreatic parenchyma with intralobular and interlobular fibrosis, marked acinar parenchymal loss and pseudolipomatous atrophy (history of hereditary pancreatitis)
- Low grade pancreatic intraepithelial neoplasia
- Benign cystic dilation of small and large pancreatic ducts with associated reactive epithelial changes including squamous metaplasia
- Reactive bile duct mucosal changes with associated fibrosis
- 15 benign lymph nodes
- Negative for malignancy

Differential diagnosis

Cystic fibrosis:
- Autosomal recessive disorder caused by CFTR mutation
- Progressive pancreatitis also characterized by lipomatous pseudohypertrophy; may share a common pathophysiological mechanism
- Majority of patients present with pancreatic insufficiency in utero or early infancy
Alcoholic / obstruction associated chronic pancreatitis:
- Fibrosis in PRSS1 hereditary pancreatitis is relatively thinner and less compact (Am J Surg Pathol 2014;38:346)
Lipomatous pseudohypertrophy of the pancreas:
- Common degenerative change in the obese and elderly
- Typically presents as a focal lesion and not as extensive as seen in PRSS1 pancreatitis
Other conditions associated with lipomatous pseudohypertrophy include Cushing syndrome, steroid therapy, malnutrition, viral infection, main pancreatic duct obstruction and other genetic syndromes

Additional references

Gastroenterology 1952;21:54, Gastroenterology 1996;110:1975

Board review style question #1

PRSS1

Diagnosis is made based primarily on radiology
Most common PRSS1 mutations are N29I and A16V
Patients are at an increased risk of pancreatic cancer
Pattern of inheritance for this entity is autosomal recessive

Board review style answer #1

C. Patients are at an increased risk of pancreatic cancer. This picture shows a pancreas with partial replacement of normal parenchyma with loose perilobular and interlobular fibrosis with scattered adipocytes. In a patient with a family history of recurrent pancreatitis, identification of a pathologic mutation in PRSS1 in this patient establishes a diagnosis of PRSS1 hereditary pancreatitis. As the patient's disease progresses, the pancreas will continue to undergo replacement largely by adipocytes with primarily perilobuductal fibrosis. PanIN has been seen in several cases of hereditary pancreatitis and these patients are at an increased risk of pancreatic cancer.

Inheritance is in an autosomal dominant pattern with variable penetrance. The most common PRSS1 mutations are R122H and N29I. Patients' clinical, laboratory and radiological presentations of acute and chronic pancreatitis are the same as for other etiologies. Careful family history taking and testing for a PRSS1 mutation in a suspected individual is what establishes the diagnosis.

Comment Here

Reference: PRSS1 hereditary pancreatitis

Board review style question #2

PRSS1

Definitive diagnosis can be made if lipomatous atrophy is present
Islets of Langerhans are preferentially lost in early stages of the disease while acinar tissue is preserved
Pancreatic intraepithelial neoplasia can be present at any age
Presence of intraductal calcifications is associated with an increased risk of pancreatic cancer

Board review style answer #2

C. Pancreatic intraepithelial neoplasia can be present at any age. PRSS1 hereditary pancreatitis is a progressive disease. In early stages, fibrosis and loss of acinar and ductal tissue is mild and patchy while islets of Langerhans are relatively preserved, which can result in a hyperplastic appearance. As the disease progresses, the pancreatic parenchyma undergoes near complete replacement by mature adipose tissue and fibrosis. Lipomatous atrophy is a nonspecific finding, which can be seen as a degenerative change in the obese and elderly or in patients with cystic fibrosis or other genetic syndromes. Intraductal calcifications are not associated with an increased risk of cancer and are one of several nonspecific microscopic changes seen in hereditary pancreatitis, along with ductal dilatation, squamous metaplasia and amyloid deposition. Patients with PanIN are at an increased risk of pancreatic cancer and PanIN can be seen at any age.

Comment Here

Reference: PRSS1 hereditary pancreatitis

Pseudocysts

Table of Contents

Definition / general

Encapsulated collection of homogenous fluid with a well defined fibrous / inflammatory wall
Localized collections of pancreatic secretions that usually develop after pancreatitis (acute or chronic), trauma, ductal calculi or obstructive neoplasms

Essential features

There is no epithelial lining
Fluid content
Nonneoplastic nature

Terminology

Pseudocyst is the only standard term to indicate this condition
Older terms (e.g., false cyst) are discouraged

ICD coding

ICD-10: K86.3 - pseudocyst of pancreas

Epidemiology

Male prevalence (M:F = 4:1)
Peak of incidence in fourth to fifth decade
Virtually all patients with pancreatic pseudocyst have symptoms and show an history of acute or chronic pancreatitis (Am J Gastroenterol 2018;113:464)
Typically, pancreatic pseudocyst is unilocular and does not display calcification
Involvement of main pancreatic duct is common and it might be irregularly dilated with stones (Pancreatology 2017;17:738)

Sites

All parts of the pancreatic gland may be involved
Distal location (body / tail) is more frequent than the cephalic presentation (65% of cases show body / tail involvement)

Etiology

Thought to arise from disruption of the main pancreatic duct (or its intrapancreatic branches) and the consequent leakage of pancreatic juice that results in a persistent, localized fluid collection (Gut 2013;62:102)
May also arise in the setting of acute necrotizing pancreatitis as a result of a disconnected duct syndrome, whereby pancreatic parenchymal necrosis of the neck or body of the gland isolates a still viable distal pancreatic remnant (Gastrointest Endosc 2008;68:91)

Clinical features

Pseudocysts are detectable at least 4 weeks after the clinical presentation of acute pancreatitis, which requires at least 2 of the 3 following features:
- Abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe, epigastric pain, often radiating to the back)
- Serum lipase activity (or amylase activity) at least 3 times greater than the upper limit of normal
- Characteristic findings of acute pancreatitis on contrast enhanced CT; less commonly on MRI or transabdominal ultrasonography (Gut 2013;62:102)

Diagnosis

First line of imaging to study pancreatic lesions is represented by CT / MRI
Second line is represented by endoscopic ultrasound (EUS) with cyst fluid analysis
Histopathology (Pathologica 2020;112:197)

Laboratory

EUS could be easily associated with additional investigation, such as
- Cyst fluid analysis; in particular, in pseudocyst, there is usually a marked increase in amylase activity and a very low carcinoembryonic antigen (CEA) concentration in the cyst fluid (Gut 2013;62:102, Gastrointest Endosc Clin N Am 2018;28:549)
Pathology: see Cytology description and Microscopic (histologic) description

Radiology description

In particular, CT is indicated for the detection of parenchymal, mural or central calcification, especially when differentiating pseudocysts associated with chronic pancreatitis from pancreatic cystic neoplasm (Gut 2018;67:789)
If CT / MRI is not sufficient, EUS examination is recommended
- Presence of hyperenhancing solid components within cystic lesion rules out the diagnosis of pseudocyst

Case reports

7 year old boy with pancreatic pseudocyst caused by blunt abdominal trauma (J Med Case Rep 2017;11:217)
13 year old boy with pancreatic pseudocyst in a setting of incomplete pancreas divisum and recurrent acute pancreatitis (J Int Med Res 2021;49:3000605211014395)
40 year old woman with pseudocyst arising in gastric ectopic pancreas (Clin Res Hepatol Gastroenterol 2014;38:389)
41 year old woman with pancreatic pseudocyst treated with endoscopic management after stent displacement (World J Gastroenterol 2015;21:2249)
49 year old man with pancreatic pseudocyst that was suspected to be a cystic neoplasm, specifically a solid pseudopapillary neoplasm (Cureus 2020;12:e9883)

Treatment

For evacuation of the material that sustains the pseudocyst, 2 major approaches (endoscopic or laparoscopic) are used
- Endoscopic drainage consists of stent implantation by endoscopic retrograde cholangiopancreatography or by EUS
  - Advantages: short operation time, low intraoperative blood loss, low to null intra-abdominal sewing, low chances of injury to blood vessels and nerves, short hospital stay, low opioid demand
  - Disadvantages: complications, such as hemorrhage, recurrence and stent exchange, occur in 5 - 19% of procedures
- Laparoscopic drainage
  - Advantages: removal of more consistent quantities of necrotic tissue and better exploration of cyst wall structure than with the endoscopic approach
  - Disadvantages: complications such as abdominal contamination, incomplete anastomosis, gastric perforation (Pancreas 2021;50:788)
Current guidelines for treatment of cystic pancreatic lesions discourage surgical treatment of pancreatic cystic lesions, unless there is a high probability of neoplastic degeneration or in order to relieve symptoms of clinical pancreatitis (Pancreatology 2017;17:738)
Patients with asymptomatic cysts do not require treatment or surveillance if they are diagnosed as pseudocysts on initial imaging and clinical history or if they have a very low risk of malignant transformation (e.g., serous cystadenoma of the pancreas) (Am J Gastroenterol 2018;113:464)

Gross description

Typically unilocular
Diameter is variable; can be > 20 cm in size
Thick, irregular wall that contains turbid, sometimes blood tinged fluid (Pathologica 2020;112:197)

Gross images

Contributed by Paola Mattiolo, M.D. and Claudio Luchini, M.D., Ph.D.

Large pancreatic pseudocyst

Fibrous wall of pseudocyst

Large pseudocyst of the pancreatic head

Cut surface of the pseudocyst of figure 3

Images hosted on other servers:

Multiseptated lesion filled with fluid

Encapsulated cystic lesion with yellow-green material

Resembling cystic neoplasm

Microscopic (histologic) description

By definition, there is no epithelial lining; please note that large pancreatic ducts may interface between pseudocyst and adjacent pancreas
Cyst wall may contain histiocytes, giant cells, granulation tissue, rarely eosinophils
To rule out the presence of neoplastic epithelium or dysplastic changes, examination of the entire cyst wall is strongly suggested (Pathologica 2020;112:197, Am J Gastroenterol 2018;113:464)

Microscopic (histologic) images

Contributed by Paola Mattiolo, M.D., Claudio Luchini, M.D., Ph.D. and AFIP images

Absence of an epithelial lining

Inflammation of pseudocyst wall

Fibrotic reaction

Hemorrhagic modifications

Patient with chronic pancreatitis and pseudocyst

Cytology description

Cyst fluid cytology typically demonstrates hemosiderin laden macrophages, acute inflammatory cells or lymphocytes, fibrin, debris, bile pigment and lack of neoplastic cells
Through the needle microforceps biopsy: modality that allows the collection of samples from pancreatic cystic wall for microscopic histological examination through a 19 gauge needle
- Advantages: diagnostic accuracy is high (up to around 80%) (Gastrointest Endosc 2019;90:784)
- Disadvantages: the procedure is burdened by the occurrence of adverse effect in ~9% of cases, 4% of cases with severe adverse events and 1% of cases with fatality, while it changes the clinical management in ~11% of cases; thus, patient selection should be strictly managed and limited to those in whom sampling has a high probability of changing the clinical management (Endoscopy 2021;53:44)

Negative stains

Cytokeratin (all types) are negative: by definition, no epithelial cells are present in pseudocyst lining

Sample pathology report

Duodenum and pancreatic head, pancreaticoduodenectomy:
- Pancreatic head with the presence of cyst without an epithelial lining (see comment)
- The pancreatic cyst has been entirely analyzed
- Regional lymph nodes with reactive changes; duodenum without pathological modifications
- Comment: The histological appearance is consistent with the diagnosis of pancreatic pseudocyst. Correlation of histology with clinical history and radiology is strongly suggested.

Differential diagnosis

Pancreatic cystic neoplasm:
- Particularly if multiloculated, may display significant denudation of the lining epithelium (Dig Liver Dis 2020;52:547)
  - Intraductal papillary mucinous neoplasms (IPMNs)
  - Serous cystic neoplasms:
    - Even if completely denudated, it displays a subepithelial network of delicate capillary channels (Am J Surg Pathol 2012;36:726)
  - Mucinous cystic neoplasms (MCNs):
    - Even if completely denudated, it displays ovarian type stroma
  - Cystic neuroendocrine neoplasms:
    - Display a neuroendocrine epithelial lining, positive at immunohistochemistry for chromogranin A and synaptophysin
  - Solid pseudopapillary neoplasms:
    - Present neoplastic tissue, with necrotic / hemorrhagic cystic changes and tumor cells that are positive at immunohistochemistry for beta catenin (nuclear), LEF1 and CD10
  - Cystic pancreatic ductal adenocarcinoma:
    - Display malignant ductal epithelial lining, which is positive at immunohistochemistry for CK7 and CK8/18
Acute necrotic collection:
- Differs from pseudocyst because it is not well defined and it is filled by a commixture of fluid and necrosis, with different density
- Appears during the clinical manifestation of the necrotizing pancreatitis
Walled off necrosis:
- Differs from pseudocyst because it is filled by a commixture of fluid and necrosis, with different density
Infective cysts:
- Secondary bacterial infection may produce cyst
- Rarely, Echinococcus spp. may cause hydatid cyst in the pancreas and it should be suspected in endemic region (Diagn Cytopathol 1992;8:65, World J Gastrointest Surg 2014;6:190)
Cystic lymphangiomas:
- Lesion associated with prominent lymphoid tissues that demonstrates ectatic spaces lined by endothelial type cells
Lymphoepithelial cysts:
- Radiologically and sonographically indistinguishable from pseudocyst
- Smears show abundant anucleated squamous cells, keratinous debris, nucleated squamous cells and it is possible to recognize squamous cell block with preserved granular layer (Cancer 2006;108:501)
Cysts associated with paraduodenal pancreatitis:
- Differential diagnosis is given by the clinicopathological context
Squamoid cysts of the pancreas:
- Extremely uncommon cyst that is lined exclusively by squamous epithelium, lacking in solid areas
Acinar cystic transformation of the pancreas:
- Cystic lesion lined by acinar epithelium
- Not excluded the presence of foci of mucinous or squamous epithelium
Congenital cysts of the pancreas:
- Rare cysts that arise by developmental errors of pancreatic ducts, presumably related to localized obstruction of the duct in the utero
- Typically, these cysts are symptomatic before the second year of age and histologically, they present nonmucin producing cuboidal, columnar or flattened cells (Semin Diagn Pathol 2000;17:7)
Enteric duplication cysts:
- Rare congenital malformations that are most commonly diagnosed in children
- These cysts display gastric or intestinal type lining epithelium and a well developed, bilayered muscular wall
Ciliated foregut cysts:
- Cytology is characterized by amorphous debris, rare macrophages and ciliated columnar cells and detached ciliary tufts, which distinguish ciliated foregut cyst from pseudocyst
Epidermoid cysts:
- Presence of squamous epithelium and keratin flakes
Colliquated metastasis:
- Renal cell carcinoma is the most common source of metastasis to the pancreas
- Other malignancies that involve the pancreatic district are melanoma, pulmonary, mammary, gastric and colonic adenocarcinoma

Additional references

Odze: Odze and Goldblum Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas, 3rd Edition, 2014

Board review style question #1

Is this histological image of pancreatic parenchyma sufficient to support the diagnosis of pseudocyst?

No, it is necessary to examine the entire lesion in order to exclude the presence of epithelium
Yes, the image proves the absence of dysplastic epithelium
Yes, the image proves the presence of a fibrotic wall
Yes, the image shows a fibrotic wall with bona fide disepithelization
Yes, the image shows the presence of residual pancreatic parenchyma

Board review style answer #1

A. No, it is necessary to examine the entire lesion in order to exclude the presence of epithelium. For the diagnosis of pseudocysts, first it is mandatory to exclude the presence of an epithelial cell lining. A random sampling is not sufficient; the sampling should allow the examination of the entire lesion.

Comment Here

Reference: Pseudocysts

Board review style question #2

Which analysis of cystic fluid is most suspicious for pseudocyst?

High carcinoembryonic antigen (CEA), high amylase
High CEA, high lipase
High CEA, low amylase
Low CEA, high amylase
Low CEA, low amylase

Board review style answer #2

D. Low CEA, high amylase. Typically, the cyst fluid analysis of a pseudocyst usually shows a very low CEA concentration in the cyst fluid (
Comment Here

Reference: Pseudocysts

Risk stratification of IPMNs (pending)

[Pending]

Sclerosing epithelioid mesenchymal neoplasm

Table of Contents

Definition / general

A novel indolent pancreatic neoplasm with unique morphologic / immunophenotypic features and a distinct methylation pattern, different from both epithelial and mesenchymal neoplasms described in other anatomical sites (Mod Pathol 2020;33:456)
First described in 2020 (Mod Pathol 2020;33:456)

Essential features

Indolent
Well circumscribed tumor with a geographic pattern of epithelioid cell nests alternating with spindle cell fascicles
Vimentin (diffuse), CD99 (diffuse) and cytokeratin (AE1 / AE3 and CK18, dot-like) expression
Lack of abnormalities in any of key genetic drivers
Mesenchymal transcriptomic features and distinct methylation signature

Epidemiology

Mean age: 43 years (Mod Pathol 2020;33:456)
F:M = 3:1 (Mod Pathol 2020;33:456)

Sites

Mostly occurs in head and neck of the pancreas (Mod Pathol 2020;33:456)

Clinical features

Nonspecific symptoms

Laboratory

Serum tumor markers (CA19.9 and CEA) within normal limits

Prognostic factors

None known; exhibits indolent behavior (Mod Pathol 2020;33:456)

Case reports

31 year old woman with suspected solid pseudopapillary neoplasm of the pancreatic tail (Pancreas 2021;50:e47)

Gross description

Well circumscribed and solid, usually confined to the pancreatic parenchyma
White-tan and firm cut surface
Median tumor size: 1.8 cm (Mod Pathol 2020;33:456)

Gross images

Images hosted on other servers:

Well circumscribed solid lesion

Microscopic (histologic) description

Solid neoplasms associated with extensive fibrosis and dense lymphoid aggregates at the periphery (Mod Pathol 2020;33:456)
Entrapped pancreatic parenchyma may be seen at the periphery or within the tumor
Density of tumor cells varies significantly, not only among tumors but also throughout each tumor, creating a geographic appearance of hypercellular and hypocellular areas with collagenous stroma
No true epithelial structures such as glands, papillae or pseudopapillae (Mod Pathol 2020;33:456)
Most cells are epithelioid to spindled with scant cytoplasm and round to oval nuclei with open chromatin
- Others display more irregular, hyperchromatic nuclei
Occasional mitotic figures may be seen

Microscopic (histologic) images

Contributed by Olca Basturk, M.D.

Overall appearance

Well circumscribed lesion

Peripheral dense lymphoid aggregates

Entrapped pancreatic parenchyma

Hypercellular and hypocellular areas

Sheets of epithelioid cells

Atypical spindle cells

Dense hyaline fibrosis

Membranous CD99 expression

Dot-like CK18 expression

Positive stains

Vimentin, CD99, AE1 / AE3, CK18 (dot-like) (Mod Pathol 2020;33:456)

Negative stains

Synaptophysin, chromogranin, abnormal beta catenin, progesterone receptor, CD10, trypsin, chymotrypsin, MUC4, desmin, myogenin, INI1 (retained), ERG, CD31, CD34, S100, HMB45, MelanA, CD117, DOG1, TTF1, HepPar1, BCL2, ALK, STAT6, CD21, CD35, CD45 (Mod Pathol 2020;33:456)

Electron microscopy description

Nonspecific findings; occasional desmosomes, perinuclear tonofilaments and abundant rough endoplasmic reticulum (Mod Pathol 2020;33:456)

Molecular / cytogenetics description

No recurrent somatic mutations, amplifications or deletions in any known oncogenes or suppressor genes (Mod Pathol 2020;33:456)
Activation or enrichment of pathways related to the extracellular matrix, tight junctions, adherens junctions and TGFβ signaling by Gene Set Enrichment Analysis (Mod Pathol 2020;33:456)
A unique cluster by unsupervised analysis of the methylation profiles (Mod Pathol 2020;33:456)

Molecular / cytogenetics images

Images hosted on other servers:

Genomic and transcriptomic characterization

Sample pathology report

Pancreas and duodenum, pancreaticoduodenectomy:
- Sclerosing epithelioid mesenchymal neoplasm (see comment)
- Comment: The tumor is confined to the pancreatic parenchyma and measures 2.2 cm in greatest dimension. Adjacent pancreas reveals atrophy. Surgical margins are free of tumor. 16 benign lymph nodes are identified (0/16).

Differential diagnosis

Solid pseudopapillary neoplasm:
- Pseudopapillae, areas of macrophages, hyaline globules and nuclear grooves
- Abnormal beta catenin and nuclear progesterone receptor expression
- CTNNB1 mutations
Sarcomatoid carcinoma:
- Larger infiltrative tumors with considerable pleomorphism, necrosis and proliferative activity
- Glandular component may be present
- KRAS, TP53, SMAD4, CDKN2A mutations
Sclerosing epithelioid fibrosarcoma:
- MUC4 expression
- EWSR1-CREB3L1, FUS-CREB3L21 or FUS-CREB3L2 fusions
Solitary fibrous tumor:
- Ovoid to spindle shaped tumor cells with patternless pattern and staghorn-like vessels
- CD34, BCL2, CD99 and nuclear STAT6 expression
- NAB2-STAT6 fusion
Inflammatory myofibroblastic tumor:
- Loose fascicles of uniform, plump spindle cells with inflammatory infiltrate
- ALK, ROS1, SMA, desmin expression
- ALK or ROS1 fusions
Perivascular epithelioid cell neoplasm (PEComa):
- Smooth muscle (SMA, desmin, calponin, caldesmon) and melanocytic marker (HMB45, MelanA) expression
- TSC1 / TSC2 mutations
Gastrointestinal stromal tumor:
- CD117, DOG1 and CD34 expression
- KIT or PDGFRA mutations

Board review style question #1

Which one of the following stains is positive in sclerosing epithelioid mesenchymal neoplasm of the pancreas in the figure shown above?

CD34
CD99
DOG1
MUC4
S100

Board review style answer #1

B. CD99

Comment Here

Reference: Sclerosing epithelioid mesenchymal neoplasm

Board review style question #2

Which one of the following microscopic features is seen in sclerosing epithelioid mesenchymal neoplasms of the pancreas?

No entrapped pancreatic parenchyma is seen within the tumors.
They are composed of epithelioid cells only.
They are predominantly hypocellular tumors.
They have well circumscribed borders.
True epithelial structures such as glands, papillae and pseudopapillae are common.

Board review style answer #2

D. They have well circumscribed borders.

Comment Here

Reference: Sclerosing epithelioid mesenchymal neoplasm

Serous cystadenoma

Table of Contents

Definition / general

Benign pancreatic neoplasm of presumed ductal origin but of nonmucinous nature (Semin Diagn Pathol 2014;31:475, Am J Surg Pathol 2015;39:1597, Pancreatology 2009;9:182)
Characterized by glycogen rich (nonmucinous; serous) epithelial cells with distinctive cytology showing uniform round nuclei with homogenous dense chromatin
A prominent microvascular network hugging the epithelium as in other clear cell tumors with VHL pathway alterations (Am J Surg Pathol 2015;39:1597, Pancreatology 2009;9:182, Surgery 2012;152:S4)
Microcystic pattern, which is the most common, creates a unique sponge-like configuration diagnostic of this tumor type

Essential features

Rare, benign pancreatic neoplasm, more common in females and elderly patients (Semin Diagn Pathol 2014;31:475, Am J Surg Pathol 2015;39:1597, Pancreatology 2009;9:182)
Characterized by numerous, small cystic spaces (synonym: microcystic adenoma) lined by distinctive glycogen rich epithelial cells (synonym: glycogen rich adenoma) with uniform round nuclei and a prominent microvascular network hugging the epithelium (Am J Surg Pathol 2015;39:1597, Pancreatology 2009;9:182, Surgery 2012;152:S4)
Microcystic pattern, which is the most common, creates a unique sponge-like configuration diagnostic of this tumor type

ICD coding

ICD-O: 8441/0 - serous cystadenoma, NOS
ICD-10: K86.2 - cyst of pancreas

Epidemiology

Rare pancreatic tumor that often presents as a cystic mass occurring predominantly in women (F:M = 3:1)
Mean age of patients is 58 years (Am J Surg Pathol 2015;39:1597)

Sites

Can be found anywhere but more frequently in the tail of the pancreas

Etiology

VHL pathway alterations (and can occur in VHL syndrome patients) but no known etiology

Clinical features

Mean age: 58
F:M = 3:1
Frequently occurs sporadically but rarely arises in von Hippel-Lindau (VHL) syndrome
- VHL associated cases are sometimes patchy, multifocal (Pancreas 2012;41:380, Surgery 2012;152:1106)
Often asymptomatic; rarely can be symptomatic due to obstruction of the biliary or GI tract (Am J Gastroenterol 2011;106:1521)
Abdominal pain is occasionally attributed to this tumor
Solid variant is often clinically misdiagnosed as pancreatic neuroendocrine tumor (PanNET)
Macrocystic / oligocystic variants are often misdiagnosed as other cystic tumors
Association with other tumors is common (13%), especially PanNET
Typically, these minute cysts / glands are back to back and form a distinct mass but sometimes they can be dispersed in between native pancreatic elements

Radiology description

CT typically demonstrates a demarcated, lobulated mass in the pancreas that is often interpreted as cystic (J Family Med Prim Care 2019;8:2744)

Prognostic factors

Most serous tumors of the pancreas are benign with excellent prognosis (World J Surg 2003;27:319)
Some of these tumors may attain a large size and push into (invade) the neighboring organs but overt malignant transformation and mortality is exceedingly uncommon (Dig Surg 2016;33:240)
- Synchronous or metachronous liver lesions are debated as to whether metastatic or multifocality (Am J Surg Pathol 2015;39:1597)

Case reports

17 year old girl with unilocular macrocystic serous cystadenoma of pancreas (Rev Med Brux 2017;38:39)
67 year old woman with serous cystic neoplasm at the pancreatic body and high grade PanIN lesions at the main and branch pancreatic ducts (Int J Surg Pathol 2018;26:551)
67 year old woman with macrocystic multilocular cystic lesion in the pancreatic head with proximal dilatation of Wirsung duct (J Gastrointest Surg 2019;23:176)
72 year old woman with hypervascular solid mass in the tail of the pancreas (Case Rep Surg 2016;2016:3730249)
75 year old woman with duodenal neuroendocrine tumor and pancreatic serous cystic neoplasm (Int J Surg Pathol 2018;26:551)

Treatment

Watchful waiting because invariably benign (Zhonghua Wai Ke Za Zhi 2018;56:591)
Surgical treatment should be proposed in a minority of patients, only for uncertain diagnosis remaining after complete workup, including CT scan, MRI and endoscopic ultrasound, significant and related symptoms or exceptionally, when concern for malignancy exists (Gut 2016;65:305)
Rarely, local adhesion / infiltration into the adjacent lymph nodes or adjacent organs (colon, stomach) is seen in larger tumors
Occurrence of similar tumors in the liver is being debated as whether synchronicity, multifocality or metastasis; behavior of those is also excellent
True malignant degeneration or mortality due to this tumor is virtually nonexistent (exceedingly uncommon, dubious cases)

Gross description

Favors the pancreatic body / tail region over the head / neck (ratio of 1.6:1) (Am J Surg Pathol 2015;39:1597)
Well demarcated, large mass lesion (mean: 6 cm; range: 1 - 30 cm)
Often has a central stellate scar
Microcystic type: most common; characterized by a collection of innumerable microcysts (each within millimeters) creating the pathognomonic sponge-like configuration with gray to beige / cream color; rare large loculi measuring within centimeters are often seen dispersed within the lesion
Oligocystic (macrocystic; megacystic) type: composed of fewer and larger loculi, with the overall picture closely resembling other megacystic tumors such as mucinous cystic neoplasms
Solid type: homogenous, demarcated, beige-tan nodule with shiny gelatinous appearance; often mistaken as PanNETs clinically and grossly
In the cystic types, the fluid is clear and watery; hemorrhage can occur
Rarely multifocal or dispersed (especially VHL associated cases) (J Gastrointest Cancer 2010;41:197)

Gross images

Contributed by Pınar Bulutay, M.D.

Central scar

Thin fibrous septa

Macrocystic and solid variant

Images hosted on other servers:

Solid variant

Microscopic (histologic) description

Innumerable small, irregularly contoured tubular structures of variable shapes ranging from submillimeter to centimeters
Cystic spaces lined by bland appearing cuboidal to low columnar epithelial cells with abundant clear, glycogen rich (PAS+, diastase sensitive) cytoplasm
Nuclei are round and remarkably uniform with dense, homogenous chromatin and inconspicuous nucleoli
Degenerative atypia leading to pleomorphic cells can be encountered as scattered cells
Mitoses are typically absent
Stroma ranges from edematous to fibrotic, myxoid or hyalinized with an intimately admixed capillary network; calcifications can be seen (Pancreatology 2009;9:182)
Occasionally, the neoplastic cells form intraluminal minute papillary projections, usually without a fibrovascular stalk
Some cases have more oncocytic cells with granular cytoplasm
Solid variant is composed of tightly packed, back to back, uniform, small glands with only minimal or no lumen formation, showing the typical cytologic characteristics described above

Microscopic (histologic) images

Contributed by Pınar Bulutay, M.D.

Innumerable submillimeter cysts

Prominent capillary network

Cellular details

Intracystic papillary projections

Macrocystic type

Cellular details, macrocystic type

Papillary projections, macrocystic type

Cytology description

Scant amount of serous fluid
Smears with very low cellularity, rich in protein; seldom diagnostic (Acta Cytol 2017;61:27)
Epithelial cells arranged in flat sheets or singly (Cancer Cytopathol 2014;122:33)
Stripped nuclei, clear cytoplasm
Cytoplasmic borders well defined
Round nuclei, evenly distributed chromatin
Capillarization may be helpful

Positive stains

Epithelial markers (keratins, EMA)
MUC1 (often), MUC6 (common) (Am J Surg Pathol 2004;28:339)
Inhibin A (Am J Surg Pathol 2004;28:339)
GLUT1, HIF1α, CAIX, VEGF (Pancreatology 2009;9:182)
Endothelial markers (highlight the rich periepithelial capillary network) (Pancreatology 2009;9:182)

Negative stains

Electron microscopy description

Tumor tissue consists of cysts lined by columnar epithelium
Tumor cells have intervening cell junctions and desmosomes
Many small blood vessels in the subepithelial layer, the latter being intimately associated with the basal portions of epithelial tumor cells (Ultrastruct Pathol 2006;30:119)
Organelle deficient and lack mucin, zymogen and dense glycogen granules; surface microvilli and cilia have rarely been reported (Pathology 2002;34:148)
Myoepithelial cells have also rarely been reported (Ultrastruct Pathol 2006;30:119)

Molecular / cytogenetics description

VHL gene alterations; loss of heterozygosity of the chromosome 3p region is most common in patients with VHL (Am J Pathol 2001;158:317)
VHL gene alterations may also be detected in sporadic cases

Sample pathology report

Partial distal pancreatectomy:
- Serous cystadenoma (see comment)
- Comment: There are multiple cystic spaces lined by a simple cuboidal to flattened epithelium with round, uniform nuclei and clear cytoplasm. Significant nuclear atypia or mitotic activity was not seen. There is some acellular fibrous tissue with a variable degree of hyalinization and edematous change in the stroma. Immunohistochemically the tumor cells are positive with EMA and MUC1 while negative for HMB45. The morphologic and immunohistochemical features are consistent with pancreatic serous cystadenoma.

Differential diagnosis

Lymphangioma:
- Peripancreatic tissue, lymphoid aggregates between the cystic spaces attenuated cells with pale chromatin
- Cytokeratin-
Metastatic renal cell carcinoma:
- Solid and acinar regions, prominent nuclear atypia, sinusoidal vascular pattern
- PAX8+
Mucinous cystic neoplasm:
- Ovarian type stroma, mucinous or nonmucinous ductal cells (Am J Surg Pathol 2017;41:121)
Clear cell (sugar) tumor (PEComa):
- Epitheloid spindle cells with cytoplasmic vacuolization
- HMB45+

Board review style question #1

Which of the following is true about pancreatic serous cystadenoma?

It affects males and females equally
It usually carries risk of malignant transformation
Macrocystic type is the most frequent histologic subtype
Some cases are associated with von Hippel-Lindau (VHL) syndrome
Synaptophysin and chromogranin are positive for immunohistochemistry

Board review style answer #1

D. Some cases are associated with von Hippel-Lindau (VHL) syndrome. Pancreatic serous cystadenoma frequently occurs sporadically but rarely arises in von Hippel-Lindau (VHL) syndrome. VHL associated cases are sometimes patchy or multifocal.

Comment Here

Reference: Serous cystadenoma

Board review style question #2

A 47 year old woman presented with abdominal pain. CT images showed a 4 cm well circumscribed mass in the tail of the pancreas. Repeated fine needle aspiration biopsy did not yield specific diagnostic findings. The tumor was resected and showed a well demarcated tumor with innumerable tiny cystic spaces that created a sponge-like appearance, with beige-tan color and a central stellate scar. On microscopic examination, there were tightly packed small glandular / cystic elements of variable sizes lined by clear cells with nuclei that were small, round and uniform with dense homogeneous chromatin and devoid of mitotic activity (as shown in the picture). What is the most likely diagnosis and expected immunoprofile of this tumor?

Mucinous cystic neoplasm: progesterone receptor in the stroma, mucicarmine, MUC5AC
Pancreatic ductal adenocarcinoma: CEA, SMAD4 loss, p53
Pancreatic serous cystadenoma: pancytokeratin, inhibin, GLUT1
Solid pseudopapillary neoplasm: diffuse nuclear beta catenin, synaptophysin, CD10
Solid serous adenoma: pancytokeratin, MUC6

Board review style answer #2

C. Pancreatic serous cystadenoma: pancytokeratin, inhibin, GLUT1

Comment Here

Reference: Serous cystadenoma

Simple mucinous cyst

Table of Contents

Definition / general

Mucinous pancreatic cyst with minimal cytologic atypia, grossly > 1 cm, lined by single layer of gastric type flat epithelium without ovarian type stroma

Essential features

Unilocular or multilocular mucinous cyst (> 1 cm) with single layer of columnar or cuboidal cells and low grade dysplasia
Paucicellular fibrotic wall with no ovarian type stroma or lymphoid band
Cyst rarely communicates with pancreatic duct
High cyst fluid CEA, low amylase
KRAS and KMT2C mutations in a subset of cases
Follows benign clinical course, no reported progression to carcinoma

Terminology

Also called mucinous nonneoplastic cyst, first proposed by Kosmahl et al. in 2002 (Mod Pathol 2002;15:154)

ICD coding

ICD-10: K86.2 - cyst of pancreas

Epidemiology

2 - 3.4% of pancreatic resections, 2.2 - 6.7% of pancreatic cyst resections and 7.6 - 10.3% of pancreatic mucinous cyst resections (Arch Pathol Lab Med 2017;141:1330)
Mean age: 64 (range, 20 - 88) (Arch Pathol Lab Med 2017;141:1330)
More common in females, F:M = 2.8:1 to 4:1 (Arch Pathol Lab Med 2017;141:1330, Am J Surg Pathol 2017;41:121)

Sites

Body, tail (53 - 69%)
Head, neck, uncinate (31 - 47%) (Arch Pathol Lab Med 2017;141:1330, Am J Surg Pathol 2017;41:121)

Clinical features

Asymptomatic or incidental (41 - 49%), abdominal pain (34 - 44%), jaundice (4 - 7%), back pain (11%) (Arch Pathol Lab Med 2017;141:1330, Am J Surg Pathol 2017;41:121)
Size: 1 - 12 cm (mean 2.5 cm) (Arch Pathol Lab Med 2017;141:1330)

Diagnosis

CT or MRI of abdomen
EUS with FNA or biopsy
Cyst fluid analysis
Cytology
Surgical specimen (StatPearls: Pacreatic Cysts [Accessed 8 June 2020])

Laboratory

Cyst fluid: often elevated CEA, mean 6,797 ng/mL (range, 11 - 64,000 ng/mL) (Arch Pathol Lab Med 2017;141:1330, Am J Surg Pathol 2017;41:121)
Low amylase (unless connected to duct)

Radiology description

CT / MRI:
- Unilocular (55 - 59%), multilocular or septated (41 - 45%)
- Rare communication with pancreatic duct (3 - 7%) or mural nodule (Arch Pathol Lab Med 2017;141:1330, Am J Surg Pathol 2017;41:121)
- Upstream main pancreatic duct dilatation (Abdom Radiol (NY) 2017;42:2827)
- Low signal intensity of cyst fluid on T1 weighted, high on T2 weighted and low on diffusion weighted
- Most with thin cyst wall but can have cyst wall enhancement
EUS:
- Septate in 26.3%, solid component in 10.5%, possible communication with pancreatic duct in 21% (Pancreas 2012;41:813)

Radiology images

Contributed by Amanda Kitson, M.D. and Jiaqi Shi, M.D., Ph.D.

CT: abdomen coronal

CT abdomen, transverse section

T2 MRI: abdomen coronal

Prognostic factors

Overall benign behavior with no recurrence or malignant transformation (Am J Surg Pathol 2015;39:1730, Arch Pathol Lab Med 2017;141:1330)

Case reports

52 year old man with hematochezia and active bleeding from ampulla (Korean J Gastroenterol 2017;70:301)
71 year old woman with a cystic tumor in the body of the pancreas (World J Gastroenterol 2005;11:2045)
75 year old man with pancreatic cyst (J Med Case Rep 2019;13:264)

Treatment

Often treated with surgical resection due to preoperative imaging indistinguishable from other mucinous neoplasms
Surveillance

Clinical images

Images hosted on other servers:

Hematochezia and active bleeding from ampulla

Pancreatic cyst and elevated posterior wall of gastric body

Gross description

Unilocular or multilocular cyst, mean size 2.5 cm, range 1.0 - 12 cm (Arch Pathol Lab Med 2017;141:1330, Am J Surg Pathol 2017;41:121)
No or rare communication with pancreatic duct (Arch Pathol Lab Med 2017;141:1330, Am J Surg Pathol 2017;41:121)
Usually clear or serous fluid, ~33% with mucinous fluid, rarely serosanguinous or brown-green thick fluid (Arch Pathol Lab Med 2017;141:1330, Am J Surg Pathol 2017;41:121)
Smooth cyst lining, no or minimal focal papillary excrescences (Arch Pathol Lab Med 2017;141:1330, Am J Surg Pathol 2017;41:121)
Submit entire lining (or extensive sampling if large cyst) to rule out high grade dysplasia or invasive carcinoma

Gross images

Contributed by Amanda Kitson, M.D. and Jiaqi Shi, M.D., Ph.D.

Multiloculated cyst in pancreatic head

Cyst in pancreatic body

Frozen section description

> 1 cm unilocular or multilocular cyst
Flat gastric type mucinous epithelium
No significant atypia
No ovarian type stroma

Frozen section images

Contributed by Amanda Kitson, M.D. and Jiaqi Shi, M.D., Ph.D.

Monolayer of mucinous epithelium

Epithelium with minimal atypia

Fibrotic cyst wall

Microscopic (histologic) description

Flat monolayer of columnar mucinous epithelium or attenuated cuboidal epithelial cells, often resembling gastric type mucinous epithelium (Arch Pathol Lab Med 2017;141:1330, Am J Surg Pathol 2017;41:121)
Low grade dysplasia, which may mimic low grade pancreatic intraepithelial neoplasia (PanIN)
- Focal high grade dysplasia in 8% cases in one study (Am J Surg Pathol 2017;41:121)
No or minimal papillary architecture (Arch Pathol Lab Med 2017;141:1330, Am J Surg Pathol 2017;41:121)
Paucicellular fibrotic wall with no ovarian type stroma or lymphoid band (Arch Pathol Lab Med 2017;141:1330, Am J Surg Pathol 2017;41:121)
Degenerative changes in cyst wall common:
- Hyalinization, myxoid stroma, hemorrhage, calcifications, macrophage clusters, granulation-like tissue (Arch Pathol Lab Med 2017;141:1330, Am J Surg Pathol 2017;41:121)

Microscopic (histologic) images

Contributed by Amanda Kitson, M.D. and Jiaqi Shi, M.D., Ph.D.

Cuboidal to columnar epithelium

Gastric type mucinous epithelium

Hypocellular stroma

Focal atypia

Virtual slides

Images hosted on other servers:

Cyst and uninvolved pancreas

Fibrotic cyst wall

Frozen section, mucinous cyst

Columnar lining, focal atypia

Focal papillary excrescences

Cytology description

Flat honeycomb sheets / nests of cuboidal or columnar cells without significant atypia (100%) (Pancreas 2013;42:27, Pancreas 2012;41:813)
Round to oval nuclei, small to slightly enlarged, 1 - 2 inconspicuous nucleoli, fine granular chromatin, smooth nuclear contour, nuclear grooves (43.5%), nuclear pseudoinclusions (26.1%) (Pancreas 2013;42:27)
Delicate, vacuolated cytoplasm (60.9%), variable in amount (Pancreas 2013;42:27)
May show papillary architecture (10.5%), acini formation (10.5%), 3D clusters (5.3%), single cell pattern (5.3%), goblet cells (17.4%) (Pancreas 2013;42:27)
Background mucin, macrophages (43.5%), rarely stroma (17.4%) (Pancreas 2013;42:27)
Limitations: may not be representative of entire cyst lining
Unremarkable mucin

Positive stains

MUC5AC (77 - 90%), MUC6 (74 - 93%), MUC1 (35 - 37%), CK7 (Arch Pathol Lab Med 2017;141:1330, Am J Surg Pathol 2017;41:121)

Negative stains

MUC2, retained SMAD4 (Arch Pathol Lab Med 2017;141:1330, Am J Surg Pathol 2017;41:121)
CDX2 (can be focal)
p53

Molecular / cytogenetics description

KRAS mutations in 13 - 55% (Arch Pathol Lab Med 2017;141:1330, Am J Surg Pathol 2017;41:121)
KMT2C (MLL3) mutations in 62% (Hum Pathol 2020;101:1)
BRAF, RNF43, CDKN2A, SMAD4 mutations in 8% (Hum Pathol 2020;101:1)
TP53 mutations in 15% (Hum Pathol 2020;101:1)
Loss of heterozygosity at 10q (PTEN) or 17q (ubiquitin E3 ligase ring finger 43 / RNF43) reported in 2 cases (Hum Pathol 2016;55:159)
Clonality analysis with HUMARA gene showed polymorphism (Hum Pathol 2010;41:513)

Sample pathology report

Pancreas, resection:
- Simple mucinous cyst (see comment)
- Comment: Many of these lesions have KRAS mutation. Although there is no consensus, many authors consider this entity a neoplastic process. However, they tend to have a benign behavior with no reported recurrence or malignant transformation after resection.

Differential diagnosis

Intraductal pancreatic mucinous neoplasm (IPMN):
- Increased amylase in cyst fluid (Arch Pathol Lab Med 2017;141:1330, Am J Surg Pathol 2017;41:121)
- More commonly head of pancreas
- More papillary architecture
- Communicates with pancreatic duct
- Can have high grade dysplasia or be associated with invasive carcinoma
Mucinous cystic neoplasm (MCN):
- Almost exclusively in women
- Body and tail of pancreas
- Can have papillary epithelium
- Can have high grade dysplasia
- Ovarian type stroma (progesterone receptor / PR positive) (Arch Pathol Lab Med 2017;141:1330, Am J Surg Pathol 2017;41:121)
- Can be associated with invasive carcinoma
Retention cyst:
- Cystic dilation of pancreatic duct
- Intraluminal obstruction (Clin Endosc 2015;48:31)
Lymphoepithelial cyst:
- Squamous or columnar epithelium
- Lymphocytes and germinal centers within the wall
Epidermoid cyst:
- Keratinizing squamous epithelium
Squamoid cyst:

Metaplastic squamous / transitional epithelium (Clin Endosc 2015;48:31)

Board review style question #1

High grade dysplasia is often present
KRAS mutations have been demonstrated in a subset of cases
Often communicate with pancreatic duct
Ovarian type stroma is diagnostic of this entity
Papillary architecture is common

Board review style answer #1

B. KRAS mutations have been demonstrated in a subset of cases

Comment Here

Reference: Simple mucinous cyst

Board review style question #2

Intraductal pancreatic mucinous neoplasm
Mucinous cystic neoplasm
Pancreatic pseudocyst
Retention cyst
Simple mucinous cyst

Board review style answer #2

E. Simple mucinous cyst

Comment Here

Reference: Simple mucinous cyst

Solid pseudopapillary neoplasm

Table of Contents

Definition / general

Low malignant potential tumors with unclear cell of origin and pathogenesis
May be derived from pluripotent stem cells of the genital ridges that become attached to the pancreas during embryogenesis (Semin Diagn Pathol 2014;31:484)
First described by V.K. Frantz in 1959; incorporated into the WHO classification in 1996 (Br J Surg 1959;47:334)

Essential features

Presents in younger women, classically as solitary body / tail mass
Variable amount of solid and cystic areas grossly
Papillary fronds on myxoid or hyalinized vascular stalk lined by poorly cohesive, uniform cells with nuclear grooves comprising solid and cystic areas beta catenin nuclear / cytoplasmic positive

Terminology

Also known as solid pseudopapillary tumor, papillary epithelial neoplasm, papillary cystic neoplasm, solid and papillary neoplasm, low grade papillary neoplasm and Hamoudi or Frantz tumor

Epidemiology

Represents 1 - 2% of pancreatic neoplasms
F:M = 10:1 (accounts for 30% tumors in < 40 year old women) (Arch Pathol Lab Med 2020;144:829)
Usually presents in the third to fourth decade of life (mean age 35 years)
In men, tends to occur at an older age with more aggressive behavior (Surgery 2008;143:29)
Occasional cases have been reported in patients with familial adenomatous polyposis (Intern Med 2015;54:1349, Surg Case Rep 2021;7:35)

Sites

Located throughout the pancreas but more frequently in the body or tail in adults, while more frequent in the head of pancreas in children (Arch Surg 2008;143:1218)
Rarely reported in extrapancreatic sites, such as mesocolon, omentum, ovary and testis (Virchows Arch A Pathol Anat Histopathol 1991;418:179, Am J Surg Pathol 2010;34:1514, Int J Gynecol Pathol 2011;30:539, Ann Diagn Pathol 2018;35:42)

Clinical features

Most common symptoms are abdominal pain and a palpable, nontender, upper abdominal mass
Also symptoms related to an intra abdominal mass effect, such as discomfort, nausea, vomiting and early satiety
However, most cases are incidentally discovered on imaging
Reference: Arch Pathol Lab Med 2017;141:990

Diagnosis

Solid / solid cystic mass in the tail of pancreas on imaging, especially in young women (Diagn Interv Radiol 2017;23:94)
Cyst fluid chemistry shows low CEA and amylase (Ann Gastroenterol 2013;26:122)
Cytology / histology are necessary for confirmation of diagnosis

Laboratory

Cyst fluid is often bloody with low CEA and low amylase (Ann Gastroenterol 2013;26:122)

Radiology description

Well circumscribed, encapsulated, heterogeneous pancreatic lesion with cystic degeneration on CT or MRI

Radiology images

Contributed by Omid Savari, M.D.

MR of abdomen

Images hosted on other servers:

Hypodense lesion

Endoscopic ultrasound

Multiple metastases

Prognostic factors

Poor prognostic factors include: size > 5 cm, male gender, necrosis, cellular atypia, vascular invasion, perineural invasion and invasion into adjacent structures (Dig Liver Dis 2013;45:703)

Case reports

14 year old Hispanic girl with silent presentation of a solid pseudopapillary neoplasm of the pancreas (Am J Case Rep 2017;18:656)
16 year old boy with tonic convulsions (J Clin Res Pediatr Endocrinol 2017;9:375)
40 year old man with subsequent multiple metastases (World J Gastrointest Oncol 2017;9:497)
45 year old woman with situs invertus (Medicine (Baltimore) 2018;97:e0205)
62 year old woman with IgG4 related pancreatitis (Int J Surg Pathol 2017;25:271)

Treatment

Surgical resection is curative in > 95% of cases

Gross description

Range from 0.5 to 34.5 cm, with a mean diameter of 6 cm
Well defined, encapsulated, with variable amount of solid and cystic patterns
Smaller lesions tend to be more solid but less sharply circumscribed
Larger tumors demonstrate a fibrous pseudocapsule and have a variegated and friable cut surface
Cystic degeneration and hemorrhage are common findings in larger specimens
Rarely, may extend into adjacent structures, such as duodenum
Reference: Arch Pathol Lab Med 2020;144:829

Gross images

Contributed by Omid Savari, M.D., Dr. Andreas Schulz, Manfred Stolte, M.D., Dr. Helmut Luchtrath and Case #121

Predominately solid tumor

Partially necrotic tumor

Invasion of spleen

Cystic lesion

Multilocular cystic mass

Microscopic (histologic) description

Tumors are heterogeneous, with variable admixture of solid and pseudopapillary areas
Solid areas are comprised of uniform cells admixed with capillary sized blood vessels
Pseudopapillae are formed due to tumor cells getting detached from blood vessels forming fibrovascular stalks or rosette-like structures (Arch Pathol Lab Med 2020;144:829)
Stroma usually shows various degrees of hyalinization or evidence of degeneration, such as hemorrhage, foamy macrophages, calcification and cholesterol clefts
Tumor cells usually have a moderate amount of eosinophilic cytoplasm with intracytoplasmic hyaline globules (PAS+ and diastase resistant, positive for alpha-1-antitrypsin) and perinuclear vacuoles (Am J Surg Pathol 2011;35:981)
Relatively uniform nuclei with finely textured chromatin, inconspicuous nucleoli and characteristic longitudinal grooves
Variants include clear cell, oncocytic and pleomorphic
Rare mitotic figures
Although grossly well circumscribed, microscopic finding of infiltration to the surrounding pancreatic tissue is not uncommon
Rare cases of highly aggressive behavior; histological features in those cases included diffuse growth pattern, extensive necrosis, significant nuclear atypia, high mitotic count (35 - 70/50 high power fields) or sarcomatoid features (Am J Surg Pathol 2005;29:512)

Microscopic (histologic) images

Contributed by Monika Vyas, M.D., Omid Savari, M.D. and Raul S. Gonzalez, M.D.

Pleomorphism and cytologic atypia

Intracytoplasmic eosinophilic hyaline globules

Tumor infiltration by foamy histiocytes

Solid pseudopapillary neoplasm

Solid pattern

Clear cell changes

Cholesterol cleft, scattered giant cells

Tumor invading parenchyma

Beta catenin

CD10

Ki67

Metastasis to liver

Cytology description

Cellular smears with delicate papillary fronds
Tumor cells are usually bland and uniform with a moderate amount of cytoplasm, which usually contains variable sized clear perinuclear vacuoles or cytoplasmic eosinophilic hyaline globules
Nuclei are round to oval with grooves and finely granular chromatin (J Cytol 2010;27:118, Arch Pathol Lab Med 2017;141:990)
Cercariform cells, cytoplasmic vacuolation, reniform nuclei, hyaline globules and degenerative features, such as cholesterol crystals, calcifications, foam cells or giant cells, are more commonly seen in solid pseudopapillary neoplasms, compared with acinar cell carcinomas / neuroendocrine tumors (Cancer Cytopathol 2013;121:298)

Cytology images

Contributed by Omid Savari, M.D. and @ThatGlassTho on Twitter

Diff-Quik

Pap

Cell block

Solid pseudopapillary neoplasm

Positive stains

Beta catenin (98%): aberrant nuclear expression
E-cadherin (loss of membranous expression) (Hum Pathol 2008;39:251)
p120 (cytoplasmic staining with loss / reduction of membranous expression) (Am J Clin Pathol 2008;130:71)
Alpha-1-antichymotrypsin (95%), alpha-1-antitrypsin (82%)
Vimentin (88%)
Cyclin D1
CD10 (63%)
SOX11 (100%)
Androgen receptor (81%), TFE3 (75%), LEF1 (93%), FUS (85%), progesterone receptor (63%), claudin7, claudin5 (Am J Surg Pathol 2009;33:768)
CD56 (96%), neuron specific enolase (70%), synaptophysin (55%)
Cytokeratin (52%)
CD99 (dot-like) (Am J Surg Pathol 2011;35:799)

Negative stains

Chromogranin A (positive in only 9%)
CEA
Estrogen receptor
Reference: Arch Pathol Lab Med 2017;141:990

Electron microscopy description

Mitochondria rich cytoplasm with electron dense granules and rough endoplasmic reticulum

Electron microscopy images

Contributed by Dr. H.D. John, Mainz

Abundant mitochondria

Granules

Molecular / cytogenetics description

Point mutation in exon 3 of β catenin gene (CTNNB1) is present in > 90%
Gene mutation results in the accumulation of β catenin in the cytoplasm and formation of a β catenin Tcf / Lef complex, through which the Wnt signaling pathway activates several oncogenic genes, such as MYC and cyclin D1 (Am J Clin Pathol 2017;149:67)
Rarely, mutations in APC gene (also associated with familial adenomatous polyposis) have been described (Pathol Int 2019;69:193)

Sample pathology report

Pancreas and spleen, distal pancreatectomy and splenectomy:
- Solid pseudopapillary neoplasm (XX cm), confined to pancreas (see comment)
- Resection margins are free of tumor
- Unremarkable spleen, (x g)
- X benign lymph nodes (0/12)
- Comment: Immunohistochemical stains show the neoplastic cells are positive for CD10 and exhibit nuclear expression of beta catenin while negative for synaptophysin and chromogranin.

Pancreas, mass, biopsy:
- Epithelial neoplasm, most consistent with solid pseudopapillary neoplasm (see comment)
- Comment: By immunohistochemistry, the neoplastic cells are positive for CD56, pancytokeratin (focal) and show rare focal positivity for synaptophysin while being negative for chromogranin. Aberrant nuclear expression of beta catenin is present. The histologic and immunohistochemical findings are in keeping with a solid pseudopapillary neoplasm.
Pathological staging (AJCC 8th edition) - similar to exocrine pancreatic tumors

Differential diagnosis

Pancreatic neuroendocrine tumor:
- Small to medium sized cells with uniform nuclei and finely granular chromatin (salt and pepper appearance), arranged in organoid, trabecular or nested patterns
- Positive for neuroendocrine markers and negative for nuclear beta catenin
Acinar cell carcinoma:
- Prominent acinar formation and cells with finely granular cytoplasm
- Positive for pancreatic enzymes (trypsin, chymotrypsin), BCL10 and variable staining for beta catenin
Pancreatoblastoma:
- Primitive pancreatic elements with acinar, ductal and neuroendocrine differentiation
- Also squamoid corpuscles; more common in children younger than 10 years
- Positive for beta catenin (80%), neuroendocrine markers and pancreatic enzymes (trypsin, chymotrypsin and lipase) and BCL10

Board review style question #1

What is the most common gene mutation in pancreatic solid pseudopapillary neoplasm?

CTNNB1
KIT
PDGFRA
RAS

Board review style answer #1

A. Somatic point mutation of β catenin gene (CTNNB1) is present in > 90% of pancreatic solid pseudopapillary neoplasms

Comment Here

Reference: Solid pseudopapillary neoplasm

Board review style question #2

What is the composition of intracytoplasmic hyaline globules in solid pseudopapillary neoplasms?

Alpha-1-antitrypsin
Fibrinogen
Glycogen
Mucin

Board review style answer #2

A. The hyaline globules are immunoreactive for alpha-1-antitrypsin and are also PAS+ and diastase resistant

Comment Here

Reference: Solid pseudopapillary neoplasm

Somatostatinoma

Table of Contents

Definition / general

Neuroendocrine neoplasm (may be well differentiated tumor or poorly differentiated carcinoma) that secretes somatostatin, leading to diabetes, cholecystolithiasis, steatorrhea and diarrhea (J Hepatobiliary Pancreat Sci 2015;22:578)

Essential features

Rare functional neuroendocrine neoplasm that secretes somatostatin
May appear microscopically as a well differentiated tumor or a poorly differentiated carcinoma

Terminology

Also called delta cell tumor

ICD coding

ICD-10:
- C7A.8 - other malignant neuroendocrine tumors
- E16.8 - other specified disorders of pancreatic internal secretion

Epidemiology

Rare; fewer than 1% of gastroenteropancreatic neuroendocrine neoplasms (J Gastroenterol Hepatol 2008;23:521)

Sites

Can occur in the pancreas or in the ampulla / duodenum

Clinical features

Rare; may be more common in women
May occur in patients with NF1 (Clin Gastroenterol Hepatol 2009;7:A28)
Most lesions that stain for somatostatin by immunohistochemistry do not produce somatostatinoma syndrome and arguably do not qualify to be diagnosed as somatostatinomas (Endocr Relat Cancer 2008;15:229)
Often metastasizes but still usually has good prognosis

Diagnosis

Imaging to detect pancreatic mass
Elevated plasma somatostatin levels

Radiology images

Images hosted on other servers:

CT pancreas mass

PET with metastases

Case reports

57 year old woman with tumors in pancreas and duodenum (World J Gastroenterol 2009;15:5859)
72 year old woman with pancreatic tumor and lymph node metastasis (JOP 2014;15:66)
4 patients with tumor in the pancreas and peripancreas (Ann R Coll Surg Engl 2011;93:356)

Treatment

Surgical resection of primary lesion, if possible
Hepatic metastases can be resected or embolized
Octreotide for metastatic disease

Gross images

Images hosted on other servers:

Pancreatic and duodenal tumors

Microscopic (histologic) description

Some cases are well differentiated neuroendocrine tumor, with nests of monotonous low grade neuroendocrine cells with salt and pepper nuclei and ample amphophilic cytoplasm
Other cases are poorly differentiated neuroendocrine carcinoma, with nests and sheets of mildly / moderately pleomorphic cells with high mitotic rate, small cell or large cell features (no salt and pepper nuclei) and foci of necrosis
May rarely feature psammoma bodies (which are common in duodenal somatostatinomas) (J Surg Oncol 1995;59:67)

Microscopic (histologic) images

Contributed by Raul S. Gonzalez, M.D.

Nests and cords of cells

Positive stains

Somatostatin (though this does not establish the diagnosis)
Synaptophysin, chromogranin
PDX1, INSM1 (Am J Surg Pathol 2012;36:737)

Negative stains

CK7 (8%) (Am J Surg Pathol 2012;36:737)
CDX2
BCL10 (Pathol Int 2013;63:176)
Nuclear beta catenin (World J Gastrointest Onc 2016;8:615)

Electron microscopy description

Tumor cells resemble normal D cells (N Engl J Med 1977;296:963)

Electron microscopy images

AFIP image

D cell granules

Sample pathology report

Pancreas and duodenum, Whipple procedure:
- Well differentiated neuroendocrine tumor of pancreas (see comment and synoptic report)
- Comment: Based on the patient’s clinical symptoms, this neuroendocrine tumor is best considered a somatostatinoma.

Differential diagnosis

Nongastrin secreting pancreatic neuroendocrine tumor or carcinoma:
- No histopathologic differences
- Must be determined on clinical grounds

Additional references

Best Pract Res Clin Endocrinol Metab 2016;30:3

Board review style question #1

Cholelithiasis and steatorrhea
High volume watery diarrhea
Hypoglycemia
Nausea, vomiting and peptic ulcer disease
Necrolytic migratory erythema

Board review style answer #1

A. Cholelithiasis and steatorrhea

Comment Here

Reference: Somatostatinoma

Board review style question #2

They are common in patients with von Hippel-Lindau syndrome
They are the most common functional pancreatic neuroendocrine neoplasm
They are typically localized and rarely metastasize
They may be neuroendocrine tumors or carcinomas
They usually contain psammoma bodies

Board review style answer #2

D. They may be neuroendocrine tumors or carcinomas

Comment Here

Reference: Somatostatinoma

Staging-exocrine

Table of Contents

Pathologic TNM staging of exocrine tumors of the pancreas, AJCC 8th edition

Definition / general

All exocrine tumors of the pancreas (including any lesion designated as carcinoma, as well as solid papillary neoplasm and pancreaticoblastoma) are covered by this staging system
Not covered by this staging system are well differentiated neuroendocrine tumors at this location (use the pancreas neuroendocrine staging system instead)
The 8th edition staging has been shown to be more prognostically relevant than the 7th edition staging for pancreatic ductal adenocarcinoma (Pancreas 2018;47:742)

Essential features

AJCC 7th edition staging was sunset on December 31, 2017; as of January 1, 2018, use of the AJCC, 8th Edition, 2018 is mandatory

ICD coding

ICD-10: C25.9 - malignant neoplasm of pancreas, unspecified

Primary tumor (pT)

pTX: primary tumor cannot be assessed
pTis: carcinoma in situ (this includes high grade pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm with high grade dysplasia, intraductal tubulopapillary neoplasm with high grade dysplasia and mucinous cystic neoplasm with high grade dysplasia)
pT1: tumor ≤ 2 cm in greatest dimension
- pT1a: tumor ≤ 0.5 cm in greatest dimension
- pT1b: tumor > 0.5 and < 1 cm in greatest dimension
- pT1c: tumor 1 - 2 cm in greatest dimension
pT2: tumor > 2 cm and ≤ 4 cm in greatest dimension
pT3: tumor > 4 cm in greatest dimension
pT4: tumor involves celiac axis, superior mesenteric artery or common hepatic artery, regardless of size

Regional lymph nodes (pN)

pNX: regional lymph nodes cannot be assessed
pN0: no regional lymph node involvement
pN1: metastasis in one to three regional lymph nodes
pN2: metastasis in four or more regional lymph nodes

Notes:

Regional lymph nodes depend on tumor site
- For tumors of the head or neck of the pancreas, regional nodes include common bile duct, common hepatic artery, portal vein, pyloric, posterior and anterior pancreatoduodenal arcades, superior mesenteric vein and right lateral wall of superior mesenteric vein nodes
- For tumors of the body or tail of the pancreas, regional nodes include common hepatic artery, celiac axis, splenic artery and splenic hilum nodes
Minimum of 12 lymph nodes must be recovered for lymph node staging to be considered accurate in curative resections

Distant metastasis (pM)

pM0: no distant metastasis
pM1: distant metastasis

Prefixes

y: preoperative radiotherapy or chemotherapy
r: recurrent tumor stage

Stage grouping

Stage IA:T1 N0 M0
Stage IB:T2 N0 M0
Stage IIA:T3 N0 M0
Stage IIB:T1 - 3 N1 M0
Stage III:T1 - 3 N2 M0
T4 any N M0
Stage IV:any T any N M1

Registry data collection variables

Preoperative CA 19-9
Preoperative carcinoembryonic antigen (CEA)

Histologic grade

GX: grade cannot be assessed
G1: well differentiated
G2: moderately differentiated
G3: poorly differentiated

Histopathologic type

Ductal adenocarcinoma
Adenosquamous carcinoma
Hepatoid carcinoma
Medullary carcinoma
Mucinous noncystic carcinoma (colloid carcinoma)
Signet ring cell carcinoma
Undifferentiated carcinoma
Undifferentiated carcinoma with osteoclast-like giant cells
Acinar cell carcinoma
Acinar cell cystadenocarcinoma
Intraductal papillary mucinous neoplasm with associated invasive carcinoma
Intraductal tubulopapillary neoplasm with associated invasive carcinoma
Mucinous cystic neoplasm with associated invasive carcinoma
Pancreaticoblastoma
Serous cystadenocarcinoma
Solid pseudopapillary neoplasm
Neuroendocrine carcinoma
Small cell neuroendocrine carcinoma
Large cell neuroendocrine carcinoma
Mixed acinar ductal carcinoma
Mixed acinar neuroendocrine carcinoma
Mixed acinar neuroendocrine ductal carcinoma
Mixed neuroendocrine ductal carcinoma

Board review style question #1

Under 8th edition AJCC staging criteria, which of the following would categorize a pancreatic ductal adenocarcinoma as pT3?

Involvement of the duodenum
Involvement of the peripancreatic fat
Involvement of the superior mesenteric artery
Size > 4 cm

Board review style answer #1

D. Size > 4 cm

Comment Here

Reference: Staging - exocrine

Staging-neuroendocrine

Table of Contents

Definition / general

All well differentiated neuroendocrine tumors of the pancreas are covered by this staging system
Not covered by this staging system are poorly differentiated neuroendocrine carcinomas at this location (use the pancreas exocrine staging system instead)

Essential features

AJCC 7th edition staging was sunset on December 31, 2017; as of January 1, 2018, use of the 8th edition is mandatory
AJCC 9th edition was released in 2023, with minimal changes from the 8th edition

ICD coding

ICD-10: C25.4 - malignant neoplasm of endocrine pancreas

Primary tumor (pT)

pTX: tumor cannot be assessed
pT1: tumor limited to the pancreas, ≤ 2 cm in greatest dimension
pT2: tumor limited to the pancreas, > 2 cm but ≤ 4 cm in greatest dimension
pT3: tumor limited to the pancreas, > 4 cm in greatest dimension or tumor invading the duodenum, ampulla of Vater or common bile duct
pT4: tumor invading adjacent organs (stomach, spleen, colon, adrenal gland) or the wall of large vessels (celiac axis, superior mesenteric artery / vein, splenic artery / vein, gastroduodenal artery / vein, portal vein)

Notes:

Limited to the pancreas means no extension into adjacent organs or structures; invasion of peripancreatic adipose tissue does not impact staging
When multiple tumors are present, the largest tumor should be used to assign the T category
Use T(#) (e.g., pT3[4] N0 M0) or use the m suffix, T(m) (e.g., pT3[m] N0 M0)

Regional lymph nodes (pN)

NX: regional lymph nodes cannot be assessed
N0: no tumor involvement of regional lymph node(s)
N1: tumor involvement of regional lymph node(s)

Notes:

Regional lymph nodes depend on tumor site
- For tumors of the head of the pancreas, regional nodes include common bile duct, common hepatic artery, portal vein, posterior and anterior pancreatoduodenal arcades, superior mesenteric vein and right lateral wall of superior mesenteric vein nodes
- For tumors of the body or tail of the pancreas, regional nodes include common hepatic artery, celiac axis, splenic artery and splenic hilum nodes

Distant metastasis (pM)

cM0: no distant metastasis
cM1: distant metastasis
- cM1a: metastasis confined to liver
- cM1b: metastasis in at least 1 extrahepatic site (e.g., lung, ovary, nonregional lymph node, peritoneum, bone)
- cM1c: both hepatic and extrahepatic metastasis
pM1: microscopic confirmation of distant metastasis
- pM1a: microscopic confirmation of metastasis confined to liver
- pM1b: microscopic confirmation of metastasis in at least 1 extrahepatic site (e.g., lung, ovary, nonregional lymph node, peritoneum, bone)
- pM1c: microscopic confirmation of both hepatic and extrahepatic metastasis

Prefixes

c: clinical
p: pathological
yc: posttherapy clinical
yp: posttherapy pathological

Primary tumor suffix

(m): multiple synchronous primary tumors

Regional lymph nodes suffix

(f): fine needle aspiration (FNA) or core needle biopsy

AJCC prognostic stage groups

Stage I:	T1	N0	M0
Stage II:	T2, T3	N0	M0
Stage III:	T4	N0	M0
	any T	N1	M0
Stage IV:	any T	any N	M1

Prognostic tumor characteristics

Mitotic count
Ki67 index
Associated genetic syndrome
Chromogranin A (CgA)
Functionality
DAXX / ATRX
ARX, PDX1 expression

Registry data collection variables

Size of tumor (value, unknown)
Presence of invasion into adjacent organs / structures
- If yes, which ones (pick all that apply)
  - Stomach (yes / no)
  - Duodenum (yes / no)
  - Spleen (yes / no)
  - Colon (yes / no)
  - Other:
- If yes, were multiple adjacent organs involved (yes / no)
Presence of necrosis
Number of tumors (multicentric disease at primary site)
Lymph node status (including number of lymph nodes assessed and number of positive nodes)
Grade (based on Ki67 or mitotic count): G1, G2, G3, unknown
Mitotic count (value; unknown)
Ki67 index (value; unknown)
Perineural invasion
Lymphovascular invasion
Margin status
Functional status (yes / no, type of syndrome)
Genetic syndrome (yes / no, type of syndrome)
Location in pancreas (head, tail, body, junction body / tail, junction body / head, unknown)
Type of surgery (enucleation, distal pancreatectomy with or without splenectomy, central pancreatectomy, pancreaticoduodenectomy / Whipple procedure, unknown, other)
Preoperative CgA level (absolute value with upper limit of normal; unknown)
Age of patient

Histologic grade (G)

G1: mitotic rate 2 and Ki67 G2: mitotic rate 2 - 20 per 2 mm² or Ki67 3 - 20%
G3: mitotic rate > 20 per 2 mm² or Ki67 > 20%

Histopathologic type

Neuroendocrine tumor (NET), NOS
Neuroendocrine tumor, grade 1
Neuroendocrine tumor, grade 2
Neuroendocrine tumor, grade 3
Pancreatic neuroendocrine tumor, nonfunctioning
Insulinoma
Gastrinoma
Vasoactive intestinal peptide secreting tumor (VIPoma)
Glucagonoma
Somatostatinoma
Adrenocorticotropic hormone (ACTH) producing neuroendocrine tumor
Serotonin producing neuroendocrine tumor
Growth hormone (GH) producing neuroendocrine tumor

Residual tumor (operative factor)

R0: complete resection, margins histologically negative, no residual tumor left after resection
R1: incomplete resection, margins histologically involved, microscopic tumor remains after resection of gross disease (relevant to resection margins that are microscopically involved by tumor)
R2: incomplete resection, margins involved or gross disease remains

Board review style question #1

Invasion of which of the following structures would upstage a pancreatic neuroendocrine tumor to pT4 disease?

Common bile duct
Duodenum
Peripancreatic fat
Spleen

Board review style answer #1

D. Spleen. Direction invasion of this organ is specifically noted as upstaging a pancreatic well differentiated neuroendocrine tumor to pT4 disease. Answers A and B are incorrect because invasion of these structures is noted as signifying pT3 disease. Answer C is incorrect because invasion of peripancreatic fat does not affect the staging of these tumors.

Comment Here

Reference: Pancreas - Staging-neuroendocrine

Board review style question #2

Which of the following is true regarding staging and prognosis of pancreatic well differentiated neuroendocrine tumors?

ARX and PDX1 expression are considered prognostic indicators
More than 5 positive lymph nodes indicates pN2 disease
Regional lymph nodes are the same regardless of tumor location within the pancreas
Tumor functionality is not considered a prognostic indicator

Board review style answer #2

A. ARX and PDX1 expression are considered prognostic indicators per the AJCC, among multiple additional factors. Answer B is incorrect because there is no pN2 designation for pancreatic neuroendocrine tumors. Answer C is incorrect because the regional lymph nodes are different depending on whether the tumor arises in the head or the body / tail. Answer D is incorrect because tumor functionality is considered a prognostic indicator.

Comment Here

Reference: Pancreas - Staging-neuroendocrine

True cysts

Table of Contents

Congenital / dysgenetic cysts

Definition / general

By definition are intrapancreatic, do not communicate with duct system, lined by a single layer of cuboidal, columnar or flattened atrophic epithelium with a fibrous wall
Most congenital pancreatic cysts are multiple, almost all are associated with underlying congenital diseases that primarily affect other organ systems (AJR Am J Roentgenol 2002;179:1375)
Often associated with polycystic disease affecting kidney and liver, von Hippel-Lindau syndrome or oral-facial-digital syndrome type I (GeneReviews: Oral-Facial-Digital Syndrome Type I [Accessed 11 December 2017])
Single cysts may be due to abnormal duct development
Other syndromes: Elejalde syndrome (eMedicine: Elejalde Syndrome [Accessed 11 December 2017]), glutaric aciduria II (NIH: Glutaric Acidemia Type II [Accessed 11 December 2017]), Ivemark syndrome (NORD: Ivemark Syndrome [Accessed 11 December 2017]), Jeune syndrome (NIH: Jeune Syndrome [Accessed 11 December 2017]), Meckel-Gruber syndrome (eMedicine: Meckel-Gruber Syndrome [Accessed 11 December 2017]), short rib polydactyly syndrome type 1 (OMIM: Short Rib Thoracic Dysplasia 3 With or Without Polydactyly [Accessed 11 December 2017]), trisomy 13, 14, 15, tuberous sclerosis

Case reports

Multilocular cysts associated with choledochal cyst (Hum Pathol 2003;34:99)

Microscopic (histologic) images

AFIP images

Congenital cyst

Cysts of cystic fibrosis

Definition / general

See cystic fibrosis topic

Dermoid cysts

Definition / general

Seen in young patients (2nd - 3rd decade)

Case reports

64 year old man (World J Surg Oncol 2007;5:85)

Gross images

Images hosted on other servers:

Tail of pancreas cyst

Microscopic (histologic) images

Images hosted on other servers:

Tail of pancreas cyst

Epidermoid cysts

Definition / general

May be present within an intrapancreatic spleen (Pancreas 2011;40:956)
In tail, unilocular, typically contain concentric enzymatic concretions, may communicate with acinar system
Squamoid cyst of pancreatic ducts; has thin wall lined by transitional / squamous cells without keratinization or granular layer

Case reports

62 year old man with intrapancreatic spleen containing epidermoid cyst (JOP 2011;12:279)

Foregut cysts attached to pancreas

Definition / general

Rare; unilocular, smooth surface with clear mucoid material, ciliated epithelium resembles bronchogenic cyst but no respiratory glands, no cartilage and two smooth muscle layers (Am J Surg Pathol 1996;20:476)

Case reports

34 year old woman with pancreatic mass (JSLS 2008;12:183)
37 year old woman with acute cholangitis (JOP 2011;12:420)

Microscopic (histologic) images

Images hosted on other servers:

Foregut cyst attached to pancreas

Cytology images

Images hosted on other servers:

Ciliated foregut cyst: FNA

Mesothelial cysts

Definition / general

May be multiple and involve pancreas, liver, kidney or other abdominal structures

Case reports

36 year old man with 3 cm cyst (Ann Diagn Pathol 2006;10:371)

Pancreatic hamartoma

Case reports

Initial report in 20 month old girl with 9 cm cystic mass (Hum Pathol 1992;23:1309)
52 year old woman with 2.5 cm mass in pancreatic head (J Korean Surg Soc 2012;83:330)
Well demarcated and composed of cystic ductal structures embedded in focally inflamed stromal tissue (Am J Surg Pathol 2005;29:797)

Microscopic (histologic) images

Images hosted on other servers:

Various images

Nonepithelial cysts

Definition / general

Includes endometrial cyst, lymphangioma, pseudocysts, parasitic cyst

Pancreatic tissue derived cysts

Definition / general

May appear in thorax or mediastinum, as components of gastroenteric duplication cysts, intralobar pulmonary sequestrations, teratomas or rarely from ectopic pancreatic tissue (Mod Pathol 1996;9:210)
Paraduodenal wall cyst (cystic dystrophy): patients with paraduodenal (groove) pancreatitis, cysts may enlarge and adhere to duodenal wall, mimicking duodenal duplication; lined by granulation tissue, may be partly lined by ductal epithelium (Semin Diagn Pathol 2004;21:247)

Gross images

Images hosted on other servers:

Ectopic pancreas with cystic change in mediastinum

Microscopic (histologic) images

Images hosted on other servers:

Ectopic pancreas with cystic change in mediastinum

Tumors that are cystic

Definition / general

Cystic tumors include ductal adenocarcinoma, IOPN, IPMN, lymphoepithelial cyst, mucinous cystic neoplasm, mucinous nonneoplastic cyst, serous cystadenoma, solid papillary neoplasm

Undifferentiated carcinoma

Table of Contents

Definition / general

Carcinoma of the pancreas that does not show a definitive direction of differentiation
Under this definition, there are 4 variants: anaplastic, sarcomatoid, rhabdoid and carcinosarcoma (Mod Pathol 2015;28:248)

Essential features

Undifferentiated carcinoma with atypical neoplastic cells and without gland formation
Absence of osteoclast-like giant cells
Very poor prognosis

Terminology

Undifferentiated carcinoma of the pancreas
Old terminology, not in use: spindle cell carcinoma, pleomorphic carcinoma

ICD coding

ICD-O:
- 8020/3 - carcinoma, undifferentiated, NOS
- 8021/3 - carcinoma, anaplastic, NOS
ICD-10:
- C25.9 - malignant neoplasm of pancreas, unspecified

Epidemiology

M:F = 2:1 (World J Gastroenterol 2016;22:8631)
Commonly presents in the sixth to seventh decades (World J Gastroenterol 2016;22:8631, J Am Coll Surg 2012;215:627)
1 - 5% of all pancreatic cancers (World J Gastroenterol 2016;22:8631, J Am Coll Surg 2012;215:627)

Sites

Head of the pancreas (50% of cases), body / tail (45%), entire pancreas (5%) (World J Gastroenterol 2016;22:8631)

Pathophysiology

The process of epithelial to mesenchymal transition may play an important role (Pancreas 2019;48:36, Virchows Arch 2021;478:319)
Chronic inflammation with histiocytes is not a crucial mechanism as in undifferentiated carcinoma with osteoclast-like giant cells (Hum Pathol 2018;81:157)

Clinical features

Presenting symptoms include jaundice (tumors in the pancreatic head), abdominal or back pain, weight loss, nausea and anemia (Diagn Cytopathol 2016;44:538, World J Gastroenterol 2016;22:8631, World J Clin Cases 2019;7:236)

Diagnosis

CT scan and MRI are the preferred imaging modality (J Med Imaging Radiat Oncol 2019;63:580)
Diagnosis is by biopsy or surgical resection

Radiology description

Usually mass lesions with delayed enhancement, intratumor calcifications (J Med Imaging Radiat Oncol 2019;63:580)

Prognostic factors

Prognosis is very poor, with an average survival time of just 5 months, making it difficult to describe significant prognostic factors (J Am Coll Surg 2012;215:627)
Absence of osteoclast-like giant cells is important for the diagnosis of real, undifferentiated carcinoma (i.e., to avoid misdiagnosis) but is essential for the prognosis as well, since the prognosis of real, undifferentiated carcinoma is very poor, compared with that of carcinoma with osteoclast-like giant cells

Case reports

59 year old man with undifferentiated carcinoma of the pancreas, sarcomatoid type (World J Clin Cases 2019;7:236)
63 year old man with undifferentiated carcinoma of the pancreas, rhabdoid type, with multiple metastases (autopsy report) (Pathol Int 2015;65:264)
64 year old woman with undifferentiated carcinoma of the pancreas, anaplastic type, associated with cystic degeneration of the lesion (World J Gastroenterol 2016;22:8631)
65 year old man with undifferentiated carcinoma of the pancreas, anaplastic type, involving the ampullary region (Am J Case Rep 2019;20:597)
73 year old woman with undifferentiated carcinoma of the pancreas, carcinosarcoma type (Pancreas 2017;46:1225)

Treatment

Surgical resection if possible; gemcitabine based chemotherapy / radiotherapy (J Surg Res 2017;219:238)
A recent study highlighted a possible role of immunotherapy in selected cases, PDL1 positive (Expert Opin Ther Targets 2021;25:1007)

Gross description

Very often similar to conventional pancreatic ductal adenocarcinoma
May show cystic degeneration and necrosis (World J Gastroenterol 2016;22:8631)

Gross images

Contributed by Claudio Luchini, M.D., Ph.D. and AFIP

Ductal
adenocarcinoma
with undifferentiated
component

Ill demarcated tumor in head of pancreas

Extensive hemorrhagic necrosis

Frozen section description

Hypercellular neoplasm with atypical cells

Microscopic (histologic) description

Unlike conventional ductal adenocarcinoma, this tumor is composed of poorly cohesive cells
Undifferentiated carcinoma of the pancreas is a hypercellular tumor with scant stroma and scant desmoplastic reaction; this differs from conventional pancreatic ductal adenocarcinoma which has a large amount of desmoplastic stroma with few neoplastic cells / glands
- This is a major point in the differential diagnosis between these 2 entities
Perineural invasion and vascular invasion are very common
Different subtypes are characterized at the histological level by different morphologic hallmarks:
- Anaplastic subtype is a tumor composed of > 80% highly atypical cells that have pleomorphic nuclei and lack gland formation
- Sarcomatoid subtype is composed of > 80% atypical spindle cells, resembling a sarcoma (Int J Mol Sci 2022;23:1283, Hum Pathol 2022;128:124)
  - Rhabdoid subtype is a very rare sarcomatoid variant which is composed of large atypical cells with eosinophilic cytoplasm and eccentrically located nuclei
- Carcinosarcoma is a subtype in which there is a mixture of roundish epithelioid cells and spindle sarcomatous cells; each component should arbitrarily constitute 30% of the neoplasm to qualify as carcinosarcoma

Microscopic (histologic) images

Contributed by Claudio Luchini, M.D., Ph.D. and AFIP

Anaplastic undifferentiated carcinoma

Massive perineural invasion

Massive vascular invasion

Association with ductal adenocarcinoma

Invasion of duodenum

Rhabdoid aspects

Biopsy

Details on biopsy

Spindle cell sarcomatoid features

Pleomorphic large cells

Engulfment of red blood cells

Glandular differentiation

Tumor is keratin+

Tumor is CEA+ in glandular portions

Cytology description

Hypercellular neoplasm: presence of highly atypical cells

Positive stains

Vimentin and keratin

Negative stains

Neoplastic cells are negative for E-cadherin
~50% of undifferentiated rhabdoid carcinomas typically present a nuclear loss of SMARCB1 / INI1 at immunohistochemistry (J Gastrointest Oncol 2021;12:874, Mod Pathol 2015;28:248)

Molecular / cytogenetics description

Overlaps with the genetic profile of conventional ductal adenocarcinoma
In the rhabdoid variant, KRAS alterations and SMARCB1 expression status define 2 subtypes, with possible translational implications (Mod Pathol 2015;28:248)
There is an enrichment in KRAS amplification in both rhabdoid and sarcomatoid variants, if compared with conventional ductal adenocarcinoma (Mod Pathol 2015;28:248, Hum Pathol 2022;128:124)
SMAD4 alterations appear as a rare molecular event in the sarcomatoid variant, if compared with conventional ductal adenocarcinoma (Hum Pathol 2022;128:124)

Sample pathology report

Pancreas, pancreatectomy:
- Pancreatic undifferentiated carcinoma
Pancreas, biopsy / cytology:
- Pancreatic undifferentiated carcinoma (see comment)
- Comment: Cellular neoplasm with highly atypical cells is consistent with undifferentiated carcinoma of the pancreas.
- Surgical resection: percentage of the undifferentiated component; infiltration, if any, of duodenum, common bile duct, neck margin, intestinal margin and retroperitoneal margin if Whipple resection, spleen and pancreatic margin if distal pancreatectomy; vascular / perineural invasion if any; nodal metastasis (if any); pTNM staging.

Differential diagnosis

Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells:
- Presence of osteoclast-like giant cells
Sarcoma:
- Keratin is negative
Melanoma:
- Melanoma is S100+ contains melanin pigment, whereas undifferentiated carcinoma of the pancreas is S100-

Additional references

WHO Classification of Tumours Editorial Board: Digestive System Tumours, 5th Edition, 2019

Board review style question #1

This is a high magnification field of a tumor within the pancreas. Can the diagnosis of undifferentiated carcinoma be made based on morphology only?

No, electron microscopy must be used to rule out a melanoma
No, immunohistochemistry is mandatory
No, molecular analysis is mandatory
No, special histochemical stains are mandatory
Yes, morphology only is sufficient

Board review style answer #1

B. No, immunohistochemistry is mandatory. Morphology is the most important step for the diagnosis; however, immunohistochemistry for keratin and vimentin should be performed in most cases to rule out sarcoma, melanoma and metastasis. This is particularly true for undifferentiated carcinoma with sarcomatoid features, to avoid misdiagnosis with sarcomas and for anaplastic type, to rule out melanoma or metastases.

Comment Here

Reference: Undifferentiated carcinoma

Board review style question #2

How do the fibrosis and desmoplastic reactions seen in conventional ductal adenocarcinoma of the pancreas compare to that of undifferentiated carcinoma?

Conventional ductal adenocarcinoma typically has more fibrosis and desmoplasia
Only anaplastic type undifferentiated carcinoma shows more fibrosis / desmoplasia than conventional ductal adenocarcinoma
There is always more fibrosis in undifferentiated carcinoma
There is the same quantity of fibrosis in both diagnoses
They are highly variable in both diagnoses

Board review style answer #2

A. Conventional ductal adenocarcinoma usually has much more fibrosis / desmoplasia than undifferentiated carcinoma. This is a major point in the differential diagnosis between the 2 diagnoses.

Comment Here

Reference: Undifferentiated carcinoma

Undifferentiated carcinoma with osteoclast-like giant cells

Table of Contents

Definition / general

Undifferentiated carcinoma of the pancreas with no glandular differentiation and with prominent infiltration by histiocytes and osteoclast-like giant cells
May be found in association with a differentiated component of pancreatic ductal adenocarcinoma

Essential features

Undifferentiated carcinoma with atypical neoplastic cells and lacking gland formation
Presence of multinucleated giant cells resembling osteoclasts

Terminology

Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC, UCOCGC)
Old terminology, not in use: giant cell tumor of the pancreas, osteoclastoma

ICD coding

ICD-O: 8035/3 - carcinoma with osteoclast-like giant cells
ICD-10: C25.9 - malignant neoplasm of pancreas, unspecified

Epidemiology

M:F = 0.9:1 (Am J Surg Pathol 2016;40:1203, J Pathol 2017;243:148)
Commonly presents in the sixth to seventh decades (Am J Surg Pathol 2016;40:1203, J Pathol 2017;243:148)
1.4% of all pancreatic cancers (Am J Surg Pathol 2016;40:1203)

Sites

Head of the pancreas (60 - 75% of cases), body / tail (25 - 40%) (Am J Surg Pathol 2016;40:1203, J Pathol 2017;243:148)

Pathophysiology

Unknown; a role may be played by hemorrhagic / chronic inflammatory foci with recruitment of tumor supporting macrophages within the pancreas or within a pancreatic ductal adenocarcinoma (Hum Pathol 2018;81:157)

Clinical features

Presenting symptoms include jaundice (tumors in the pancreatic head), abdominal or back pain, weight loss and nausea (Am J Surg Pathol 2016;40:1203, J Pathol 2017;243:148)

Diagnosis

CT scan and MRI are the preferred imaging modalities
Diagnosis is by biopsy or surgical resection (more difficult with cytology but may be possible) (Cancer Cytopathol 2017;125:563)

Radiology description

Usually mass lesions with delayed enhancement (Am J Surg Pathol 2016;40:1203)

Radiology images

Images hosted on other servers:

Ultrasound

Prognostic factors

Presence of an associated conventional ductal adenocarcinoma component is associated with a poorer prognosis and is one of the most important prognostic moderators (Am J Surg Pathol 2016;40:1203, J Pathol 2017;243:148)
PDL1 expression by tumor cells is associated with poor prognosis (Hum Pathol 2018;81:157)

Case reports

54 year old man with a huge (28 cm) mass for which radical resection was possible (Int Cancer Conf J 2017;6:193)
54 year old woman with a large cystic mass in the pancreas (Int J Clin Exp Pathol 2015;8:11785)
61 year old woman with long term survival after surgical resection and chemotherapy (Case Rep Gastroenterol 2016;10:472)
62 year old woman with metastatic disease showing durable response to immunotherapy (tumor with high tumor mutational burden) (J Natl Compr Canc Netw 2021;19:247)
65 year old man with weight loss (Medicine (Baltimore) 2018;97:e13516)
68 year old woman with a prominent invasion of pancreatic ductal tree (JOP 2011;12:170)

Treatment

Surgical resection if possible, gemcitabine based chemotherapy (Case Rep Gastroenterol 2016;10:472)
Immunotherapy is a novel opportunity to be explored in this type of cancer (BMC Gastroenterol 2020;20:220, J Natl Compr Canc Netw 2021;19:247)

Gross description

Larger than conventional ductal adenocarcinoma (J Pathol 2017;243:148)
Brownish (not whitish) and with pushing borders
Frequent cyst formation
Hemorrhage or necrosis is typically present

Gross images

Contributed by Claudio Luchini, M.D., Ph.D.

Cystic tumor

Images hosted on other servers:

Hemorrhagic mass

Macrophotograph revealing cystic mass

Cystic mass with gastric invasion

Frozen section description

Hypercellular neoplasm with atypical cells
Multinucleated giant cells, although they cannot always be documented in small biopsy sent for frozen section (may be focal component)

Frozen section images

Contributed by Claudio Luchini, M.D., Ph.D.

Osteoclast-like giant cells and neoplastic cells

Microscopic (histologic) description

Composed of 3 cell types:
- Mononuclear neoplastic cells, sometimes very atypical
- Mononuclear histiocytes (nonneoplastic)
- Multinucleated giant cells (osteoclast-like giant cells) (nonneoplastic)
Foci of hemorrhage and necrosis are very common
Typical involvement of the pancreatic ductal tree, sometimes with a pseudopolypoid growth pattern (J Pathol 2017;243:148)
May arise in association with mucinous cystic neoplasm of the pancreas and intraductal papillary mucinous neoplasm of the pancreas (Am J Surg Pathol 2016;40:1203, World J Surg Oncol 2011;9:100, Am J Surg Pathol 2015;39:179)
Osteoid material may be found (J Pathol 2017;243:148)

Microscopic (histologic) images

Contributed by Claudio Luchini, M.D., Ph.D.

Associated conventional adenocarcinoma

Ductal tree involvement

Microhemorrhagic foci

Extensive necrotic hemorrhage

CK8/18+

Focal CK8/18+

CK8/18-

Cytology description

3 cell types (osteoclast-like giant cells, neoplastic cells and histiocytes) are present in most cases (~80%)
Cytology has a diagnostic value for this tumor in ~80% of cases (Cancer Cytopathol 2017;125:563)

Cytology images

Images hosted on other servers:

Romanowsky stain

Papanicolaou stain

Positive stains

Neoplastic cells:
- Cytokeratin AE1 / AE3, CK7, CK8/18 are usually positive but may be totally negative
- p53 in > 50% of cases
- Ki67 high proliferation index
Histiocytes:
- CD68, CD163 (Hum Pathol 2018;81:157)
Multinucleated giant cells:
- CD68, cathepsin K (Hum Pathol 2019;85:168)

Negative stains

Neoplastic cells:
- CD68, CD163, S100, CD45
Histiocytes and multinucleated giant cells:
- Cytokeratins, p53

Electron microscopy description

Neoplastic cells: abundant mitochondria, no microvilli or desmosomes (J Korean Med Sci 2005;20:516)
Multinucleated osteoclast-like giant cells: multiple nuclei with rim of chromatin; abundant mitochondria; free ribosomes; dilated, empty, rough endoplasmic reticulum cisternae (J Korean Med Sci 2005;20:516)

Electron microscopy images

Images hosted on other servers:

Neoplastic cell

Giant cell

Molecular / cytogenetics description

Overlaps with the genetic profile of conventional ductal adenocarcinoma, with the most common mutated genes being KRAS, TP53, CDKN2A and SMAD4 (J Pathol 2017;243:148)
GLI3, a gene belonging to the hedgehog signaling pathway, may be found mutated in this tumor
The same mutation (290 M > L) affecting the gene SERPINA3 has been documented in 25% of cases in a whole exome sequencing analysis (J Pathol 2017;243:148)

Sample pathology report

Pancreas, pancreatectomy:
- Pancreatic undifferentiated carcinoma with osteoclast-like giant cells (see synoptic report)

Differential diagnosis

Undifferentiated / anaplastic carcinoma of the pancreas:
- Absence of osteoclast-like giant cells
Paraduodenal (groove) pancreatitis:
- Multinucleated giant cells may be abundant but neoplastic cells are lacking (Cytopathology 2015;26:122)
Melanoma:
- Contains melanin pigment instead of or in addition to hemosiderin
- S100+

Additional references

WHO Classification of Tumours Editorial Board: Digestive System Tumours, 5th Edition, 2019

Board review style question #1

This is an immunohistochemical slide (CK8/18) from a pancreatic tumor in an elderly woman with jaundice. S100 was negative throughout and the multinucleated cells were CD68 positive. Which of the following is the most likely diagnosis?

Anaplastic lymphoma
Melanoma
Pancreatic undifferentiated carcinoma with osteoclast-like giant cells
Pancreatitis
Primitive mesenchymal tumor of the pancreas

Board review style answer #1

C. This is a pancreatic undifferentiated carcinoma with osteoclast-like giant cells. These tumors may be composed of neoplastic cells that are totally negative for cytokeratin. This finding, which is not uncommon, cannot be used to exclude this tumor entity.

Comment Here

Reference: Undifferentiated carcinoma with osteoclast-like giant cells

Board review style question #2

Which cell types usually form an undifferentiated carcinoma with osteoclast-like giant cells?

Osteoclast-like giant cells, which are tumor cells
Tumor cells and histiocytes
Tumor cells arranged in glands and osteoclast-like giant cells
Tumor cells, histiocytes and osteoclast-like giant cells
Tumor cells, lymphocytes and osteoclast-like giant cells

Board review style answer #2

D. Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells typically contains 3 types of cells: tumor cells, histiocytes and osteoclast-like giant cells.

Comment Here

Reference: Undifferentiated carcinoma with osteoclast-like giant cells

VIPoma

Table of Contents

Definition / general

Well differentiated neuroendocrine tumor that secretes vasoactive intestinal peptide (VIP), leading to chronic watery diarrhea

Essential features

Functional well differentiated neuroendocrine tumor (WD-NET) that secretes vasoactive intestinal peptides
Histology is same as other well differentiated neuroendocrine tumors in pancreas
Clinical diarrhea can be severe, possibly fatal (may exceed 8 liters of stool in 24 hours) (South Dartmouth (MA): MDText.com, Inc;2017 Jun 5)

Terminology

VIPoma syndrome is also termed Verner-Morrison syndrome and WDHA syndrome (watery diarrhea, hypokalemia, achlorhydria) (Rom J Morphol Embryol 2017;58:371)

ICD coding

ICD-10:
- C7A.8 - other malignant neuroendocrine tumors
- E16.8 - other specified disorders of pancreatic internal secretion

Epidemiology

Incidence is roughly 1 per 10 million persons per year (Surg Clin North Am 1987;67:379)
Mean age 51 years

Sites

90% of VIPomas arise from pancreas (Am J Med 1987;82:37)
Most common pancreatic location is tail (Surgery 1998;124:1050)

Pathophysiology

VIP stimulates intestinal secretion of water and electrolytes, causing VIPoma syndrome when excessive

Etiology

Most cases are sporadic but about 5% occur in the setting of multiple endocrine neoplasia 1 syndrome (MEN1)

Clinical features

Chronic secretory diarrhea hypokalemia, achlorhydria, flushing, hypercalcemia (Hepatogastroenterology 2005;52:1259)

Diagnosis

Imaging to detect pancreatic mass
Elevated plasma vasoactive intestinal levels

Radiology images

Images hosted on other servers:

Pancreatic tail mass

Liver metastasis

Prognostic factors

Often metastatic at time of diagnosis (Surgery 1998;124:1050)
Median survival is roughly 6 years (Pancreas 2019;48:934)
Poor prognostic factors: age < 40 years or > 60, size > 4 cm, poor clinical management of water, electrolyte and acid base profiles, metastatic disease, unresectability (J Clin Case Rep 2012,2:15)

Case reports

13 year old girl with multiple endocrine neoplasia 1 syndrome and pancreas mass (Indian J Endocrinol Metab 2013;17:S215)
46 year old woman with 18 cm tumor (World J Surg Oncol 2008;6:80)
47 year old man with sporadic tumor (Hematol Oncol Stem Cell Ther 2014;7:109)
74 year old man with diarrhea, weight loss and liver metastasis (Case Rep Gastroenterol 2019;13:225)

Treatment

Surgical resection of primary lesion, if possible
Hepatic metastases can be resected or embolized
Octreotide for metastatic disease

Gross description

Single or multiple lesions, most commonly in tail of pancreas
Firm, homogeneous, well circumscribed

Microscopic (histologic) description

Nests of monotonous low grade neuroendocrine cells with salt and pepper nuclei and ample amphophilic cytoplasm, as with any other well differentiated neuroendocrine tumor

Microscopic (histologic) images

Contributed by Raul S. Gonzalez, M.D.

Nests and cords of cells

Positive stains

VIP (though this does not establish the diagnosis)
Synaptophysin, chromogranin
PDX1, INSM1 (Am J Surg Pathol 2012;36:737)

Negative stains

CK7 (8%), CDX2, BCL10, nuclear beta catenin (Am J Surg Pathol 2012;36:737, Pathol Int 2013;63:176, World J Gastrointest Oncol 2016;8:615)

Electron microscopy images

AFIP images

Pancreatic VIPoma

Molecular / cytogenetics description

Overexpression of CXCR4, down regulation of MSH2 in one case (World J Surg Oncol 2012;10:264)

Sample pathology report

Pancreas and duodenum, Whipple procedure:
- Well differentiated neuroendocrine tumor of pancreas (see comment and synoptic report)
- Comment: Based on the patient's clinical symptoms, this neuroendocrine tumor is best considered a VIPoma.

Differential diagnosis

Nongastrin secreting pancreatic neuroendocrine tumor:
- No histopathologic differences; must be determined on clinical grounds

Board review style question #1

What is the most common symptom of a VIPoma?

Abdominal pain
Acromegaly
Diarrhea
Necrotizing migratory erythema
Weakness

Board review style answer #1

C. Diarrhea

Comment here

Reference: VIPoma

Board review style question #2

Where are VIPomas most likely to arise?

Body of the pancreas
Duodenum
Head of the pancreas
Ileum
Tail of the pancreas

Board review style answer #2

E. Tail of the pancreas

Comment here

Reference: VIPoma

Well differentiated neuroendocrine tumor

Table of Contents

Definition / general

Low, intermediate or high grade subset of neuroendocrine tumors (NET) that lack necrosis and express neuroendocrine markers (synaptophysin or chromogranin A)

Essential features

WHO Classification of Tumours of Endocrine Organs (2017) and WHO Classification of Tumours of the Digestive System (2019) classifies well differentiated pancreatic neuroendocrine tumors (PanNETs) as grade 1, grade 2 or grade 3 (see Diagnosis)
Classification uses criteria similar to other gastrointestinal neuroendocrine neoplasms
May be nonfunctioning or secrete 1 or more peptides; multiple tumors in the same patient may secrete the same or different peptides

Terminology

Synonyms: well differentiated neuroendocrine tumor (WD NET), pancreatic neuroendocrine tumor (PanNET), pancreatic endocrine tumor, islet cell tumor
Specific functional terms (glucagonoma, insulinoma, gastrinoma) not recommended for use unless hormonal syndrome exists clinically
Microscopic lesions < 0.5 cm are termed microadenomas
Carcinoid is a term that should be avoided if possible

ICD coding

ICD-10: C25 - malignant neoplasm of pancreas

Epidemiology

M = F
Peak incidence: 30 - 60 years
Comprise ~2 - 5% of pancreatic neoplasms (J Gastrointest Surg 2010;14:541)
Most are sporadic; risk factors include (Ann Oncol 2016;27:68):
- Family history of cancer (not site dependent; lung, colon, among others)
- Elevated BMI
- Diabetes
- Cigarette smoking
- Elevated alcohol consumption
10 - 20% are associated with syndromes:
- Multiple endocrine neoplasia type 1 (MEN1): nearly 100% pancreatic involvement at autopsy (Surgery 1979;86:475)
- Von Hippel-Lindau (VHL): 12.3 - 17% of patients (Surgery 2007;142:814, Gastroenterology 2000;119:1087)
- Neurofibromatosis type 1: 10% of patients (Crit Rev Oncol Hematol 2022;172:103648)
- Tuberous sclerosis: 1 - 9% of patients (Crit Rev Oncol Hematol 2022;172:103648)
Nonfunctional tumors represent 60 - 90% of all PanNETs (Neuroendocrinology 2016;103:153, Biomed Res Int 2017;2017:9856140)
Functional tumors (10 - 40%):
- Insulinoma (most common, account for 4 - 20% of PanNETs) (J Gastroenterol 2015;50:58)
- Gastrinoma (second most common, account for 4 - 8% of PanNETs) (J Gastroenterol 2015;50:58)
- VIPoma (Endocr J 2022;69:1201)
- Glucagnoma (1 - 2% of PanNETs) (Ann Surg Oncol 2007;14:3492)
- Somatostatinoma (J Gastroenterol Hepatol 2008;23:521)
- ACTH producing neuroendocrine tumor (Am J Surg Pathol 2015;39:374)
- Serotonin producing neuroendocrine tumor (up to 3.9%) (Am J Surg Pathol 2015;39:592)

Sites

Found throughout the pancreas
Nonfunctional, gastrinomas or serotonin producing tumors are more likely to be found in the head of the pancreas
Insulinomas, glucagonomas and VIPomas are more likely to be found in the tail (Ann Surg Oncol 2007;14:3492)

Pathophysiology

Theorized to arise from totipotent stem cells in the pancreatic ductal system and islets of Langerhans (Endotext: Pathophysiology and Treatment of Pancreatic Neuroendocrine Tumors [Accessed 30 September 2022])

Etiology

Majority are sporadic and nonsyndromic
Minority are associated with multiple endocrine neoplasia syndrome (80 - 100% incidence), tuberous sclerosis (rare), von Hippel-Lindau (VHL, 10 - 17% incidence), among others (Cancer 2008;113:1807)
Hyperplastic and preneoplastic lesions were removed from the WHO 2017; PanNEN precursor lesions have not been clearly associated with sporadic neoplasms (but are described in MEN1 and VHL)

Clinical features

Demonstrate a spectrum of clinical behavior dependent on hormones produced
Commonly causes abdominal pain, jaundice
Asymptomatic pancreatic neuroendocrine tumors are increasingly common, likely because of an increase in detection due to increased imaging frequency and improvement in imaging modalities (Cancer 2015;121:589)
Functional tumors may have elevated serum peptides corresponding to tumor cell type
May be associated with carcinoid syndrome (flushing, diarrhea) if metastatic to liver
Most nonfunctional tumors are large and detected at an advanced stage at diagnosis, with 60 - 85% having liver metastases (Cancer 2008;113:1807)
Liver is the most common site of metastasis
Insulinoma:
- Composed of insulin producing cells with uncontrolled secretion of insulin
- Clinical: Whipple triad (hypoglycemic symptoms, plasma glucose Typically, small (Neoplasma 2015;62:484)
Gastrinoma:
- Composed of gastrin producing cells with uncontrolled secretion of gastrin
- Clinical: Zollinger-Ellison syndrome (reflux symptoms and duodenal ulcers)
- Typically, large size (average 3.8 cm diameter), more common in the duodenum than in the pancreas (Wien Klin Wochenschr 2007;119:579)
VIPoma:
- Composed of uncontrolled vasoactive intestinal peptide (VIP) secreting cells
- Clinical: WDHA syndrome (watery diarrhea [persists when fasting], hypokalemia and achlorhydria)
- Typically, large (average ~5 cm diameter) and solitary (Ann N Y Acad Sci 1988;527:508)
Glucagonoma:
- Composed of cells with uncontrolled secretion of glucagon and preglucagon derived peptide
- Clinical: triad of skin rash (necrolytic migratory erythema), diabetes mellitus and weight loss
- Typically, variable in size (average 3 - 7 cm diameter) and solitary (Medicine (Baltimore) 1996;75:53)
Somatostatinoma:
- Composed of cells that demonstrate D cell differentiation with uncontrolled secretion of somatostatin
- Clinical: less distinctive than other functioning PanNETs (glucose intolerance, cholelithiasis and diarrhea)
- Typically, large (average 5 - 6 cm diameter) and multinodular (J Exp Clin Cancer Res 1999;18:13)
ACTH producing neuroendocrine tumor:
- Composed of cells secreting uncontrolled adrenocorticotropic hormone (ACTH)
  - Clinical: features of Cushing syndrome (central obesity, weight gain, moon face, hypertension, hyperglycemia, osteoporosis, hypokalemia and cutaneous hyperpigmentation)
- Typically, large (average 4.8 cm diameter) and solitary (Am J Surg Pathol 2015;39:374)
Serotonin producing neuroendocrine tumor:
- Composed of cells secreting uncontrolled serotonin
- Clinical (usually only after metastasizing to the liver): carcinoid syndrome (abdominal pain, flushing, diarrhea and weight loss)
- Typically large (average ~5 cm diameter) and solitary (Pancreas 2011;40:883)

Diagnosis

Requires neuroendocrine histology and positive staining for neuroendocrine and cytokeratin makers (and the presence of clinical symptoms if functional)
Contains mixed neuroendocrine nonneuroendocrine neoplasms [MiNEN])
Does not contain necrosis or severe atypia (otherwise, see neuroendocrine carcinoma [PanNEC])
Well differentiated tumors are classified by mitotic count and proliferative index (Ki67):
- G1 (NET G1): mitotic count < 2/2 mm² and G2 (NET G2): mitotic count 2 - 20/2 mm² or 3 - 20% Ki67 index
- G3 (NET G3): mitoses > 20/2 mm² or > 20% Ki67 index

Laboratory

Elevated serum chromogranin A levels (> 15 ng/mL) show a sensitivity of 66% and a specificity of 95% for the diagnosis pancreatic neuroendocrine tumors (World J Gastroenterol 2020;26:2305)
Elevated serum neuron specific enolase (NSE) and pancreatic polypeptide (PP) are respectively seen in up to 30 - 50% and 50% of PNET patients (Front Oncol 2020;10:831)
Specific biomarkers for functional PNET are not currently recommended due to their poor sensitivity, specificity and lack of standardization between laboratories (Surg Oncol Clin N Am 2020;29:165)

Radiology description

General: highly vascular, well circumscribed enhancing lesion that can be solid or cystic
Ultrasound: circumscribed masses with smooth margins, suboptimal visualization of the body and tail due to bowel gas obstruction, sensitivity of 20 - 80%
CT: well defined, uniformly hypervascular masses on arterial phase CT, most widely available technique
MRI: hyperintense on T1 weighted imaging due to an abundance of proteinaceous material and variable signal on T2 weighted images; better resolution than CT (Semin Ultrasound CT MR 2019;40:469)
68Ga SRS (stimulated Raman scattering) is a type of PET imaging of somatostatin receptor, current gold standard for functional imaging of NETs (Nat Rev Endocrinol 2018;14:656)

Radiology images

Images hosted on other servers:

Large mass in pancreas tail

Prognostic factors

Relatively indolent but with variable outcome
Features associated with adverse outcome (Am J Surg Pathol 2007;31:1677, HPB (Oxford) 2009;11:422, Sci Rep 2018;8:7271):
- Size > 2 cm
- Tumor necrosis
- Lymph node positivity
- Mitoses > 2/10 high powered fields
- Vascular invasion
- Perineural invasion
- High Ki67 index
- CK19 positivity
- Loss of DAXX / ATRX expression and alternative lengthening of telomeres suggest poor outcome (Clin Cancer Res 2017;23:600, Front Endocrinol (Lausanne) 2021;12:691557)

Case reports

23 year old woman with VHL and SDHA pathogenic variant co-occurrence in PanNET (Front Oncol 2022;12:925582)
43 year old man with MEN1 and metastatic grade 3 PanNET (J Endocr Soc 2022;6:bvac122)
44 year old woman with recurrent pancreatic glucagonoma (Ann Med Surg (Lond) 2022;77:103604)
62 year old man with metastases (J Med Life 2018;11:57)
69 year old man with pancreatic insulinoma presenting with postprandial hypoglycemia (AACE Clin Case Rep 2022;8:154)

Treatment

Primarily surgical (benefits shown for primary and metastatic disease)
Enucleation can be used for small and localized tumors
First line treatments for metastatic disease are somatostatin analogs (octreotide and lanreotide)
Second line treatments include tyrosine kinase inhibitors (sunitinib) and mTOR inhibitors (everolimus)
Novel chemotherapy regime of capeciabine and temozolomide (CAPTEM) and peptide receptor radionuclide therapy (PRRT) has been approved
Reference: Surg Clin North Am 2019;99:793

Gross description

Solid, well circumscribed mass, typically 2 - 5 cm in diameter
Larger tumors often show heterogenous and lobulated cut surfaces
Color can range from red-tan to brown-yellow
May show extensive fibrosis, calcification or ossification
5% are cystic (unilocular, less commonly multilocular) but necrosis is uncommon in well differentiated PanNETs
Reference: Arch Pathol Lab Med 2019;143:1317

Gross images

Contributed by Katrina Krogh, M.D.

Well circumscribed mass

Cut surface of mass

Images hosted on other servers:

Invasion of large vessel

Tumor in isthmus / body

Microscopic (histologic) description

Architecture can be solid, organoid, nesting, gyriform, trabecular or glandular
Small, round monotonous cells with coarse, salt and pepper nuclear chromatin and minimal atypia
Occasional small nucleoli are most common; large nucleoli can be seen
Cytoplasm can be pale pink, oncocytic, granular or lipid rich / vacuolated
Rarely, nuclei can be eccentrically located (rhabdoid cell appearance) (Am J Surg Pathol 2003;27:642)
Islet amyloid polypeptide (amylin) deposition is specific for insulinoma but is only seen in ~5% of cases
Psammoma bodies can be seen in somatostatinomas

Microscopic (histologic) images

Contributed by Katrina Krogh, M.D.

Trabecular growth

Neuroendocrine nuclei

PanNET (VIPoma) metastatic to liver

Ki67

Synaptophysin

Chromogranin

Contributed by @RaulSGonzalezMD on Twitter

bit.ly/3zIR8Xf for a nice review). Here's a great example of the ductulo-insular subtype, with admixed benign glandular structures. Good prognosis. #pathology #gipath #PathTwitter #PathOutPic"
Contributed by @RaulSGonzalezMD on Twitter (see original post here)"> Well differentiated neuroendocrine tumor

Well differentiated neuroendocrine tumor

Well differentiated neuroendocrine tumor

Cytology description

Single cell type; monotonous plasmacytoid cells with moderate amount of cytoplasm and distinctive neuroendocrine chromatin (Clin Cancer Res 2017;23:600)
Can have rosette-like aggregates and eccentric nuclei

Cytology images

Contributed by Katrina Krogh, M.D.

Diff-Quik

Positive stains

Chromogranin A (more specific) and synaptophysin (more sensitive): diffuse and strong
NSE, CD56, CD57
AE1 / AE3, CAM5.2 and CK8/18
Somatostatin receptor is positive in 80 - 90% and PR is positive in 58% of PanNETs (Hum Pathol 2020;96:8)
Immunohistochemistry for peptide hormones (insulin, glucagon, VIP, etc.) is rarely required and nonfunctional tumors may be positive
SMAD4 and Rb retained
- In metastatic setting: Isl1 (most sensitive) and PAX6 positivity is supportive
- PAX8 (polyclonal) is positive in 50 - 60% of cases metastatic to the liver (monoclonal PAX8 is negative) (Hum Pathol 2020;96:8)
NESP55+ and PDX1+, in the presence of negative CDX2 and TTF1, is 97% specific for pancreatic origin (Clin Cancer Res 2017;23:600)

Negative stains

CDX2, SATB2 and TTF1 (Surg Oncol Clin N Am 2020;29:185)
Nuclear beta catenin
Trypsin / chymotrypsin
BCL10
SMA

Molecular / cytogenetics description

Frequently mutated genes (Science 2011;331:1199, Endocr Relat Cancer 2009;16:1219, Expert Rev Gastroenterol Hepatol 2015;9:1407):
- MEN1 (44.1%)
- DAXX (death domain associated protein, 25%)
- ATDX ([alpha] thalassemia / intellectual disability syndrome X linked, 17.6%)
- TSC2 (8.8%)
- PTEN (7.3%)
- PI3KCA (1%)
- VHL (up to 25% including deletion by promoter methylation)

Molecular / cytogenetics images

Images hosted on other servers:

MEN1 mutation

Sample pathology report

Distal pancreas and spleen, distal pancreatectomy and splenectomy:
- Well differentiated neuroendocrine tumor, WHO grade 2, measuring 4.1 cm in greatest dimension (see comment)
- Lymphovascular and perineural invasion identified
- Pancreatic resection margin, negative for tumor
- 2 of 10 lymph nodes, positive for metastatic tumor (2/10)
- Spleen with no significant pathologic change
- Pathologic stage: pT3, pN1
- Comment: Immunohistochemical stains are performed and show the tumor cells are positive for cytokeratin AE1 / AE3, synaptophysin and chromogranin (patchy). The Ki67 proliferative index is 15%. Beta catenin shows membranous staining (negative result). Overall findings are consistent with 2019 WHO grade 2 (out of 3).

Differential diagnosis

Solid pseudopapillary neoplasm:
- Positive stains: nuclear beta catenin, cytoplasmic / perinuclear CD10, nuclear PR, synaptophysin (sometimes), pankeratins (variable)
- Negative stains: membranous E-cadherin, ER, chromogranin (usually)
- Contains pseudopapillary architecture, which is rare in neuroendocrine tumors
Mixed neuroendocrine nonneuroendocrine neoplasms (MiNEN):
- Typically, neuroendocrine component is mixed with a ductal adenocarcinoma, occasionally with acinar cell carcinoma
- Each component must account for > 30% of the tumor
Metastatic neuroendocrine tumors of other origin:
- Negative for islet 1, PAX6, PDX1
- Positive for TTF1, SATB2, CDX2 (Surg Oncol Clin N Am 2020;29:185)
Neuroendocrine carcinoma (NEC):
- High mitotic rate (> 20/2 mm² or Ki67 > 20%)
- Large or small cell with corresponding high grade morphology
Acinar cell carcinoma (Am J Surg Pathol 1992;16:815, Cancer Cytopathol 2013;121:459):
- PAS+ diastase resistant granules sometimes detected
- Positive stains: trypsin, chymotrypsin, lipase, CK8/18
- Occasionally positive for synaptophysin or chromogranin
Pancreatoblastoma (Cancer Cytopathol 2013;121:459):
- Solid and acinar patterns, squamoid nests are present
- Trypsin, chymotrypsin, lipase, BCL10, synaptophysin and chromogranin can be focally positive
Glomus tumor:
- Composed of 3 cell types: glomus, vasculature and smooth muscle cells
- Positive SMA, negative synaptophysin, chromogranin

Additional references

Lloyd: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017, WHO Classification of Tumours Editorial Board: Digestive System Tumours, 5th Edition, 2019

Board review style question #1

Which of the following statements is true regarding the pancreatic lesion seen above?

Commonly associated with familial adenomatous polyposis (FAP)
Loss of DAXX / ATRX expression are associated with better outcomes
More common than pancreatic adenocarcinoma
More likely to be nonsecreting than secreting

Board review style answer #1

D. More likely to be nonsecreting than secreting

Comment Here

Reference: Well differentiated neuroendocrine tumor

Board review style question #2

Which of the following statements is true about the Ki67 stain in a pancreatic neuroendocrine tumor seen above?

Can undergo transformation to squamous cell carcinoma
Does not metastasize
Has a high proliferation index
Treatment depends on Ki67 interpretation

Board review style answer #2

D. Treatment depends on Ki67 interpretation

Comment Here

Reference: Well differentiated neuroendocrine tumor

Board review style question #3

A patient presents to his primary care doctor with a 1 month history of constant watery diarrhea that wakes him up several times each night. Laboratory values were remarkable for a potassium of 3.2 mmol/L (normal: 3.6 - 5.2 mmol/L). An abdominal CT showed a solitary, solid, well demarcated and vascular 5 cm lesion in the tail of the pancreas that is consistent with a neoplasm. What is the most likely gene mutation in this lesion?

APC
CTNNB1
MEN1
SMAD4
STK11

Board review style answer #3

C. MEN1. The patient is presenting with WDHA syndrome (watery diarrhea that persists when fasting, hypokalemia and achlorhydria) and a pancreatic mass. This is likely due to a VIPoma, which is a type of pancreatic neuroendocrine tumor (PanNET). The most common mutation in these tumors is MEN1.

Comment Here

Reference: Well differentiated neuroendocrine tumor

WHO classification

Table of Contents

Definition / general | WHO (2019)

Definition / general

WHO classification of tumors of the pancreas
Currently on 5th edition, published in 2019
Based on histologic appearance, not molecular characteristics

WHO (2019)

Benign epithelial tumors and precursors

ICD-O codes

Serous cystadenoma, NOS 8441/0
- Macrocystic (oligocystic) serous cystadenoma
- Solid serous adenoma
- Von Hippel-Lindau syndrome associated serous cystic neoplasm
- Mixed serous-neuroendocrine neoplasm
Serous cystadenocarcinoma, NOS 8441/3
Glandular intraepithelial neoplasia, low grade 8148/0
Glandular intraepithelial neoplasia, high grade 8148/2
Intraductal papillary mucinous neoplasm with low grade intraepithelial neoplasia 8453/0
Intraductal papillary mucinous neoplasm with high grade intraepithelial neoplasia 8453/2
Intraductal papillary mucinous neoplasm with associated invasive carcinoma 8453/3
Intraductal oncocytic papillary neoplasm, NOS 8455/2
Intraductal oncocytic papillary neoplasm with associated invasive carcinoma 8455/3
Intraductal tubulopapillary neoplasm 8503/2
Intraductal tubulopapillary neoplasm with associated invasive carcinoma 8503/3
Mucinous cystic neoplasm with low grade intraepithelial neoplasia 8470/0
Mucinous cystic neoplasm with high grade intraepithelial neoplasia 8470/2
Mucinous cystic neoplasm with associated invasive carcinoma 8470/3

Malignant epithelial tumors

ICD-O codes

Duct adenocarcinoma, NOS 8500/3
- Colloid carcinoma 8480/3
- Poorly cohesive carcinoma 8490/3
- Signet ring cell carcinoma 8490/3
- Medullary carcinoma, NOS 8510/3
- Adenosquamous carcinoma 8560/3
- Epidermoid carcinoma 8576/3
- Large cell carcinoma with rhabdoid phenotype 8014/3
- Carcinoma, undifferentiated, NOS 8020/3
- Undifferentiated carcinoma with osteoclast-like giant cells 8035/3
Acinar cell carcinoma 8550/3
- Acinar cell cystadenocarcinoma 8551/3
- Mixed acinar-neuroendocrine carcinoma 8154/3
- Mixed acinar-endocrine-ductal carcinoma 8154/3
- Mixed acinar-ductal carcinoma 8552/3
Pancreatoblastoma 8971/3
Solid pseudopapillary neoplasm of the pancreas 8452/3
- Solid pseudopapillary neoplasm with high grade dysplasia

Pancreatic neuroendocrine neoplasms

ICD-O codes

Pancreatic neuroendocrine microadenoma 8150/0
Neuroendocrine tumor, NOS 8240/3
- Neuroendocrine tumor, grade 1 8240/3
- Neuroendocrine tumor, grade 2 8249/3
- Neuroendocrine tumor, grade 3 8249/3
Pancreatic neuroendocrine tumor, nonfunctioning 8150/3
- Oncocytic pancreatic neuroendocrine tumor, nonfunctioning
- Pleomorphic pancreatic neuroendocrine tumor, nonfunctioning
- Clear cell pancreatic neuroendocrine tumor, nonfunctioning
- Cystic pancreatic neuroendocrine tumor, nonfunctioning
Functioning pancreatic neuroendocrine tumors
- Insulinoma 8151/3
- Gastrinoma 8153/3
- VIPoma 8155/3
- Glucagonoma 8152/3
- Somatostatinoma 8156/3
- ACTH producing tumor 8158/3
- Enterochromaffin cell carcinoid 8241/3
- Serotonin producing tumor 8241/3
- Neuroendocrine carcinoma, NOS 8246/3
  - Large cell neuroendocrine carcinoma 8013/3
  - Small cell neuroendocrine carcinoma 8041/3
- Mixed neuroendocrine - nonneuroendocrine neoplasm (MiNEN) 8154/3
  - Mixed acinar-endocrine carcinoma 8154/3
  - Mixed acinar-neuroendocrine carcinoma 8154/3
  - Mixed acinar-endocrine-ductal carcinoma 8154/3

WHO reporting system for pancreaticobiliary cytopathology

Table of Contents

Definition / general

The Papanicolaou Society of Cytopathology (PSC) developed guidelines in 2014 for interpreting and reporting pancreaticobiliary cytology
- PSC was comprised of international, multidisciplinary pancreaticobiliary experts who met over an 18 month period to provide recommendations for:
  - Clinical and imaging workup (Diagn Cytopathol 2014;42:325)
  - Techniques for sampling lesions (Diagn Cytopathol 2014;42:333)
  - Standardized terminology and nomenclature (Diagn Cytopathol 2014;42:338)
  - Ancillary studies (Diagn Cytopathol 2014;42:351)
  - Patient follow up and treatment (Diagn Cytopathol 2014;42:363)
Standardization provides uniform diagnostic reporting, reproducibility and clinically relevant risk stratification
Resulted in a 6 tiered reporting system: nondiagnostic, negative (for malignancy), atypical, neoplastic (benign or other), suspicious (for malignancy) and positive or malignant
- Second edition may consider the 2019 World Health Organization proposed updates (Diagn Cytopathol 2020;48:494, Cancer Cytopathol 2022;130:195)

Essential features

Internationally adopted recommendations for sampling, diagnosing and managing pancreaticobiliary cytology lesions
6 tiered categorical system resulting in overall improved sensitivity / specificity and risk stratification
Risks of malignancy inform multidisciplinary patient care

Techniques for cytologic sampling of pancreatic and bile duct lesions

Primary method for sampling solid mass and cysts: endoscopic ultrasound fine needle aspiration (EUS FNA)
- Different biopsy devices may improve diagnostic yield of pancreatic cyst wall components (Cancer Cytopathol 2018;126:414, Endosc Ultrasound 2018;7:323, Gastrointest Endosc 2018;87:495)
Primary method for sampling strictures: endoscopic retrograde cholangiopancreatography (ERCP) guided brush cytology
- Risk of pancreatitis
- Endoscopic forceps biopsy may improve poor sensitivity (Diagn Cytopathol 2014;42:333)

Metrics

Risk of malignancy (ROM) = total number FNA specimens that proved malignant on follow up / total number of surgical resections and clinical follow ups (Cancer Cytopathol 2020;128:29)
- Average ROM for each diagnostic category (next section) is provided by the Saieg and Pitman review of several studies (Diagn Cytopathol 2020;48:494)
Diagnostic variation due to:
- Operator skill, experience and medical device
- Variation in prevalence of pathology and patient populations
- Limited availability of ancillary tests (Cytopathology 2020;31:564)
- Absence of rapid on site assessment (ROSE) (Oncotarget 2017;8:8154)

Papanicolaou system for reporting pancreaticobiliary cytology

Category I: nondiagnostic
- Provides no useful diagnostic or useful information about the solid or cystic lesion sampled
- Entities include:
  - Cells obscured by artifacts such as hemorrhage or necrosis
  - Pure gastrointestinal contamination indicates missed lesion
  - Acellular specimens obtained from cyst with no evidence of mucinous etiology
  - Benign pancreatic parenchyma with well defined mass on imaging
- Ancillary testing may result in reduced utilization of this category for cystic lesions (Diagn Cytopathol 2017;45:303)
- Average ROM: 23.1%
- Management: reassess or repeat sampling
Category II: negative (for malignancy)
- Contains adequate cellular or extracellular tissue to evaluate or define a lesion that is identified on imaging
  - Minor degree of loss of cell or nuclear polarity
  - No cytologic atypia observed
- Entities include:
  - Acute, chronic or autoimmune pancreatitis
  - Pseudocyst
  - Lymphoepithelial cyst
  - Splenule or accessory spleen
  - Benign pancreatic parenchyma with no discrete mass on imaging
- Ancillary tests such as amylase and carcinoembryonic antigen cyst fluid analysis can be helpful for cystic lesions (Diagn Cytopathol 2017;45:303)
- Increased false negative rate in biliary brushings due to underlying inflammatory lesions and subepithelial tissue entrapped within desmoplasia
- Average ROM: 8.2%
- Management: respective conservative care unless patients have irretractable symptoms or high risk of malignancy
Category III: atypical
- Cells present with cytoplasmic, nuclear or architectural features that are not consistent with normal or reactive changes of the pancreas and bile ducts and insufficient to classify as neoplasm or suspicious for high grade malignancy
  - Slight nuclear membrane irregularity, nuclear crowding with minor degree of overlap, nuclei haphazardly occupy lower 66% of the cell at the base, minimal degree of anisonucleosis (2:1), near normal N:C ratio, parachromatin clearing, background smear is clean or contains red blood cells
  - Also includes entities with abundant intracytoplasmic mucin in the epithelium without overt cytologic atypia
  - Absent features: necrosis, true nuclear molding, macronucleoli and features of malignancy
- Category with the widest range of reported ROM: 28 - 100%, average of 46.8%
- Management: repeat sampling, additional ancillary studies, continued conservative care or surgery referral as determined by team
Category IV: neoplastic
- Neoplastic: benign
  - Cytological specimen sufficiently cellular and representative (with or without the context of clinical, imaging and ancillary studies) to be diagnostic of a benign neoplasm
  - Entities include:
    - Serous cystadenoma (most common)
    - Lymphangioma
    - Cystic teratoma
    - Schwannoma
  - Average ROM: 20.2%
  - Management: conservative unless irretractable symptoms, large sized lesions at risk for rupture (> 4 cm serous cystadenomas) or increased risk of recurrence (lymphangiomas)
- Neoplastic: other
  - Neoplasm that is either premalignant or low grade malignant
  - Does not define the neoplasm as benign or malignant
  - Entities include:
    - Premalignant
      - Intraductal papillary mucinous neoplasm (IPMN) with low and high grade dysplasia
      - Intraductal papillary neoplasm of the bile duct (IPNB) with low and high grade dysplasia
      - Mucinous cystic neoplasm (MCN) with low grade dysplasia
      - Note that cases with prominent high grade dysplasia may often end up in the suspicious for malignancy category
    - Low grade malignant
      - Pancreatic neuroendocrine tumor (PanNET)
        
        Infers well differentiated neoplasm > 0.5 cm unless otherwise classified
      - Solid pseudopapillary neoplasm (SPN)
        
        If FNA is suggestive but not diagnostic, categorize as atypical rather than suspicious
      - Gastrointestinal stromal tumor (GIST)
      - Extra-adrenal paraganglioma
      - Novel reports of preoperatively diagnosing pancreatic solitary fibrous tumor by FNA (Cytopathology 2022;33:222, J Am Soc Cytopathol 2020;9:272)
    - Average ROM: 37.5%
    - Management: conservative, especially if lesion is small (PanNET < 2 cm)
Category V: suspicious for malignancy
- Some (but an insufficient number) of the typical features of a specific neoplasm are present, mainly pancreatic adenocarcinoma
- Significant cellular or architectural atypia but insufficient qualitative / quantitative findings for conclusive diagnosis, insufficient tissue for confirmative ancillary testing or rare cells with multiple major criteria, as listed below:
  - Significant nuclear enlargement, nuclear membrane irregularities, course chromatin pattern, distinct nucleoli, increased N:C ratio, anisonucleosis (3:1 to 4:1), sometimes mucinous metaplasia
  - Loss of cellular and architectural polarity
- Entities include:
  - Pancreatic adenocarcinoma (most common)
  - Solid cellular smear patterns suggestive of:
    - PanNET, acinar cell carcinoma, pancreatoblastoma, solid pseudopapillary neoplasm (SPN)
  - Cyst aspirates with solid mural nodule or cyst wall mass
  - Lymphoma
  - Metastases
  - High grade biliary intraepithelial neoplasia (BilIN) sampled by brushing (not high grade PanIN)
- Average ROM: 92.1%
- Management: reassess or repeat sampling; perform ancillary testing (may refer for surgery if positive FISH or loss of SMAD4 staining); consult experts
Category VI: positive for malignancy
- Neoplasms that unequivocally display malignant cytologic characteristics
  - Pancreatic ductal adenocarcinoma (PDAC) (most common):
    - Well differentiated
      - Difficult to diagnose; often classified as suspicious unless clearly malignant
    - Moderately and poorly differentiated:
      - Nuclear overlap and molding, marked loss of nuclear polarity, anisonucleosis > 4:1, disorganization (drunken honeycomb), macronucleoli, bizarre nuclei, nuclear hyperchromasia, elevated N:C ratio > 0.6, irregular chromatin distribution, lack of glandular differentiation, presence of cell balls, papillary fragments, cell in cell arrangements, tumor diasthesis, 3 dimensional fragments, cytoplasmic mucin vacuoles, background necrosis and mitoses
- Entities include:
  - Pancreatic ductal adenocarcinoma and its variants
  - Cholangiocarcinoma
  - Acinar cell carcinoma
  - High grade neuroendocrine carcinoma (small cell and large cell)
  - Pancreatoblastoma
  - Lymphomas
  - Sarcomas
  - Metastases to the pancreas
- Average ROM: 99.6%
- Management: surgical resection; may also consider neoadjuvant therapy or clinical trials if lesions are unresectable

Diagrams / tables

Table 1: Papanicolaou reporting system for pancreaticobiliary cytology

Diagnostic categories	Average risk of malignancy	Examples of entities	Selected ancillary testing	Management
I. Nondiagnostic	23.1%	• Cellular artifact, obscuring hemorrhage or necrosis • Pure GI contamination • Acellular cyst aspirate with no evidence of mucinous etiology • Benign pancreatic parenchyma with clearly defined mass on imaging	Cyst fluid analysis: CEA and amylase (no mucinous etiology = lack of mucin, lack of elevated CEA, lack of KRAS or GNAS mutations)	Reassess / repeat
II. Negative	8.2%	• Pancreatitis • Pseudocyst • Lymphoepithelial cyst • Splenule / accessory spleen • Benign pancreatic parenchyma with no mass on imaging	Pseudocyst: high amylase + low CEA	Conservative
III. Atypical	46.8% (range: 28 - 100)	• Ductal cells with indeterminate atypia (reactive versus low grade dysplasia, versus scant lesional tissue) • Abundant intracytoplasmic mucin in the epithelium	Cyst fluid analysis: CEA and amylase	Conservative, repeat or surgery
IV. Neoplastic: benign	20.2%	• Serous cystadenoma (SCA) • Lymphangioma • Cystic teratoma • Schwannoma	SCA: low amylase + low CEA, VHL mutation, positive inhibin staining	Conservative
IV. Neoplastic: other	37.5%	• GIST • Extra-adrenal paraganglioma • Pancreatic solitary fibrous tumor Premalignant • IPMN with dysplasia • IPNB • MCN with dysplasia Low grade malignant • PanNET • Solid pseudopapillary neoplasm (SPN)	Solitary fibrous tumor: STAT6 mutation Intraductal papillary mucinous neoplasm: KRAS, RNF43, GNAS (specific), TP53, SMAD4 mutations Solid pseudopapillary neoplasm: CTNNB1 (beta catenin) mutation	Surgery with an option for conservative management in select scenarios
V. Suspicious	92.1%	• Pancreatic ductal adenocarcinoma (PDAC) • PanNET • Acinar cell carcinoma • Pancreatoblastoma • Solid pseudopapillary neoplasm • Cyst aspirate with solid mural nodule or cyst wall mass • Lymphoma • Metastases • High grade BilIN	Immunocytochemistry, FISH molecular analysis Cyst fluid analysis: CEA and amylase	Surgery
VI. Positive	99.6%	• PDAC and variants • Cholangiocarcinoma • Acinar cell carcinoma • Small and large cell neuroendocrine carcinoma • Pancreatoblastoma • Lymphomas • Sarcomas • Metastases to the pancreas	Immunocytochemistry patterns in malignancy: • Positive: S100P, IMP3, MUC4, mesothelin • Negative: pVHL, CD10, clusterin beta, SMAD4 FISH significantly improves diagnostic sensitivity of adenocarcinoma (copy number abnormalities in CEP3, CEP7, CEP17 and of band 9p21)	Surgery or neoadjuvant therapy / clinical trials

Reference: Diagn Cytopathol 2020;48:494

Laboratory

Pancreaticobiliary strictures (Diagn Cytopathol 2014;42:351)
- Fluorescence in situ hybridization (FISH)
  - DNA probe set for biliary brush specimens; outperforms routine cytology in sensitivity, thus is the preferred complement
    - Malignancy: chromosomal copy number abnormalities in CEP3, CEP7, CEP17 and of band 9p21 (CEP = centromere enumeration probe)
  - Successful for evaluating negative, inconclusive and malignant specimens
- Immunocytochemistry
  - Marker patterns frequently observed in malignancy: S100P+, pVHL-, IMP3+, CD10-, MUC4+, mesothelin+, clusterin beta-
- KRAS mutational analysis
  - Sensitive for invasive carcinomas and PDAC but not specific
    - Abnormalities also observed in low grade dysplasias and chronic pancreatitis
  - Shown utility in distinguishing benign from malignant in atypical specimens
  - Not supported as useful in diagnosing solid pancreatic masses and bile duct strictures
Pancreatic cystic lesions
- Histochemical stains
  - Positive staining of mucin (mucicarmine and Alcian blue / PAS)
  - Diagnostically useful to identify mucinous lesions
- Biochemical tests
  - Amylase and carcinoembryonic antigen (CEA) levels help diagnose:
    - Pseudocysts (high amylase in the 1,000s U/L, low CEA)
    - Serous cystadenomas (low amylase < 1,000 U/L, low CEA)
    - Mucinous cysts (CEA > 192 ng/mL)
    - Cyst fluid CEA alone reliably distinguishes mucinous from nonmucinous lesions (Diagn Cytopathol 2014;42:351)
      - Not useful for predicting malignancy
      - Optimal CEA cutoff of 192 is supported by meta analysis and is the most widely accepted and utilized (Dig Dis Sci 2021 Nov 16 [Epub ahead of print])
  - CA125 and CA19-9 generally not useful for diagnosis
  - MUC2, MUC4 and MUC7 useful in recognizing dysplasia and malignancy in cystic neoplasms
- DNA analysis
  - Aneuploid and tetraploid results support malignancy
  - Elevated cyst fluid DNA supports malignancy
  - No significantly improved diagnostic accuracy over routine cytology
- Molecular tests
  - Mutations: supported diagnosis
    - KRAS, GNAS, RNF43: IPMN and MCN (GNAS absent in MCN)
    - TP53, SMAD4, CTTNB1, mTOR genes: advanced neoplasia (high grade dysplasia or carcinoma)
    - VHL: serous cystadenomas
    - CTNNB1 (beta catenin): solid pseudopapillary neoplasms
Solid pancreatic neoplasms
- Immunohistochemical tests
  - Adenocarcinoma: DPC4 / SMAD4-
  - PanNET: chromogranin+, synaptophysin+, INSM1+, CD56+, neuron specific enolase+, CK8/18+
  - Acinar cell carcinoma: BCL10+, amylase+, trypsin+, chymotrypsin+, lipase+, CK7+
  - Solid pseudopapillary neoplasm: nuclear beta catenin+, alpha-1 antitrypsin+, CD10+, SOX11+, synaptophysin+, chromogranin-, trypsin- (Cancer Cytopathol 2017;125:831)
  - Pancreatic and biliary tract lymphoma: will be dependent on the type of lymphoma
- Molecular analysis
  - Adenocarcinoma
    - KRAS mutation not used due to low specificity for malignancy
    - p16 / CDKN2A, TP53 and SMAD4 inactivation
    - FISH significantly improves diagnostic sensitivity; the most reliable adjunct test for confirmation for biliary tract brushing
      - Copy number abnormalities in CEP3, CEP7, CEP17 and of 9p21
    - MicroRNA and loss of heterozygosity: clinical use and importance to be determined
  - PanNET
    - Loss of heterozygosity: malignant associations but clinical importance to be determined
    - ATRX FISH performed by some labs along with DAXX IHC to identify patients with a poor prognosis (Cancer Cytopathol 2017;125:544)
  - Acinar cell carcinoma
    - Associated with losses of 11p; diagnostic significance unclear
  - Solid pseudopapillary neoplasm
    - Somatic point mutation in exon 3 of beta catenin

Case reports

31 year old man with pancreatoblastoma (positive) (Clin J Gastroenterol 2018;11:161)
58 year old man with intraductal papillary neoplasm of the biliary tract (atypical) (Diagn Cytopathol 2019;47:922)
60 year old man with paraduodenal pancreatitis found after an initially nondiagnostic biopsy (nondiagnostic) (Case Rep Surg 2020;2020:5021578)
62 year old man with pancreatic lymphoepithelial cyst (negative) (Case Rep Med 2020;2020:4590758)
67 year old woman with cystic lymphangioma of the pancreas (neoplastic) (Gland Surg 2018;7:487)
84 year old man with pancreatobiliary neoplasm of the duodenum (suspicious) (Diagn Cytopathol 2019;47:1059)

Cytology description

See Papanicolaou system for reporting pancreaticobiliary cytology

Cytology images

Contributed by Derek Allison, M.D.

Duodenal contaminant only

GI contaminant only

Benign pancreatic parenchyma

Pancreatic splenule

Pancreatic splenule (CD8+)

Pancreatic splenule (CD45+)

Lymphoepithelial cyst

Clean mucin

IPMN with cytologic atypia

Reactive atypia; chronic pancreatitis

Biliary brush stricture

Serous cystadenoma

Serous cystadenoma: inhibin

Well differentiated
NET, WHO grade 1

Solid pseudopapillary neoplasm

Mucinous cystic neoplasm

Suspicious for pancreatic adenocarcinoma

Pancreatic ductal adenocarcinoma

Well differentiated pancreatic adenocarcinoma

PDAC by biliary brush

Additional references

Pitman: The Papanicolaou Society of Cytopathology System for Reporting Pancreaticobiliary Cytology, 1st Edition, 2015

Board review style question #1

According to the Papanicolaou reporting system for pancreaticobiliary cytology, what is the most likely category of this adequate pancreatic FNA biopsy specimen?

Negative for malignancy
Neoplastic: benign
Neoplastic: other
Suspicious for malignancy

Board review style answer #1

C. Neoplastic: other. Solid pseudopapillary neoplasm of the pancreas, characterized by small, discohesive cells surrounding branching capillaries, is considered a low grade malignant entity. The neoplastic: other category includes neoplasms that are either premalignant or low grade malignant.

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Reference: Pancreas - Papanicolaou system

Board review style question #2

Which ancillary test result supports the FNA diagnosis of this pancreatic body mass?

Copy number abnormalities in CEP4, CEP10 and CEP14
Negative DPC4 / SMAD4 by IHC
Nuclear beta catenin
VHL mutation

Board review style answer #2

B. Negative DPC4 / SMAD4 by IHC. Pancreatic adenocarcinoma is supported by DPC4 / SMAD4 loss. The presence of copy number abnormalities in CEP3, CEP7, CEP17 (note the correct chromosomes) and of band 9p21 are characteristic of pancreatic and biliary malignancies. Serous cystadenoma is associated with mutated VHL. Nuclear beta catenin supports a diagnosis of solid pseudopapillary neoplasm.

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Reference: Pancreas - Papanicolaou system

Recent Pancreas Pathology books

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