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Pancreas

Neuroendocrine neoplasms

Poorly differentiated neuroendocrine carcinoma


Editorial Board Member: Wei Chen, M.D., Ph.D.
Deputy Editor-in-Chief: Catherine E. Hagen, M.D.
Maria Gaia Mastrosimini, M.D.
Claudio Luchini, M.D., Ph.D.

Last author update: 8 August 2022
Last staff update: 31 October 2023

Copyright: 2003-2024, PathologyOutlines.com, Inc.

PubMed Search: Pancreas neuroendocrine carcinoma

Maria Gaia Mastrosimini, M.D.
Claudio Luchini, M.D., Ph.D.
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology / etiology | Diagrams / tables | Clinical features | Diagnosis | Laboratory | Radiology description | Grading | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Frozen section description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2
Cite this page: Mastrosimini MG, Luchini C. Poorly differentiated neuroendocrine carcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/pancreasneuroendocrinecarcinoma.html. Accessed December 25th, 2024.
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
Pathophysiology / etiology
  • Largely unknown
  • Tobacco smoking
Diagrams / tables

Images hosted on other servers:
Missing Image

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
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
Gross images

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Small cell carcinoma

Frozen section description
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
Negative stains
Molecular / cytogenetics description
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
Board review style question #1
Which are the molecular hallmarks of PanNEC?

  1. CCND1 amplification
  2. DAXX and ATRX mutation
  3. EGFR alteration
  4. KRAS mutation
  5. 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?

  1. Acinar-like appearance
  2. Focal tumor necrosis and nuclear features
  3. Glandular formation
  4. Perineural invasion
  5. 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
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