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Salivary glands

Authors: Karina Aivazian, M.B.B.S., Derek Allison, M.D., F. Zahra Aly, M.D., Ph.D., Saeed Asiry, M.D., Rebecca Tian Mei Au, M.B.B.S., Sapna Balgobind, M.B.B.Ch., Tamar C. Brandler, M.D., M.S., Manish Mahadeorao Bundele, M.B.B.S., M.D. , Rebecca Chernock, M.D., Chun Chau Lawrence Cheung, M.D., Jonathan Clark, M.B.B.S., Kim A. Ely, M.D., Timothy Fielder, M.B.B.S., B.Med.Sci., Umamaheshwari Golconda, M.D., Ruta Gupta, M.D., Jose Manuel Gutierrez Amezcua, M.D., Adriana Handra-Luca, M.D., Ph.D., Jen-Fan Hang, M.D., Theoni Haralabopoulos, M.D., Min Li Huang, M.B.B.S., Jalal B. Jalaly, M.B.B.S., M.S., Treeva Jassim, M.D., Arash H. Lahoutiharahdashti, M.D., Kelly Magliocca, D.D.S., M.P.H., Zahra Maleki, M.D., Michael Mikula, M.D., Alice Ormandy, M.B.B.S., M.P.H., Nat Pernick, M.D., Natasha Prosser, B.Sc., M.B.B.S., Rema A. Rao, M.D., Lisa Rooper, M.D., Abeer Salama, M.D., Sadia Sayeed, M.D., Molly Housley Smith, D.M.D., Lulu Sun, M.D., Ph.D., Aditya Talwar, M.D., Sally Tanakchi, M.D., Shuanzeng (Sam) Wei, M.D., Ph.D., Bin Xu, M.D., Ph.D., Xiaofeng Zhao, M.D., Ph.D.

Resident / Fellow Advisory Board: David B. Chapel, M.D.

Editorial Board Members: Bonnie Choy, M.D., Ricardo R. Lastra, M.D., Kelly Magliocca, D.D.S., M.P.H., Marc Pusztaszeri, M.D., Lisa Rooper, M.D., Molly Housley Smith, D.M.D., Bin Xu, M.D., Ph.D.

Deputy Editors-in-Chief: Andrey Bychkov, M.D., Ph.D., Kelly Magliocca, D.D.S., M.P.H.

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Superpage Topics

Acinic cell carcinoma Acinic cell carcinoma Adenocarcinoma, NOS Adenoid cystic carcinoma Adenomatoid hyperplasia and sialadenosis Anatomy & histology Atypia of undetermined significance (AUS) Basal cell adenocarcinoma Basal cell adenoma Canalicular adenoma Carcinoma ex pleomorphic adenoma Carcinosarcoma Chronic sialadenitis / sialolithiasis Clear cell carcinoma Cystadenoma Ductal papilloma Epithelial myoepithelial carcinoma Genetic alterations in salivary gland tumors (pending) Grossing, frozen section & features to report Heterotopia HIV salivary gland disease (HIV-SGD) (pending) IgG4 related sialoadenitis Intercalated duct hyperplasia Intraductal carcinoma Keratocystoma Lipoma / sialolipoma Lipomatosis Lymphadenoma Lymphoepithelial carcinoma Lymphoepithelial cyst Lymphoepithelial sialadenitis Malignant Metastases Microsecretory adenocarcinoma Milan reporting system for salivary gland cytopathology Mucinous adenocarcinoma (pending) Mucocele / ranula Mucocele / ranula (pending) Mucoepidermoid carcinoma Myoepithelial carcinoma Myoepithelioma Necrotizing sialometaplasia Neoplasm-benign Neoplasm-salivary gland neoplasm of uncertain malignant potential (SUMP) Neuroendocrine carcinoma Nodular oncocytic hyperplasia Nondiagnostic Nonneoplastic Oncocytoma Oncocytosis (pending) Pleomorphic adenoma Polymorphous adenocarcinoma Primary salivary gland neoplasms-general Salivary duct carcinoma Sclerosing microcystic adenocarcinoma Sclerosing polycystic adenoma Sebaceous adenocarcinoma (pending) Secretory carcinoma Sialadenitis-infectious Sialadenoma papilliferum Sialoblastoma Sjögren syndrome Squamous cell carcinoma Staging Striated duct adenoma (pending) Suspicious for malignancy Warthin tumor WHO classification (pending)

Acinic cell carcinoma

Table of Contents

Definition / general

Malignant epithelial neoplasm of the salivary glands characterized by serous acinar cell differentiation (cytoplasmic zymogen granules) in at least some of the neoplastic cells

Essential features

~6 - 8% of all salivary gland neoplasms and 10 - 17% of primary salivary gland malignancies
Parotid gland is the most common site
Solid, microcystic, papillary cystic or follicular growth of acinar cells, with granular to vacuolated cytoplasm and eccentric round nuclei with conspicuous nucleoli
Neoplastic cells positive for pankeratins, DOG1, SOX10 and PASD
Favorable prognosis, with low rates of local recurrence, distant metastasis and high grade transformation

Terminology

N/A

ICD coding

ICD-O: 8550/3 - acinic cell carcinoma
ICD-10: C08.9 - malignant neoplasm of salivary gland, unspecified

Epidemiology

~6 - 8% of all salivary gland neoplasms
~10 - 17% of primary salivary gland malignancies (Laryngoscope 2014;124:172, Int J Radiat Oncol Biol Phys 2012;84:189)
Wide age range, from children to older adults (median: 52 years)
- Second most common salivary malignancy in children (after mucoepidermoid carcinoma)
- Third most common salivary malignancy in adults (after mucoepidermoid carcinoma and adenoid cystic carcinoma)
Slightly more common in females than in males (F:M = 1.6:1) (Eur Arch Otorhinolaryngol 2020;277:2673)
More common in White populations
Reference: Oral Oncol 2018;82:53

Sites

Most common site: parotid gland (80%)
Submandibular, sublingual and minor salivary glands rarely involved (13 - 17%)
- Most common sites in the oral cavity are the buccal mucosa and upper lip (Cancer 1983;52:542)

Pathophysiology

N/A

Etiology

Familial predisposition (Case Rep Oncol 2015;8:1, Hematol Oncol Stem Cell Ther 2009;2:259)
Previous radiation exposure

Diagrams / tables

N/A

Clinical features

Typical clinical presentation is a slow growing mass
Pain, fixation to surrounding tissues and cranial nerve VII dysfunction are uncommon
Cervical lymph node metastasis uncommon (up to 10%)
Reference: Cancer 1991;67:172

Diagnosis

Radiology (ultrasound [US], computed tomography [CT] or magnetic resonance imaging [MRI]) demonstrates presence and extent of mass lesion
- MRI is superior to CT in assessing invasion of adjacent structures
Fine needle aspiration cytology and core biopsy
- Low sensitivity in parotid
  - High false negatives due to morphologic overlap with normal acini (Arch Pathol Lab Med 2005;129:26)
  - Diagnosis more challenging if tumor cells lack secretory granules
  - Diagnostic accuracy higher in cases with high grade transformation
Definitive diagnosis most often established on a surgical excision specimen (e.g., parotidectomy)
Positron emission tomography (PET) may be done postoperatively in cases of high grade transformation (Eur Arch Otorhinolaryngol 2016;273:3511)

Laboratory

N/A

Radiology description

Ultrasound: well demarcated, lobular, hypoechoic, heterogeneous and poorly vascularized
Computed tomography
- Findings are nonspecific and there is an overlap with benign tumors
- Solid to cystic mass
- Focal low attenuating portions on CT may be present, corresponding to cystic degeneration or hemorrhage (J Comput Assist Tomogr 2005;29:121)

Radiology images

Images hosted on other servers:

MRI: cystic lesion of the upper lip

CT and US: right parotid nodule

Prognostic factors

5 year survival: 97%
May recur years or decades after initial diagnosis
Metastatic rate ~ 16%
Local recurrence rate is up to 33%; 12% in another large study (Cancer 1978;41:924, Cancer 1983;52:542)
Adverse prognostic factors include
- Male gender
- Age > 45 (JAMA Otolaryngol Head Neck Surg 2013;139:1195)
- Tumor > 3 cm at presentation (Oral Oncol 2018;82:53)
- Metastatic disease
- Tumor necrosis
- Nuclear pleomorphism
- Mitosis (> 2/10 high power fields [HPF])
- Ki67 index > 5%
- High grade transformation
- Vascular and perineural invasion
- Extracapsular extension (Cancer 2009;115:2128)
- Positive resection margins
- Invasion of the skull base
- Depletion of lymphocytes within the stroma

Case reports

31 year old man with a left upper lip nodule (J Clin Exp Dent 2016;8:e638)
46 year old man with hypertension, new onset diabetes and hypokalemia (Case Rep Endocrinol 2019;2019:3196283)
48 year old woman with a 6 month history of a right parotid swelling that rapidly and progressively increased in size (Case Rep Otolaryngol 2017;2017:7296467)

Treatment

Complete surgical excision (J Oral Maxillofac Surg 2005;63:917)
Radiotherapy may be indicated for tumors that metastasize or cannot be completely excised
Systemic therapy may be indicated for high grade tumors, positive margins, advanced stage disease or metastatic tumors

Clinical images

Images hosted on other servers:

1.2 cm upper lip nodule

Gross description

Tumor dimensions range from < 1 cm to 13 cm (85% of the lesions are < 3 cm) (Cancer 1983;52:542)
Well circumscribed, soft rubbery, tan-yellow to pink mass with homogeneous cut surface
Cystic change and hemorrhage may occur

Gross images

Images hosted on other servers:

Well circumscribed multilobulated mass

Frozen section description

N/A

Frozen section images

N/A

Microscopic (histologic) description

Multiple cell types are noted
- Cell types include serous acinar, intercalated ductal, vacuolated, nonspecific glandular and clear cells
Acinar cells are large and polyhedral, with basophilic granular cytoplasm and eccentric nuclei
- Cytoplasmic diastase resistant positive periodic acid-Schiff (PAS) reaction may be focal
Variety of morphologic patterns, including solid, microcystic, papillary cystic and follicular (Cancer 1983;52:542)
Prominent lymphoid infiltrate may be present (tumor associated lymphoid proliferation varies from randomly scattered, patchy collections of lymphocytes to diffuse, dense infiltrates with well formed follicles throughout the tumor) (Oral Surg Oral Med Oral Pathol 1994;77:19)
Mitosis, necrosis and significant pleomorphism usually absent
Proposed grading system (Am J Surg Pathol 2022;46:933)
- Low to intermediate grade: mitotic count < 5/10 HPF and no necrosis
- High grade: mitotic count ≥ 5/10 HPF or necrosis

Microscopic (histologic) images

Contributed by Rema A. Rao, M.D. and Arash H. Lahouti, M.D.

Well circumscribed tumor

Finely vacuolated cytoplasm

Tumor associated lymphoid proliferation

Cystic pattern and hemorrhage

NR4A3 nuclear stain

Virtual slides

Images hosted on other servers:

Acinic cell carcinoma, parotid

Acinic cell carcinoma, cystic change

Cytology description

Cellular aspirates
Cytologic diagnosis based on identifying acinar-like cells
Tend to form small groups and loosely cohesive clusters as well as single cells (Diagn Histopath 2018;24:417)
Cells are large but morphologically resemble normal acinar cells
- Round nuclei with tiny nucleoli
- Abundant finely vacuolated to granular cytoplasm
Stripped or bare nuclei may be present in the background, can mimic lymphocytes
Lymphocytic infiltrate may be prominent
Laminated psammoma body-like calcification may be present
Pitfall: acinic cells may resemble oncocytes and in the presence of lymphocytic infiltrate, the tumor may be misdiagnosed as Warthin tumor

Cytology images

Contributed by Rema A. Rao, M.D. and Arash H. Lahouti, M.D.

Loosely cohesive groups

Cellular smears

Finely vacuolated to granular cytoplasm

Round eccentric nuclei

Loosely cohesive clusters

PASD

Immunofluorescence description

N/A

Immunofluorescence images

N/A

Positive stains

Pancytokeratins, EMA and CEA
DOG1: intense positivity (Laryngoscope Investig Otolaryngol 2018;3:268)
- Admixture of apical membranous, cytoplasmic and complete membranous staining
- Nonspecific (expressed in adenoid cystic carcinoma and epithelial myoepithelial carcinoma)
SOX10
PASD
NR4A3 (novel, highly specific marker) (Cancer Cytopathol 2021;129:104)

Negative stains

Calponin, p63 and actin (Head Neck Pathol 2013;7:64)
Mammaglobin (useful in distinction from secretory carcinoma)
S100 may be focally positive
Reference: Wenig: Atlas of Head and Neck Pathology, 3rd Edition, 2015

Electron microscopy description

N/A

Electron microscopy images

N/A

Molecular / cytogenetics description

Recurrent (t[4;9][q13;q31]) genomic rearrangement (resulting in translocation of active enhancer regions from the secretory Ca binding phosphoprotein [SCPP] gene cluster to the region upstream of nuclear receptor subfamily 4 group A member 3 [NR4A3], leading to NR4A3 IHC overexpression) (Cancer Cytopathol 2021;129:104)
Loss of function mutations of CDKN2A / B gene are associated with high grade histology and distant metastasis (Mod Pathol 2023;36:100150)

Molecular / cytogenetics images

Images hosted on other servers:

FISH, NR4A3 break apart probe

Videos

N/A

Sample pathology report

Parotid gland, right, inferior, partial parotidectomy:
- Acinic cell carcinoma, 1.7 cm (see synoptic report)
- No lymphovascular invasion identified
- No perineural invasion identified
- Resection margins uninvolved by carcinoma
- 2 lymph nodes, negative for carcinoma (0/2)
- Tumor associated lymphoid proliferation present

Differential diagnosis

Normal acinar elements:
- Appear as grape-like clusters in cytology or tight lobulated clusters in histology
- Lacks cellularity, looseness of the malignant clusters and numerous bare nuclei
Secretory carcinoma (formerly mammary analogue secretory carcinoma):
- Lack of zymogen-like secretory granules
- Diffuse and strong positivity for S100 and mammaglobin
- ETV6::NTRK3 translocation
- DOG1 negative
- Lacks NR4A3 translocation and immunostaining (Cancer Cytopathol 2021;129:104)
Mucoepidermoid carcinoma:
- Presence of extracellular and intracellular mucin, mucicarmine positive
- Has 3 cell types (mucinous, intermediate and epidermoid) in low and intermediate grade
- Harbors CRTC1::MAML2 translocation
When clear cell component predominates:
- Myoepithelioma:
  - Calponin, SMA, p63 and S100 positive
- Epithelial myoepithelial carcinoma:
  - Has a dual staining pattern of malignant epithelial and myoepithelial cells
- Oncocytoma:
  - Large polyhedral cells with dense eosinophilic cytoplasm, prominent cell outlines, lacks purplish granules
  - Positive phosphotungstic acid hematoxylin (PTAH) staining
  - Negative PASD staining
- Metastatic clear cell renal cell carcinoma:
  - PAX8+
When follicular pattern predominates:
- Thyroid follicular neoplasms:
  - TTF1, thyroglobulin, PAX8 stains positive

Additional references

WHO Classification of Tumours Editorial Board: Head and Neck Tumours, 5th Edition, 2024

Board review style question #1

Which of the following statements is true regarding acinic cell carcinoma of salivary glands?

Acinic cell carcinoma is a high grade malignant neoplasm
Most commonly occurs in minor salivary glands
Neoplastic cells express DOG1 and SOX10
Younger age at presentation and presence of tumor associated lymphocytes are associated with a poor prognosis

Board review style answer #1

C. Neoplastic cells express DOG1 and SOX10. DOG1 and SOX10 are expressed in benign acinar cells and intercalated duct cells and other salivary gland neoplasms. However, strong diffuse expression of these markers can help distinguish acinic cell carcinoma from other salivary gland neoplasms. Answer A is incorrect because acinic cell carcinoma is considered low intermediate grade malignancy of salivary glands, although high grade transformation may occur. Answer B is incorrect because the majority of cases arise in the parotid gland. Answer D is incorrect because older age at the onset (> 45) and depletion of lymphocytes within the stroma are linked to worse outcomes.

Comment Here

Reference: Acinic cell carcinoma

Board review style question #2

A 51 year old woman presents with a left parotid mass. CT images show a well circumscribed cystic lesion measuring 3 cm. An excisional biopsy is performed (see image above). The neoplastic cells are positive for periodic acid-Schiff with diastase (PASD). Which of the following statements is true regarding this lesion?

Cytology aspirates of this tumor can show predominance of extracellular mucin
Mitosis, necrosis and significant pleomorphism are usually present
MYB immunohistochemical staining in FNA specimens is useful in the diagnosis of this tumor
Pain and facial nerve dysfunction are uncommon presenting symptoms

Board review style answer #2

D. The most common initial presentation in patients with acinic cell carcinoma is a painless mass without facial nerve involvement. Answer C is incorrect because MYB immunohistochemical staining is useful in the diagnosis of adenoid cystic carcinoma. Answer A is incorrect because the presence of extracellular mucin in aspirates is a feature of mucoepidermoid carcinoma. Answer B is incorrect because acinic cell carcinoma is usually a low grade malignant neoplasm without significant mitosis, necrosis or pleomorphic nuceli.

Comment Here

Reference: Acinic cell carcinoma

Acinic cell carcinoma

Table of Contents

Definition / general

Low / intermediate grade malignant epithelial neoplasm of the salivary glands characterized by serous acinar cell differentiation (cytoplasmic zymogen granules) in at least some of the neoplastic cells (El-Naggar: WHO Classification of Head and Neck Tumours, 4th Edition, 2017)

Essential features

Approximately 6 - 8% of all salivary gland neoplasms and 10 - 17% of primary salivary gland malignancies
Parotid gland is the most common site
Solid, microcystic, papillary cystic or follicular growth of acinar cells, with granular to vacuolated cytoplasm and eccentric round nuclei with conspicuous nucleoli
Neoplastic cells positive for pankeratins, DOG1, SOX10 and PAS-D
Favorable prognosis, with low rates of local recurrence, distant metastasis and high grade transformation

ICD coding

ICD-O: 8550/3 - acinic cell carcinoma
ICD-10: C08.9 - malignant neoplasm of salivary gland, unspecified

Epidemiology

Approximately 6 - 8% of all salivary gland neoplasms
Approximately 10 - 17% of primary salivary gland malignancies (Laryngoscope 2014;124:172, Int J Radiat Oncol Biol Phys 2012;84:189)
Wide age range, from children to older adults (median: 52 years)
- Second most common salivary malignancy in children (after mucoepidermoid carcinoma)
- Third most common salivary malignancy in adults (after mucoepidermoid carcinoma and adenoid cystic carcinoma)
Slightly more common in females than in males (F:M = 1.6:1) (Eur Arch Otorhinolaryngol 2020;277:2673)
More common in Caucasians
Reference: Oral Oncol 2018;82:53

Sites

Most common site: parotid gland (80%)
Submandibular, sublingual and minor salivary glands rarely involved (13 - 17%)
- Most common sites in the oral cavity are the buccal mucosa and upper lip (Cancer 1983;52:542)

Etiology

Familial predisposition (Case Rep Oncol 2015;8:1, Hematol Oncol Stem Cell Ther 2009;2:259)
Previous radiation exposure

Clinical features

Typical clinical presentation is a slow growing mass
Pain, fixation to surrounding tissues and cranial nerve VII dysfunction are uncommon
Cervical lymph node metastasis uncommon (up to 10%)
Reference: Cancer 1991;67:172

Diagnosis

Radiology (ultrasound, CT or MRI) demonstrates presence and extent of mass lesion
- MRI superior to CT in assessing invasion of adjacent structures
Fine needle aspiration cytology and core biopsy
- Low sensitivity in parotid:
  - High false negatives due to morphologic overlap with normal acini (Arch Pathol Lab Med 2005;129:26)
  - Diagnosis more challenging if tumor cells lack secretory granules
  - Diagnostic accuracy higher in cases with high grade transformation
Definitive diagnosis most often established on a surgical excision specimen (e.g., parotidectomy)
Positron emission tomography (PET) may be done postoperatively in cases of high grade transformation (Eur Arch Otorhinolaryngol 2016;273:3511)

Radiology description

Ultrasound: well demarcated, lobular, hypoechoic, heterogeneous and poorly vascularized
Computed tomography (CT):
- Findings are nonspecific and there is an overlap with benign tumors
- Solid to cystic mass
- Focal low attenuating portions on CT may be present corresponding to cystic degeneration or hemorrhage (J Comput Assist Tomogr 2005;29:121)

Radiology images

Images hosted on other servers:

MRI: cystic lesion of the upper lip

CT and US: right parotid nodule

Prognostic factors

5 year survival: 97%
May recur years or decades after initial diagnosis
Metastatic rate ~ 16%
Local recurrence rate is up to 33%; 12% in another large series (Cancer 1978;41:924, Cancer 1983;52:542)
Adverse prognostic factors include
- Male gender
- Age > 45 (JAMA Otolaryngol Head Neck Surg 2013;139:1195)
- Tumor > 3 cm at presentation (Oral Oncol 2018;82:53)
- Metastatic disease
- Tumor necrosis
- Nuclear pleomorphism
- Mitosis (> 2/10 high power fields)
- Ki67 index > 5%
- High grade transformation
- Vascular and perineural invasion
- Extracapsular extension (Cancer 2009;115:2128)
- Positive resection margins
- Invasion of the skull base
- Depletion of lymphocytes within the stroma

Case reports

31 year old man with a left upper lip nodule (J Clin Exp Dent 2016;8:e638)
46 year old man with hypertension, new onset diabetes and hypokalemia (Case Rep Endocrinol 2019;2019:3196283)
48 year old woman with a 6 month history of a right parotid swelling that rapidly and progressively increased in size (Case Rep Otolaryngol 2017;2017:7296467)

Treatment

Complete surgical excision (J Oral Maxillofac Surg 2005;63:917)
Radiotherapy may be indicated for tumors that cannot be completely excised or metastatic disease
Systemic therapy may be indicated for high grade tumors, positive margins, advanced stage disease, or metastatic tumors

Clinical images

Images hosted on other servers:

1.2 cm upper lip nodule

Gross description

Tumor dimensions range from less than 1 cm to 13 cm (85% of the lesions less than 3 cm) (Cancer 1983;52:542)
Well circumscribed, soft rubbery, tan-yellow to pink mass with homogeneous cut surface
Cystic change and hemorrhage may occur

Gross images

Images hosted on other servers:

Well circumscribed multilobulated mass

Microscopic (histologic) description

Multiple cell types are noted
- Cell types include serous acinar, intercalated ductal, vacuolated, nonspecific glandular and clear cells
Acinar cells are large and polyhedral, with basophilic granular cytoplasm and eccentric nuclei
- Cytoplasmic diastase resistant positive periodic acid-Schiff (PAS) reaction may be focal
Variety of morphologic patterns, including solid, microcystic, papillary cystic and follicular (Cancer 1983;52:542)
Prominent lymphoid infiltrate may be present (tumor associated lymphoid proliferation varies from randomly scattered, patchy collections of lymphocytes to diffuse, dense infiltrates with well formed follicles throughout the tumor) (Oral Surg Oral Med Oral Pathol 1994;77:19)
Mitosis, necrosis and significant pleomorphism usually absent
No specific histologic grading system

Microscopic (histologic) images

Contributed by Rema A. Rao, M.D. and Arash H. Lahouti, M.D.

Well circumscribed tumor

Finely vacuolated cytoplasm

Tumor associated lymphoid proliferation

Cystic pattern and hemorrhage

NR4A3 nuclear stain

Virtual slides

Images hosted on other servers:

Acinic cell carcinoma, parotid

Acinic cell carcinoma, cystic change

Cytology description

Cellular aspirates
Cytologic diagnosis based on identifying acinar-like cells
Tend to form small groups and loosely cohesive clusters as well as single cells (Diagn Histopath 2018;24:417)
Cells are large but morphologically resemble normal acinar cells
- Round nuclei with tiny nucleoli
- Abundant finely vacuolated to granular cytoplasm
Stripped or bare nuclei may be present in the background, can mimic lymphocytes
Lymphocytic infiltrate may be prominent
Laminated psammoma body-like calcification may be present
Pitfall: acinic cells may resemble oncocytes and in the presence of lymphocytic infiltrate, the tumor may be misdiagnosed as Warthin tumor

Cytology images

Contributed by Rema A. Rao, M.D. and Arash H. Lahouti, M.D.

Loosely cohesive groups

Cellular smears

Finely vacuolated to granular cytoplasm

Round eccentric nuclei

Loosely cohesive clusters

PASD

Positive stains

Pancytokeratins, EMA and CEA
DOG1: intense positivity (Laryngoscope Investig Otolaryngol 2018;3:268)
- Admixture of apical membranous, cytoplasmic and complete membranous staining
- Nonspecific (expressed in adenoid cystic carcinoma and epithelial myoepithelial carcinoma)
SOX10
PASD
NR4A3 (novel, highly specific marker) (Cancer Cytopathol 2021;129:104)

Negative stains

Calponin, p63 and actin (Head Neck Pathol 2013;7:64)
Mammaglobin (useful in distinction from secretory carcinoma)
S100 may be focally positive
Reference: Wenig: Atlas of Head and Neck Pathology, 3rd Edition, 2015

Molecular / cytogenetics description

Recurrent (t[4;9][q13;q31]) genomic rearrangement (resulting in translocation of active enhancer regions from the secretory Ca binding phosphoprotein [SCPP] gene cluster to the region upstream of nuclear receptor subfamily 4 group A member 3 [NR4A3], leading to NR4A3 IHC overexpression) (Cancer Cytopathol 2021;129:104)

Molecular / cytogenetics images

Images hosted on other servers:

FISH, NR4A3 break apart probe

Sample pathology report

Parotid gland, right, inferior, partial parotidectomy:
- Acinic cell carcinoma, 1.7 cm (see synoptic report)
- No lymphovascular invasion identified
- No perineural invasion identified
- Resection margins uninvolved by carcinoma
- Two lymph nodes, negative for carcinoma (0/2)
- Tumor associated lymphoid proliferation present

Differential diagnosis

Normal acinar elements:
- Appear as grape-like clusters in cytology or tight lobulated clusters in histology
- Lacks cellularity, looseness of the malignant clusters and numerous bare nuclei
Secretory carcinoma (formerly mammary analogue secretory carcinoma):
- Lack of zymogen-like secretory granules
- Diffuse and strong positivity for S100 and mammaglobin
- ETV6-NTRK3 translocation
- DOG1 negative
- Lacks NR4A3 translocation and immunostaining (Cancer Cytopathol 2021;129:104)
Mucoepidermoid carcinoma:
- Presence of extracellular and intracellular mucin, mucicarmine positive
- Has 3 cell types (mucinous, intermediate and epidermoid) in low and intermediate grade
- Harbors CRTC1-MAML2 translocation
When clear cell component predominates:
- Myoepithelioma:
  - Calponin, SMA, p63 and S100 positive
- Epithelial myoepithelial carcinoma:
  - Has a dual staining pattern of malignant epithelial and myoepithelial cells
- Oncocytoma:
  - Large polyhedral cells with dense eosinophilic cytoplasm, prominent cell outlines, lacks purplish granules
  - Positive PTAH staining
  - Negative PASD staining
- Metastatic clear cell renal cell carcinoma:
  - PAX8+
When follicular pattern predominates:
- Thyroid follicular neoplasms:
  - TTF1, thyroglobulin, PAX8 stains positive

Board review style question #1

Which of the following statements is true regarding acinic cell carcinoma of salivary glands?

Acinic cell carcinoma is a high grade malignant neoplasm
Most commonly occurs in minor salivary glands
Younger age at presentation and presence of tumor associated lymphocytes are associated with a poor prognosis
Neoplastic cells express DOG1 and SOX10

Board review style answer #1

D. Neoplastic cells express DOG1 and SOX10. DOG1 and SOX10 are expressed in benign acinar cells and intercalated duct cells and other salivary gland neoplasms. However, strong diffuse expression of these markers can help distinguish acinic cell carcinoma from other salivary gland neoplasms. Acinic cell carcinoma is considered low intermediate grade malignancy of salivary glands, although high grade transformation may occur (answer A). The majority of cases arise in the parotid gland (answer B). Older age at the onset (> 45) and depletion of lymphocytes within the stroma are linked to worse outcomes (answer C).

Comment Here

Reference: Acinic cell carcinoma

Board review style question #2

Pain and facial nerve dysfunction are uncommon presenting symptoms
Mitosis, necrosis and significant pleomorphism are usually present
MYB immunohistochemical staining in FNA specimens is useful in diagnosis of this tumor
Cytology aspirates of this tumor can show predominance of extracellular mucin

Board review style answer #2

A. Pain and facial nerve dysfunction are uncommon presenting symptoms

The most common initial presentation in patients with acinic cell carcinoma is painless mass. Clinical examination shows a firm, mobile nodule in the parotid gland. Facial nerve paralysis or paresis is an uncommon initial finding. MYB immunohistochemical staining is useful in diagnosis of adenoid cystic carcinoma. The presence of extracellular mucin in aspirates is a feature of mucoepidermoid carcinoma.

Comment Here

Reference: Acinic cell carcinoma

Adenocarcinoma, NOS

Table of Contents

Definition / general

Invasive tumor, often aggressive, with glandular or ductal differentiation but no features characteristic of other specific types (Arch Pathol Lab Med 2004;128:1385)
Common, 5 - 10% of salivary gland tumors
6 - 10% of salivary gland malignancies, 17% of parotid gland malignancies, 15% of minor salivary gland malignancies

Sites

Parotid gland, submandibular gland, palate, buccal mucosa

Clinical features

Mean age 58 years (median 67 years), range 10 - 93 years
Usually asymptomatic
Often fixed to skin or deep tissues
Palatal lesions often ulcerated and involve bone
Gender predominance debated, recent reports show male predominance
Cervical lymph node metastases in 23%, distant metastases in 37%
Diagnosis of exclusion (not metastatic, not another salivary gland carcinoma)
5 year disease specific survivals is 57%

Case reports

49 year old man with parotid mass (Arch Pathol Lab Med 2004;128:487)

Treatment

Complete surgical excision

Gross description

Poorly circumscribed with infiltrative borders
Solid tan cut surface with hemorrhage and necrosis

Microscopic (histologic) description

Invasive with glandular or ductal differentiation but no features characteristic of other specific types
Patterns include glandular spaces with cyst formation, papillary formation, solid sheets, comedonecrosis, hyalinized "shadow" nodules
Small clusters of cuboidal, round or ovoid cells with distinct borders and abundant cytoplasm
May have clear cell or oncocytic features
Low, intermediate or high grade based on cytomorphic features
In situ component in 68% (Virchows Arch 2006;449:159)

Microscopic (histologic) images

Contributed by Marino Leon, M.D.

Oncocytic carcinoma, H&E and p63

Positive stains

CK7+ / CK20- (Mod Pathol 2004;17:407), positive for EGFR, survivin, phospho-STAT3, CK18, HER2
Uniform periductal staining of reactive myofibroblastic cells with calponin, smooth muscle actin, smooth muscle myosin heavy chain (Arch Pathol Lab Med 1999;123:801)

Negative stains

MYB (Mod Pathol 2011;24:1169)

Molecular / cytogenetics description

EGFR gene amplification, increased EGFR gene copy number
HER2 amplification, high HER2 gene copy number
KRAS mutation rarely (Arch Pathol Lab Med 2000;124:836)

Differential diagnosis

Hybrid carcinoma
Membranous adenoma
Metastatic adenocarcinoma
Polymorphous low grade adenocarcinoma
Undifferentiated carcinoma

Adenoid cystic carcinoma

Table of Contents

Definition / general

A carcinoma of primary salivary gland or minor salivary gland of upper aerodigestive tract characterized by its biphasic ductal and myoepithelial differentiation, tubular / cribriform / solid architecture (Head Neck 2017;39:456)
May occur in major and minor salivary glands
- Among major salivary glands, the most commonly affected site is the parotid gland
- Minor salivary glands that may be affected include those of oral cavity, sinonasal tract, nasopharynx, oropharynx and trachea

Essential features

Grows in tubular, cribriform, and/or solid patterns: solid pattern is associated with adverse outcome
60% - 90% carry MYB-NFIB or MYBL1-NFIB fusion
Biphasic tumor showing ductal and myoepithelial differentiation
Frequent perineural invasion

Epidemiology

M=F (Head Neck 2017;39:456)
Mean age 57 (Head Neck 2017;39:456)

Diagrams / tables

Images hosted on other servers:

Histologic impact on survival

Clinical features

Characterized by a propensity of perineural invasion, high frequency of local and distant recurrence and poor long term prognosis (Eur J Cancer 2015;51:2768, Head Neck 2017;39:456, Braz J Otorhinolaryngol 2015;81:329, Head Neck 2014;36:998)
5 year overall survival 55 - 89%
15 year or 20 year survival is dismal, in the range of 20 - 40%
Rates of local recurrence and distant metastasis are 16 - 67% and 8 - 46%
Lung is most common site of distant metastasis (Head Neck 2017;39:456)

Diagnosis

Diagnosis is based on tissue examination findings of typical histologic features or the presence of fusion involving MYB, MYBL1 or NFIB genes

Radiology images

Images hosted on other servers:

MRI parotid mass

Lung metastases

Prognostic factors

Independent prognostic predictors include AJCC TNM staging, margin status, high mitotic index (defined as ≥ 5 per 10 high power fields) and solid architecture (Am J Surg Pathol 2017;41:1422)

Presence and percentage of solid architecture reflects clinical outcome and should be reported in the pathology report

Some studies showed that the presence but not the percentage of solid growth is an independent predictor for adverse outcome (Am J Surg Pathol 2017;41:1422, Oral Surg Oral Med Oral Pathol Ora Radio 2013;115:368, Head Neck 2017;39:456)
Other studies show that tumors with higher percentage of solid pattern, defined as 30% or more, are associated with increased risk of recurrence and decreased survival (Cancer 1984;54:1062, Cancer 1978;42:265)
Based on the above data, 2 grading systems have been proposed (table)
Current WHO classification does not endorse any specific grading system (IARC: WHO Classification of Head and Neck Tumours, 4th Edition, 2017)
Other poor prognostic factors include female sex, older age, sinonasal location, lymphovascular invasion, high grade transformation and intraneural invasion


Perzin 1978 and Szanto 1984	Van Weert 2015, Zhang 2013 and Xu 2018
Grade 1 (low grade): no solid component	Grade 1: no solid component
Grade 2 (intermediate grade): 1 - 29% solid component	Grade 2 (high grade): with solid component
Grade 3 (high grade): ≥ 30% solid component

Perzin 1978 (Cancer 1978;42:265) and Szanto 1984 (Cancer 1984;54:1062)
Van Weert 2015 (Head Neck 2017;39:456), Zhang 2013 (Oral Surg Oral Med Oral Pathol Ora Radio 2013;115:368) and Xu 2018 (Am J Surg Pathol 2017;41:1422)

Case reports

27 year old woman with parotid adenoid cystic carcinoma and high grade transformation (Diagn Pathol 2013;8:113)
36 year old man with tracheal tumor: an autopsy case (Head Neck Pathol 2019;13:243)
39 year old woman with lacrimal gland tumor (Head Neck Pathol 2013;7:85)
70 year old woman with soft palate adenoid cystic carcinoma extending to bilateral orbits through perineural spread along cranial nerves (Digit J Ophthalmol 2018;24:1)
70 year old man with laryngeal tumor (Oncol Lett 2018;16:2783)

Treatment

Complete surgical resection with appropriate margins is the mainstream treatment
Most patients receive adjuvant radiation therapy given the high rate of local recurrence and dismal long term survival
Chemotherapy for patients with distant metastasis
Multiple clinical trials are ongoing investigating the effects of tyrosine kinase inhibitors, e.g. axitinib (Ann Oncol 2016;27:1902) and dovitinib (Clin Cancer Res 2017;23:4138)

Clinical images

Images hosted on other servers:

Vocal cord mass

Gross description

Infiltrative ill defined firm mass

Gross images

Contributed by Bin Xu, M.D., Ph.D. and Kelly Magliocca, D.D.S., M.P.H.

Parotid mass

Cut section turbinate to palate

Frozen section description

Biphasic pattern of epithelial and myoepithelial cells and the typical tubular / cribriform / solid architecture are useful diagnostic cues

Microscopic (histologic) description

Biphasic salivary gland tumor, composed of ductal and myoepithelial cells
Myoepithelial cells have dark angulated nuclei and scanty cytoplasm, giving a basaloid appearance
Tubular, cribriform and solid architecture
Tubular pattern contains simple tubules composed of inner ductal and outer myoepithelial cells
Cribriform pattern is composed of predominantly myoepithelial cells with myxoid or hyalinized globules
Scattered ductal elements may be seen within the cribriform area
Solid pattern is solid nests composed of sheets of basaloid cells
Perineural invasion is frequent
High grade transformation can be seen in a small number of cases, defined as comedo type tumor necrosis, frequent mitoses (often > 10 per 10 high power fields) and marked nuclear atypia; high grade transformation is associated with high risk of lymph node metastasis, distant metastasis and disease related death (Am J Surg Pathol 2007;31:1683)
Other rare features that may present occasionally include:
- Focal squamous metaplasia / differentiation, especially in cases with high grade transformation (Am J Surg Pathol 2007;31:1683, Am J Surg Pathol 2017;41:1422)
- Areas in which myoepithelial cells show clear cell changes, resembling epithelial myoepithelial carcinoma (Am J Surg Pathol 2018;42:319)

Microscopic (histologic) images

Contributed by Bin Xu, M.D., Ph.D. and Kelly Magliocca, D.D.S., M.P.H.

Tubular pattern

Cribriform pattern

Solid pattern

High grade transformation

Perineural invasion

Squamous metaplasia

Clear myoepithelial cells

p40

SMA

CAM5.2

MYB

H&E of turbinate to palate

Cytology description

Matrix containing and basaloid
Diff-Quik stained smears: metachromatic matrix spheres with sharply defined border (hyaline globules) surrounded by basaloid tumor cells
Uniform basaloid cells with scant cytoplasm, oval to angulated hyperchromatic nuclei and indistinct nucleoli
Various architecture patterns, including microcystic, tubular and syncytial clusters
Characteristic extracellular hyaline globules or cylinders of acellular metachromatic stroma with sharp borders best seen on Romanowsky type stain
Marked cytologic atypia and necrosis in cases with high grade transformation

Cytology images

Contributed by Bin Xu, M.D., Ph.D. and Jen-Fan Hang, M.D.

Smear, Diff-Quik

Smear, Papanicolaou

Basaloid cells

Microcystic pattern

Branching pattern

Positive stains

Ductal component is typically positive for CK7 and CAM 5.2
Myoepithelial component is positive for myoepithelial markers, e.g. SMA, S100, calponin, p40, p63, GFAP and cytokeratins
Other positive stains: c-KIT (CD117)
MYB overexpression is a sensitive but nonspecific immunomarker for adenoid cystic carcinoma (Am J Surg Pathol 2017;41:1422)

Molecular / cytogenetics description

Absence of high risk HPV bby DNA or RNA in situ hybridization
60 - 90% have characteristic and diagnostic fusion involving MYB, MYBL1 or NFIB gene, the most common being t(6,9) MYB-NFIB fusion (Nat Genet 2013;45:791, Proc Natl Acad Sci U S A 2009;106:18740, Cancer Discov 2016;6:176)
Additional mutations involving FGF-IGF-PI3K pathway (in 30%) and chromatin state regulators (e.g. SMARCA2, CREBBP and KDM6A) are reported (Nat Genet 2013;45:791)
Although commonly overexpresses c-KIT by immunohistochemistry, it is not associated with c-KIT mutation

Sample pathology report

Left parotid, parotidectomy:
- Adenoid cystic carcinoma, solid, cribriform and tubular pattern (see synoptic report)
- Comment: Solid component accounts for 20% of total tumor volume.

Differential diagnosis

Epithelial myoepithelial carcinoma:
- Also biphasic with ductal and myoepithelial differentiation
- Typically contains compact branching tubules (adenoid cystic carcinoma contains simple tubules)
- Generally lacks cribriform growth pattern: if present, cribriform pattern is often very focal
- Papillocystic architecture may be seen (typically absent in adenoid cystic carcinoma)
- Contains clear myoepithelial cells (adenoid cystic carcinoma contains myoepithelial cells with dark angulated nuclei and scanty cytoplasm)
- Characterized by HRAS mutation; lacks fusions involving MYB, NFIB or MYBL1
Basal cell adenocarcinoma:
- Also biphasic and basaloid
- Trabecular, tubular and solid growth and usually lacks cribriform growth (adenoid cystic carcinoma lacks trabecular growth)
- Prominent peripheral palisading and may contain areas with squamoid eddies
- Characterized by mutation of Wnt / beta catenin pathway leading to abnormal nuclear accumulation of beta catenin by immunohistochemistry; lacks fusions involving MYB, NFIB or MYBL1
Polymorphous adenocarcinoma:
- Also may show tubular, cribriform and solid growth
- May have other growth patterns, e.g. single files, trabecular or papillary architecture
- Shows cytologic monotony with only one type of tumor cells
  - Nuclei contain open chromatin resemble nuclei of papillary thyroid carcinoma
- Typically p63 positive / p40 negative, whereas adenoid cystic carcinoma is typically positive for both p63 and p40 (Am J Surg Pathol 2014;38:257)
HPV related multiphenotypic sinonasal carcinoma:
- Also can affect sinonasal tract and show similar morphology and expression
- May have surface dysplasia
- Positive for high risk HPV; negative for MYB-NFIB fusion
Squamous cell carcinoma:
- Basaloid squamous cell carcinoma and HPV+ oropharyngeal squamous cell carcinoma may contain adenoid cystic carcinoma-like areas
- Typically shows more pleomorphism, is negative for MYB-NFIB fusion, is diffusely positive for squamous markers (p40, p63 and CK5/6), is negative for myoepithelial markers (S100, calponin and SMA) and may be HPV+

Board review style question #1

It has an excellent prognosis with 5% risk of recurrence following complete resection of the primary tumor
It is characterized by point mutation involving MYB gene
Solid pattern is associated with adverse clinical outcome
The most common site of this tumor is the parotid gland, followed by submandibular gland

Board review style answer #1

C. Solid pattern is associated with adverse clinical outcome

Comment Here

Reference: Adenoid cystic carcinoma

Board review style question #2

t(6,9) MYB-NFIB fusion
t(11,19) MAML2-CRTC1 fusion
t(12,15) ETV6-NTRK3 fusion
t(12,22) ATF1-EWSR1 fusion

Board review style answer #2

A. t(6,9) MYB-NFIB fusion

Comment Here

Reference: Adenoid cystic carcinoma

Board review style question #3

Which histological diagnosis is most likely to correspond to this cytologic aspirate?

Acinic cell carcinoma
Adenoid cystic carcinoma
Mucoepidermoid carcinoma
Secretory carcinoma

Board review style answer #3

B. Adenoid cystic carcinoma

Basaloid tumor cells with prominent hyaline globules arranging in cribriform pattern are characteristic for an adenoid cystic carcinoma.

Comment Here

Reference: Adenoid cystic carcinoma

Adenomatoid hyperplasia and sialadenosis

Table of Contents

Definition / general | Microscopic (histologic) description

Definition / general

Presents as submucosal nodule or mass; may be hyperplastic or hamartomatous in nature
Usually hard palate, also retromolar but may occur anywhere in the oral cavity
Called sialadenosis in major salivary glands
Etiology unknown; in major salivary glands, sialadenosis is associated with metabolic conditions

Microscopic (histologic) description

Coalescing lobules of normal mucinous acini

Anatomy & histology

Table of Contents

Definition / general

3 paired major salivary glands:
- Parotid glands
- Submandibular glands
- Sublingual glands
In addition, there are numerous (600 - 1000) minor salivary glands distributed throughout the submucosa of the upper aerodigestive tract

Essential features

Functional unit of all salivary glands consists of acini and ducts
Acini can be composed predominantly of serous or mucous cells or can be mixed seromucous type
3 main types of ducts are intercalated, striated or interlobular
Myoepithelial cells embrace the secretory unit and are critical for the expulsion of saliva
Saliva has a crucial protective and digestive function within the upper aerodigestive cavity, providing mucosal lubrication, alkaline environment for dental protection, facilitating taste, initiating enzymatic digestion of carbohydrates and contributing to oral immunity
Unique to the parotid gland is the presence of sebaceous glands and intraparenchymal lymph nodes

Embryology

Salivary glands are of ectodermal origin
Developmental process begins when preacinar buds invaginate the adjacent mesenchyme, proliferating through cords, which eventually form clefts and produce extensive branching; end result is terminal bulbs, which form the secretory unit (Eur J Mol Clin Med 2020;764)
Parotid anlage appears in the fifth week, followed by the submandibular and sublingual primordia in the sixth and eighth weeks, respectively
Minor salivary glands develop during ninth to twelfth weeks
Connective tissue component of the developing glands progressively lessens with maturation
Capsule of each gland is formed by the surrounding mesenchyme, a process which is delayed for the parotid gland, therefore allowing the integration of parotid buds and lymphoid tissue:
- Results in the presence of both intraparotid lymph nodes as well as lymph nodes containing glandular and ductal inclusions
As the parotid gland forms, its embryologic branches intertwine with branches of the facial nerve
Minor salivary glands develop in a similar fashion to the major glands; however, the branching is less extensive and remains located within the submucosa

Anatomy

Parotid gland:
- Largest of the major salivary glands (weight 15 - 30 g)
- Pyramidal shaped and encased in robust parotid fascia, which is a continuation of deep cervical fascia as it travels superiorly
- Located in a shallow, preauricular compartment defined by:
  - Superficially: the superficial musculoaponeurotic system (SMAS) forming parotid fascia and platysma
  - Inferiorly: the sternocleidomastoid muscle
  - Medially: the parapharyngeal space
  - Anteromedially: the mandibular ramus covered by the masseter muscle
  - Posteriorly: the cartilage of the ear canal and temporal bone
- Extracranial trunk of the facial nerve extends from the stylomastoid foramen into the parotid gland and divides into upper and lower division
  - Branches of the facial nerve traverse the body of the parotid gland to artificially divide the gland into superficial and deep lobes and exit in the form of 5 terminal branches from its anteromedial surface to supply 22 muscles of facial expression
  - Parotidectomy requires precise dissection of the parotid gland to identify and preserve the integrity of the facial nerve, preventing ipsilateral hemifacial paralysis
- Stensen duct (~7 cm) is the main excretory duct of the parotid gland and emerges from the anterior border of the gland to travel horizontally along the superficial surface of the masseter muscle before turning medially to pierce the buccinator muscle and enter the oral cavity adjacent to the second maxillary molar
- Accessory parotid tissue, usually adjacent to Stensen duct, can be identified in approximately 20% of individuals (Otolaryngol Clin North Am 2016;49:273)
  - Clinically important as salivary gland tumors can arise in this location
Submandibular gland:
- Second largest of the major salivary glands (weight 7 - 15 g)
- Hook shaped around the mylohyoid muscle and enveloped by a capsule continuous with the superficial layer of the deep cervical fascia
- Divided into superficial and deep arms
  - Superficial (largest) portion lies outside the oral cavity below the mylohyoid muscle in the submandibular triangle bound by:
    - Superficial: platysma
    - Superior: mandible
    - Inferior: digastric muscle
  - Deep portion is formed as the gland curves around the posterior border of the mylohyoid muscle to enter the oral cavity
- Wharton duct (~5 cm) is the main excretory duct of the submandibular gland, arises from the deep part of the gland, courses anteriorly and opens onto the sublingual caruncle adjacent to the frenulum of the tongue
- Lingual nerve crosses Wharton duct twice lateral to medial and the hypoglossal nerve (CN XII) travels inferior to the duct (Folia Morphol (Warsz) 2018;77:521)
- Vertical posterior edge of the submandibular gland and the digastric muscle can be used as a boundary between levels I and II of the neck (Arch Otolaryngol Head Neck Surg 2008;134:536)
Sublingual gland:
- Smallest of the major salivary glands (weight 2 - 4 g)
- Almond shaped and enveloped by loose connective tissue (no discrete capsule)
- Located above the mylohyoid muscle lateral to the submandibular duct and lingual nerve
- Fills the medial groove or sublingual fossa of the mandible
- Superiorly, the gland creates a mucosal elevation (sublingual fold) on the floor of the oral cavity
- There may be multiple minor sublingual ducts, also known as ducts of Rivinus, opening directly onto the crest of the sublingual fold; these may be replaced anteriorly by the major sublingual duct (Bartholin duct), which may connect with the submandibular duct at the sublingual caruncle
Minor salivary glands:
- Scattered throughout the oral submucosa, with the exception of the gingiva and anterior hard palate
- Not encapsulated and each gland possesses 1 duct draining directly into the oral cavity
- Predominantly mucinous apart from the purely serous von Ebner glands of the dorsal tongue that surround the circumvallate papillae
Vasculature:
- Arterial supply
  - External carotid artery supplies the major salivary glands, coursing superiorly from the carotid bifurcation and providing the facial and lingual arteries that supply the submandibular and sublingual glands
    - Facial artery is intimately associated with the submandibular gland and is routinely divided above and below the submandibular gland during its removal as there are numerous branches
  - External carotid artery arrives at the posteromedial surface of the parotid gland, dividing into 2 terminal branches, the superficial temporal artery and maxillary artery, which exit from superior and anteromedial surfaces, respectively
  - Superficial temporal artery provides the transverse facial artery, which travels anteriorly to supply the parotid gland and parotid duct
- Venous outflow
  - Retromandibular vein is formed in the body of the parotid gland by the union of the superficial temporal and maxillary veins and provides venous return for the gland, descending superficial to the external carotid artery and deep to the facial nerve before eventually joining the external jugular vein
    - Retromandibular vein is intimately associated with the facial nerve and is used as a surrogate anatomic landmark to determine whether tumors are in the deep or superficial lobe of the parotid gland
  - Lingual and facial veins drain the submandibular and sublingual glands and flow into the internal jugular vein
    - Facial vein lies over the submandibular gland and needs to be ligated to access the gland during surgery
  - Venous anatomy can be variable
- Lymphatic drainage
  - Lymphatic drainage of the parotid gland follows the venous system, draining to a superficial (fascial) and deep (intraparenchymal) group of lymph nodes before flowing into the superior deep cervical nodes
  - Lymphatic drainage of the submandibular and sublingual glands is received predominantly by the submandibular lymph nodes before progressing to the jugular chain
Innervation:
- Both parasympathetic and sympathetic fibers innervate the salivary glands
  - Parasympathetic syndromes cause salivation
  - Sympathetic syndromes, anxiety cause dry mouth
- Within the oral cavity, parasympathetic innervation to salivary glands is by the facial nerve (VII), branches of which join the maxillary (V2) and mandibular (V3) nerves
  - Parasympathetic fibers conveyed by the chorda tympani branch of the facial nerve (VII) innervate the submandibular and sublingual glands via the lingual nerve
  - Chorda tympani nerve unites with the lingual nerve of V3 in the infratemporal fossa before entering the oral cavity to synapse with postganglionic fibers in the submandibular ganglion
  - Submandibular ganglion is suspended from the lingual nerve and located inferior to the submandibular duct, supplying postganglionic parasympathetic fibers that pass directly to the submandibular and sublingual glands
    - Branches from lingual nerve to the submandibular gland are ligated during gland excision
- Beyond the oral cavity, the parotid gland receives parasympathetic innervation by the auriculotemporal nerve (branch of the mandibular nerve [V3]), a nerve which derives its fibers from the glossopharyngeal nerve (IX) in the infratemporal fossa
  - Delayed complication of parotid surgery is Frey syndrome, characterized by gustatory sweating
- Postganglionic sympathetic fibers branch from the carotid plexus of the external carotid artery and innervate the salivary glands along blood vessels

Physiology

Saliva has a crucial protective and digestive function within the upper aerodigestive cavity, providing mucosal lubrication and dental protection, facilitating taste, initiating enzymatic digestion of carbohydrates and contributing to oral immunity
Saliva synthesizing acinar cells are capable of producing a volume of up to 1.5 L daily, secreted in response to parasympathetic and sympathetic stimulation
- Parasympathetic activity favors the production of serous or watery solution
- Sympathetic activity triggers protein secretion
Parotid glands are responsible for up to 50% of saliva production upon stimulation (J Med Life 2009;2:303)
Saliva primarily contains the enzymes amylase and lysozyme, IgA and IgG antibodies, inorganic ions and a variable quantity of mucous
Serous and mucous cells of the salivary glands contribute to the composition of saliva and the striated ducts perform critical modification processes, specifically electrolyte reabsorption and secretion
- Initially isotonic, saliva becomes a hypotonic, bicarbonate rich solution as it passes through the mitochondria packed striated ducts that facilitate ion transport

Diagrams / tables

Contributed by Theoni Haralabopoulos, M.D. and AFIP

3 major salivary glands (left side)

Schematic representation of acinus and ductal system

Embryological development of oral cavity

Parotid gland lymph nodes

Horizontal section through parotid gland

Images hosted on other servers:

Overview of major salivary gland anatomy

Clinical implications

Each cellular component can give rise to benign and malignant lesions that may present as swellings, with or without associated discomfort or pain
Salivary gland inflammation (sialadenitis) manifests as lymphoid infiltration and destruction of serous and mucinous acini, leading to pain, swelling and dry mouth; this can be secondary to
- Bacterial or viral infection
- Autoimmune (e.g., Sjögren syndrome and IgG4 related disease)
- Impaction of calculi (sialolithiasis)
- Trauma
- Irradiation
Dilatation of salivary gland ducts (sialectasis) may be associated with recurrent sialadenitis and typically presents as painful, diffuse parotid gland swelling
Xerostomia following irradiation of the major or minor salivary gland tissues
Neoplasms:
- Most (80%) of the salivary gland neoplasms arise in the parotid gland
  - 80% of these are benign; on the other hand, most neoplasms of the sublingual gland are malignant
- Primary epithelial
  - Pleomorphic adenoma, a benign, morphologically diverse tumor, displays both epithelial and myoepithelial derivation
    - Most common (80%) salivary gland tumor
    - Typically, the lesion presents as a slow growing, painless and mobile parotid mass (Wiad Lek 2020;73:2339)
  - Warthin tumor, the second most frequent benign epithelial neoplasm, originates from heterotrophic salivary ducts present in intra or periparotid lymph nodes
    - Dual morphological components of a lymphoid stroma and a bilayered, oncocytic epithelium that lines papillary and cystic structures
    - Oncocytic epithelium rich in mitochondria is derived from the striated ducts
    - This entity displays male predominance and usually presents as a symptomless, fluctuant parotid lump (J Clin Diagn Res 2014;8:ZD37)
    - Mitochondria rich oncocytic epithelium can often appear PET avid
  - Interlobular and intralobular salivary duct epithelium gives rise to the most common salivary gland malignancy, mucoepidermoid carcinoma, comprising mucinous, squamoid and intermediate cells arranged in a solid and cystic architecture
    - Mucoepidermoid carcinoma predominantly presents as a solitary asymptomatic swelling within the parotid gland; pain and facial paralysis may occasionally occur (Adv Anat Pathol 2006;13:293)
  - WHO classification system of salivary gland tumors includes nearly 30 other subtypes including adenoid cystic carcinoma, secretory carcinoma, epithelial myoepithelial carcinoma, salivary duct carcinoma and carcinoma ex pleomorphic adenoma
- Other neoplasms include lymphomas and metastatic malignancies from the skin and soft tissues of the scalp (squamous cell carcinoma, melanoma, angiosarcoma, pleomorphic dermal sarcoma); these are more likely to occur in the parotid gland due to the presence of native lymph nodes
- Malignancies of the parotid gland can involve the facial nerve as the nerve passes through the gland
- Minor salivary gland neoplasms generally manifest as submucosal nodules

Gross description

See Anatomy

Gross images

Contributed by Ruta Gupta, M.B.B.S., M.D. and Theoni Haralabopoulos, M.D.

Parotid gland

Cut surface of parotid gland

Submandibular gland

Cut surface of submandibular gland

Sublingual gland

Cut surface of sublingual gland

Microscopic (histologic) description

Functional unit of all salivary glands consists of acini and ducts
Within the major salivary glands, these functional secretory units are arranged in lobules
Interlobular regions include large excretory ducts and neurovascular bundles (Anat Rec A Discov Mol Cell Evol Biol 2006;288:498)
Acini can be composed predominantly of serous or mucous cells or can be mixed seromucous type
- Serous acini
  - Dominant component in the parotid gland and von Ebner glands of the tongue
  - Polygonal shaped cells with dense, intracytoplasmic, basophilic zymogen enzyme containing granules
  - Cells are periodic acid-Schiff (PAS) reagent positive
- Mucous acini
  - Dominant component in the minor salivary glands of the palate and base of tongue
  - Round cells filled with mucin and containing a basally located, condensed nucleus
  - Positive for mucicarmine, alcian blue and PAS with diastase resistance (DPAS)
- Mixed seromucous acini
  - Dominant component in the submandibular (serous predominance) and sublingual (mucous predominance) glands, minor salivary glands of the lip, cheek and anterior tongue
  - Mucous acini with crescent shaped caps (demilunes) of serous cells
3 main types of ducts are intercalated, striated or interlobular:
- Intercalated ducts
  - Smallest caliber
  - Emerge from the acinar unit
  - Lined by a single layer of cuboidal epithelium
  - Contain reserve cells that regenerate the terminal secretory unit
- Striated ducts
  - Proceed from the intercalated ducts
  - Intralobular
  - Intermediate caliber between intercalated and interlobular ducts
  - Lined by columnar epithelium containing basal cytoplasmic striations, formed by rows of mitochondria alternating with folded cell membrane (Anat Rec 2001;264:121)
  - Contribute to the ionic composition of the saliva
  - Drain into interlobular ducts
- Interlobular ducts
  - Largest caliber
  - Located within interlobular septa and lined by pseudostratified columnar epithelium
  - Merge to form the major excretory duct outside the gland, lined distally by nonkeratinized stratified squamous epithelium
Myoepithelial cells are critical for the expulsion of saliva
- Contractile myoepithelial cells surround acini, intercalated ducts and striated ducts
- Located between epithelial cells and the basement membrane, embracing the secretory unit with long cytoplasmic processes
- Generally spindle shaped with blunt ended nuclei and elongated cytoplasmic processes (Microsc Res Tech 1993;26:5)
Normal inclusions within the salivary glands:
- Presence of sebaceous glands within the parotid gland is common and are usually found associated with interlobular ducts or may exist as isolated cells within the wall of intercalated or striated ducts (Am J Surg Pathol 1989;13:879)
- Unique to the parotid gland is the presence of intraparotid lymph nodes, most of which are located superficial to the facial nerve (Br J Plast Surg 1985;38:1)
  - Often the lymph nodes may lack a well defined capsule and merge with the adjacent salivary gland acini
- Fatty infiltration of the major salivary glands is an age induced variation (Am J Surg Pathol 1989;13:879)

Microscopic (histologic) images

Contributed by Ruta Gupta, M.B.B.S., M.D. and Theoni Haralabopoulos, M.D.

Major salivary glands:

Parotid gland

Serous acini of Parotid gland

Striated ducts of parotid gland

Interlobular duct of parotid gland

Intraparotid lymph node

Intraparotid lymph node with glandular inclusions

Sebaceous cells in parotid gland

Submandibular gland

Mucous acinar cells of submandibular gland

Sublingual gland

Seromucous acini of sublingual gland

Minor salivary glands:

Minor salivary glands

Minor salivary glands are unencapsulated

Special stains and immunohistochemistry:

Mucicarmine stain of sublingual gland

PAS stain of sublingual gland

SMA positivity of myoepithelial cells

EMA positivity of ductal cells

AE1 / AE3 positivity of all cell types

p63 positivity of myoepithelial cells

Positive stains

Acinar cells
- Zymogen granules of serous acinar cells are periodic acid-Schiff (PAS) reagent positive
- Low molecular weight cytokeratins (e.g. CK7, CK8, CK19)
- Alpha-amylase
Mucinous cells
- Mucous cells are positive for mucicarmine, alcian blue and PAS with diastase resistance (DPAS)
- CK5/6
- p63
Ductal cells
Myoepithelial cells
- May coexpress CK14, CK19 and vimentin
- Alpha smooth muscle actin (SMA)
- Calponin
- Muscle specific actin (MSA)
- p63
- Caldesmon
- Myosin heavy chain (MHC)
- Glial fibrillary acidic protein (GFAP) (variable)
- S100 (variable) (Acta Histochem Cytochem 2012;45:269)

Videos

Shotgun histology parotid gland

Shotgun histology submandibular gland

Shotgun histology sublingual gland

Board review style question #1

Which type of salivary duct, pictured above, is responsible for the ion transport that alters the isotonic secretion produced by acinar cells to hypotonic saliva?

Intercalated duct
Interlobular duct
Major excretory duct
Striated duct

Board review style answer #1

D. The striated ducts contain abundant mitochondria to provide the energy for ion transport

Comment Here

Reference: Salivary glands - Anatomy & histology

Board review style question #2

Which of the following is true about the parotid gland?

The acini are purely of mucous type
Intraparenchymal lymph nodes may contain glandular inclusions
Wharton duct, the main excretory duct, pierces the masseter muscle to enter the oral cavity
Sebaceous cells may be found within fatty tissue
The facial nerve traverses the superficial surface of the gland

Board review style answer #2

B. Intraparenchymal lymph nodes may contain glandular inclusions. A is incorrect because the acini are purely of serous type in the parotid gland. C is incorrect since the main excretory duct of the parotid gland is Stensen duct, which emerges from the anterior border of the gland, courses horizontally along the masseter muscle and turns medially to pierce the buccinator muscle. D is incorrect because sebaceous cells may exist within the wall of intercalated or striated ducts. E is incorrect because the facial nerve traverses the body of the gland to divide it into superficial and deep lobes.

Comment Here

Reference: Salivary glands - Anatomy & histology

Atypia of undetermined significance (AUS)

Table of Contents

Definition / general

A diagnostic category of the Milan System for Reporting Salivary Gland Cytopathology which addresses when the differential diagnosis includes both neoplastic and nonneoplastic lesions (Faquin: The Milan System for Reporting Salivary Gland Cytopathology, 1st Edition, 2018)
Occasionally, FNAs with atypical cells which may be otherwise considered nondiagnostic are also included

Essential features

Category is heterogeneous in nature
Differential includes nonneoplastic and neoplastic entities
Risk of malignancy is ~20%; the implied risk of malignancy was estimated to be ~20% in the 1st edition of the Milan system but was found to be higher (~30% on average) in subsequent studies with surgical follow up
It is recommended that no more than 10% of FNAs should be interpreted as atypia of undetermined significance

CPT coding

88172 - determination of adequacy of specimen, first pass
88177 - determination of adequacy of specimen, subsequent pass
88173 - FNA interpretation
88305 - cell block

Sites

Major salivary glands (parotid, submandibular, sublingual), less frequent in minor salivary glands

Case reports

10 year old boy presented with swelling of the left parotid gland (Cytopathology 2021;32:257)
55 year old woman presented with a 2 year complaint of fluctuating painless right parotid swelling (J Family Med Prim Care 2020;9:1202)
56 year old woman with a 2 year history of a painless mass in the left parotid gland (Acta Cytol 2008;52:369)

Treatment

Repeat FNA or FNA under ultrasound guidance if prior was palpation guided
Close clinical follow up
Additional imaging (such as MRI or CT) for further characterization
Tissue sampling or surgical excision if clinically suspicious for malignancy
Reference: Faquin: The Milan System for Reporting Salivary Gland Cytopathology, 1st Edition, 2018

Cytology description

Atypia in a scant cellularity specimen which may represent reactive or reparative atypia but is indeterminate for a neoplastic process
Epithelial cells which have squamous, oncocytic or metaplastic changes but have limited cellularity and are indeterminate for a neoplastic process
Scant cellularity specimens which are suggestive of but not diagnostic of a neoplasm
Poorly preserved specimens which preclude determination of a neoplastic versus nonneoplastic diagnosis
A predominantly cystic lesion with a mucinous background with rare or absent epithelial cells
A lymphoid predominant aspirate in which a hematolymphoid neoplasm cannot be excluded
Rare atypical cells present when the differential includes a basaloid neoplasm
Reference: Faquin: The Milan System for Reporting Salivary Gland Cytopathology, 1st Edition, 2018

Cytology images

Contributed by Umamaheshwari Golconda, M.D.

Rare atypical cells

Lymphoid rich aspirate

Abundant extracellular mucin

Sample pathology report

Parotid, right, fine needle aspiration smears:
- Atypia of undetermined significance
- Scant histiocytes in a background of abundant mucin (see comment)
- Comment: The specimen is limited by scant cellularity. The differential includes a mucinous cyst, though a low grade mucoepidermoid carcinoma is not entirely excluded. Clinical and radiologic correlation is suggested.

Submandibular, left, fine needle aspiration smears:
- Atypia of undetermined significance
- Heterogenous lymphoid elements (see comment)
- Comment: Insufficient material was available for flow cytometry. Additional sampling with dedicated material for flow cytometry is suggested if clinical suspicion for a lymphoproliferative disorder persists.

Parotid, right, fine needle aspiration smears:
- Atypia of undetermined significance
- Rare atypical cells (see comment)
- Comment: The specimen is limited by scant cellularity. The differential includes reactive atypia, though a neoplastic process cannot be entirely excluded. Clinical and radiologic correlation is suggested.

Differential diagnosis

Differential diagnosis of lymphocyte rich aspirates includes:
- Nonneoplastic:
  - Chronic sialadenitis:
    - Hypocellular aspirate with basaloid (atrophic) or metaplastic ductal cells and few / absent acinar cells
    - Chronic inflammation (lymphocytes and plasma cells)
  - Lymphoepithelial sialadenitis:
    - More common in parotid gland (~90% of cases), in women and associated with autoimmune conditions like Sjögren syndrome
    - Cellular aspirate with large sheets of reactive ductal cells with or without squamous metaplasia and percolating mature lymphocytes
  - Lymphoepithelial cyst (HIV associated) cyst:
    - Associated with autoimmune disease (e.g., Sjögren syndrome) or young HIV+ individuals (usually multiple and bilateral) (Diagn Cytopathol 2012;40:684)
    - Proteinaceous and keratin debris with squamous cells (without significant atypia), lymphocytes and lymphohistiocytic aggregates
- Neoplastic:
  - Warthin tumor:
    - FNA with predominant dirty granular background material and scant epithelial component can be falsely interpreted as necrosis
  - False negative rate: 1.3% (4/304) (Cancer Cytopathol 2021;129:43)
  - Mucoepidermoid carcinoma:
    - Predominantly mucus cells floating in extracellular mucin (low grade)
      - High grade nuclear features with pleomorphic nuclei, prominent nucleoli, intermediate cells and mucous cells are rare
  - Acinic cell carcinoma:
    - Cells are large but morphologically resemble normal acinar cells
      - Round nuclei with small nucleoli
      - Abundant finely vacuolated to granular cytoplasm
  - Malignant lymphoma:
    - Lymphomas originating from the salivary glands are rare, accounting for ~3% of all malignant tumors which more commonly affect the parotid glands
Differential diagnosis of lesions that can yield cystic fluid includes:
- Nonneoplastic:
  - Obstructive sialoadenopathy
    - Retention cyst:
      - Mucoid secretion surrounded by a bilayer of cuboidal or columnar stratified salivary duct epithelium
    - Mucocele:
      - There is no true salivary gland duct epithelial lining and instead this is mimicked by epithelioid macrophages (muciphages) at the periphery of the extravasated mucin
    - Lymphoepithelial (HIV associated cyst):
      - Associated with autoimmune disease (e.g., Sjögren syndrome) or young HIV+ individuals (usually multiple and bilateral) (Diagn Cytopathol 2012;40:684)
  - Neoplastic:
    - Warthin tumor:
      - Sheets of oncocytes and mixed population of lymphocytes in a characteristic dirty proteinaceous background
    - Pleomorphic adenoma:
      - Mixture of myoepithelial cells, ductal cells and extracellular stroma
    - Mucoepidermoid carcinoma:
      - Predominantly mucus cells floating in extracellular mucin (low grade)
        
        High grade nuclear features with pleomorphic nuclei, prominent nucleoli, intermediate cells and mucous cells are rare
    - Acinic cell carcinoma:
      - Cells are large but morphologically resemble normal acinar cells
        
        Round nuclei with small nucleoli
        Abundant finely vacuolated to granular cytoplasm
      Cystadenoma:
      - Cyst wall with simple lining of glandular cells, oncocytic cells or squamous cells
    - Secretory carcinoma:
      - Cohesive clusters or sheets of epithelial cells with variable eosinophilic, granular to vacuolated cytoplasm and uniform nuclei with single nucleoli

Board review style question #1

This aspirate smear contains abundant extracellular mucin without epithelial cells. Under which category should this be placed according to the Milan system for reporting salivary gland cytopathology?

Atypia of undetermined significance
Nondiagnostic
Salivary gland neoplasm of uncertain malignant potential
Suspicious for malignancy

Board review style answer #1

A. Atypia of undetermined significance. The image shows abundant extracellular mucin. The differential diagnosis of mucin containing cysts includes mucocele, mucus retention cysts and low grade mucoepidermoid carcinoma. Therefore, atypia of undetermined significance is the correct interpretation on FNA.

Comment Here

Reference: Atypia of undetermined significance (AUS)

Board review style question #2

What is the implied risk of malignancy on excision if a diagnosis of atypia of undetermined significance is rendered on a fine needle aspiration (FNA) of the parotid?

< 5%
20%
45%
90%

Board review style answer #2

B. 20%. The implied risk of malignancy is ~20% as per the Milan system for reporting salivary gland cytopathology (1st edition 2018), based on a limited number of studies. However, subsequent studies using the Milan system criteria have found the risk of malignancy for a diagnosis of atypia of undetermined significance with surgical follow up to be significantly higher (30% on average) with wide variations across institutions that reflect different types of practices.

Comment Here

Reference: Atypia of undetermined significance (AUS)

Basal cell adenocarcinoma

Table of Contents

Definition / general

Primary biphasic carcinoma of the salivary glands; composed of basal and ductal cells (Surg Pathol Clin 2021;14:25)

Essential features

Biphasic, low grade malignancy of salivary gland
Parotid is the most common location; rare in other salivary glands and minor salivary gland tissue
Histologic features similar to basal cell adenoma but with evidence of invasive growth pattern
Diagnosis based on demonstration of a dual cell population of centrally located ductal cells and abluminal basal cells with peripheral palisading of nuclei
Squamous and sebaceous differentiation may be seen
Surgery with clear margins is the mainstay of treatment

Terminology

Basal cell adenocarcinoma (BCAC)
Use of other terminology is not recommended

ICD coding

ICD-O: 8147/3 - basal cell adenocarcinoma

Epidemiology

Rare primary salivary gland tumor, accounting for < 1 - 2% of salivary gland malignancies
Wide age range (40 - 90)
Most frequent in adults in seventh to eighth decade; exceedingly rare in children
Slight female predominance (F:M = 1.2:1) (Surg Pathol Clin 2021;14:25)

Sites

Parotid (75 - 90%), submandibular, minor salivary gland of oral cavity

Etiology

Arises from pluripotential, ductal and myoepithelial cells
Majority arise de novo; approximately 25% of cases arise from basal cell adenoma (Cancer 1996;78:2471)
Rare examples may occur in the context of familial cylindromatosis syndromes, such as Brooke-Spiegler syndrome (Surg Pathol Clin 2021;14:25)

Clinical features

Slow growing, painless mass; often present for many years
Rare association with dermal cylindromas (Case Rep Radiol 2012;2012:249583)
~50% recur locally; 15% metastasize to lymph nodes, rarely to lungs (Head Neck Pathol 2015;9:205, Thompson: Diagnostic Pathology - Head and Neck, 2nd Edition, 2016)

Diagnosis

Imaging modalities for workup of salivary gland neoplasms include ultrasonography, CT and MRI (Otolaryngol Head Neck Surg 2021;164:27)
Cytologic diagnosis exceedingly difficult due to morphologic overlap with other more common biphasic salivary gland neoplasms, including pleomorphic adenoma and adenoid cystic carcinoma (Diagn Pathol 2013;8:171)

Radiology description

No specific radiological findings

Prognostic factors

BCAC is a low grade malignant tumor with good long term prognosis; death from disease is rarely reported (Head Neck Pathol 2015;9:205, Head Neck Pathol 2009;3:69)
May be locally destructive and recurrences are seen in 50%, up to 10 years later (Thompson: Diagnostic Pathology - Head and Neck, 2nd Edition, 2016)
Poorer prognostic features include location in minor salivary gland, advanced stage, incomplete excision and recurrence (Thompson: Diagnostic Pathology - Head and Neck, 2nd Edition, 2016)

Case reports

57 year old man with epistaxis and decreased hearing for 1 month duration, found to have a nasopharyngeal tumor (BMC Cancer 2018;18:878)
66 year old woman with 2 year history of slow growing painless mass in parotid (Turk Arch Otorhinolaryngol 2017;55:187)
86 year old man with diplopia, epistaxis and buccal swelling (SAGE Open Med Case Rep 2021;9:2050313X211048041)

Treatment

Surgical resection of tumor with clear margins is first line treatment (Oncotarget 2017;8:3946)
Neck dissection if evidence of lymph node metastases present (Oncotarget 2017;8:3946)
Postoperative radiotherapy if adverse prognostic features present or lesion originating in minor salivary gland (Arch Pathol Lab Med 2007;131:1602)

Gross description

Typically presents as a well circumscribed, unencapsulated lesion
Solid to focally cystic with white / cream to tan cut surface
Size usually < 5 cm (Thompson: Diagnostic Pathology - Head and Neck, 2nd Edition, 2016)

Gross images

Contributed by Natasha Prosser, B.Sc., M.B.B.S.

Parotid gland tumor

Images hosted on other servers:

Bisected specimen with focal hemorrhage

Frozen section description

Should not be used; diagnosis may not be possible on frozen section

Microscopic (histologic) description

Unencapsulated, with circumscribed to infiltrative edges with infiltration into salivary gland parenchyma, fat, nerve or lymphovascular spaces (Head Neck Pathol 2015;9:205, Diagn Pathol 2013;8:171)
Solid, trabecular, tubular and membraneous growth patterns (Head Neck Pathol 2015;9:205)
Biphasic tumors with central ductal cells and abluminal basal cells (Thompson: Diagnostic Pathology - Head and Neck, 2nd Edition, 2016)
Ductal cells appear cuboidal, with moderate amounts of eosinophilic cytoplasm and round to ovoid nuclei (Thompson: Diagnostic Pathology - Head and Neck, 2nd Edition, 2016)
Basal cells show scanty cytoplasm and hyperchromatic ovoid nuclei (Head Neck Pathol 2015;9:205)
Nuclear palisading of the peripheral basal cells is seen (Head Neck Pathol 2015;9:205)
Basement membrane-like eosinophilic material separates nests (Head Neck Pathol 2015;9:205)
Squamous and sebaceous differentiation may be present (J Clin Pathol 2000;53:153)
Necrosis may be seen in 45% of tumors, with an increase in mitoses (Thompson: Diagnostic Pathology - Head and Neck, 2nd Edition, 2016)

Microscopic (histologic) images

Contributed by Natasha Prosser, B.Sc., M.B.B.S. and Ruta Gupta, M.D.

Peripheral palisading

Biphasic tumor composition

Solid pattern

Tubular and trabecular growth patterns

Membranous pattern

Glandular elements

Squamous morules

Invasion

Perineural invasion

DPAS special stain

Beta catenin IHC

Cytokeratin 7 IHC

p63 IHC

Ki67 IHC

Cytology description

Cytologic diagnosis of basal cell adenocarcinoma is exceedingly difficult as the smears show a dual cell population and are rich in stroma, similar to several biphasic salivary gland neoplasms:
- Cellular smears with irregular cohesive cell clusters
- Small and intermediate sized basaloid cells with peripheral palisading
- Dense, nonfibrillary stroma at the periphery of cell groups
Malignant features with nuclear atypia, mitotic activity or necrosis are rare
References: Diagn Cytopathol 2015;43:432, Acta Cytol 2018;62:346, Cibas: Cytology - Diagnostic Principles and Clinical Correlates, 5th Edition, 2020

Positive stains

Pancytokeratin, CK7
CEA-M luminal cells
p63, p40, S100, calponin in basal / myoepithelial cell
CK5/6 highlighting areas of squamous differentiation (Surg Pathol Clin 2021;14:25)

Negative stains

Beta catenin (Surg Pathol Clin 2021;14:25)

Electron microscopy description

Not used in routine practice
Ultrastructural features identical for basal cell adenoma and BCAC
Cells show basal, myoepithelial and ductal differentiation
Excess basal lamina, marginally and intercellularly seen around nonluminal cells
Reference: Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87:485

Molecular / cytogenetics description

CYLD alterations, usually in membranous type (Mod Pathol 2018;31:1064)

Sample pathology report

Left superficial parotid, excision:
- Basal cell adenocarcinoma (see comment)
- Comment: The sections show a partly encapsulated tumor composed of anastomosing tubules and ductules with a prominent hyaline stroma. In most areas, there appears to be a double cell layer, with CK7 positive pale cells surrounded by SMA positive darker cells abutting the hyaline stroma. There is invasion of adipose tissue with an extension close to the parotid gland. No perineural invasion was found. The tumor is 0.8 mm from the nearest inked margin of excision. Mitoses are sparse.

Differential diagnosis

Basal cell adenoma:
- Well circumscribed, no invasion / infiltration into adjacent tissues
- Multifocal or membranous type can simulate invasion
- Nuclear beta catenin+
Pleomorphic adenoma:
- Presence of myxoid / chondromyxoid matrix
- Plasmacytoid and spindled cells frequent
- Epithelial / myoepithelial cells blend into stroma; BCAC has abrupt border with matrix
- Multinodular growth may simulate invasion
Canalicular adenoma:
- May be multifocal but nearly always involves upper lip / minor salivary gland
- Beaded chains of short columnar cells
- No basement membrane material
- S100+, SOX10+, GFAP+ (only at periphery)
- p63-, actin-
Adenoid cystic carcinoma:
- Cribriform patterns and punched out spaces surrounded by small cells with minimal cytoplasm
- Palisading not prominent
- Lacks large pale and small dark cells common in BCAC
- Coarse nuclear chromatin, high mitotic rate
- Of note: basal cell adenocarcinoma may occasionally show MYB overexpression (J Oral Pathol Med 2017;46:798)
Basaloid squamous cell carcinoma:
- High grade neoplasm, usually oral or sinonasal tract rather than salivary glands
- Basaloid, comedonecrosis and hyaline type material seen in both
- Abrupt squamous differentiation
Polymorphous adenocarcinoma:
- Occurs in minor salivary glands only
- Polymorphous architectural patterns
- Monotonous population of single cell type neoplastic proliferation
- Cells have open, vesicular nuclear chromatin with small nucleoli (not basaloid cells)
- Perineural invasion
- Immunohistochemistry highlights only single cell population (not biphasic)
Skin basal cell carcinoma:
- Skin tumors may metastasize to intraparotid lymph nodes or directly invade parotid
- Palisading, basaloid architecture, necrosis and increased mitotic figures
- Lacks biphasic appearance and myoepithelial cells
- BerEP4+

Additional references

Chan: WHO Classification of Head and Neck Tumours, 4th Edition, 2017, Thompson: Head and Neck Pathology, 3rd Edition, 2018

Board review style question #1

A 70 year old man presents with a slow growing, painless lesion in the parotid. On gross examination, the lesion is well circumscribed, with a cream, partly cystic lesion. Which of the following is correct?

Cytology is helpful in the diagnosis of this lesion
Invasion distinguishes this lesion from its benign counterpart
Molecular features are often used to differentiate this tumor from mimics
This low grade neoplasm frequently metastasizes to the lung

Board review style answer #1

B. Invasion distinguishes this lesion from its benign counterpart. The tumor is a basal cell adenocarcinoma, a rare, indolent malignant counterpart to basal cell adenoma. Evidence of invasion is essential for diagnosis.

Comment Here

Reference: Basal cell adenocarcinoma

Basal cell adenoma

Table of Contents

Definition / general

Benign salivary tumor composed of nests and cords of small basaloid cells with inner ductal epithelial cells
First described by Kleinasser and Klein in 1967 (Arch Klin Exp Ohren Nasen Kehlkopfheilkd 1967;189:302)
Initially included in the group of monomorphic adenoma (unfavored term) along with canalicular adenoma; in 1991, recognized as an independent entity in the second edition of the Salivary Gland Tumors Classification by the WHO

Essential features

Rare benign epithelial tumor of the salivary gland, displaying monomorphic basaloid cells without a myxochondroid component

Terminology

Also called monomorphic adenoma, basaloid salivary gland adenoma
Membranous adenoma also called dermal analogue tumor

ICD coding

ICD-O: 8147/0 - basal cell adenoma
ICD-10: D11.9 - benign neoplasm of major salivary gland, unspecified

Epidemiology

1 - 3.7% of all salivary gland tumors (Med Oral Patol Oral Cir Bucal 2006;11:E206)
Frequent in elderly adults between fifth and seventh decades; uncommon in young adults (J Dent (Shiraz) 2015;16:291)
Female predilection (2:1) except for the membranous type, which bears an equal M:F distribution (J Laryngol Otol 1989;103:756)
Membranous type basal cell adenomas can associate with Brooke-Spiegler syndrome (Eur J Dermatol 2004;14:139)

Sites

> 80% arise in the major salivary glands, mostly parotid gland (mainly in the superficial lobe), followed by the submandibular gland (5%) and 6% in intraoral location with upper lip being the most common site, followed by the buccal mucosa

Pathophysiology

Intercalated duct lineage (IDL) could be precursor; IDL, tubular basal cell adenoma (BCA) and nontubular BCA form a continuum of lesions in which IDLs are related closely to tubular BCA (Histopathology 2014;64:880)
According to some studies, myoepithelial or intercalated duct lineage might be the origin of BCA (J Maxillofac Oral Surg 2010;9:289)
Epithelial tumor cells of pleomorphic adenoma (PA) may form BCA through certain differentiation mechanisms; basal cells of the epithelium of PA possess reserve cell functions, through epithelial - mesenchymal transdifferentiation, forming the predominant basaloid cell population of basal cell adenoma (Auris Nasus Larynx 2006;33:97)

Etiology

Etiology and risk factors for BCA are unknown
Membranous type basal cell adenomas can associate with Brooke-Spiegler syndrome (multiple familial trichoepithelioma) caused by CYLD mutation (Eur J Dermatol 2004;14:139)

Clinical features

Rare, 1 - 2% of epithelial tumors of salivary glands; 2% of benign salivary gland tumors
Solitary or part of turban tumor, Brooke-Spiegler syndrome
Usually adults, 67% female, mean age 58 years
Rarely is congenital and resembles embryoma
Almost all arise in parotid gland, with submandibular gland being a distant second
Usually appears as a firm and mobile, slow growing, asymptomatic mass
Low recurrence rate except for membranous type
Rarely transforms into malignancy; more likely if membranous type (4% malignant transformation)
Usually some myoepithelial differentiation using immunostains (Arch Pathol Lab Med 2000;124:401)
Membranous type may present as multiple nodules; may coexist with dermal cylindromas or trichoepitheliomas

Diagnosis

Diagnosis is established by the histological study; generally, biopsy is accepted as the most accurate method to obtain the diagnosis, although some authors advocate for fine needle aspiration if physical access to the tumor is available

Radiology description

Nonspecific
Oval to round tumor with smooth distinct margin and high incidence of internal macro or microcysts
Soft tissue components with relative high attenuation on unenhanced CT and enhance well on contrast enhanced CT (AJR Am J Roentgenol 2007;189:W254, AJNR Am J Neuroradiol 2012;33:434)
Relatively homogenous signal intensity of the solid portion; tumor capsule is low signal intensity on T2 weighted images (Dentomaxillofac Radiol 2010;39:349)

Radiology images

Images hosted on other servers:

Basal cell adenoma in left parotid gland

Basal cell adenoma versus pleomorphic adenoma of the parotid gland

Prognostic factors

Recurrence rate ~ 2% on average; almost nonexistent for the solid and trabecular - tubular variants
Membranous type most commonly associated with recurrence (25 - 37%), likely due to the multicentricity rather than because of true recurrences (Acta Otolaryngol 1998;118:588)
Malignant transformation is more common in the membranous type (4%) than in the other types; total parotidectomy rather than superficial parotidectomy is proposed in the membranous type of BCA (J Oral Maxillofac Pathol 2016;20:142, Acta Otolaryngol 1998;118:588)

Case reports

22 year old man with cytological diagnosis of basal cell adenoma (J Oral Maxillofac Pathol 2015;19:106)
43 year old woman with basal cell adenoma of sublingual gland (Ann Otol Rhinol Laryngol 2003;112:1066)
51 year old man with 6 cm parotic mass of 8 years' duration (Case #375)
54 year old woman with basal cell adenoma extending to skull base and mastoid (World J Clin Cases 2019;7:1351)
55 year old woman with basal cell adenoma of palate (J Dent (Shiraz) 2015;16:291)
59 year old Japanese man with basal cell adenoma of upper lip (Case Rep Med 2014;2014:795356)
65 year old woman with bilateral parotid basal cell adenoma (J Oral Maxillofac Surg 2010;68:179)
19 cases of basal cell adenoma with cribriform pattern (Ann Diagn Pathol 2014;18:5)

Treatment

Excision: surgical resection with a cuff of normal salivary tissue as the main treatment

Gross description

Small (mostly < 5 cm), round or oval, encapsulated nodule (Br J Radiol 2005;78:642)
Membranous subtype often nonencapsulated, multicentric and multilobular (Pilch: Head and Neck Surgical Pathology, 1st Edition, 2001)
Usually brownish appearance; typically uniform and solid, without necrosis; can be cystic (Arch Otolaryngol 1974;99:84)

Frozen section description

Adequate sectioning including the capsule should be made on frozen section

Microscopic (histologic) description

2 types of tumor cells:
- Basaloid cells with basal cells or myoepithelial phenotype
- Luminal cells
Fibrocellular stroma can be present
4 histologic patterns: mixture of at least 2 patterns is common (Ellis: Surgical Pathology of the Salivary Glands, 1st Edition, 1991)
- Solid pattern: most common, basaloid cells are present in the form of solid masses which may show peripheral palisading
- Trabecular pattern: narrow or broad trabeculae which may get interconnected with each other creating a reticular pattern
- Tubular pattern: numerous tubules consisting of a central lumen and an outer single layer or double layered lining of cuboidal and basaloid cells is seen; the lumen often contains an eosinophilic secretion / mucin which is PAS positive
- Membranous types: histologically identical to dermal cylindroma, eosinophilic hyaline membranes separating cell nests; BCA with greater than 50% membranous pattern should be designated as membranous type
Cyst formation is common and can be a main histopathologic feature of basal cell adenoma
Occasionally has acinar cells, squamous whorls or keratinization
No invasion, no perineurial invasion, no chondromyxoid matrix

Microscopic (histologic) images

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

Solid pattern

Trabecular pattern

Tubular pattern

Membranous type

Virtual slides

Images hosted on other servers:

Basal cell adenoma with oncocytic features

Cytology description

Monomorphic basaloid cels with round nuclei and scant cytoplasm (Diagn Cytopathol 2007;35:85)
Irregular nests and trabecula, tubular or peripheral palisading architecture
Benign mimickers: cellular pleomorphic adenoma (with chondromyxoid stroma) and myoepithelioma
Malignant mimickers: basal cell adenocarcinoma and basaloid squamous cell carcinoma (with significant cytological atypia, mitosis and necrosis) (Am J Clin Pathol 2002;118:S100)
Membranous basal cell adenoma simulates adenoid cystic carcinoma (J Cytol 2018;35:55)

Cytology images

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

Diff-Quik stain

Pap stain

Membranous type Pap stain

Positive stains

Ductal cells: keratin, alpha-1-antichymotrypsin, CEA, EMA, CD117 (Pathol Res Pract 1991;187:145)
Basaloid cells: vimentin, actin, calponin, S100, p63, GFAP
Spindle cell in the stroma is positive for S100, negative for p63
Can be positive for BCL2 and nuclear beta catenin (Am J Surg Pathol 2016;40:1143)

Electron microscopy description

Myoepithelial cells show microfilaments, desmosomes, junctional complexes, reduplicated basal lamina (Dardick: Salivary Gland Tumor Pathology, 1st Edition, 1996)
Ductal cells show microvilli, tight junctions, desmosomes (Acta Otorhinolaryngol Ital 2005;25:150)

Molecular / cytogenetics description

CTNNB1 mutations are common in BCA, especially those with tubular or tubulotrabecular patterns (Am J Surg Pathol 2016;40:1143)
CYLD1 mutations and loss in sporadic and Brooke-Spiegler syndrome associated basal cell adenoma (Mod Pathol 2018;31:1064, Am J Surg Pathol 2002;26:778)

Sample pathology report

Parotid, left, parotidectomy:
- Basal cell adenoma, 1.6 cm, membranous type, margins negative for tumor

Differential diagnosis

Adenoid cystic carcinoma:
- Infiltrative growth pattern, perineural invasion
Basal cell adenocarcinoma:
- Invasive growth pattern
Pleomorphic adenoma:
- Chondromyxoid stroma blended with epithelial cells, BCA with prominent myoepithelial derived stroma and stroma in BCA does not blend into the epithelial nests
Canalicular adenoma:
- Double columns of cells forming anastomosing canaliculi with paucicellular stroma

Additional references

El-Naggar: WHO Classfication of Head and Neck Tumours, 4th Edition, 2017, Wenig: Atlas of Head and Neck Pathology (Atlas of Surgical Pathology), 3rd Edition, 2015

Board review style question #1

A 56 year old woman presents with a nodule close to the left ear. Imaging reveals a well circumscribed 1.6 cm nodule in parotid gland. Biopsy findings are shown in the picture above. Which of the following statements is true about this entity?

Cystic change is uncommon
Due to the high recurrence rate, total excision is required for all of these neoplasms
It is one of the most common neoplasms in the salivary glands
It occurs more often in younger patients
It can be associated with Brooke-Spiegler syndrome

Board review style answer #1

E. It can be associated with Brooke-Spiegler syndrome. Brooke-Spiegler syndrome is a rare genetic disease characterized as an inherited skin tumor predisposition syndrome presenting with skin appendage tumors (cylindromas, spiradenomas and trichoepitheliomas) and salivary gland tumor. Some patients can have a membranous basal cell adenoma of the salivary gland. It is caused by germline mutations in the CYLD gene (16q12-q13).

Comment Here

Reference: Basal cell adenoma

Board review style question #2

Which of the following markers is most useful to differentiate tubular / trabecular predominant basal cell adenoma from pleomorphic adenoma?

Beta catenin
Calponin
CMA
p63
S100

Board review style answer #2

A. Beta catenin. Jo et al. reported that nuclear beta catenin staining can be present in 83% of basal cell adenomas. All adenoid cystic carcinomas (0/20) and pleomorphic adenomas (0/20) were negative. 4 of 5 basal cell adenomas had exon 3 CTNNB1 mutations (Am J Surg Pathol 2016;40:1143).

Comment Here

Reference: Basal cell adenoma

Canalicular adenoma

Table of Contents

Definition / general

1942 (McFarland) first description; variant of monomorphic / basal cell adenoma (Am J Med Sci 1942;203:502)
1991 identified as separate entity in the WHO classification (Seifert: Histological Typing of Salivary Gland Tumours, 2nd Edition, 1991)
Benign epithelial neoplasm composed of cubocolumnar cells disposed in branching and interconnecting cords and associated with a paucicellular, vascular stroma
1 - 3% of salivary gland tumors (Int J Oral Maxillofac Surg 2005;34:533, Oral Oncol 2008;44:407)
4 - 6% of minor salivary gland tumors (Oral Oncol 2007;43:463, Head Neck Pathol 2015;9:181, Oral Surg Oral Med Oral Pathol 1988;66:323, Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:230)

Essential features

Monotonous, benign epithelial neoplasm; no basal / myoepithelial layer
Most frequently located in the minor salivary glands
May be multifocal
Treatment by surgical resection

Terminology

Retired terminology: canalicular tumor; canalicular mixed tumor; monomorphic adenoma, canalicular type; cystic adenoma; adenomatosis of accessory salivary glands

ICD coding

ICD-O: 8149/0 - canalicular adenoma

Epidemiology

Adults; female gender predominance (Oral Surg Oral Med Oral Pathol 1984;57:181, Head Neck Pathol 2015;9:181)
Peak seventh decade; usually ages 50+ years
Non-Asian population (Adv Ther 2019;36:1950)

Sites

Upper lip (80%), followed by buccal mucosa, lower lip, hard and soft palate (Head Neck Pathol 2015;9:181)
Extremely rare in major salivary glands (parotid); consider HMGA2-WIF1 fusion pleomorphic adenoma in differential diagnosis

Pathophysiology

Derives from terminal ducts of salivary glands; intralobular ducts resemble intercalated ducts (Head Neck Pathol 2015;9:181)

Etiology

Unknown

Clinical features

Painful or painless, mucosal ulceration, tumor duration months to years (slow growing) (Head Neck Pathol 2015;9:181)
Swelling; tumor may be multifocal, bilateral (Oral Surg Oral Med Oral Pathol 1982;53:375, Br J Oral Maxillofac Surg 1995;33:299, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87:346)
Discomfort (with / without prothesis), pressure (J Craniomaxillofac Surg 2017;45:1754)

Diagnosis

Clinical examination: movable, well circumscribed nodule (0.5 - 2 cm); unique or multiple nodules; possibly bilateral; exophytic mass or swelling; bluish or ulcerated mucosa (J Craniomaxillofac Surg 2017;45:1754)
Clinical differential diagnosis: mucocele, thrombosed vessel, lipoma, salivary gland tumor (Head Neck Pathol 2015;9:181)

Laboratory

Lack of specific laboratory tests

Radiology description

Ultrasonography: relatively homogeneous, poorly echoic mass, containing a liquid region with relatively low viscosity (J Oral Maxillofac Surg Med Pathol 2020;32:525)
Magnetic resonance imaging / MRI (J Oral Maxillofac Surg Med Pathol 2020;32:525):
- Axial T1 weighted MRI: isointense mass
- T2 weighted MRI: increased signal intensity

Radiology images

Images hosted on other servers:

Ultrasound examination (1B) and MRI (1C)

Prognostic factors

Favorable prognosis: complete resection
Persistence due to multifocality may be indistinguishable from recurrence (Head Neck Pathol 2015;9:181)
Recurrence rates: 3% recurrence, 5% recurrence after surgery

Case reports

61 year old woman with synchronous polymorphous adenocarcinoma (Head Neck Pathol 2018;12:145)
78 year old woman with synchronous, multiple, bilateral tumors (Clin Exp Dermatol 2009;34:e587)

Treatment

Surgical excision; although multifocality may suggest recurrence (Head Neck Pathol 2015;9:181)

Clinical images

Images hosted on other servers:

Oral nodule

Oral swelling / tumefaction / lesion

Oral lesion after resection, postresection zone

Oral nodule

Nodules (lip)

Oral nodules / lesions

Gross description

Often encapsulated; may be multifocal
Tumor may be resected as 1 or fragmented specimens
On cut surface: homogeneous or cystic spaces
Reference: Head Neck Pathol 2015;9:181

Gross images

Images hosted on other servers:

2 resected nodules

Resected specimen

Resected specimen / nodule

Resected lesion

Resected nodule

Frozen section description

See Microscopic (histologic) description

Microscopic (histologic) description

Tumors may be single or multifocal
Bilayered strands or ribbons or anastomosing cords or branching tubules
Canalicular to cystic spaces between the cell strands; trabecular features
Lack of an outer layer of myoepithelial cells
Beading pattern, club ended cords
May infiltrate capsule and show extracapsular tumor islands (including in the normal salivary gland / multiple tumors)
Often cystic change
Tumoral columnar or cuboidal cells, foci of basaloid cells
Amphophil to eosinophilic cytoplasm, apocrine / oncocytic
Round to elliptical, uniform nuclei, focally nucleoli, basophilic chromatin, rare to absent mitoses
Mucous / mucinous metaplasia (Head Neck Pathol 2015;9:181)
Pigmented cells
Lacks or has exceptional necrosis (Head Neck Pathol 2015;9:181)
Microliths, tyrosine crystals, morules and squamous balls (intraluminal) (J Craniomaxillofac Surg 2017;45:1754, Head Neck Pathol 2015;9:181, Histopathology 1999;35:502)
Well vascularized, loose stroma; possibly sclerotic; perivascular eosinophil cuffs
Luminal or stromal histiocytes (foamy, lipofuscin, hemosiderin), luminal hemorrhage, degenerated / infarcted stroma (Head Neck Pathol 2015;9:181)
Malignant transformation not reported; lack of atypical figures (Head Neck Pathol 2015;9:181)
Occasionally reported as collision tumors or hybrid tumors (Eur J Cancer B Oral Oncol 1996;32B:251)

Microscopic (histologic) images

Contributed by Adriana Handra-Luca, M.D., Ph.D. (slides courtesy of Emmanuelle Vaz, M.D.)

Cystic tumor zone

Solid tumor zone

Microscopy

Canalicular pattern

Alcian blue stain

BCL2 expression

Virtual slides

Images hosted on other servers:

Canalicular adenoma

Cytology description

FNA smears (hematoxylin, eosin and May-Grünwald-Giemsa stains) pseudopapillary clusters, oval, spindle basaloid cells, scant cytoplasm or eosinophilic, isolated cells, bland nuclear chromatin, no visible nucleoli, no chondroid or myxoid substance (Head Neck Oncol 2014;6:32)

Cytology images

Images hosted on other servers:

Cytology of parotid case

Slides with cytology material

Positive stains

S100, AE1 / AE3, CK19
Pancytokeratin (heterogeneous intensity), CK7, CK8, CK13, CK14 basally (Gerodontology 2014;31:320)
Focal GFAP; distinctive linear immunoreactive pattern of GFAP among cells in proximity to connective tissue interface (Gerodontology 2014;31:320)
CD117 (Pol J Pathol 2013;64:71)
BCL2
Varied p63 expression, nuclear p63 in squamoid foci, lack of p63+ duct surrounding cells (Appl Immunohistochem Mol Morphol 2016;24:501, J Craniomaxillofac Surg 2017;45:1754, Adv Ther 2019;36:1950, Am J Surg Pathol 2021 Jul 29 [Epub ahead of print])
Nuclear CAM 5.2, nuclear SOX10, nuclear and cytoplasmic p16, vimentin variably positive (J Craniomaxillofac Surg 2017;45:1754)
Squamous balls: p16 and CK5/6 positive
Heterogeneous, moderate to strong cytoplasmic WT1 (periphery of ribbon-like structures); in microadenomatous foci, associated with cuboidal cells (Pathol Res Pract 2014;210:726)
Stroma: blue on Alcian blue / PAS stain and CD15+ (Adv Ther 2019;36:1950)

Negative stains

E-cadherin
Myoepithelial markers (alpha smooth muscle actin, smooth muscle myosin heavy chain, calponin)
p40 (Head Neck Pathol 2015;9:181)
DOG1 (Ann Diagn Pathol 2019;43:151408)
CEA and EMA variable or negative (Adv Ther 2019;36:1950)

Electron microscopy description

2 rows of cells (tall columnar cells surrounding the canalicular lumina and conical cells situated between columnar cells, with direct contact with stromal connective tissue); interdigitating cells
Canalicular lumen: minimum amount of cell debris; no mucoid material
Small number of desmosomes
Ovoid nuclei, moderately prominent nucleoli, patchy condensation of chromatin
Reference: Cancer 1980;46:552

Electron microscopy images

Images hosted on other servers:

Apical zone of columnar cells

Basal zone of canalicular cells

Zone of 2 parallel rows of tumor cells

Basal zone of tumor cells

Molecular / cytogenetics description

1/21 cells: a doubled normal complement (Hereditas 1996;124:105)
No fusions identified to date (Am J Surg Pathol 2021 Jul 29 [Epub ahead of print])

Sample pathology report

Minor salivary gland, nodule resection:
- Canalicular adenoma (1.5 cm); excised

Differential diagnosis

Adenocarcinoma, NOS:
- Tumoral glands and duct-like structures
- Infiltrative growth pattern
- Nuclear atypia, mitoses
- Presence of vascular emboli, perineural invasion
Adenoid cystic carcinoma:
- Ductal and modified myoepithelial cells with hyperchromatic angular nuclei
- Hyalinized stroma
- Destructive infiltration; cribriform / tubular pattern
- Lack of capillaries in the stroma
Pleomorphic adenoma (with canalicular-like pattern) (Adv Ther 2019;36:1950, Am J Surg Pathol 2021 Jul 29 [Epub ahead of print]):
- Presence of myxoid, chondroid mesenchymal tumor component
- HMGA2-WIF1 described
Polymorphous low grade adenocarcinoma:
- Infiltrative growth pattern
- Small tumor cells
- Papillary pattern
- Neurotropism
- Vimentin negative
- Lack of linear GFAP at the tumor / connective tissue interface
Basal cell adenoma:
- Majority of basaloid cells
- Myoepithelial differentiation (expression of smooth muscle actin)
- Stroma: more collagenous
- Squamous differentiation
- LEF1 and beta catenin nuclear positive (Hum Pathol 2015;46:255)
- p63 positive

Additional references

Board review style question #1

Which of the following is true about salivary gland canalicular adenoma?

Cannot be multifocal
Is a benign tumor
Is rare in minor salivary glands
Lacks stromal tissue

Board review style answer #1

B. Is a benign tumor

Comment Here

Reference: Canalicular adenoma

Board review style question #2

Which of the following is true about salivary gland canalicular adenoma?

Is a type of adenocarcinoma
Is often associated with lymph node metastases
May contain squamous balls
May show vascular emboli

Board review style answer #2

C. May contain squamous balls

Comment Here

Reference: Canalicular adenoma

Carcinoma ex pleomorphic adenoma

Table of Contents

Definition / general

Epithelial or myoepithelial malignancy developing from primary or recurrent pleomorphic adenoma

Essential features

Identification of both malignant and benign components is essential for diagnosis; in cases where the benign component has been obliterated by carcinoma, a history of pleomorphic adenoma at the site must be documented
5% of pleomorphic adenomas undergo malignant transformation, with the highest risk associated with recurrent or longstanding pleomorphic adenoma
Typical clinical presentation is a longstanding palpable mass in the parotid region that has undergone recent rapid growth
Salivary duct carcinoma and adenocarcinoma NOS are the most frequently encountered malignant components; other malignant components can be myoepithelial carcinoma or epithelial myoepithelial carcinoma
Main predictors of outcome are patient age, tumor diameter, degree of capsule invasion, histological subtype of malignant component and lymph node or distant metastases

Terminology

Malignant mixed tumor (not recommended due to possible confusion with carcinosarcoma)
Carcinoma ex mixed tumor

ICD coding

ICD-O: 8941/3 - carcinoma in pleomorphic adenoma

Epidemiology

Uncommon malignancy; annual incidence of 0.17 tumors per 1 million people (Pathol Annu 1993;28 Pt 1:279)
11.6% of all malignant salivary gland neoplasms
5% of pleomorphic adenomas undergo malignant transformation
Peak incidence in seventh decade of life (range: 17 - 97 years) (Am J Otolaryngol 2019;40:102279)
Slight male predominance (Am J Otolaryngol 2019;40:102279)

Sites

Parotid gland (77%), submandibular gland (18%); other major salivary glands less common (Am J Otolaryngol 2019;40:102279)
Rare sites include oral cavity, pharynx, lacrimal gland, trachea, nasal cavity (Laryngoscope 2003;113:940, Histopathology 2007;51:868, Head Neck Pathol 2011;5:405)

Pathophysiology

Incompletely understood
Concept of stepwise acquisition of genetic aberrations with associated progression
Earliest change is malignant transformation of ductal epithelial cells associated with dysfunctional p53 protein (Histopathology 2007;51:362)
Subsequent progression to intracapsular carcinoma, minimally invasive carcinoma and widely invasive carcinoma (Histopathology 2011;59:741)
- Associated with:
  - HER2 amplification (Histopathology 2012;60:E131)
  - Loss of PLAG1 expression (Hum Pathol 2016;57:152)
Myoepithelial carcinomas may progress by different mechanisms (Histopathology 2011;59:741)

Etiology

Unknown

Clinical features

Most common presentation is palpable mass in parotid region (Ear Nose Throat J 2019;98:504)
May present as a sudden increase in size of a preexisting lump, pain or facial paresis / paralysis
Long history of a mass prior to sudden increase in size is common, suggesting that long delays in treatment of pleomorphic adenoma increase the likelihood of malignant transformation (Acta Oncol 2009;48:132)
≤ 25% of patients have a history of previously treated pleomorphic adenoma (Plast Reconstr Surg 2005;116:1206)
Advanced cases may present with skin ulceration or dysphagia (Head Neck 2001;23:705)

Diagnosis

Definitive diagnosis rests on microscopic analysis with documentation of both benign pleomorphic adenoma and malignant components
Sudden increase in size of a longstanding pleomorphic adenoma can raise clinical suspicion of carcinoma ex pleomorphic adenoma

Radiology description

MRI is superior to CT as it is most sensitive in detecting malignancy and allows better delineation of tissue planes and infiltrative edges (Head Neck Pathol 2012;6:1)
Characteristic MRI finding is the presence of both encapsulated and invasive components
Encapsulated (pleomorphic adenoma) component:
- Shows a variety of signal intensities on MRI, reflecting the variability in architectural and cytomorphologic features (AJNR Am J Neuroradiol 2008;29:865)
Invasive component:
- Hemorrhage, necrosis, irregular margin or infiltration of surrounding tissues
- Low to intermediate signal intensities on T2 weighted images (Acta Radiol 2012;53:303)
Diffusion weighted images may help differentiate between benign and malignant components (AJNR Am J Neuroradiol 2008;29:865)
PET signal avidity is inconsistent in salivary gland tumors and therefore not recommended (Head Neck 2019;41:269)

Radiology images

Images hosted on other servers:

Axial T2 weighted and ADC mapping

Salivary duct carcinoma ex PA, axial T2 weighted

Prognostic factors

Noninvasive or minimally invasive carcinoma ex pleomorphic adenoma have exceptionally good prognosis (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;81:655)
Older age, male gender, tumor diameter (> 40 mm), degree of capsule invasion, lymph node metastasis, histological subtype are independent predictors of disease specific survival (Am J Otolaryngol 2019;40:102279, Head Neck 2017;39:2416, Oral Surg Oral Med Oral Pathol Oral Radiol 2016;122:598)
Some studies suggest worse outcomes when the malignant component is myoepithelial carcinoma (Hum Pathol 2010;41:927)
Histological grade, invasiveness, lymph node involvement and perineural invasion are associated with distant metastases (World J Surg Oncol 2013;11:180)
Prognosis for carcinoma ex recurrent pleomorphic adenoma is significantly worse than the prognosis for carcinoma ex primary pleomorphic adenoma (Histopathology 2011;59:741)
Lymph node metastases may occur in 30% of cases (J Surg Oncol 2021;123:446)
Distant metastases may occur in 4% of cases (J Surg Oncol 2021;123:446)

Case reports

28 year old woman presents with a painful growing swelling of the left face (Case Rep Otolaryngol 2020;2020:8325374)
40 year old man with an 8 year history of right parotid swelling presents with recent growth (J Cancer Res Ther 2018;14:706)
60 year old woman with a remote history of a left buccal lesion presents with a growing buccal mass (Clin Case Rep 2019;7:1994)
62 year old man presents with longstanding left temple swelling that has increased in size over several months (Case Rep Oncol Med 2020;2020:1790106)
64 year old man with a history of surgery for pleomorphic adenoma presents with a mass in the central face (Head Neck Pathol 2021 Jan 4 [Epub ahead of print])

Treatment

Successful treatment requires input from a multidisciplinary team (Head Neck 2019;41:269)
Surgical excision with negative surgical margins is the mainstay of treatment
Extent of surgery depends on the size and location of the tumor, status of the adjacent cervical nodal basins and relationship to facial nerve, mandible, ear canal and lateral temporal bone
Adjuvant radiotherapy should be considered in some cases, including (Int J Radiat Oncol Biol Phys 2005;61:103, Otolaryngol Head Neck Surg 2019;160:1048):
- Positive surgical margins
- Advanced stage
- Bone, perineural or lymphovascular invasion
- Involved cervical lymph nodes
Adjuvant chemotherapy may be required in cases with distant metastases

Gross description

Gross appearance depends on the proportion of pleomorphic adenoma to carcinoma (Hum Pathol 2001;32:596, Head Neck 2001;23:705)
If pleomorphic adenoma is the dominant component, it may appear circumscribed and gray, glistening or white
If pleomorphic adenoma is not apparent, it may be a poorly circumscribed irregular infiltrative mass involving adjacent structures
Malignant component can show necrosis or hemorrhage

Gross images

Contributed by Ruta Gupta, M.B.B.S., M.D.

Parotid mass

2 distinct tumor components

Parotid mass involving skin

Frozen section description

Routine use of frozen section for salivary gland tumors is not appropriate (Head Neck 2019;41:269)
May be useful in some settings (e.g. in cases of facial nerve sacrifice to ensure negative nerve stump margin) (Head Neck 2019;41:269)

Microscopic (histologic) description

Must have either:
- Microscopic confirmation of both benign and malignant components or
- Microscopic diagnosis of carcinoma (see below) and previously documented pleomorphic adenoma at the site
Stratification based on extent of capsule invasion:
- Intracapsular: good prognosis
- Minimally invasive: generally considered as < 1.5 mm
  - Poorly defined category
  - Extent of invasion may be less relevant in intrinsically aggressive carcinomas, such as salivary duct carcinoma (Histopathology 2014;65:854)
  - Requires histologic evaluation of the entire lesion and possible examination through multiple deeper levels / sections
- Widely invasive: ≥ 1.5 mm
Carcinomatous component may be salivary duct carcinoma, myoepithelial carcinoma or epithelial myoepithelial carcinoma
If adenocarcinoma:
- Often high grade
- Salivary duct carcinoma and adenocarcinoma NOS are most common
- Other types of differentiation may be seen, including squamous, mucoepidermoid and polymorphous adenocarcinoma
If myoepithelial carcinoma, it is often low grade
Mixture of subtypes may also occur (Int J Oral Maxillofac Surg 2009;38:1116)

Microscopic (histologic) images

Contributed by Ruta Gupta, M.B.B.S., M.D.

2 distinct microscopic components

Interface of distinct components

Infiltrative component

DCIS-like morphology

HER2 IHC

Androgen receptor IHC

Cytology description

Pleomorphic adenoma component:
- Sheets or cohesive groups of ductal cells
- Myoepithelial cells individually dispersed or in loose clusters
- Dense fibrillary metachromatic matrix is the most characteristic finding: appears magenta in Romanowsky type stains
Carcinomatous component:
- Pleomorphic, hyperchromatic cells, clumped chromatin, high N/C ratio (Cytojournal 2015;12:7)
- Necrotic background
- Features specific to the type of carcinoma may be seen (e.g. mucous cells, squamoid cells)
Fine needle aspiration has low sensitivity in the diagnosis of carcinoma ex pleomorphic adenoma, likely due to sampling error (Plast Reconstr Surg 2005;116:1206)
Even when a diagnosis is possible, cannot differentiate between noninvasive and invasive tumors (Cytojournal 2015;12:7)
Carcinomatous component is more likely to be identified on FNA if it is high grade and extensive (Diagn Cytopathol 2020;48:149)

Positive stains

Pleomorphic adenoma:
- Ductal cells: pancytokeratin, CK7, CK18, EMA, CEA
- Myoepithelial cells: SMA, calponin, muscle specific actin, SMMHC, p63, CK14, GFAP, S100
Carcinoma ex pleomorphic adenoma:
- Immunohistochemistry depends on the classification of the malignant component
- Salivary duct carcinoma: CK7, EMA, HER2, AR, p53 overexpressed in 60% of cases (Am J Surg Pathol 2015;39:744)
- Adenocarcinoma NOS: no useful stains
- Myoepithelial carcinoma: calponin, p63, p40, SMMHC (see above)
- Mucoepidermoid carcinoma: CK7, CK5/6 (squamoid cells), p63 (squamous cells), mucin stains (mucous cells)
Ki67 is useful to highlight benign and malignant components:
- Labels < 5% of cells in pleomorphic adenoma, even in recurrences (Laryngoscope 2004;114:158)
- Can be very high in malignant component
HMGA2 immunohistochemistry has high specificity but low sensitivity for carcinoma ex pleomorphic adenoma (Histopathology 2017;71:511)

Negative stains

ER, PR, Melan A, HMB45, desmin

Molecular / cytogenetics description

Gene rearrangements or amplifications are seen in both pleomorphic adenoma and carcinoma ex pleomorphic adenoma involving:
- PLAG1 (Head Neck Pathol 2012;6:328)
- HMGA2 (Hum Pathol 2015;46:26)
- HMGIC and MDM2 (Am J Pathol 2002;160:433)
HER2 amplification was found in 39% of carcinoma ex pleomorphic adenoma (Histopathology 2012;60:E131)
TP53 mutations were detected in 37% of intracapsular carcinoma ex pleomorphic adenoma (Histopathology 2007;51:362)
Copy number gains in 9p and 22q have been detected in carcinoma ex pleomorphic adenoma of lacrimal gland (Ophthalmology 2014;121:1125)

Sample pathology report

Carcinoma ex pleomorphic adenoma (see comment)
- Comment: In large areas, the tumor shows a sclerotic nodule. Several infiltrative glands and ducts are seen extending from the periphery of this sclerotic nodule into the adjacent residual salivary gland and attached skeletal muscle. Occasional glands show internal cribriform architecture with Roman bridges and arches and resemble ductal carcinoma in situ of the breast. The glands are lined by cells with an apocrine appearance with apical snouts, moderate eosinophilic cytoplasm and enlarged nuclei with distinctive nucleoli. Mitoses are present. Multiple foci of lymphovascular involvement are present. Perineural involvement is seen. The tumor is present at the margin of resection. In addition, 5/25 lymph nodes in the accompanying neck dissection show metastatic carcinoma. History of a longstanding nodule in the region of the parotid gland with sudden increase in size and new onset facial palsy is noted. The clinical history and the morphologic features support a diagnosis of a carcinoma ex pleomorphic adenoma.

Differential diagnosis

Recurrent pleomorphic adenoma:
- Commonly multinodular; may show numerous disconnected nodules with no obvious capsule, simulating invasion (Laryngoscope 2004;114:158)
- History of incompletely resected or previously recurrent pleomorphic adenoma is a clue to the diagnosis
Pleomorphic adenoma with pseudopodia:
- Small protrusions of tumor beyond the tumor capsule, found in up to a quarter of cases and without clinical consequence unless incompletely excised (Laryngoscope 2001;111:2195, Cancer 1998;82:617)
- Must not be confused with malignant transformation
De novo carcinoma:
- Identification of residual pleomorphic adenoma (or a history of recurrent / incompletely excised pleomorphic adenoma) is essential for diagnosis of carcinoma ex pleomorphic adenoma
- PLAG1 and HMGA2 genetic aberrations are seen in carcinoma ex pleomorphic adenoma but not its malignant de novo counterparts (Hum Pathol 2015;46:26)
Metastatic carcinoma:
- History of other primary head and neck malignancy
- Absence of pleomorphic adenoma component

Board review style question #1

Regarding carcinoma ex pleomorphic adenoma, which of the following statements is true?

Fine needle aspiration is a highly sensitive technique for the diagnosis of this entity
Malignant transformation is equally likely to occur in a primary pleomorphic adenoma as it is in recurrent pleomorphic adenoma
Not always possible to identify the preexisting pleomorphic adenoma macroscopically
Submandibular gland is the most common site of origin

Board review style answer #1

C. It is sometimes not possible to identify the pleomorphic adenoma macroscopically or even microscopically; this is one of the reasons why thorough sampling is required. This is because the malignant component may overgrow and subsume the benign component. In such circumstances, a history of pleomorphic adenoma, particularly if longstanding or recurrent, is vital for correct diagnosis. Like pleomorphic adenoma, carcinoma ex pleomorphic adenoma arises most commonly in the parotid gland. Recurrent pleomorphic adenoma has a higher risk of malignant transformation than primary pleomorphic adenoma. Fine needle aspiration has low sensitivity in the diagnosis of carcinoma ex pleomorphic adenoma, largely due to sampling error.

Comment Here

Reference: Carcinoma ex pleomorphic adenoma

Board review style question #2

A 57 year old man presents with right facial swelling and paralysis. Following appropriate workup, he undergoes surgical resection of the right facial mass. A representative histological image is provided above. Regarding his diagnosis, which statement is true?

Component on the left is commonly encountered in this entity
Molecular features of the cellular component are completely distinct from those of the paucicellular component
Paucicellular component on the right is irrelevant to the final diagnosis
Presence or absence of a complete capsule around the cellular component does not alter the patient’s prognosis

Board review style answer #2

A. The correct diagnosis is carcinoma ex pleomorphic adenoma. The component on the left is morphologically identical to salivary duct carcinoma, the most common malignant component of carcinoma ex pleomorphic adenoma other than adenocarcinoma NOS. The component on the right is the preexisting pleomorphic adenoma, which is a requirement for diagnosis. PLAG1 and HMGA2 molecular aberrations are encountered in both pleomorphic adenoma and carcinoma ex pleomorphic adenoma. The presence of a tumor capsule is of paramount prognostic significance, as noninvasive or minimally invasive carcinoma ex pleomorphic adenoma is associated with excellent outcomes.

Comment Here

Reference: Carcinoma ex pleomorphic adenoma

Carcinosarcoma

Table of Contents

Definition / general

First described by Kirklin in 1951 (Surg Gynecol Obstet 1951;92:721)
Characterized by a variable combination of malignant epithelial and sarcomatous tumor components

Essential features

High grade, aggressive salivary gland malignancy
Combined salivary tumor with malignant epithelial and mesenchymal component
May arise from pre-existing pleomorphic adenoma (PA)
Necrosis and hemorrhage are frequently seen
Poor prognosis

Terminology

Also known as true mixed malignant tumor
Sometimes named carcinosarcoma ex pleomorphic adenoma when tumor arises from longstanding or recurrent pleomorphic adenoma

ICD coding

ICD-O: 8980/3 - carcinosarcoma, NOS
ICD-11
- 2B67.Y & XH2W45 - other specified malignant neoplasms of parotid gland & carcinosarcoma, NOS
- 2B68.2 & XH2W45 - other specified malignant neoplasms of submandibular or sublingual glands & carcinosarcoma, NOS

Epidemiology

Patients are usually in their sixth to seventh decade of life
Mean age: 60.1 years (Histopathology 2023;82:576)
Range: 10 - 86 years (Histopathology 2023;82:576)
M:F = ~3:2 (Histopathology 2023;82:576)
Represents ~0.4% of all salivary gland malignancies (Pathol Annu 1993;28:279)
Cases of salivary carcinosarcoma ex pleomorphic adenoma (SCS ex PA) represent 3 - 6% in large carcinoma ex pleomorphic adenoma (CA ex PA) series (Histopathology 2023;82:576, Virchows Arch 2017;470:601)

Sites

Most commonly affects the parotid glands (70.3%), followed by submandibular gland (18.9%)
Rarely affects the minor salivary glands (11.8%), with palate most commonly involved (Histopathology 2023;82:576)

Pathophysiology

Molecular mutations are heterogeneous
Clonal relationship between carcinomatous and sarcomatous components (Am J Surg Pathol 1996;20:277, Oral Oncol 2009;45:259)
Derivation of the sarcomatous component has been postulated from myoepithelial cells of pleomorphic adenoma and primary carcinomatous components (Histopathology 2023;82:576)
Recently proposed to arise with a complex multistep adenoma - carcinoma - sarcoma progression developing from a pleomorphic adenoma (Histopathology 2023;82:576, Virchows Arch 2017;470:601)

Etiology

Tumor conventionally thought to develop from a pre-existent pleomorphic adenoma for half of the cases and de novo for the rest (Oral Surg Oral Med Oral Pathol 1986;61:597, Kurume Med J 2000;47:307)
Recent molecular studies suggest that tumor almost always develops from pleomorphic adenoma (Histopathology 2023;82:576)
Few cases occurred after radiotherapy (Virchows Arch A Pathol Anat Histopathol 1986;409:93, J Laryngol Otol 1994;108:443, B-ENT 2016;12:339)

Clinical features

Large, rapidly growing infiltrative mass
May have a longstanding mass or history of recurrent mass that represents a pleomorphic adenoma (Laryngoscope 2020;130:E335)
Facial pain and paresis (facial nerve palsy)
Otalgia
Dysphagia
Skin ulceration
May have a history of radiation therapy for pleomorphic adenoma
Advanced stage of presentation with lymph node metastasis and distant hematogenous spread (17.2%), mostly to lung and liver; there is a high frequency of local recurrence (Laryngoscope 2020;130:E335, Histopathology 2023;82:576)

Diagnosis

Neck mass that typically leads to imaging studies (computed tomography [CT] / magnetic resonance imaging [MRI]) and fine needle aspiration (FNA)
Definite diagnosis only rendered after surgical resection

Radiology description

CT
- Irregular, heterogeneously enhancing lesion
- Peripheral, septal contrast enhancement
- May show cystic necrotic areas and marked restricted diffusion on apparent diffusion coefficient (ADC) maps (Ear Nose Throat J 2022 Sep 28 [Epub ahead of print])
- Calcifications may be present (World J Surg Oncol 2018;16:103)
MRI
- T1 hypointense and T2 hyperintense heterogenous contrast enhancing lesion on MRI (Ear Nose Throat J 2022 Sep 28 [Epub ahead of print], J Nippon Med Sch 2018;85:51)
- Thick, irregular enhancing rim (Oral Oncol 2006;42:323)
- May be lobulated or multilobed (Case Rep Otolaryngol 2015;2015:694684)
- May show solid cystic or cystic necrotic appearance

Radiology images

Images hosted on other servers:

CT of head and neck

CT showing cystic necrotic areas

MRI of parotid lesion

MRI of heterogeneous mass lesion

Prognostic factors

Prognosis is poor
Mortality of 50% and mean survival of 2.4 - 3.6 years (Oral Surg Oral Med Oral Pathol 1986;61:597, Pathol Annu 1993;28:279, Laryngoscope 2020;130:E335)
With a median follow up of 36 months, the 3 year overall survival was 57.6% (Otolaryngol Head Neck Surg 2023;168:775)
5 year overall survival was 37% and 5 year disease specific survival was 62% (Laryngoscope 2020;130:E335)

Case reports

41 year old woman with dysphagia, facial pain and swelling of left face and 56 year old man with dysphagia and facial pain (Ear Nose Throat J 2022 Sep 28 [Epub ahead of print])
50 year old man with longstanding right submandibular swelling (Indian J Surg Oncol 2019;10:61)
67 year old man with right floor of mouth ulcer (Cureus 2023;15:e37206)
72 year old man with rapidly enlarged parotid mass (World J Surg Oncol 2018;16:103)
75 year old man with longstanding right parotid swelling (J Surg Case Rep 2021;2021:rjab361)

Treatment

Typically, surgical resection followed by adjuvant radiotherapy or chemotherapy

Clinical images

Images hosted on other servers:

Swelling of right parotid

Gross description

Often large (> 6 cm, mean size: 4 cm; range: 2 - 9 cm), infiltrating tumor (Laryngoscope 2020;130:E335)
Noncapsulated to poorly circumscribed
Can be a solid or solid cystic lesion
Gray-white to yellow appearance in solid area
Necrosis and hemorrhage are frequently seen
Calcifications may be seen (World J Surg Oncol 2018;16:103)
Smaller, often sclerotic nodule may be present that represents a pre-existing pleomorphic adenoma (Histopathology 2023;82:576)

Gross images

Contributed by Alexander Tang, M.B.B.S.

Cut section of tan, fleshy carcinosarcoma

Frozen section description

Diagnosis of high grade carcinoma or raising a possibility of sarcoma component is required from a representative section of the tumor for appropriate surgical management, including defining the extent of resection and the levels of neck dissection required

Microscopic (histologic) description

Variable combination of malignant epithelial and sarcomatous tumor components
There may be more than 1 type of carcinoma or sarcoma
Carcinomatous component commonly an adenocarcinoma (43%), salivary duct carcinoma (29.1%), undifferentiated carcinoma (26.7%), squamous cell carcinoma (18.6%) or myoepithelial carcinoma (2.3%) (Histopathology 2023;82:576)
Recent case series showed higher frequency of myoepithelial carcinoma (31.3%) (Histopathology 2023;82:576)
Other rare carcinomatous components include epithelial myoepithelial carcinoma, papillary cystadenocarcinoma, mucoepidermoid carcinoma, large cell neuroendocrine carcinoma (Mod Pathol 2006;19:350, Case Rep Otolaryngol 2015;2015:694684, Head Neck Pathol 2013;7:163)
Sarcomatous component most commonly a chondrosarcoma (51.2%), osteosarcoma (29.1%), spindle cell sarcoma (27.9%), pleomorphic sarcoma (8.1%), rhabdomyosarcoma (7%)
Heterologous component seen in 75.6% (Histopathology 2023;82:576)
Uncommon / rare sarcoma types reported include leiomyosarcoma, liposarcoma and malignant giant cell tumor (Arch Pathol Lab Med 2001;125:812, Arch Pathol Lab Med 1995;119:69, Histopathology 1993;23:594, Arch Pathol Lab Med 1998;122:743, Oral Surg Oral Med Oral Pathol 1986;61:597, Ann Maxillofac Surg 2015;5:240)
Intraductal pathway of tumorigenesis displays intraductal neoplasia, combined with dominant undifferentiated or salivary duct type carcinoma as an epithelial component and with pleomorphic or osteo / chondrosarcoma as a mesenchymal component
Myoepithelial pathway of tumorigenesis displays an absence of intraductal neoplasia and almost obligate combination of myoepithelial carcinoma and chondrosarcomatous differentiation
Sarcomatous components frequently dominate
High grade cytomorphology; mitotic figures and necrosis are frequently seen
Pre-existing PA may be seen and may be suggested by the presence of extensive hyalinized stroma (Head Neck Pathol 2013;7:163, Histopathology 2023;82:576)

Microscopic (histologic) images

Contributed by Manish Mahadeorao Bundele, M.B.B.S., M.D.

Carcinomatous and intervening sarcomatous components

Carcinosarcoma with residual PA

Sarcomatoid component with storiform pattern

Undifferentiated carcinoma with necrosis

Undifferentiated carcinoma / pleomorphic sarcoma

Focal squamoid component

p40+ / SOX10- squamoid component

p40+ squamoid component

Focal SOX10 staining

Nonspecific CD117 staining

High proliferative index

Diffuse positive p53

AE1 / AE3 + sarcomatoid component

Calponin weak positive

Variably increased p53 staining

Myoepithelial cells in PA

Cytology description

Scattered fragments of large epithelial cells
Epithelial cells have abundant cytoplasm; enlarged, pleomorphic, hyperchromatic nuclei and prominent nucleoli
Epithelial component can show squamoid features
Epithelial cells arranged in pseudoacinar pattern entrapped in myxoid materials have been reported (Diagn Cytopathol 2009;37:680)
Often show features of a high grade carcinoma without sarcomatous component
When sarcomatous component is present, it may appear as spindle cells showing atypical nuclei and giant cells in a background of necrosis (J Pathol Transl Med 2018;52:136, Acta Cytol 1998;42:1027)

Cytology images

Contributed by Manish Mahadeorao Bundele, M.B.B.S., M.D.

Cell block showing sheets of carcinoma cells

Cell block

Parotid FNA (high grade carcinoma)

Pleural fluid metastasis

Cytokeratin positive

CK7

Nonspecific CD117 positive

Positive stains

Immunohistochemistry depends on the classification of the malignant components
Carcinomatous component
- Cytokeratin AE1 / AE3, CK7 positive
- Salivary duct carcinoma: AR, GATA3 and HER2 positive
- Myoepithelial carcinoma: myoepithelial markers positive such as smooth muscle actin, calponin, S100 / SOX10, p63 / p40, glial fibrillary acidic protein, vimentin
- Squamous cell carcinoma: p40 and CK5/6 positive
- Adenocarcinoma, NOS: SOX10 positive; indicates intercalated duct phenotype
Sarcomatous component
- Positive for specific markers of sarcoma subtypes
- Chondrosarcoma and liposarcoma: S100 protein
- Rhabdomyosarcoma: desmin, myogenin, MyoD1
- Leiomyosarcoma: actin, desmin, caldesmon
May have strong aberrant nuclear p53 expression in both carcinomatous and sarcomatous components (Head Neck Pathol 2013;7:163, Histopathology 2023;82:576)
Often high Ki67 proliferation index
Pleomorphic adenoma component: CAM5.2 in luminal component and myoepithelial cell markers p63 / p40, S100 / SOX10, smooth muscle actin, calponin, glial fibrillary acidic protein, vimentin in abluminal component

Negative stains

Carcinomatous component
- Adenocarcinoma, NOS: AR and SOX10 negative
- Salivary duct carcinoma: SOX10 negative
- Squamous cell carcinoma: myoepithelial markers negative

Molecular / cytogenetics description

PLAG1::CTNNB1, PLAG1::FGFR1, PLAG1::HNRNPA2B1 and HMGA2::WIF1 fusions have been reported (Histopathology 2023;82:576)

Sample pathology report

Left parotid, parotidectomy:
- Carcinosarcoma (see comment)
- Comment: The biphasic tumor features both malignant epithelial (undifferentiated carcinoma) and sarcomatous (chondrosarcoma) components. Focally, there is a sclerotic area with myoepithelial cells, which could be suggestive of residual pleomorphic adenoma component.

Differential diagnosis

Carcinoma ex pleomorphic adenoma:
- Absence of sarcomatous component
- Rarely > 60 mm (Histopathology 2023;82:576)
- Intraductal intracapsular carcinoma can be seen
Pleomorphic adenoma:
- Lack of invasive features, completely encapsulated
- Absence of carcinomatous and sarcomatous areas
Salivary carcinoma with sarcomatoid differentiation:
- Generally smaller in size (< 30 mm) (Histopathology 2023;82:576)
- Very rare heterologous differentiation
- No pleomorphic adenoma component
Spindle cell squamous cell carcinoma:
- Absence of heterologous differentiation
- Absence of residual / sclerotic pleomorphic adenoma
Biphasic synovial sarcoma:
- Most cases in adolescents and young adults
- Monomorphic blue spindle cell sarcoma showing variable epithelial differentiation
- Diffuse and strong nuclear immunostaining for TLE1
- Demonstration of specific SS18::SSX1 / SS18::SSX2 / SS18::SSX4 gene fusion
Sarcoma, primary or metastatic:
- Absence of carcinomatous and pleomorphic adenoma component
- Clinicopathological correlation

Additional references

WHO Classification of Tumors Editorial Board: Head and Neck Tumors, 5th Edition, 2024

Board review style question #1

A 68 year old man who has a history of longstanding right parotid mass presented with a rapidly enlarging mass of the right parotid. A radical resection is performed. What is the diagnosis?

Carcinoma ex pleomorphic adenoma
Carcinosarcoma
Pleomorphic adenoma
Spindle cell squamous carcinoma

Board review style answer #1

B. Carcinosarcoma. The slide shows a mixture of undifferentiated carcinoma and spindle / pleomorphic sarcoma components. Along with the history of longstanding right parotid mass, which is typically associated with pleomorphic adenoma, the histological features are consistent with carcinosarcoma. Answer C is incorrect because pleomorphic adenoma does not show carcinoma and sarcoma components. Answer A is incorrect because a sarcomatous component is not present in carcinoma ex pleomorphic adenoma. Answer D is incorrect because although spindle cell squamous carcinoma can exhibit a sarcomatoid appearance, there is a conventional squamous cell component in the form of intraepithelial dysplasia, carcinoma in situ or invasive squamous cell carcinoma. It is also typically not associated with a longstanding parotid mass.

Comment Here

Reference: Carcinosarcoma

Board review style question #2

Which of the following statements is true about salivary carcinosarcoma?

It is a low grade indolent salivary gland malignancy
Most common sarcomatous component is chondrosarcoma
No necrosis and hemorrhage is seen
There is no association with pleomorphic adenoma

Board review style answer #2

B. Most common sarcomatous component is chondrosarcoma. The most common sarcomatous component in salivary carcinosarcoma is chondrosarcoma (51.2%). Answer A is incorrect because salivary carcinosarcoma is a high grade salivary gland malignancy. Answer D is incorrect because salivary carcinosarcoma may arise from pre-existing pleomorphic adenoma and may be suggested by the presence of extensive hyalinized stroma. Answer C is incorrect because necrosis and hemorrhage are commonly seen in salivary carcinosarcoma.

Comment Here

Reference: Carcinosarcoma

Chronic sialadenitis / sialolithiasis

Table of Contents

Definition / general

Repeated episodes of pain and inflammation due to impedance of salivary flow with stasis as a result of a stone

Essential features

Results from impedance of salivary flow with stasis as a result of obstruction from a sialolith
Affects the submandibular gland (80%) unilaterally without a side predilection

Terminology

Obstructive sialadenitis

ICD coding

ICD-10: K11.23 - chronic sialadenitis
ICD-10: K11.20 - sialadenitis, unspecified

Epidemiology

Sialolithiasis is estimated to affect 1/10,000 - 1/30,000 individuals (Otolaryngol Head Neck Surg 2011;145:935)
30 - 60 year old adults with a higher incidence in males

Sites

Obstructive sialadenitis due to stones mostly affects the submandibular gland (80%) unilaterally without a side predilection (Oral Surg Oral Med Oral Pathol 1972;33:2)
- Alkaline pH, increased mucinous and mineral content of its saliva (elevated calcium and phosphate concentrations) predisposes to calculi
- Wharton duct runs upward, making saliva flow against gravity and is narrow and tortuous, further contributing to salivary stasis (Mayo Clin Proc 2018;93:266)
Approximately 15% of salivary stones occur within the parotid gland
- Sublingual and other minor salivary glands are rarely affected

Pathophysiology

Mechanism is unclear and may be due to:
- Multiple intracellular microcalculi which accumulate during secretory inactivity and are excreted into the ducts where they act as a nidus for the eventual formation of a sialolith (Otolaryngol Clin North Am 2009;42:927)
- Bacteria or food debris enter the distal submandibular or parotid ducts and act as a nidus for the development of larger calculi (Arch Otolaryngol Head Neck Surg 2001;127:66)

Etiology

Uncertain but possible factors for stone formation include:
- Anatomic, affecting saliva formation or flow, such as duct stenosis or inflammation
- Composition factors, such as increased calcium content or altered enzyme function (StatPearls Publishing: Sialolithiasis [Accessed 16 September 2020])

Clinical features

Intermittent, periprandial pain and swelling of a single salivary gland
Risk factors include reduced fluid intake, tobacco use, prolonged illness, diuretics and drugs that diminish saliva (Otolaryngol Head Neck Surg 2011;145:935)

Diagnosis

If inconclusive clinically, sialography is the gold standard for the diagnosis

Radiology images

Images hosted on other servers:

Hypoechoic mass

Case reports

35 year old man with swelling below jaw (Mayo Clin Proc 2018;93:266)
39 year old woman with a history of migraines presented for evaluation of recurrent left sided submandibular swelling (J Oral Maxillofac Surg 2016;74:2447)
67 year old woman with mass of the upper lip (Oral Maxillofac Surg 2019;23:91)

Treatment

Treatment is conservative, with excision reserved for the minority of cases

Gross images

Images hosted on other servers:

Smooth mass

Sialolith

Microscopic (histologic) description

Varying degrees of acinar destruction, fibrosis and chronic inflammation, with lymphoid aggregates containing prominent germinal centers
Ducts may undergo squamous and mucous metaplasia
Lobular arrangement is maintained
May see microliths
Otolaryngol Clin North Am 2009;42:927

Microscopic (histologic) images

Contributed by James S. Lewis, M.D.

Preservation of lobular architecture

Intense chronic inflammation

Acinar destruction

Sample pathology report

Submandibular gland, left, excision:
- Chronic sialadenitis (see comment)
- Comment: There is a prominent periductal lymphoplasmacytic infiltrate containing lymphoid aggregates with prominent germinal centers. Some ducts appear ectatic and filled with debris suggestive of a microlith. Others are affected by squamous and mucinous metaplasia. These changes are associated with varying degrees of acinar atrophy and fibrosis.

Differential diagnosis

Mucoepidermoid carcinoma:
- Infiltrative growth pattern
- Complex architecture
IgG4 related sialadenitis:
- Dense chronic inflammatory infiltrate rich in plasma cells
  - IgG4/IgG ratio greater than 40%
- Fibrosis which focally is storiform
- Obliterative phlebitis (Head Neck Pathol 2016;10:530)
Lymphoepithelial sialadenitis (LESA):
- Affects the parotid, usually women
- Contains lymphoepithelial islands

Board review style question #1

A 55 year old man presents with a history of intermittent pain and swelling of the submandibular gland after eating. A biopsy with immunostains for IgG4 and IgG was performed and demonstrated a positive plasma cell ratio of 20%. Which of the following is the most likely diagnosis?

Chronic sialadenitis
IgG4 related sialadenitis
Lymphoepithelial sialadenitis
Mucoepidermoid carcinoma

Board review style answer #1

A. Chronic sialadenitis

Comment Here

Reference: Chronic sialadenitis / sialolithiasis

Board review style question #2

Why is it thought that stones most commonly arise in the submandibular gland?

Acid pH of its saliva predisposes to the precipitation of minerals
Caliber of Wharton duct is wide, causing stasis of secretions
Mucinous and viscous nature of its saliva results in a more stagnant flow of secretions
Wharton duct descends precipitously leading to pooling of saliva

Board review style answer #2

C. Mucinous and viscous nature of its saliva results in a more stagnant flow of secretions

Comment Here

Reference: Chronic sialadenitis / sialolithiasis

Clear cell carcinoma

Table of Contents

Definition / general

Unique malignancy commonly arising in minor salivary glands, usually intraoral
Molecularly defined by expression of EWSR1::ATF1 fusion oncogene or related fusion variants
Low grade salivary gland tumor composed of bland monomorphic tumor cells with clear to eosinophilic cytoplasm, arranged in nests, trabeculae and cords in a hyalinized stoma

Essential features

Rare salivary gland neoplasm
Most commonly involves intraoral minor salivary glands (> 80%)
2 stroma types: dense hypocellular hyalinized tissue, juxtaposed to a desmoplastic stroma, is virtually pathognomonic
Molecularly defined by presence of EWSR1 fusion (ATF1 most common partner)
Low grade with few nodal and distant metastases

Terminology

Clear cell carcinoma (2017 WHO)
Clear cell adenocarcinoma (2008 AFIP )
Clear cell carcinoma, not otherwise specified (2005 WHO)

ICD coding

ICD-9: 142.9 - malignant neoplasm of salivary gland, unspecified
ICD-10: C08.9 - malignant neoplasm of major salivary gland, unspecified

Epidemiology

Rare
Typically > 60 years old; however, broad age range (Genes Chromosomes Cancer 2011;50:559)
Slight female predominance

Sites

> 80% arise in intraoral minor salivary glands (most commonly base of tongue and soft palate) (Am J Surg Pathol 1994;18:74)
Minority present in major salivary glands, nasopharynx or larynx (Am J Surg Pathol 1994;18:74, Genes Chromosomes Cancer 2011;50:559)

Etiology

Ultrastructural and immunohistochemical (i.e., HMWK and p63+) findings support a squamous lesion / differentiation (Am J Surg Pathol 1994;18:74, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108:399, Head Neck Pathol 2011;5:101)
Occasional glands and intracellular mucin suggest that it may be a special type of adenosquamous carcinoma (Head Neck Pathol 2013;7:28)

Clinical features

Submucosal swelling that may ulcerate
Many are found on routine dental exam
Majority endorse a short history prior to medical attention (Head Neck Pathol 2013;7:S20)

Diagnosis

Definitive diagnosis may be difficult on histology alone due to its wide range of appearance and both morphologic and immunohistologic overlap with other entities in the differential; thus, FISH analysis for ESWR rearrangements is often necessary

Radiology description

Nonspecific findings, including well demarcated and isointense on T1 weighted, and hyperintense on T2 weighted imaging (AJNR Am J Neuroradiol 2007;28:127)

Radiology images

Contributed by Tony Ng, M.D., Ph.D.

CT scan

Images hosted on other servers:

Echo, CT, MRI

Prognostic factors

No formal grading system
Low grade with few nodal and distant metastases (Arch Pathol Lab Med 2002;126:676, Am J Surg Pathol 1994;18:74)
Locoregional recurrence, 12 - 17% (Arch Pathol Lab Med 2002;126:676, Head Neck Pathol 2012;6:389)
Necrosis, positive margins and lymph node status associated with recurrence (Head Neck 2016;38:426)
Rare high grade transformation (Head Neck Pathol 2012;6:389)

Case reports

25 year old woman with a 4.5 cm mass of the right orbit / lacrimal gland (Head Neck Pathol 2009;3:179)
53 year old man with an enlarged mass on the left side of the palate (Acta Cytol 2006;50:687)
54 year old man developed a mouth ulcer of the right oral mucosa after biting his cheek (Head Neck Pathol 2022;16:560)
55 year old man with a lung mass (Head Neck Pathol 2017;11:575)
61 year old man with recurrent tumor at the base of the tongue (Head Neck Pathol 2012;6:389)
66 year old woman with shortness of breath (Lung Cancer 2018;125:100)
74 year old woman with an asymptomatic swelling in the lingual region of teeth 32, 33 and 34 (Oral Oncol 2022;126:105753)

Treatment

Primary resection if in amenable location
Tongue base may have primary radiation (Head Neck Pathol 2013;7:S20)
With or without neck dissection (Cancer 2009;115:75)
Radiotherapy, alone or in combination with chemotherapy, may play a role in recurrent disease; however, evidence is weak (Crit Rev Oncol Hematol 2016;102:55)

Clinical images

Contributed by Pallavi Parashar, D.D.S.

Submucosal mass

Images hosted on other servers:

Buccal mass

Gross description

Gray-white, firm, appears well circumscribed (Am J Surg Pathol 1994;18:74)
Ranges from 1.0 - 4.5 cm (Genes Chromosomes Cancer 2011;50:559)

Gross images

Contributed by Erin Chapman, M.D

https://www.pathologyoutlines.com/imgau/salivaryglandsclearcellcarcinomaGrossChapman1.jpg

Well demarcated mass

Microscopic (histologic) description

Monomorphic cells with clear or eosinophilic cytoplasm arranged in anastomosing nests, trabeculae or cords (Am J Surg Pathol 1994;18:74)
2 stroma types: dense hypocellular hyalinized tissue, juxtaposed to a desmoplastic stroma that may appear myxoid, is virtually pathognomonic (Head Neck Pathol 2013;7:S20)
Often connects to surface, abruptly or in a pagetoid manner (Head Neck Pathol 2013;7:S20)
Mucinous differentiation in up to 50% (Genes Chromosomes Cancer 2011;50:559)
May have pseudoepitheliomatous hyperplasia (Head Neck Pathol 2013;7:S20)
Perineural invasion in about 50% of cases (Genes Chromosomes Cancer 2011;50:559)
Has squamoid appearance but lacks overt keratinization (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108:399)
17% show bone invasion (Genes Chromosomes Cancer 2011;50:559)
Mitotic rate is usually low and necrosis relatively uncommon (Am J Surg Pathol 1994;18:74, Head Neck Pathol 2013;7:S20)

Microscopic (histologic) images

Contributed by Pooja Navale, M.D. (Case #483), Tony Ng, M.D., Ph.D. and Erin Chapman, M.D

Circumscribed lesion

Cord-like to trabecular architecture

Hyalinzied stroma

Anastomosing nests

Monotonous cells

Clear to eosinophilic cytoplasm

Bland nuclei

Centrally placed nuclei

Inconspicuous nucleoli

Soft palate mass

Clear cell proliferation

Base of tongue mass

Clear cell and columnar phenotype

Buccal mass

Nests and cords of clear cells

Submucosal tissue

Posterior maxilla submucosal tumor

Islands and cords of tumor cells

p40

PASD

Cytology description

Cohesive clusters of monotonous epithelial cells with abundant clear cytoplasm, uniform round to oval nuclei, granular chromatin, small nucleoli, nuclear grooves and intranuclear cytoplasmic inclusions
Naked nuclei
Prominent tigroid background (Liu stain) (Diagn Cytopathol 2016;44:338)
Lacks myoepithelial cells (Diagn Cytopathol 2000;23:333)

Positive stains

Pancytokeratin, p63, EMA, CK7, CK19 and CAM5.2 (Head Neck Pathol 2013;7:S20)
p40 (Diagn Pathol 2022;17:18)
Variable p16 reactivity that can be > 70% in a subset of cases (Am J Surg Pathol 2018;42:367)

Negative stains

S100, SMA, MSA, calponin and GFAP (Head Neck Pathol 2013;7:S20)
High risk HPV by RNA ISH (Am J Surg Pathol 2018;42:367)

Electron microscopy description

Abundant glycogen, desmosomes, peripheral tonofilaments and prominent interdigitating microvilli (Am J Surg Pathol 1994;18:74)
Some basal lamina reduplication (Oral Oncol 2002;38:364)

Molecular / cytogenetics description

> 80% of cases have EWSR1::ATF1 fusion (Genes Chromosomes Cancer 2011;50:559)
Variant fusion described, EWSR1::CREM (Am J Surg Pathol 2018;42:1182)
Lacks MAML2 fusions
Lacks rearrangements with PBX1, ZNF444 and POU5F1, suggesting it is not the salivary gland equivalent of soft tissue myoepithelial tumor (Head Neck Pathol 2013;7:S20)

Sample pathology report

Oropharynx, right base of tongue, complete excision:
- Hyalinizing clear cell carcinoma (see comment)
- Comment: The carcinoma is composed of cells with abundant clear to variably eosinophilic cytoplasm, which are arranged in long cords, interconnecting trabeculae and nests. Nuclei are centrally placed with inconspicuous nucleoli. The background is remarkable for a myxoid appearing stroma that is sharply demarcated from a hyalinized basement membrane-like material. There is no evidence of necrosis or perineural invasion. Immunohistochemical stains were performed with the following results: cytokeratin and p40 positive; S100, SMA and calponin negative.

Differential diagnosis

Mucoepidermoid carcinoma:
- Predominantly major salivary glands (parotid)
- Greater tendency for cysts lined by goblet cells (Head Neck Pathol 2013;7:S20)
- MAML2 fusion
- Lacks EWSR1::ATF1 fusion
- Lacks cord-like and trabecular arrangements (Autops Case Rep 2020;10:e2020156)
- Lacks sclerosis / hyalinization and small nests and cords of tumor (Head Neck Pathol 2013;7:S20)
Squamous cell carcinoma:
- Overt keratinization
- More atypia and mitotic activity
- Overlying mucosal dysplasia
- Lacks EWSR1::ATF1 fusion
- No mucin
Clear cell odontogenic carcinoma:
- Arises within bone from dental lamina (odontogenic analogue of hyalinizing clear cell carcinoma)
Epithelial myoepithelial carcinoma:
- Biphasic with myoepithelial differentiation
- Larger nuclei
- S100, actin and calponin positive
- Spindling and oncocytic change
- Lacks EWSR1::ATF1 fusion
Metastatic clear cell renal cell carcinoma:
- Renal mass
- More vascular
- Nuclei larger and more atypical
- PAX8 and CAIX positive
- p63 negative (Head Neck Pathol 2007;1:123)
- Lacks squamous differentiation and dual stroma
- Lacks EWSR1::ATF1 fusion
Clear cell myoepithelial carcinoma:
- Very rare, only few case reports
- S100 and actin positive (Histopathology 1996;28:309)
- Lacks cords of tumor
- Can demonstrate EWSR1 fusions, although ATF1 not an expected fusion partner (Am J Surg Pathol 2015;39:338)

Additional references

El-Naggar: WHO Classification of Head and Neck Tumours, 4th Edition, 2017, Ellis: Tumors of the Salivary Glands, 4th Series, 2008, Barnes: Pathology and Genetics of Head and Neck Tumours, 3rd Edition, 2005

Board review style question #1

A mass from the soft palate of a 54 year old woman is resected. A representative image of the tumor is shown above. Which of the following statements is true regarding this entity?

By definition, it does not contain mucin, making it distinct from mucoepidermoid carcinoma
Microscopically, these are characterized by 2 stroma types: dense hypocellular hyalinized tissue, juxtaposed to a desmoplastic stroma that may appear myxoid; this finding is virtually pathognomonic
Most behave in an aggressive fashion
These carcinomas should be graded according to the 3 tiered system described by Milchgrub
While it can arise from the minor salivary glands, the majority occur in the parotid

Board review style answer #1

B. Microscopically, these are characterized by 2 stroma types: dense hypocellular hyalinized tissue, juxtaposed to a desmoplastic stroma that may appear myxoid; this finding is virtually pathognomonic. Most cases of hyalinizing clear cell carcinoma (HCCC) arise from the intraoral minor salivary glands, commonly those of the base of tongue and soft palate. A minority occur in the major salivary glands. Mucinous differentiation can be seen in up to 50% of cases, ranging from focal dot-like to diffuse. This can make the distinction from mucoepidermoid carcinoma challenging. There is no formal grading system for HCCC (Milchgrub first described HCCC, however). While most tumors are low grade, there are a few cases in the literature with high grade transformation. Finally, HCCC is characterized microscopically by cells with abundant clear to variably eosinophilic cytoplasm, which are arranged in long cords, interconnecting trabeculae and nests. The background is remarkable for 2 stroma types: dense hypocellular hyalinized tissue, juxtaposed to a desmoplastic stroma that may appear myxoid. The latter finding is virtually pathognomonic.

Comment Here

Reference: Hyalinizing clear cell carcinoma

Board review style question #2

Hyalinizing clear cell carcinoma of salivary gland is most commonly associated with which of the following gene fusions?

CRTC1 (MECT1)::MAML2
ETV6::NTRK3
EWSR1::ATF1
EWSR1::CREM
EWSR1::PBX1

Board review style answer #2

C. EWSR1::ATF1. Greater than 80% of hyalinizing clear cell carcinomas (HCCCs) have EWSR1::ATF1 fusions. Albeit, anchored multiplex polymerase chain reaction has demonstrated a novel variant EWSR1::CREM fusion in a minority of cases. This finding is biologically justified as CREM and ATF1 both belong to the CREB family of transcription factors. Soft tissue myoepithelial tumors (SMET) also harbor EWSR1 rearrangements. The partner genes in these neoplasms include PBX1, ZNF444 and POU5F1, suggesting that HCCC is not the salivary gland equivalent of soft tissue myoepithelial tumor. HCCC can be difficult to discriminate from mucoepidermoid carcinoma (MEC). Both can have mucinous differentiation. The former, however, possesses a characteristic myxoid appearing stroma that is sharply demarcated from a hyalinized basement membrane-like material. MEC predominantly affects the parotid and has a greater tendency for cysts lined by goblet cells rather than a cord-like or anastomosing trabeculae architecture. Lastly, MEC contains MAML2 fusions.

Comment Here

Reference: Hyalinizing clear cell carcinoma

Cystadenoma

Table of Contents

Definition / general

Rare neoplasm of salivary glands (1 - 4% of all salivary gland neoplasms)
Papillary and cystic-like architecture

Essential features

Unilocular or multicystic lesion
Cyst is frequently lined by papillary projections
Frequently oncocytic cells but minimal or absent lymphoid tissue
No atypia, mitoses or invasion (Head Neck Pathol 2015;9:354, Surg Pathol Clin 2021;14:53)

Terminology

Not recommended: Lymphocyte poor Warthin tumors, monomorphic adenoma, cystic duct adenoma, intraductal papillary hyperplasia
Subtypes: oncocytic cystadenoma, oncocytic cystadenoma, mucinous cystadenoma

ICD coding

ICD-O: 8440/0 - cystadenoma, not otherwise specified
ICD-10:
- D10 - benign neoplasm of minor salivary gland
- D11 - benign neoplasm of major salivary gland
ICD-11:
- 2E90 - benign neoplasm of lip, oral cavity or pharynx
- 2E91 - benign neoplasm of major salivary glands

Epidemiology

F > M
Fifth to seventh decades

Sites

45% in the parotid; clinically indistinguishable from other primary benign cystic salivary gland lesions
Minor salivary gland neoplasms mimic mucocele; lip and buccal mucosa most common sites among minor salivary glands

Pathophysiology

No clear pathogenesis

Clinical features

In major salivary glands: usually a painless slow growing mass or lump
In minor salivary glands: usually painless and compressible, mimicking mucocele
Slightly higher incidence in women (Head Neck Pathol 2015;9:354, Surg Pathol Clin 2021;14:53)

Diagnosis

Cystic or solid well circumscribed masses on ultrasound, CT or MRI
- May appear solid due to internal hemorrhage or infection
No other typical imaging patterns

Laboratory

No distinct serologic testing available

Radiology description

Well circumscribed mass with a clear capsule
Cystic or solid without internal flow
Capsule may show contrast enhancement if infected (Cancer Imaging 2007;7:52)

Radiology images

Contributed by Aditya Talwar, M.D.

Palpable mass, left neck

Left parotid lesion

Prognostic factors

Simple excision of the lesion is curative

Case reports

19 year old man with asymptomatic swelling of roof of mouth (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:e28)
40 year old woman with swelling below right ear (J Clin Diagn Res 2016;10:ED01)
52 year old man, a smoker with 2 lesions of the right parotid gland (Rom J Morphol Embryol 2019;60:993)
58 year old woman with tumor of the right temporomandibular joint (World J Clin Cases 2019;7:366)
63 year old man with nodule on right side of tongue (J Surg Case Rep 2020;2020:rjaa269)

Treatment

Simple excision is curative; recurrence is rare

Gross description

Uni or multicystic spaces within salivary gland tissue, well circumscribed

Gross images

Contributed by Jalal B. Jalaly, M.B.B.S., M.S.

Parotid gland

Frozen section description

Cyst wall with simple lining of glandular cells, oncocytic cells or squamous cells
Papillae lack lymphoid infiltrate seen in Warthin tumor
Should not see infiltration, atypia or mitoses
Mucinous or intermediate cells should bring up the differential of mucoepidermoid carcinoma
Oncocytic variant may be confused with macrocystic secretory carcinoma (Head Neck Pathol 2015;9:354, Oral and Maxillofacial Pathology Journal 2017;8:28, Surg Pathol Clin 2021;14:53)

Frozen section images

Contributed by Aditya Talwar, M.D.

Prominent papillary architecture with oncocytic cells

Microscopic (histologic) description

Uni or multiloculated cystic lesion (multiloculated growth is more common)
Well circumscribed, with peripheral entrapment of benign salivary gland tissue
Simple papillary architecture, should not have complex architecture, mitoses or atypia
Lining epithelial cells are commonly a mixture of columnar, cuboidal and oncocytic cells
May also see mucinous, squamous and rarely ciliated cells
- Mucinous cystadenoma is rare; lacks architectural and nuclear atypia
- Consider unicystic mucoepidermoid carcinoma in the differential diagnosis
Prominent multiloculated / multicystic growth pattern gives a low power appearance of more lumens than epithelial cells
Simple papillary projections and true papillae are common; however, complex papillary tufting should alert the pathologist to other differential diagnoses (e.g. intraductal carcinoma)
Immunohistochemical stains are useful to rule out macrocystic secretory carcinoma and intercalated type intraductal carcinoma (Head Neck Pathol 2015;9:354, Oral and Maxillofacial Pathology Journal 2017;8:28, Surg Pathol Clin 2021;14:53)

Microscopic (histologic) images

Contributed by Aditya Talwar, M.D.

Parotid gland cyst

Epithelial lining

Oncocytic variant

Cytology description

Cohesive groups of epithelial cells
Oncocytic variants will have ample granular cytoplasm, well defined cell borders and central nuclei
May see squamous differentiation as well
- Squamous or mucinous differentiation should bring a low grade mucoepidermoid carcinoma in the differential diagnosis (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:e28)

Cytology images

Contributed by Aditya Talwar, M.D.

Salivary gland lesion, Diff-Quik

Salivary gland lesion, Pap stain

Positive stains

p63 (basal cells)
CK8/18

Negative stains

S100, SOX10 (negative or patchy in basal cells)
Mammaglobin
GATA3

Sample pathology report

Parotid gland, right, superficial parotidectomy:
- Cystadenoma, 1.3 cm, not present at inked margin
- Background salivary gland tissue with no specific pathologic change

Differential diagnosis

Ductal ectasia:
- Ductal dilation, due to obstruction or stones
- May see squamous metaplasia
- May also see duct wall fibrosis, hyalinization and inflammatory infiltrate
Cystic oncocytic mucoepidermoid carcinoma:
- Nuclear atypia, infiltrative border and 3 cell types of MEC (mucous cells, epidermoid cells and intermediate cells)
Warthin tumor:
- Bilayer of oncocytic cells and prominent inflammatory infiltrate in papillary cores
Cystic oncocytic myoepithelioma:
- Myoepithelial in origin, usually no papillary architecture
Macrocystic secretory carcinoma:
- Characteristic ETV6-NTRK3 translocation
- Eosinophilic or vacuolated cytoplasm
- CK7, GATA3, mammaglobin, SOX10 and S100 positive
Low grade apocrine intraductal carcinoma:
- Resembles apocrine intraductal carcinoma of the breast with monotonous population of neoplastic cells usually filling the duct space with large nuclei and prominent nucleoli
- May have cribriform, micropapillary or solid growth pattern
Intraductal papilloma:
- Resembles intraductal papilloma of breast with arborizing fibrovascular cores lined by ductal epithelial cells
Salivary duct cyst / oncocytic salivary duct cyst:
- Due to obstruction, most common sites are labial and buccal mucosa
- May represent a true developmental cyst, rather than secondary cyst formation due to obstruction
Intercalated duct type intraductal carcinoma:
- Prominent complex or arborizing papillae and tufting
Mucocele:
- Reactive extravasation of mucin lined by compressed granulation tissue containing muciphages and inflammatory cells
- Not a true cyst with epithelial lining, although adjacent ductal epithelium may be seen
- Most commonly found in the lower labial mucosa / buccal mucosa

Board review style question #1

Which of the following FISH tests is useful in ruling out malignancy in equivocal cases of cystadenoma with mucinous metaplasia?

ETV6
EWSR1
MAML2
MYB
PLAG1

Board review style answer #1

C. MAML2 is positive in up to 80% of low grade mucoepidermoid carcinoma. Mucinous metaplasia may occur in cystadenoma. Typically, these cases will lack intermediate cells and infiltrative edges seen in cases of mucoepidermoid carcinoma. However, for equivocal cases, a negative MAML2 FISH analysis can provide additional support to exclude malignancy.

Comment Here

Reference: Cystadenoma

Board review style question #2

Which immunohistochemical panel would be most useful in supporting the diagnosis of macrocystic secretory carcinoma over that of cystadenoma?

GATA3+, S100+, SOX10+, MUC4+
KIT+, SOX10+, mammaglobin+, MYB+
Mammaglobin+, CK20+
S100-, p63+, P40+

Board review style answer #2

A. A panel type approach is often beneficial in salivary gland tumors. GATA3 is a nuclear stain that is positive in many malignancies, particularly breast and urothelial carcinomas. In the salivary gland, GATA3 stains secretory carcinoma, salivary duct carcinoma and other types of salivary gland neoplasms (Head Neck Pathol 2013;7:311). The addition of S100+, SOX10+ and MUC4+, in addition to mammaglobin+ weighs against cystadenoma and with the correct morphology, supports macrocystic secretory carcinoma. Nuclear stains are generally easier to interpret than cytoplasmic stains, like mammaglobin, due to high background staining. S100 stains most salivary gland neoplasms including secretory carcinoma and is not specific for it. KIT is seen in adenoid cystic carcinoma.

Comment Here

Reference: Cystadenoma

Ductal papilloma

Table of Contents

Definition / general

Category includes both Intraductal papillomas and inverted ductal papillomas
Benign papillary neoplasms that generally occur in minor salivary glands
Rare, benign papillary proliferations of bland cuboidal / columnar epithelial cells with fibrovascular cores, inflammation

Epidemiology

Usually adults, no gender preference (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92:68)

Sites

Usually in minor salivary glands, rare in parotid or sublingual glands

Pathophysiology

Derives from proximal salivary gland excretory duct (Cancer 1982;49:519)

Clinical features

Painless submucosal lesions, most frequently in the oral cavity
Patients present with mass, discomfort with chewing (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92:68)
Probably of luminal ductal origin

Case reports

41 year old man with parotid mass (Acta Otolaryngol 2002;122:314)
47 year old man with minor salivary gland tumor (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;107:e34)
49 year old man with inverted ductal papilloma in buccal mucosa of mandible (Pathol Int 2006;56:457)
70 and 72 year old men with benign sublingual tumor and parotid papilloma with microinvasion and intraparotid lymph node metastases (Arch Pathol Lab Med 2000;124:291)

Treatment

Surgery; does not recur

Microscopic (histologic) description

Intraductal papilloma
- Centered in excretory ducts of minor salivary gland
- Unicystic lesion lined by apillary proliferation composed of bland cuboidal to columnar epithelial cells with fibrovascular cores
- Rarely has intermixed mucinous cells
- No cytologic atypia and only rare mitotic figures
Inverted ductal papilloma
- Generally has central opening that communicates with surface mucosa
- Unencapsulated lesion composed of complex endophytic proliferation of non-keratinizing squamous epithelium which resembles inverted papilloma of nasal cavity
- Can have intermixed goblet cells and columnar cells
- No cytologic atypia and only rare mitotic figures

Microscopic (histologic) images

Images hosted on other servers:

Upper lip tumor has papillary
proliferation of epithelial
cells with branching fronds
in cystically dilated duct lumen

Cytology description

Compact clusters of papillary monomorphic columnar cells with abundant finely vacuolar cytoplasm; oval nuclei basally located, indistinct nucleol; no squamous cells (Acta Cytol 1999;43:457)

Positive stains

Alcian blue and PAS+ mucous cells, CK7, CK18, EMA, vimentin; variable CEA, S100, GCDFP-15

Negative stains

HER2, smooth muscle actin, GFAP, CK14

Electron microscopy images

Images hosted on other servers:

A: secretary granules, rough endoplasmic reticulum, golgi apparatus
and mitochondria; B: microvilli on luminal surface of epithelial cells
appear to be secretory; C: annulate lamellae composed of parallel
arrays of cisternae have small annuli or fenestrae

Differential diagnosis

Acinic cell carcinoma - papillary cystic variant
Metastatic papillary thyroid carcinoma
Papillary cystadenocarcinoma
Papillary cystadenoma
Polymorphous low grade adenocarcinoma
Salivary duct carcinoma
Sialadenoma papilliferum

Epithelial myoepithelial carcinoma

Table of Contents

Definition / general

Uncommon malignant biphasic salivary gland neoplasm composed of luminal ductal cells surrounded by myoepithelial cells

Essential features

Rare primary salivary gland neoplasm
Biphasic neoplasm with a combination of both epithelial and myoepithelial elements
Generally good prognosis; poorer prognosis associated with minor salivary gland location, large tumor (> 4 cm), high proliferation index, margin status, high grade transformation

Terminology

Adenomyoepithelioma (not recommended)

ICD coding

ICD-O: 8562/3 - epithelial myoepithelial carcinoma

Epidemiology

1 - 2% of all salivary gland tumors
Wide age range; mean 64 years (standard deviation ± 15.4) (BMC Ear Nose Throat Disord 2018;18:15)
M:F = 1:1.6 (BMC Ear Nose Throat Disord 2018;18:15)

Sites

Major salivary glands
- Most common parotid (70%), submandibular (12%) (Am J Surg Pathol 2007;31:44, BMC Ear Nose Throat Disord 2018;18:15)
Minor salivary glands
- Palate and upper aerodigestive tract (Am J Surg Pathol 2007;31:44)

Pathophysiology

Presumed to be of intercalated duct origin
Up to 85% of epithelial myoepithelial carcinomas carry an HRAS mutation (Am J Surg Pathol 2019;43:984)

Etiology

Subset may be associated with preexisting pleomorphic adenoma (Am J Surg Pathol 2018;42:18)
Subset may arise de novo (Am J Surg Pathol 2018;42:18)

Clinical features

Slow growing, painless mass
Usually unilateral
Rarely presents with facial nerve palsy and lymphadenopathy, may indicate high grade transformation (Medicine (Baltimore) 2017;96:e8988)

Diagnosis

Clinical examination and investigations such as magnetic resonance imaging and fine needle aspiration generally do not provide a definitive preoperative diagnosis

Prognostic factors

Mean survival up to 165 months; another group found up to 81% of patients to be disease free at 15 years (BMC Ear Nose Throat Disord 2018;18:15, Otolaryngol Head Neck Surg 2015;153:569)
- Univariate tumor related predictors of lower disease free survival include margin status, lymphovascular invasion, tumor necrosis, myoepithelial anaplasia (> threefold variation in size, irregular nuclear membranes, coarse chromatin, macronucleoli) (Am J Surg Pathol 2007;31:44)
- Multivariate patient related predictors of lower disease free survival include > 80 years at time of diagnosis, worse in African American population, nonsurgical treatment (BMC Ear Nose Throat Disord 2018;18:15)
Poorer prognosis associated with minor salivary gland location, large tumor (> 4 cm), high proliferation index, margin status, high grade transformation (Am J Surg Pathol 2010;34:1258)

Case reports

52 year old man presented with dysarthria and dysphagia secondary to a base of tongue lesion (Case Rep Otolaryngol 2017;2017:4973573)
70 year old woman presented with a painless nodule at the angle of the left mandible (Head Neck Pathol 2020;14:554)
75 year old woman presented with 3 year history of nasal obstruction and epistaxis (Medicine (Baltimore) 2020;99:e19072)

Treatment

Complete surgical resection
Adjuvant radiotherapy provides no survival benefit but reduces locoregional recurrence (Medicine (Baltimore) 2020;99:e22671, Radiother Oncol 2019;140:125)

Gross description

Lobulated, may be partially encapsulated
Firm gray-tan rubbery mass
Cystic change seen in up to 30% (Am J Surg Pathol 2007;31:44)

Gross images

Contributed by Ruta Gupta, M.B.B.S., M.D.

Solid tumor

Frozen section description

Should not be used; a reliable diagnosis of epithelial myoepithelial carcinoma may not be possible on frozen section

Microscopic (histologic) description

Bilayered arrangement of small luminal cells with eosinophilic cytoplasm and outer myoepithelial cells with clear cytoplasm rich in glycogen (diastase sensitive PAS+)
A few morphologic types may be seen, depending on the proportion of epithelial and myoepithelial cells present
- Classic
- Epithelial dominant
- Myoepithelial dominant
Tubular, glandular, solid growth patterns
Papillary and cystic areas may also be present (Am J Surg Pathol 2019;43:984)
Basement membrane-like hyalinized matrix may be present
Myoepithelial component can often be spindled or have clear cells
High grade transformation (20%) infers poorer prognosis (Head Neck Pathol 2013;7:S37)
- Usually the epithelial component
- Sheets and solid nests of markedly atypical cells with increased mitoses and necrosis
Other morphological variants
- Oncocytic (Head Neck Pathol 2013;7:S77, Arch Pathol Lab Med 2009;133:950)
  - Usually presents in older patients
  - Shows papillary growth pattern with calcifications
  - Luminal cells contain densely granular cytoplasm
- Apocrine (Head Neck Pathol 2013;7:S77, Arch Pathol Lab Med 2009;133:950)
  - Brightly eosinophilic ductal cells with apical snouts and luminal secretions
  - Cribriform to solid growth patterns
  - Positive for androgen receptor and GCDFP-15
Rare findings of squamous, sebaceous differentiation as well as ancient and Verocay-like change (Arch Pathol Lab Med 2009;133:950)

Microscopic (histologic) images

Contributed by Ruta Gupta, M.B.B.S., M.D.

Nodular growth pattern

Biphasic morphology

Biphasic pattern

Spindled myoepithelial cells

Clear myoepithelial cells

Cytology description

Cytology is not reliable, has a high false negative rate (Cancer Cytopathol 2020;128:392)
- Most cases may be misdiagnosed as pleomorphic adenoma due to overlapping cytological features
Biphasic clusters of ductal cells admixed with larger clear myoepithelial cells
Background naked myoepithelial nuclei with scant stromal fragments
Occasional globules of hyalinized basal luminal material (Diagn Cytopathol 2003;28:163)
Generally bland cytological features

Positive stains

Ductal: AE1 / AE3 (100%), EMA (100%), DOG1 (53% apical) (Mod Pathol 2012;25:919)
Myoepithelial: p63 (100%), smooth muscle actin (83%), calponin (64%), DOG1 (53% membranous), CK5/6, p40, SMMHC (Mod Pathol 2012;25:919)
Both: S100 (49 - 95%), SOX10 (J Pathol Transl Med 2019;53:23)

Negative stains

PAX8, HER2, GATA3, KIT and androgen receptor

Electron microscopy description

Usually not required for diagnosis
Ductal cells attached with junctional complexes and desmosomes and showing microvilli on luminal surface (J Med Assoc Thai 1998;81:712)
Myoepithelial cells contain abundant glycogen (electron lucent) with cytokeratin filaments, subplasmalemmal plaques and multilayered basal lumina

Molecular / cytogenetics description

HRAS mutations (codon 61) (Am J Surg Pathol 2019;43:984)
PLAG1 or HMGA2 (residual pleomorphic adenoma) (Am J Surg Pathol 2018;42:18)
Rarely SMARCB1 deletion and mutations in FBXW7 or TP53 (Am J Surg Pathol 2018;42:18)

Sample pathology report

Left parotid, excision:
- Epithelial myoepithelial carcinoma (see comment)
- Comment: There is a lobulated and unencapsulated biphasic primary neoplasm. The tumor shows a nodular growth pattern. The tumor is composed of bilayered arrangement of small luminal cells with eosinophilic cytoplasm and outer polygonal clear, rich in glycogen (diastase sensitive PAS+) myoepithelial cells. Immunohistochemically the inner epithelial cells are positive for AE1 / AE3 and EMA, while the outer myoepithelial layer shows staining for p63, smooth muscle actin and S100. There is no evidence of necrosis or high grade transformation.

Differential diagnosis

Pleomorphic adenoma:
- Multinodular with bosselated growth
- Chondromyxoid matrix
- Can have adipose tissue as a stromal element imparting a permeative appearance
- Can show pseudopodia extending into the adjacent tissues
Adenoid cystic carcinoma:
- Cribriform growth pattern (less common in epithelial myoepithelial carcinoma)
- MYB rearrangement
Basal cell adenoma:
- Prominent stromal hyalinization
- Lacks invasive growth and nuclear pleomorphism
- Nuclear beta catenin
Mucoepidermoid carcinoma, clear cell variant:
- Presence of mucocytes and cyst formation
- MAML2 translocation

Board review style question #1

A 65 year old woman presented with a 3 month history of unilateral cheek lump that recently increased in size. A histologic image of the resection is provided above. What is the most common histological feature associated with this lesion?

Anaplasia
High proliferation index
Lymphovascular invasion
Necrosis
Perineural invasion

Board review style answer #1

E. Perineural invasion

Comment Here

Reference: Epithelial myoepithelial carcinoma

Board review style question #2

Which of the following immunohistochemical combinations is most helpful in diagnosing epithelial myoepithelial carcinoma?

AE1 / AE3, CD117 and p63
AE1 / AE3, EMA and CK7
AE1 / AE3, S100 and p63
Nuclear beta catenin
p63, SMA and calponin

Board review style answer #2

C. AE1 / AE3, S100 and p63

Comment Here

Reference: Epithelial myoepithelial carcinoma

Genetic alterations in salivary gland tumors (pending)

[Pending]

Grossing, frozen section & features to report

Table of Contents

Grossing | Frozen section | Features to report

Grossing

At least one section per 1 cm of tumor for large tumors, including tumor center and periphery
Submit entire tumor if can do so in 5 sections or less
Submit resection margins
Save intervening levels on biopsies for special stains
For neck dissections, should have 6 or more lymph nodes if selective dissection and 10 or more if modified radical neck dissection

Note also presence or absence of:

Capsule
Cartilage, calcific deposits
Cystic change
Extraglandular extension
Localized / diffuse nature of tumor
Margin involvement
Necrosis
Solitary / multifocal tumor

Frozen section

Useful to determine extent of surgery needed, particularly for parotid tumors
Most common error is to diagnose mucoepidermoid carcinoma as benign

Features to report

Tumor histologic type and pattern
Anatomic site of origin / location, side
Tumor size
Tumor histologic grade (for mucoepidermoid carcinoma, adenocarcinoma, NOS, malignant mixed tumor, adenoid cystic carcinoma)
Tumor extension (intra or extraglandular), to adjacent structures
Status of resection margins
Vascular invasion
Perineural invasion
Lymph nodes: for each level, number obtained, number involved by tumor, size of largest nodal metastases, presence of extracapsular spread, side, if appropriate - major nerve (e.g. facial) or vessel (e.g. jugular vein), bone, skin involvement

Features to report by organization:

Heterotopia

Table of Contents

Definition / general | Intranodal | Extranodal | Case reports | Additional references

Definition / general

Also called ectopia
Normal salivary gland tissue at a site where normally not present
Usually in head and neck
Due to abnormal persistence and development of vestigial structures, misplacement of salivary gland rests along embryologic pathways of migration during development or by salivary differentiation from remnants of primitive embryologic structures
Intranodal (periparotid most common) or extranodal
May undergo same pathologic processes as usual salivary gland tissue
Most common neoplasm is Warthin tumor

Intranodal

More common than extranodal
In infants, most nodes within / near parotid gland contain salivary gland tissue, usually in medullary portion of node
Frequent but less common in adults
Usually composed of intercalated and intralobular ducts but also serous type acini and immature ducts

Extranodal

May be high or low in head and neck
High: mandible, mastoid bone, external and middle ear, tonsil, mylohyoid muscle, palatine tonsil, gingiva, pituitary gland, cerebellopontine angle; due to abnormalities in migration of embryonic tissue
Low: related to bronchial pouches in lower neck, thyroid gland or parathyroid gland; most commonly at medial border of right sternocleidomastoid muscle near sternoclavicular joint

Case reports

53 year old woman with cerebellopontine angle solitary fibrous tumor with ectopic salivary gland tissue (Am J Surg Pathol 2004;28:139)

Additional references

Am J Surg Pathol 2000;24:837

HIV salivary gland disease (HIV-SGD) (pending)

[Pending]

IgG4 related sialoadenitis

Table of Contents

Definition / general

Presents as painless, bilateral enlargement of lacrimal and salivary glands with mild secretory dysfunction
IgG4 related disease is now recognized as systemic disorder, characterized by high serum IgG4, marked infiltration of IgG4 positive plasma cells and severe fibrosis
Diagnosis depends on histologic appearance, elevated ratio of IgG4/IgG, variable elevated serum IgG4 levels
Submandibular gland biopsy is more useful than labial salivary gland biopsy
Corticosteroids and rituximab (by targeting peripheral CD20 positive plasma cells) appear to be effective for IgG4 related diseases

Terminology

Previously called Mikulicz disease and Mikulicz syndrome, but these terms are considered ambiguous and outdated by some sources

Case reports

54 year old man with IgG4 related sclerosing disease in lacrimal and submandibular glands (Korean J Ophthalmol 2012;26:216)
76 year old man with IgG4 related Mikulicz disease (Ocul Immunol Inflamm 2015;23:173)

Gross description

Solid, gray-white areas and occasional cysts

Microscopic (histologic) description

Lymphoplasmacytic infiltration with lymphoid follicles surrounding solid epithelial nests (epimyoepithelial islands)
Also scattered histiocytes and dendritic cells
Excess hyaline basement membrane material deposited between cells
Mild acinar destruction, lymphoepithelial lesions, monocytoid B cells
Fibrosis has a characteristic irregular whorled pattern, termed "storiform fibrosis"
Multiple germinal center formation in granular tissue

Microscopic (histologic) images

Images hosted on other servers:

Figure 2B

Lacrimal gland

IgG4 positive plasma cells

Differential diagnosis

Sjögren syndrome: no association with IgG4, female predominance, presence of SS-A and SS-B antibodies, severe acinar destruction

Additional references

Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;100:334, Arthritis Rheum 2012;64:3061, Mod Pathol 2012;25:1181, Clin Immunol 2015;156:9

Intercalated duct hyperplasia

Table of Contents

Definition / general | Microscopic (histologic) description | Additional references

Definition / general

Incidental microscopic finding (70% incidence) during histologic examination of a salivary gland tumor
Predominates in male patients (3:1) in sixth decade of life
More frequent in parotid compared to submandibular gland (3:1)
Hypothesized to be a precursor lesion of salivary gland tumor, especially epithelial myoepithelial carcinoma

Microscopic (histologic) description

Proliferating ducts admixed with acinar cell complexes
Ducts are frequently lined with single layer of cells; on occasion, may have luminal and abluminal lining cells
Acinar cells are characterized by atrophic changes (loss of zymogen granules, decrease in cell volume) resulting in morphologic resemblance to intercalated ducts

Additional references

Adv Anat Pathol 2002;9:251

Intraductal carcinoma

Table of Contents

Definition / general

Rare tumor usually involving the parotid, which is characterized by intracystic / intraductal proliferations of neoplastic epithelial cells
Exists in at least 3 variations, each with unique histologic, immunophenotypic and molecular features
While the apocrine variant is likely related to salivary duct carcinoma, the intercalated duct-like and oncocytic variants are not

Essential features

Resembles ductal carcinoma in situ of the breast, with cribriform, micropapillary, solid, comedo or clinging patterns (Cancer 1996;78:958)
At least 3 variants
- Intercalated duct-like (most common) (Am J Surg Pathol 2018;42:442)
- Apocrine (Am J Surg Pathol 2006;30:1014)
- Mixed / hybrid
- Possibly oncocytic but may be a variant of intercalated duct type (Histopathology 2018;73:314)
Diagnosis requires thorough sampling to rule out invasion or presence of a myoepithelial layer by immunohistochemistry
No purely intraductal carcinomas have definitively recurred or distantly metastasized

Terminology

Low grade cribriform cystadenocarcinoma
Low grade intraductal carcinoma
Low grade salivary duct carcinoma
Salivary duct carcinoma in situ
All alternate terminologies are not recommended

ICD coding

ICD-9: 142.9 - malignant neoplasm of salivary gland, unspecified
ICD-10: C08.9 - malignant neoplasm of salivary gland, unspecified

Epidemiology

Rare, with an estimated 93 cases reported (APMIS 2020;128:191)
Affects a wide age range; F:M = 1.5:1 (Head Neck Pathol 2013;7:S59)

Sites

Parotid (84.6%), intraparotid lymph nodes (5.1%), accessory parotid gland (2.6%), submandibular gland (2.6%) and minor salivary glands (5.1%) (Head Neck Pathol 2013;7:S59)

Clinical features

Asymptomatic and slow growing mass (Head Neck Pathol 2013;7:S59)

Diagnosis

Must exclude invasion by thorough sampling or presence of a myoepithelial layer by immunohistochemistry (Am J Surg Pathol 2004;28:266)

Prognostic factors

No purely intraductal carcinomas have definitively recurred or distantly metastasized (Head Neck Pathol 2013;7:S59)
Few show invasive growth, several with widespread invasion (Am J Surg Pathol 2019;43:1303)

Case reports

59 year old woman with a left parotid mass (Head Neck Pathol 2011;5:321)
61 year old man with a 1 month history of a painless mass in the left buccal mucosa (Int Cancer Conf J 2015;5:53)
75 year old woman with a 1 year history of a hard swelling of the left parotid gland (Pathol Res Pract 2017;213:706)

Treatment

Complete tumor excision (Head Neck Pathol 2020;14:869)
No current data to support radiation after surgical excision (Am J Surg Pathol 2006;30:1014)

Gross description

Circumscribed and focally to predominantly cystic (Cancer 1996;78:958)

Microscopic (histologic) description

General (criteria by Cheuk et al.) (Am J Surg Pathol 2004;28:266)
- Resembles mammary intraductal carcinoma with cribriform, micropapillary, solid, comedo or clinging patterns
- Exclusion of an invasive component by extensive sampling or demonstration by immunohistochemistry of a myoepithelial layer around epithelial nests
- Grade low, intermediate or high (Am J Surg Pathol 2004;28:266)
  - No standardized criteria for grading (Head Neck Pathol 2020;14:869)
Well circumscribed and unencapsulated at low power
Variably sized cysts and ducts (Cancer 1996;78:958)
May see a tumor associated lymphoid proliferation (Pathol Res Pract 2017;213:706)
Intercalated duct-like
- Small cuboidal cells with eosinophilic to amphophilic cytoplasm and small, oval nuclei with dispersed chromatin and inconspicuous nucleoli (Cancer 1996;78:958)
- Low grade nuclear features (Head Neck Pathol 2020;14:869)
Apocrine type
- Abundant granular eosinophilic cytoplasm
- Large, round, vesicular nuclei with macronucleoli (Am J Surg Pathol 2006;30:1014)
- Apocrine snouts and secretions (Am J Surg Pathol 2018;42:442)
- High grade nuclear features (Histopathology 2008;53:416)
Hybrid / mixed, both intercalated duct-like and apocrine features (Am J Surg Pathol 2018;42:442)
Oncocytic possible variant or oncocytic metaplasia of another intraductal carcinoma (Histopathology 2018;73:314)
- Medium sized round nuclei and abundant granular cytoplasm (Histopathology 2018;73:314)

Microscopic (histologic) images

Contributed by Kim A. Ely, M.D.

Well circumscribed

Cystic foci

Cribriform pattern

Intercalated duct-like subtype

Cytology description

Overlapping sheets and groups of cells with tight intercellular connections (Diagn Cytopathol 2011;39:218)
Cribriform / microcystic, solid, pseudopapillary configurations (Korean J Pathol 2013;47:592)
Round to oval and slightly irregular nuclei
Nucleoli may be evident
Cytoplasm can be abundant, well delimited and apocrine

Positive stains

Epithelial cells: AE1 / AE3, CAM 5.2, cytokeratin 7 and EMA (Am J Surg Pathol 2019;43:1303)
Myoepithelial cells: p63, p40, calponin, smooth muscle actin (Histopathology 2020 Nov 1 [Epub ahead of print])
Intercalated duct-like:
- S100 (Cancer 1996;78:958)
- SOX10 (Am J Surg Pathol 2018;42:1445)
Apocrine:
- Androgen receptor (AR) (Am J Surg Pathol 2006;30:1014)
- GCDFP-15 (Am J Surg Pathol 2006;30:1014)
Mixed / hybrid:
- Each component has the expected immunoprofile
Oncocytic:
- S100 (Histopathology 2018;73:314)

Negative stains

Intercalated duct-like:
- AR (Am J Surg Pathol 2004;28:1040)
- GCDFP-15 (Cancer 1996;78:958)
Apocrine:
- S100 and SOX10 (Am J Surg Pathol 2019;43:1303)
Mixed / hybrid: each component has the expected immunoprofile
Oncocytic:
- AR and GCDFP-15 (Histopathology 2018;73:314)

Molecular / cytogenetics description

Intercalated duct-like: frequent RET fusions, commonly NCOA4-RET (Am J Surg Pathol 2018;42:442)
- RET rearrangement is seen in epithelial and myoepithelial cells, suggesting that both populations are neoplastic (Am J Surg Pathol 2021;45:507)
Apocrine: complex genetics including HRAS and PIK3CA hotspot mutations (Am J Surg Pathol 2018;42:442)
Mixed / hybrid: RET fusions, especially TRIM27 (Am J Surg Pathol 2018;42:1445)
Oncocytic: RET fusions TRIM33 and BRAF V600E mutations (Histopathology 2020 Nov 1 [Epub ahead of print])

Sample pathology report

Parotid, right, complete excision:
- Intraductal carcinoma (see comment)
- Comment: The neoplasm is well circumscribed and consists of a complex intraductal proliferation of epithelial cells arranged in cribriform and papillary patterns. A p63 immunostain highlights the myoepithelial layer surrounding these intraductal nests. Comprising cells contain abundant granular eosinophilic cytoplasm and nuclei with prominent nucleoli. Mitoses are inconspicuous and necrosis absent. Additional immunohistochemical stains were performed and are positive for androgen receptor (AR), while negative for S100 and SOX10.

Differential diagnosis

Cystadenoma:
- Papillae lined by oncocytes, similar to Warthin tumor
- Typically lacks complex internal architecture resembling atypical ductal hyperplasia
- Tends to be S100- and GCDFP-15- (Head Neck Pathol 2015;9:354)
Cystadenocarcinoma:
- Prominent infiltrative growth and lacks a myoepithelial cell layer (Am J Surg Pathol 1996;20:1440)
Sclerosing polycystic adenosis:
- Serous acini with prominent hypereosinophilic granules
- Lacks an invasive component (Am J Surg Pathol 1996;20:161)
Salivary duct carcinoma:
- Comedonecrosis with widespread infiltrative growth
- Perineural and lymphovascular invasion (Oral Surg Oral Med Oral Pathol 1994;78:64)
- AR+ (Am J Surg Pathol 2000;24:579)
- GCDFP-15+ (Am J Surg Pathol 2015;39:705)
- S100- (Cancer 1996;77:223)
- SOX10- (Hum Pathol 2016;56:134)
Papillary cystic variant of acinic cell carcinoma:
- S100- (Am J Surg Pathol 2012;36:343)
Secretory carcinoma:
- Lacks a significant intraductal component (Am J Surg Pathol 2018;42:442)
- Lacks diffuse network of myoepithelial cells
- Contains ETV6-NTRK3 fusions (Am J Surg Pathol 2010;34:599)

Board review style question #1

Which of the following is true regarding this variant of intraductal carcinoma with the following immunophenotype: S100 and SOX10+; AR-?

It is associated with HRAS and PIK3CA hotspot mutations
It is the most common variant
It is the type most likely to exhibit high grade nuclear features
It is usually GCDFP-15+

Board review style answer #1

B. It is the most common variant

The photomicrograph shows an intraductal proliferation of bland appearing cuboidal cells arranged in cribriform and clinging patterns. Nuclei are small and oval with a dispersed chromatin distribution. Immunohistochemical studies were positive for S100 and SOX10, while negative for AR (androgen receptor) and GCDFP-15. This constellation of findings is characteristic of the intercalated duct-like variant, which is the most common of the variants. It is frequently associated with RET fusions, commonly NCOA4-RET. HRAS and PIK3CA hotspot mutations are usually seen in the apocrine variant, which is the form more likely to exhibit higher grade atypia. It has the following immunophenotype: S100-, SOX10-, AR+ and GCDFP-15+. This staining pattern is similar to that of salivary duct carcinoma, leading to some to believe that apocrine intraductal carcinoma may be a precursor to conventional salivary duct carcinoma.

Comment Here

Reference: Intraductal carcinoma

Board review style question #2

Which of the following is true regarding intraductal carcinoma?

A diagnosis can be made on core biopsy
Has a marked predilection for women
It is most common in the submandibular gland followed by the parotid
No purely intraductal carcinomas have definitively recurred or distantly metastasized

Board review style answer #2

D. No purely intraductal carcinomas have definitively recurred or distantly metastasized.

Intraductal carcinoma involves the parotid (84.6%), intraparotid lymph nodes (5.1%), accessory parotid gland (2.6%), submandibular gland (2.6%) and minor salivary glands (5.1%). Women and men are almost equally affected, with a female to male ratio of 1.5:1. According to the diagnostic criteria outlined by Cheuk et al., a diagnosis of intraductal carcinoma can be made once an invasive component is excluded. This requires thorough sampling or the demonstration of a myoepithelial layer around the epithelial nest by immunohistochemistry. This is more confidently accomplished on an excisional specimen. When confined by a myoepithelial cell layer, no intraductal (or in situ) carcinomas have definitively recurred or distantly metastasized.

Comment Here

Reference: Intraductal carcinoma

Keratocystoma

Table of Contents

Definition / general

Rare benign tumor with multicystic spaces lined by squamous cells with focal solid epithelial nests
First reported by Seifert (as choristoma, Virchows Arch 1999;434:355) and Nagao (Mod Pathol 2002;15:1005)

Clinical features

Very rare neoplasm of children / adults, < 20 cases reported
Usually parotid gland; may derive from salivary ducts undergoing squamous metaplasia
Excision appears to be adequate treatment

Case reports

37 year old man with parotid nodule (J Clin Pathol 2010;63:758)

Microscopic (histologic) description

Benign tumor with multicystic spaces, without lobular architecture, lined by squamous cells with focal solid epithelial nests
Parakeratotic and orthokeratotic keratinization without a granular layer
Outer layer has bud-like protrusions
Cells have abundant eosinophilic cytoplasm and bland, uniform nuclei
May have collageneous stroma, expansive growth
Focal foreign body reaction against keratin
Occasional normal mitotic figures
No necrosis, no invasion, no angiolymphatic invasion, no perineurial invasion, no atypia, no mucous cells

Microscopic (histologic) images

Images hosted on other servers:

37 year old man with parotid tumor

Positive stains

Cytokeratin (AE1 / AE3, CK14, CK17; focal CK13, focal CK19), Ki67 (outer basal layer only), collagen type IV positive material around cysts / cell nests

Negative stains

Alpha smooth muscle actin, S100, CK8, CK18

Differential diagnosis

Epidermal / dermoid cysts
Mucoepidermoid carcinoma
Necrotizing sialmetaplasia
Squamous cell carcinoma
Squamous metaplasia in other conditions

Lipoma / sialolipoma

Table of Contents

Definition / general

Lipoma:
- Benign tumor; rare in salivary glands but usually involves parotid gland (Laryngol Rhinol Otol 1986;65:485)
- More common than lipomatosis
- Clinical findings are nonspecific (J Oral Maxillofac Surg 2006;64:1583)
Sialolipoma:
- Uncommon lipoma variant composed of mature adipose tissue mixed with acinar, ductal, basal and myoepithelial cells of normal salivary gland
- First described in 2001 by Nagao (Histopathology 2001;38:30)
Lipoadenoma:
- Slow growing tumor with glandular structures with sertoliform features and adipose tissue; oncocytic and sebaceous differentiation
- Initially described by Yau in 1997 (Mod Pathol 1997;10:242)

Clinical features

Lipoma:
- 3% of parotid tumors - #2 most common benign mesenchymal neoplasms of major salivary glands (#1 is schwannoma)
- Often incidental (Rev Stomatol Chir Maxillofac 1988;89:117)
- Ages 40+, usually men, occasionally children
Sialolipoma:
- Mean age 61 years but wide age range at presentation
- Female gender predominance for minor salivary gland location
- Parotid and submandibular glands, hard and soft palate
- May be due to entrapment of salivary gland elements by lipoma
- Benign behavior, no recurrences reported

Case reports

Lipoma:
- Infant girl with parotid angiolipoma (Laryngoscope 1988;98:818)
- 36 year old woman with 3.5 cm parotid lipomatous pleomorphic adenoma (Pathol Res Pract 1999;195:247)
- 44 year old man with slow growing, asymptomatic parotid mass (Diagn Cytopathol 2013;41:171)
- 47 year old man with spindle cell lipoma of parotid gland diagnosed by fine needle aspiration (Arch Pathol Lab Med 2001;125:820)
- 55 year old woman with oncocytic lipoadenoma (Int J Clin Exp Pathol 2012;5:1000)
- 56 year old man (Br J Oral Maxillofac Surg 2010;48:203)
- 64 year old man with oncocytic lipoadenoma (Pathol Res Pract 2010;206:66)
- 66 year old woman with 11 cm oncocytic tumor (Hum Pathol 1998;29:410)
Sialolipoma:
- Newborn girl with slight facial asymmetry (Head Neck Pathol 2008;2:36)
- Infant girl with congenital sialolipoma (Int J Pediatr Otorhinolaryngol 2005;69:429)
- 3 year old girl with sialolipoma with diffuse sebaceous differentiation (Pediatr Dev Pathol 2007;10:138)
- 3 year old boy with submandibular gland tumor (J Pediatr Surg 2011;46:408)
- 18 year old man with submandibular sialoangiolipoma (Natl J Maxillofac Surg 2012;3:98)
- 68 year old woman with sensation of "large foreign body" in throat (Case #49)
- 72 year old woman with painless swelling of hard palate (Head Neck Pathol 2010;4:249)
- 73 year old man with submandibular mass (Indian J Pathol Microbiol 2009;52:379)
- 77 year old woman with submandibular mass (Br J Oral Maxillofac Surg 2008;46:599)

Treatment

Simple excision, usually do not recur (J Korean Med Sci 1996;11:522, Arch Otolaryngol 1976;102:230, Ann Diagn Pathol 2011;15:6)

Gross description

Well circumscribed, resembles lipoma at other sites
Median 2 cm (range, 1 - 4 cm)

Gross images

Case #49

Well circumscribed tumor

Images hosted on other servers:

Parotid sialoangiolipoma

Microscopic (histologic) description

Lipoma: bland appearing adipose tissue; osteolipoma or angiolipoma variants exist
Lipoadenoma: mature adipose cells (> 90% mass) and proliferated glandular tissue (sharply demarcated, duct - acinar units or proliferated glands, may resemble sertoliform tubules), oncocytic change, sebaceous differentiation, squamous metaplasia
Sialolipoma:
- Mature adipose tissue mixed with acinar, ductal, basal and myoepithelial cells of normal salivary gland
- Also duct ectasia with fibrosis, prominent lymphoid infiltrates with nodular aggregates in stroma, oncocytic changes, sebaceous differentiation
- Vascular variant is sialoangiolipoma

Microscopic (histologic) images

Case #49

Acini and dilated ducts

Ducts with fibrosis of wall infiltrated by lymphocytes

Peripheral
lipomatous tissue
with central salivary
gland elements

Lipoma-like areas

Images hosted on other servers:

Lower lip tumor

Submandibular sialoangiolipoma

Parotid sialoangiolipoma

Pleomorphic lipoma with classic floret-like cells

Chondroid lipoma
of lip has chondroid
and lipomatous
features

Oncocytic lipoadenoma of parotid

Spindle cell lipoma of parotid gland

Cytology description

Nonspecific findings (Eur Arch Otorhinolaryngol 2008;265:S47); spindle cell lipomas have bland appearing spindle cells in myxoid background, CD34+ mature fat cells; S100 may be negative

Immunohistochemistry & special stains

Oncocytic lipoadenoma:
- Positive for EMA, cytokeratin, CK19, CK7, CK14, CK5 / 6, alpha-1-antichymotrypsin (Virchows Arch 2006;449:722)
- Negative for calponin, actin
- Dual epithelial population with ductal (CK19, CK7) and basal cell (p63, CK14, CK5 / 6) differentiation in oncocytic areas

Molecular / cytogenetics description

t(12,14) / HMGA rearrangements

Differential diagnosis

Pleomorphic adenoma: may have extensive lipometaplasia / lipomatosis (Am J Surg Pathol 2005;29:1389)

Lipomatosis

Table of Contents

Definition / general | Case reports | Microscopic (histologic) images | Differential diagnosis

Definition / general

Diffuse deposition of adipose tissue (usually throughout parotid gland) with overall enlargement of gland but no distinct mass
Associated with alcoholism, cirrhosis, diabetes, hormonal abnormalities, malnutrition
May be preceded by sialadenosis (acinar cell hypertrophy, interstitial edema, ductal atrophy)
Slow growing, usually in parotid gland, may affect children
May recur

Case reports

5 month old girl with rapidly progressive parotid lipomatosis (Saudi Med J 2003;24:898)
9 year old boy (Int J Clin Pract 2009;63:335)
38 year old man with myoepithelioma of minor palatinal salivary glands with extensive lipomatosis (Laryngorhinootologie 2005;84:432)
47 year old man with well circumscribed 3 cm parotid nodule (Ann Pathol 2002;22:219)
Slow growing parotid mass (J Pediatr Surg 1996;31:1422)

Microscopic (histologic) images

Images hosted on other servers:

In parotid gland of HIV+ man

Differential diagnosis

Myoepithelioma: some cases have coexisting lipomatosis
Pleomorphic adenoma: some cases have lipometaplasia or lipomatous foci (Am J Surg Pathol 2005;29:1389)

Lymphadenoma

Table of Contents

Definition / general

Rare benign tumor with nests and islands of bland epithelium composed in part of sebaceous elements, with lymphoid stroma
Called sebaceous lymphadenoma if lymphoid stroma is prominent
Also called benign lymphoepithelial cyst with sebaceous differentiation

Clinical features

0.1% of salivary gland neoplasms, < 0.5% of salivary adenomas
Over 90% occur in or near the parotid gland or in minor salivary glands
May arise from salivary duct inclusions within parotid lymph node, similar to Warthin tumor (Am J Clin Pathol 1980;74:683)
Fine needle aspiration cytology identifies a benign process but usually not diagnosed prior to excision (Acta Otorhinolaryngol Ital 2007;27:144)

Case reports

53 year old woman with progressively enlarging, painless parotid mass (University of Pittsburgh: Parotid Gland Mass [Accessed 19 March 2018])
57 year old man with neck mass (Arch Pathol Lab Med 2005;129:e171)
67 year old woman with parotid mass (Acta Otorhinolaryngol Ital 2007;27:147)
68 year old woman with synchromous squamous cell carcinoma (World J Surg Oncol 2003;1:30)
86 year old man with stable parotid mass (Case #103)
Benign tumor with transition to sebaceous adenocarcinoma (Eur Arch Otorhinolaryngol 2006;263:940)

Treatment

Excision is curative, no / rare recurrences, rare malignant transformation (Eur Arch Otorhinolaryngol 2006;263:940)

Gross description

Solid or cystic, well circumscribed, tan-yellow mass, up to 3 cm, with variable encapsulation

Gross images

Case #103

Large nodule is
sebaceous adenoma,
small nodule on left
is oncocytoma

Images hosted on other servers:

Parotid gland masses

Microscopic (histologic) description

Benign, encapsulated, solid and cystic (Mod Pathol 2012;25:26)
Nests and islands of benign squamous cells, often lining a cyst; epithelial nests have focal sebaceous differentiation
Background is prominent lymphoid infiltrate, often with germinal centers
May be associated foreign body reaction, histiocytes, oncocytic change
Rarely malignant change to sebaceous carcinoma
May be combined / hybrid / synchronous tumors with Warthin tumor, acinic cell carcinoma, adenoid cystic carcinoma, squamous cell carcinoma (Eur J Cancer B Oral Oncol 1996;32B:251, Pathol Res Pract 1993;189:577, J Oral Surg 1979;37:826)

Microscopic (histologic) images

Case #103

Large nodule

Images hosted on other servers:

Benign parotid mass with sebaceous features and lymphoid stroma

Parotid gland mass

With synchronous squamous cell carcinoma

Cytology description

Mixed population of large and small lymphocytes, plasma cells and occasional tingible body macrophages
3 dimensional, cohesive aggregates of epithelial cells, often with cytoplasmic vacuoles characteristic of sebaceous differentiation, surrounded by layers of basaloid cells (Acta Cytol 2004;48:551)

Cytology images

Case #103

Diff-Quik touch prep

Positive stains

p63, 34 beta E12, CK5 / 6, CK18, CK7

Negative stains

EBV, HPV, HHV8

Molecular / cytogenetics description

May have trisomy 9 (Oncol Rep 1994;1:561)

Differential diagnosis

Low grade mucoepidermoid carcinoma: epithelial islands, ducts and cysts tend to be haphazardly distributed with variable shapes and sizes; usually infiltration of connective tissue or parenchyma; cells have some atypia, cells are mucin+
Normal sebaceous glands: present in 10% of parotid glands but no mass
Warthin tumor: prominent cysts and lymphoid stroma, cysts have bilayered oncocytic epithelium

Lymphoepithelial carcinoma

Table of Contents

Definition / general

Undifferentiated carcinoma common / familial in the Inuit and Chinese; presents as unilateral mass of parotid gland, submandibular gland or minor salivary glands in adults

Clinical features

May be associated with uterine lymphoepithelioma-like carcinoma
Metastases common to regional lymph nodes; distant metastases to liver, lung, bone
Treatment with surgery and radiotherapy; relatively good outcome (Br J Radiol 2006;79:52)

Case reports

29 year old woman with submandibular gland tumor (Chin Med J (Engl) 2006;119:1315)
50 year old woman with EBV+, c-kit+ tumor (Head Neck 2006;28:182)

Microscopic (histologic) description

Malignant epithelial islands resembling nonkeratinizing large cell carcinoma and lymphoid tissue with germinal centers
Occasional spindled areas
Often perineurial invasion
May have starry sky pattern, granuloma, amyloid; no benign lymphoepithelial lesion

Positive stains

Keratin, EBV (Histopathology 1997;31:75, J Clin Pathol 1995;48:1022), c-kit, EMA, AE1

Negative stains

Lymphoepithelial cyst

Table of Contents

Definition / general

Unilocular cysts that involve the parotid gland
Frequently but not always HIV related
Can be associated with autoimmune disease (e.g., Sjögren syndrome) (Int J Surg Pathol 2009;17:421)

Essential features

Well defined cysts on imaging (Laryngoscope 2007;117:106)
Simple cyst lined by low stratified squamous epithelium surrounded by polymorphous lymphocytes with prominent germinal centers (Diagn Cytopathol 2012;40:684)

Terminology

Salivary type lymphoepithelial cyst
HIV associated cystic lymphoid hyperplasia (Laryngoscope 2007;117:106)

ICD coding

ICD-10: K11.8 - other diseases of salivary glands

Epidemiology

HIV
Autoimmune disease (e.g., Sjögren syndrome)

Sites

Almost all arise in parotid gland
Very rare in submandibular gland

Pathophysiology

Sporadic lymphoepithelial cyst may result from cystic dilation of ducts within intraparotid or periparotid lymph node or branchial cleft remnants
HIV associated lymphoepithelial cyst likely forms due to hyperplasia of intra-salivary gland lymph nodes and associated ductal obstruction (J Int Assoc Provid AIDS Care 2017;16:120)
Sjögren syndrome associated lymphoepithelial cysts arise secondary to infiltration of B cells into the ductal epithelium and their expansion within the striated ducts and subsequent basal ductal cell hyperplasia (Nat Rev Rheumatol 2021;17:333)

Etiology

Cystic dilation of the salivary gland ducts
HIV associated
Autoimmune disease (e.g., Sjögren syndrome) associated

Clinical features

Presents as a painless unilocular mass near or within the salivary gland
Sporadic and autoimmune related cysts are generally unilateral
HIV associated cysts can be bilateral, with an overall incidence of 3 - 5% in HIV patients

Diagnosis

Unilateral, painless cystic salivary gland mass
Unilateral or bilateral painless cystic salivary gland mass in HIV patients, with or without cervical lymphadenopathy

Radiology description

Well defined, thin, smooth walled unilocular cystic mass (Int J Surg Case Rep 2017;41:383)

Radiology images

Contributed by Michael Kraut, M.D.

Lymphoepithelial cyst on coronal section

Lymphoepithelial cyst on axial section

Images hosted on other servers:

Well defined mass

Prognostic factors

Excellent prognosis
Low to null recurrence rate for all types of salivary gland lymphoepithelial cysts (J Surg Case Rep 2020;2020:rjaa300)

Case reports

32 year old woman presented with painless swelling of the left side of the neck for 8 months (J Pharm Bioallied Sci 2014;6:S185)
35 year old man with a soft, nontender swelling of the left parotid gland for 9 - 10 months (J Oral Maxillofac Pathol 2018;22:S91)
37 year old woman with a history of HIV and Hodgkin lymphoma presented with right sided facial swelling for 4 days; 47 year old man with a history of HIV / AIDS and Mycobacterium avium complex (MAC) infection presented with right sided jaw mass for 2 months (J Int Assoc Provid AIDS Care 2017;16:120)

Treatment

Conservative therapy, with institution of highly active antiretroviral therapy medication in HIV related cases (HIV AIDS (Auckl) 2012;4:81)
Surgical treatment not indicated for HIV associated lymphoepithelial cysts unless there is doubt about the diagnosis or there are cosmetic considerations (Head Neck 2018;40:1073)
Repeated fine needle aspiration and drainage, sclerotherapy, radiotherapy, surgery (Head Neck 2018;40:1073)

Clinical images

Images hosted on other servers:

Diffuse swelling involving the left parotid gland

Gross description

Cystic structure containing a serous clear watery straw colored fluid with smooth and glistening inner lining

Gross images

Images hosted on other servers:

Unilocular cyst with straw colored fluid

Frozen section description

Benign lymphoepithelial cyst

Microscopic (histologic) description

Most cases show a unilocular cyst with a thin stratified squamous lining
Ciliated, cuboidal or columnar epithelial lining is seen in rare cases
Epithelium is surrounded by dense polymorphous lymphoid tissue with germinal centers and sinusoidal spaces
Lymphocytes frequently permeate the epithelial cyst lining cells

Microscopic (histologic) images

Contributed by Zahra Maleki, M.D.

Epithelial and lymphoid component

Squamous lining and lymphoid tissue

Lymphoepithelial cyst high magnification

Epithelium surrounded by inflammatory cells

Epithelial and inflammatory cells

Cytology description

Mature nucleated squamous cells with variable reactive atypia, anuclear cells and squamous epithelium (Int J Surg Case Rep 2017;41:383, Diagn Cytopathol 2012;40:684)
Polymorphous lymphocytes and aggregates of epithelioid histiocytes
Proteinaceous background
Variable presence of acute inflammation, and bland appearing mucinous ductal cells and ciliated columnar cells
Scant cellularity, abundant proteinaceous background, lack of squamous cells and epithelial cells, marked atypia of epithelial cells, abundance of lymphocytes pose diagnostic challenges

Cytology images

Contributed by Zahra Maleki, M.D.

Numerous lymphocytes and histiocytes

Large epithelial fragment

Dispersed squamous cells

Polymorphous lymphocytes

Cyst content

Positive stains

AE1 / AE3 in squamous or ciliated columnar cells (Int J Surg Pathol 2021;29:78)
Numerous intrafollicular CD8+ lymphocytes in HIV associated lymphoepithelial cysts (Oral Surg Oral Med Oral Pathol Oral Radiol 2019;128:52)

Sample pathology report

Parotid mass, right, resection:
- Benign lymphoepithelial cyst with reactive follicular hyperplasia

Sample cytopathology report

Parotid, left, fine needle aspiration:
- Fragments of squamous epithelium, lymphocytes and cyst content (see comment)
- Comment: The differential diagnosis includes benign lymphoepithelial cyst, cystic lymphoid hyperplasia, lymphoepithelial sialadenitis, benign cyst with lymph node sampling or a Warthin tumor.
- Recommend: Clinical and radiographic correlation.

Differential diagnosis

Branchial cleft cyst:
- May have a sinus tract or stalk, infrequently associated with parotid tissue
Extranodal marginal zone lymphoma:
- Monoclonal lymphoid population with centrocytic or monocytoid appearance
Retention cyst:
- Mucinous cystic contents without extensive surrounding chronic inflammations
Warthin tumor:
- Areas of classic bilayered oncocytic epithelium, although occasional squamous metaplasia can be seen
Cystic metastasis of squamous cell carcinoma:
- Increased cytologic atypia and expansile growth of squamous epithelium
Mucoepidermoid carcinoma with tumor associated lymphoid proliferation:
- More complex epithelial proliferation with intermixed squamoid, mucinous and intermediate cells

Differential diagnosis in cytology

Mucocele:
- Abundant mucinous content
Reactive lymph node:
- Polymorphous lymphocytes and aggregates of epithelioid histiocytes
Warthin tumor:
- Polymorphous lymphocytes and fragments of oncocytic epithelium
Squamous cell carcinoma:
- Abundant pleomorphic squamous cells with marked atypia, pleomorphism, nuclear enlargement and hyperchromasia
Low grade mucoepidermoid carcinoma:
- Fragments of malignant epithelial cells and scattered squamous cells in a background of abundant mucin

Additional references

Ann Med Surg (Lond) 2021;67:102338

Board review style question #1

A cystic parotid mass measuring 1.5 cm is resected. The lesion can be associated with which of the following?

EBV associated
HHV8 associated
HIV associated
HPV associated

Board review style answer #1

C. HIV associated

Comment Here

Reference: Lymphoepithelial cyst

Board review style question #2

FNA of a cystic parotid mass in an 11 year old child is shown here. The most likely diagnosis is

Granulomatous inflammation
Lymphoepithelial cyst
Mucoepidermoid carcinoma
Squamous cell carcinoma

Board review style answer #2

B. Lymphoepithelial cyst

Comment Here

Reference: Lymphoepithelial cyst

Lymphoepithelial sialadenitis

Table of Contents

Definition / general

Part of a heterogeneous group of lesions with a prominent lymphoid component that involves the salivary glands (Med Oral Patol Oral Cir Bucal 2007;12:E479)
May be isolated or associated with Sjögren syndrome
Histologically characterized by the lymphoepithelial lesion, which is formed by a proliferation of ductal remnants permeated by lymphocytes (Virchows Arch 1999;434:315)

Essential features

May be isolated or associated with Sjögren syndrome
Usually occurs in women
Affects the parotid (90%) and submandibular gland (10 - 15%) with rare involvement of the minor salivary glands
Histologically characterized by the lymphoepithelial lesion, which is formed by a proliferation of ductal remnants permeated by lymphocytes
Indolent behavior; however, continued observation is mandatory because of an increased risk for lymphoma development (MALT lymphoma)

Terminology

Myoepithelial sialadenitis: a misnomer as ultrastructural and immunohistochemical studies showed that the cells involved are not myoepithelial cells but rather basal epithelial cells (Virchows Arch 1999;434:315)
Autoimmune sialadenitis
Lymphoepithelial lesion
Sjögren sialadenitis

ICD coding

ICD-10: K11.2 - sialoadenitis

Epidemiology

May be isolated or associated with Sjögren syndrome (Am J Clin Pathol 1999;111:S94)
Usually affects women

Sites

Affects the parotid (90%) and submandibular gland (10 - 15%) with rare involvement of the minor salivary glands (Ellis: Tumors of the Salivary Glands, 3rd Series, 1996)
- Commonly bilateral
- If the submandibular gland is affected in patients with Sjögren syndrome, the parotid glands are usually also involved

Etiology

Cause of lymphoepithelial sialadenitis unassociated with Sjögren syndrome has not been determined (Chin Med J (Engl) 2015;128:493)
Lymphoepithelial sialadenitis in the setting of Sjögren syndrome is likely multifactorial, with environmental and genetic factors causing an abnormal autoimmune response (Pathol Int 2008;58:465)

Clinical features

Recurring, firm swelling of the affected glands, which is sometimes associated with discomfort or pain (Med Oral Patol Oral Cir Bucal 2007;12:E479)

Laboratory

Positive serum anti SSA, anti SSB or a positive rheumatoid factor and antinuclear antibody titer of 1:320 are present when associated with Sjögren syndrome (Med Clin North Am 2014;98:1407)

Prognostic factors

Indolent behavior; however, continued observation is mandatory due to increased risk for lymphoma development (MALT lymphoma) (Med Oral Patol Oral Cir Bucal 2007;12:E479)

Case reports

18 year old woman with linear cutaneous lupus erythematosus and submandibular sialadenitis (Clin Exp Dermatol 2001;26:56)
21 year old woman with an infraauricular mass (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87:721)
4 cases of thymic hyperplasia resembling lymphoepithelial sialadenitis (Am J Clin Pathol 2012;138:816)

Treatment

Corticosteroids have been used with limited success (Med Clin North Am 2014;98:1407)

Microscopic (histologic) description

Major salivary gland:
- Early, extent of inflammation varies with collections of small lymphocytes surrounding intralobular ducts, minimal epitheliotropism, plasma cells not prominent (Med Oral Patol Oral Cir Bucal 2007;12:E479)
- Inflammation intensifies, contains lymphoid follicles with germinal center formation and more frequent plasma cells
- As inflammation becomes diffuse, there is partial and then total acinar destruction with the only remaining epithelium being the ducts
- Remnant ducts proliferate and are infiltrated by lymphocytes, forming the lymphoepithelial lesion
  - Eosinophilic, hyaline basement membrane-like material may be present among the cells of the lesion (Virchows Arch 2003;443:17)
- Overall lobular architecture is maintained
Labial salivary gland:
- Adequate biopsy has a glandular area of at least 4 mm², optimally 10 mm² (Arthritis Rheum 2011;63:2021)
- Germinal centers and lymphoepithelial lesions are less common in lip biopsies

Microscopic (histologic) images

Contributed by James S. Lewis, M.D.

Maintenance of lobular architecture

Intense chronic inflammation

Plasma cells

Lymphoepithelial lesion

Positive stains

Cytokeratin, AE1 / AE3 stains lymphoepithelial lesion

Negative stains

SMA negative within lymphoepithelial lesion

Sample pathology report

Parotid, left, excision:
- Lymphoepithelial sialadenitis (see comment)
- Comment: There is extensive chronic inflammation with plasma cells and lymphocytes containing follicles with germinal centers. The infiltrate effaces the parenchyma, resulting in acinar loss. Residual ducts show hyperplasia of their lining as well as permeation by lymphocytes. These glandular complexes represent the lymphoepithelial lesion.

Differential diagnosis

Extranodal marginal zone B cell lymphoma:
- May be difficult to differentiate
- Clonal monocytoid B cells both within and encircling the lymphoepithelial lesions to form halos and anastomosing cords, which can interconnect the lymphoepithelial lesions (Med Oral Patol Oral Cir Bucal 2007;12:E479)
- Sheets of plasma cells
- Monoclonality by IHC or flow cytometry (Mod Pathol 2002;15:255)
- Extension beyond capsule into adjacent tissues
- Loss of lobular architecture
IgG4 related sialadenitis:
- Slight male predilection
- Typically submandibular gland
- Dense chronic inflammatory infiltrate rich in plasma cells with an IgG4/IgG ratio > 40%
- Fibrosis, focally storiform
- Obliterative phlebitis (Head Neck Pathol 2016;10:530)
- Absence of lymphoepithelial lesions
Lymphoepithelial cyst:
- Well defined, unilocular cyst
- Has features of a lymph node or associated with a lymph node (Hum Pathol 2009;40:683)
- Absence of lymphoepithelial lesions
Lymphadenoma:
- Well circumscribed (Virchows Arch 2012;460:467)
- Even distribution of uniformly sized and shaped epithelial components within lymphoid stroma
- Absence of lymphoepithelial lesions
Chronic sialadenitis:
- Fibrosis
- Associated with sialolithiasis
- Absence of lymphoepithelial lesions
Tumor associated lymphoid proliferation (TALP):
- Salivary gland tumor surrounded by a dense infiltrate of lymphocytes (Curr Opin Oncol 1996;8:232)
- Absence of lymphoepithelial lesions

Board review style question #1

Burkitt lymphoma
Hodgkin lymphoma
Extranodal marginal zone B cell lymphoma
Anaplastic large cell lymphoma

Board review style answer #1

C. Extranodal marginal zone B cell lymphoma. The patient has lymphoepithelial sialadenitis.

Comment Here

Reference: Lymphoepithelial sialadenitis

Board review style question #2

It is composed of myoepithelial cells, hence the name myoepithelial sialadenitis is an appropriate alternative term for this lesion
It may be isolated or associated with Sjögren syndrome
It affects women and men equally
It involves the submandibular gland most commonly, followed by the minor salivary glands

Board review style answer #2

B. It may be isolated or associated with Sjögren syndrome

Comment Here

Reference: Lymphoepithelial sialadenitis

Malignant

Table of Contents

Definition / general

FNA showing diagnostic features of malignancy (Faquin: The Milan System for Reporting Salivary Gland Cytopathology, 1st Edition, 2018)

Essential features

FNA showing diagnostic features of malignancy
10 - 15% of all salivary gland FNA
Estimated risk of malignancy (ROM) by the Milan system: 90%

Terminology

Malignant (category VI)
An attempt should be made to grade the tumor as low, intermediate or high grade (Cancer Cytopathol 2020;128:392)
Specific tumor type should be provided if possible

CPT coding

88172 - determination of adequacy of specimen
88173 - FNA interpretation

Epidemiology

Salivary gland tumors are uncommon and represent < 2% of all human tumors (Kumar: Robbins & Cotran Pathologic Basis of Disease, 10th Edition, 2020)
Epithelial tumors account for 80 - 90% and approximately 40% are malignant

Sites

Parotid gland: 65 - 80% of all salivary gland tumors (Kumar: Robbins & Cotran Pathologic Basis of Disease, 10th Edition, 2020)
- 15 - 30% are malignant
Submandibular gland: 10% of all salivary gland tumors
- 40 - 45% are malignant
Minor salivary glands (including sublingual glands and seromucinous glands of the upper aerodigestive tract): 20% of all salivary gland tumors
- 70 - 90% of sublingual gland tumors and 50% of minor salivary gland tumors are malignant

Clinical features

Frequency among all the Milan system categories: 10 - 15%
Resection rate: 36.4 - 80.9% (Cancer Cytopathol 2020;128:348)
Risk of neoplasm: > 98% (J Oral Maxillofac Surg 2010;68:2146)
Real world risk of malignancy: 97.4% (96.4 - 98.5%) (Diagn Cytopathol 2020;48:880)

Radiology description

High grade carcinoma: ill defined, infiltrative border, heterogeneous internal signal with cystic change and necrosis (Eur J Radiol 2008;66:419)
Low grade carcinoma: overlapping features with benign salivary gland tumors

Case reports

9 year old girl, 16 year old girl and 45 year old man with secretory carcinoma of the parotid gland, cytologically mimicking mucoepidermoid carcinoma or acinic cell carcinoma (Diagn Cytopathol 2016;44:519)
28 year old man with hyalinizing clear cell carcinoma of the hard palate (Diagn Cytopathol 2016;44:338)
53 year old women with Warthin-like variant of mucoepidermoid carcinoma of the parotid gland, cytologically mimicking Warthin tumor (Diagn Cytopathol 2017;45:1132)
62 year old woman with epithelial myoepithelial carcinoma of the parotid gland (Diagn Cytopathol 2016;44:422)
64 year old man with metastatic clear cell renal cell carcinoma of the parotid gland (Diagn Cytopathol 2014;42:974)
66 year old man with carcinoma ex pleomorphic adenoma of the parotid gland (Diagn Cytopathol 2017;45:651)

Treatment

Surgical excision with or without lymph node dissection

Cytology description

Low grade carcinoma
- Acinic cell carcinoma
  - Second most common (10 - 15%) malignant salivary gland tumor
  - Sheets or loosely cohesive cells without regular acinar organization
  - Plump tumor cells with abundant granular to vacuolated cytoplasm, indistinct cell borders and variable zymogen secretory granules best seen on Romanowsky type stain
  - Minimal nuclear atypia and frequent naked nuclei
  - Marked nuclear pleomorphism, prominent nucleoli, high nuclear/cytoplasmic ratio, necrotic background and loss of acinic differentiation in high grade transformation (Cancer Cytopathol 2021;129:318)
  - Ancillary testing:
    - Positive for SOX10 and DOG1 (complete membranous pattern) immunocytochemistry (Diagn Cytopathol 2017;45:808)
    - Positive for NR4A3 immunocytochemistry (sensitivity: 81.8%, specificity: 100%) and FISH (sensitivity: 36.4%, specificity: 100%) (Cancer Cytopathol 2021;129:104)
- Secretory carcinoma
  - Characterized by morphological resemblance to mammary secretory carcinoma and ETV6-NTRK3 fusion
  - Cellular smear with 2 different architectural patterns (Cancer Cytopathol 2013;121:228)
    - Papillary or sheet-like fragments
    - Dispersed or dissociated single cells
  - Polygonal tumor cells with abundant finely granular cytoplasm, occasional to prominent cytoplasmic vacuoles and rare eosinophilic secretory globules and intracytoplasmic mucin (Cancer Cytopathol 2013;121:234)
  - Mild to moderate nuclear atypia with distinct nucleoli and occasional multinucleation
  - Ancillary testing (Cancer Cytopathol 2018;126:627):
    - Positive for S100, mammaglobin, SOX10 and pan-TRK immunocytochemistry
    - Positive for ETV6 FISH
High grade carcinoma
- Salivary duct carcinoma
  - Most common in elder males (peak in the seventh decade)
  - Sheets or crowded 3 dimensional clusters of overtly high grade malignant cells resembling invasive ductal carcinoma of the breast
  - Polygonal cells with enlarged, pleomorphic nuclei and prominent nucleoli
  - Frequent mitoses and necrosis
  - Ancillary testing: positive for androgen receptor and GATA3 immunocytochemistry (Cancer Cytopathol 2018;126:627)
  - Evaluation of AR and HER2 status is recommended for potential targeted therapy (Cancer Cytopathol 2020;128:693)
- Due to overlapping cytomorphology among various high grade salivary gland carcinomas or salivary gland tumors with high grade transformation, classification of a specific tumor type might not be the most relevant and diagnosis of high grade carcinoma alone should be sufficient for most of the cases regarding the clinical decision making
Carcinoma with intermediate or multiple grades
- Mucoepidermoid carcinoma
  - Most common malignant salivary gland tumors (40 - 50%) in both children and adults
  - 3 tiered grading system for histopathology and most often graded as low grade and high grade in FNA
  - Admixture of epidermoid, intermediate and mucus cells
  - Cystic background with abundant extracellular mucin
  - Low grade mucoepidermoid carcinoma: bland epithelial cells and abundant extracellular mucin
  - High grade mucoepidermoid carcinoma: predominantly epidermoid cells with marked cytologic atypia
  - Lymphocytes can be present in 20% of the cases and sometimes are abundant
  - Ancillary testing (Cancer Cytopathol 2018;126:627):
    - Positive for p63 / p40 and negative for SOX10 immunocytochemistry in epidermoid and intermediate cells
    - Positive for mucicarmine stain in the intracytoplasmic mucin of mucus cells
    - Positive for MAML2 FISH
- Adenoid cystic carcinoma
  - Malignant basaloid tumor consisting of epithelial and myoepithelial cells in various histologic configurations, including cribriform, tubular and solid
  - Uniform basaloid cells with scant cytoplasm, oval to angulated hyperchromatic nuclei and indistinct nucleoli
  - Various architecture patterns, including microcystic, tubular and syncytial clusters
  - Characteristic extracellular hyaline globules or cylinders of acellular metachromatic stroma with sharp borders best seen on Romanowsky type stain
  - Marked nuclear pleomorphism, prominent nucleoli, high nuclear/cytoplasmic ratio and necrotic background in high grade transformation (Cancer Cytopathol 2021;129:318)
  - Ancillary testing (Cancer Cytopathol 2018;126:627):
    - Positive for MYB and KIT immunocytochemistry
    - Positive for MYB or MYBL1 FISH
- Carcinoma ex pleomorphic carcinoma
  - Approximately 7% of all pleomorphic adenoma
  - Peak incidence at the sixth to seventh decade
  - Most of the carcinoma components are high grade salivary duct carcinoma
  - Features of classic pleomorphic adenoma in various proportions, depending on the sampling
Lymphoma
- Low grade lymphoma: monotonous population of atypical small to medium sized lymphocytes (ex: extranodal marginal zone lymphoma, follicular lymphoma)
- High grade lymphoma: diffuse proliferation of large atypical cells (ex: diffuse large B cell lymphoma)
- Ancillary testing:
  - Immunocytochemistry for CD3, CD20, etc.
  - Flow cytometry if necessary

Cytology images

Contributed by Jen-Fan Hang, M.D.

Mucoepidermoid carcinoma

Acinic cell carcinoma

Salivary duct carcinoma

Adenoid cystic carcinoma

Secretory carcinoma

Videos

Malignant category 1

Malignant category 2

Sample pathology report

Submandibular gland, right, fine needle aspiration:
- Satisfactory for evaluation
- Malignant
- Low grade mucoepidermoid carcinoma
Parotid gland, left, fine needle aspiration:
- Satisfactory for evaluation
- Malignant
- High grade carcinoma, consistent with salivary duct carcinoma
Parotid gland, left, fine needle aspiration:
- Satisfactory for evaluation
- Malignant
- High grade carcinoma (see comment)
- Comment: Presence of scant chondromyxoid matrix, suggestive of carcinoma ex pleomorphic adenoma.

Differential diagnosis

Low grade carcinoma
- Acinic cell carcinoma versus
  - Nonneoplastic acinar cells:
    - Acinar cells in grape-like lobules of acinar organizations
  - Warthin tumor:
    - Densely granular cytoplasm and distinct cell borders, dirty proteinaceous background
  - Oncocytoma:
    - Oncocytic cells without intracytoplasmic zymogen granules
  - Low grade mucoepidermoid carcinoma:
    - Presence of mucous cells and extracellular mucin
- Secretory carcinoma versus
  - Pleomorphic adenoma:
    - Presence of extracellular chondromyxoid matrix
  - Acinic cell carcinoma:
    - Presence of intracytoplasmic zymogen granules
  - Low grade mucoepidermoid carcinoma:
    - Presence of abundant extracellular mucin
High grade carcinoma
- Salivary duct carcinoma versus
  - High grade mucoepidermoid carcinoma:
    - High grade tumor cells with squamoid cytomorphology and intracytoplasmic mucin
  - Metastatic carcinoma:
    - Clinical history of other primary malignancies (ex: breast, prostate, etc.)
Carcinoma with intermediate or multiple grades
- Mucoepidermoid carcinoma versus
  - Mucocele and mucin extravasation:
    - Cystic background with abundant extracellular mucin and no epithelial components diagnostic of mucoepidermoid carcinoma
    - Better classified as atypia of undetermined significance (AUS)
  - Benign tumor or nonneoplastic lesion with squamous or mucinous metaplasia:
    - Frank keratinization is not a feature of mucoepidermoid carcinoma
    - Better classified as AUS or salivary gland tumor of uncertain malignant potential (SUMP)
- Adenoid cystic carcinoma versus
  - Pleomorphic adenoma:
    - Feathery or fibrillary matrix admixed with myoepithelial cells
    - Presence of hyaline globules in rare cases
  - Basal cell adenoma or adenocarcinoma:
    - Overlapping morphology with bland basal cells and acellular metachromatic matrix
    - Better classified as SUMP with basaloid features or suspicious for malignancy (SM) in difficult cases (Diagn Cytopathol 2020;48:1282)
Lymphoma versus
- Sialoadenitis or intrasalivary gland lymph node:
  - Bland lymphocytic aspirates showing any evidence of monomorphic population should be better classified as AUS
- Lymphoid rich epithelial tumors (ex: Warthin tumor, lymphoepithelial carcinoma, etc.)

Additional references

J Am Soc Cytopathol 2019;8:270

Board review style question #1

Which histological diagnosis most likely corresponds to this cytologic aspirate?

Acinic cell carcinoma
Adenoid cystic carcinoma
Mucoepidermoid carcinoma
Secretory carcinoma

Board review style answer #1

C. Mucoepidermoid carcinoma. A fragment of intermediate cells with intermingled mucous cells containing orange colored intracytoplasmic mucin is characteristic for a mucoepidermoid carcinoma.

Comment Here

Reference: Malignant

Board review style question #2

Which histological diagnosis most likely corresponds to this cytologic aspirate?

Acinic cell carcinoma
Adenoid cystic carcinoma
Mucoepidermoid carcinoma
Secretory carcinoma

Board review style answer #2

B. Adenoid cystic carcinoma. Basaloid tumor cells with prominent hyaline globules arranging in cribriform pattern are characteristic for an adenoid cystic carcinoma.

Comment Here

Reference: Malignant

Metastases

Table of Contents

Definition / general

Metastases usually to intraparotid or submandibular lymph nodes (Pathol Res Pract 1986;181:684)
Most common submandibular metastatic tumors are metastatic squamous cell carcinoma from upper aerodigestive tract or skin or melanoma to submandibular lymph nodes
Distant metastases to salivary glands also arise from breast, colon, kidney, lung, prostate

Microsecretory adenocarcinoma

Table of Contents

Definition / general

Recently described low grade salivary gland carcinoma harboring a unique MEF2C::SS18 fusion (Am J Surg Pathol 2019;43:1023)
Vast majority of reported cases occur in minor salivary glands, particularly oral cavity sites (Head Neck Pathol 2021;15:1192)

Essential features

Primary salivary gland neoplasm characterized by MEF2C::SS18 fusion (Am J Surg Pathol 2019;43:1023)
Majority of cases occur in intraoral minor salivary glands (Head Neck Pathol 2021;15:1192, Pathol Int 2020;70:781)
Well demarcated borders with subtle invasive growth (Am J Surg Pathol 2019;43:1023)
Anastomosing microcysts composed of attenuated cells with eosinophilic cytoplasm, round oval nuclei and prominent basophilic intraluminal secretions (Surg Pathol Clin 2021;14:137)
Diffuse S100 and SOX10 expression with discordant positivity for p63 and negative for p40 (Head Neck Pathol 2021;15:1192, Pathol Int 2020;70:781)

Terminology

Most cases previously grouped within the heterogeneous adenocarcinoma, not otherwise specified category

ICD coding

ICD-10: C06.9 - malignant neoplasm of mouth, unspecified

Epidemiology

Can occur at various ages (range: 17 - 83 years; mean: 49.5 years) (Head Neck Pathol 2021;15:1192)
Slight female predominance (Head Neck Pathol 2021;15:1192, Pathol Int 2020;70:781)

Sites

Vast majority of initially reported cases in oral cavity, with most (60%) in palate and remainder in buccal mucosa (Head Neck Pathol 2021;15:1192, Pathol Int 2020;70:781)
Several cases now recognized in the skin and ear canal (J Cutan Pathol 2023;50:134, J Cutan Pathol 2023;50:106, Am J Dermatopathol 2022;44:855)
Rare cases in parotid gland (Head Neck Pathol 2021;15:1192)

Pathophysiology

Recurrent SS18::MEF2C fusions

Etiology

No known risk factors

Clinical features

Most present as small, painless, intraoral masses (Head Neck Pathol 2021;15:1192)

Diagnosis

Imaging modalities for workup of salivary gland neoplasms include ultrasonography, computed tomography (CT) and magnetic resonance imaging (MRI) (Otolaryngol Head Neck Surg 2021;164:27)
Histologic diagnosis of minor salivary gland tumors generally utilizes incisional or excisional biopsy

Prognostic factors

No known prognostic factors (Head Neck Pathol 2021;15:1192)
Generally low grade neoplasm with indolent behavior (Head Neck Pathol 2021;15:1192)
Rare cases reported with high grade features and aggressive behavior (Histopathology 2022;81:685, J Cutan Pathol 2023;50:134, Virchows Arch 2022;481:963)

Case reports

37 year old woman with painless, hard palate mass (Pathol Int 2020;70:781)
62 year old man with right cheek mass (Virchows Arch 2022;481:963)
89 year old woman with external ear canal mass (J Cutan Pathol 2023;50:106)

Treatment

Number of reported cases with available follow up data is limited; however, surgical resection was curative (Head Neck Pathol 2021;15:1192)

Gross description

Generally well circumscribed, tan-white, solid, unencapsulated lesions (Head Neck Pathol 2021;15:1192)

Microscopic (histologic) description

Unencapsulated and well circumscribed with at least focal infiltrative growth (Surg Pathol Clin 2021;14:137)
Microcystic predominant growth pattern with anastomoses between adjacent microcysts and abundant intraluminal basophilic secretions (Am J Surg Pathol 2019;43:1023)
Fibrous to myxohyaline stroma with increased sclerosis at the center of tumor (Surg Pathol Clin 2021;14:137)
Monophasic population of attenuated epithelioid intercalated duct-like cells (Surg Pathol Clin 2021;14:137)
Uniform small, oval, hyperchromatic nuclei with indistinct nucleoli (Head Neck Pathol 2021;15:1192)
Most cases lack significant cytologic atypia, mitotic activity or necrosis, although rare cases with these higher grade features have been reported (Histopathology 2022;81:685, J Cutan Pathol 2023;50:134, Virchows Arch 2022;481:963

Microscopic (histologic) images

Contributed by Michael Mikula, M.D.

Unencapsulated and well circumscribed

Subtle invasive growth

Microcysts

Basophilic secretions

Fibromyxoid stroma

Monotonous hyperchromatic nuclei

S100

p63

Positive stains

Negative stains

Electron microscopy description

Unknown at this time

Molecular / cytogenetics description

MEF2C::SS18 fusion in majority of reported cases (Head Neck Pathol 2021;15:1192, Pathol Int 2020;70:781)
SS18 break apart FISH (assay used in diagnosis of synovial sarcoma) is 93% sensitive for diagnosis (Head Neck Pathol 2021;15:1192)

Molecular / cytogenetics images

Images hosted on other servers:

SS18 rearrangement by FISH

Sample pathology report

Right buccal mucosa, excision:
- Microsecretory adenocarcinoma, low grade (1.5 cm) (see comment)
- No lymphovascular or perineural invasion is present
- Margins are uninvolved
- Comment: The tumor consists of a well demarcated but focally infiltrative neoplasm consisting of anastomosing microcysts and cords of epithelioid cells with attenuated eosinophilic cytoplasm, prominent basophilic luminal secretions and scant hyalinized stroma. Immunostains show that the tumor cells are diffusely positive for S100 and p63 but negative for p40. Fluorescence in situ hybridization using SS18 break apart probe demonstrates an SS18 rearrangement. The combined morphological and immunohistochemical features support the diagnosis of microsecretory adenocarcinoma, a recently described low grade salivary gland neoplasm that generally has an excellent prognosis.

Differential diagnosis

Polymorphous adenocarcinoma:
- Has overlapping S100+ / p63+ / p40- immunophenotype
- More architecturally diverse with less attenuated cytoplasm
- More overtly infiltrative borders with targetoid perineural invasion
- Intraluminal secretions are uncommon (Am J Surg Pathol 2016;40:1526)
- Chromatin clearing resembling that of papillary thyroid carcinoma
- PRKD gene family alterations (Mod Pathol 2020;33:65)
Secretory carcinoma:
- Demonstrates overlapping S100+ immunophenotype
- More architecturally diverse with microcystic, cribriform and papillary patterns
- More abundant and vacuolated eosinophilic cytoplasm (Cancer Cytopathol 2013;121:228)
- Predominantly eosinophilic secretions (Cancer Cytopathol 2013;121:228)
- p63- to focal p63+ (Histopathology 2021;79:315)
- ETV6::NTRK3 or ETV6::RET fusions in majority
Microcribriform adenocarcinoma:
- Emerging entity with overlapping SS18::ZBTB7A fusions and S100+ / SOX10+ (Am J Surg Pathol 2023;47:194)
- More heterogeneous architecture with confluent microcribriform and solid patterns
- More abundant amphophilic to eosinophilic cytoplasm
- Areas of biphasic cell populations with abluminal expression of myoepithelial markers, including p63, p40, calponin and SMA
Sclerosing microcystic adenocarcinoma:
- Similar minor salivary location and predominant tubular growth
- More infiltrative border with prominent desmoplastic stroma (Head Neck Pathol 2016;10:501)
- Biphasic population of ductal and myoepithelial cells (Head Neck Pathol 2016;10:501)
- p40+ in myoepithelial cells (Surg Pathol Clin 2021;14:137)
Adenoid cystic carcinoma:
- Shares prominent basophilic luminal secretions and can have overlapping tubular pattern
- Biphasic population of ductal and myoepithelial cells
- Most cases show some degree of cribriform architecture (Oral Oncol 2015;51:652)
- Widely infiltrative borders with extensive perineural invasion
- p40+ in myoepithelial cells
- MYB and MYBL1 fusions detected in 50 - 80% of cases (Surg Pathol Clin 2021;14:137)

Board review style question #1

A 42 year old woman presents for a routine dental cleaning and a small, firm, painless mass involving the hard palate is discovered. At higher power, the tumor cells are monotonous with hyperchromatic nuclei. They show diffuse positivity for S100 and p63 and are negative for p40. Break apart fluorescence in situ hybridization reveals a rearrangement of SS18. What is the diagnosis?

Microsecretory adenocarcinoma
Polymorphous adenocarcinoma
Sclerosing microcystic adenocarcinoma
Secretory carcinoma
Tubular adenoid cystic carcinoma

Board review style answer #1

A. Microsecretory adenocarcinoma. The image shows a well demarcated mass composed of anastomosing microcysts containing prominent basophilic secretions. Answer B is incorrect because polymorphous adenocarcinoma can show tubular and microcribriform architecture with S100 positivity and discordant p63 and p40 staining; however, polymorphous adenocarcinoma typically shows more infiltrative borders and heterogeneous architecture. Answer C is incorrect because sclerosing microcystic adenocarcinoma can show microcystic architecture but demonstrates an infiltrative growth pattern and biphasic cell populations with a relatively abundant desmoplastic stromal component. Answer D is incorrect because secretory carcinoma demonstrates a microcystic architecture and is positive for S100 but tends to show predominantly eosinophilic secretions and is generally negative for p63. Answer E is incorrrect because tubular adenoid cystic carcinoma often shows some microcystic architecture with basophilic intraluminal secretions but shows widely infiltrative borders and at least focal cribriform architecture. Evidence of SS18 rearrangement is highly specific for microsecretory adenocarcinoma, which has been shown to harbor a unique MEF2C::SS18 fusion.

Comment Here

Reference: Microsecretory adenocarcinoma

Milan reporting system for salivary gland cytopathology

Table of Contents

Definition / general

The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) was developed by an international consortium of experts and endorsed by the American Society of Cytopathology (ASC) and the International Academy of Cytology (IAC)
The effort started in September 2015 in Milan and the atlas was published in 2018
Aims to standardize reporting terminology in order to replace the conventional, descriptive interpretation for salivary gland fine needle aspirations (FNA) for better communication between clinicians and between institutions
Main outputs useful for clinical decisions and lab quality control are risk of malignancy (ROM) and frequency of each diagnostic category

Essential features

Consists of 6 diagnostic categories:
- Nondiagnostic
- Nonneoplastic
- Atypia of undetermined significance (AUS)
- Neoplasm (benign and salivary gland neoplasm of uncertain malignant potential [SUMP])
- Suspicious for malignancy (SM)
- Malignant

CPT coding

88172 - determination of adequacy of specimen
88173 - FNA interpretation

Nondiagnostic (category I)

10 - 20% of salivary gland FNA (Cancer Cytopathol 2020;128:348)
Diagnostic criteria:
- Insufficient cellular material: less than 60 lesional cells for a cytologic diagnosis
- Nonneoplastic acinar cells only in the setting of a clinically defined nodule
- Nonmucinous cyst fluid only
- Poorly prepared slides with artifacts (ex: air drying, obscuring blood, poor staining, etc.)
Exceptions which should be diagnosed as atypia of undetermined significance (AUS):
- Presence of any amount of cells with significant cytologic atypia
- Mucinous cyst lesions with an absent or a very limited epithelial component
Estimated risk of malignancy: 25%
Real world risk of malignancy:
- With surgical follow up only: 16.3% (12.6 - 19.9%) (Diagn Cytopathol 2020;48:880)
- Overall: 4.4% (Am J Clin Pathol 2019;151:613)
Management: clinical and radiologic correlation, repeat FNA

Nonneoplastic (category II)

15 - 25% of salivary gland FNA (Cancer Cytopathol 2020;128:348)
Diagnostic criteria:
- Benign nonneoplastic conditions (ex: sialadenitis, sialolithiasis, granulomatous inflammation, infection, reactive lymph node, etc.)
Common false negative conditions:
- Lymphoid rich tumors: low grade lymphoma, Hodgkin lymphoma, lymphoepithelial carcinoma
- Cystic tumors: mucoepidermoid carcinoma
Exceptions which should be diagnosed as atypia of undetermined significance (AUS):
- Bland lymphocytic aspirates showing any evidence of monomorphic population; also consider flow cytometry
Estimated risk of malignancy: 10%
Real world risk of malignancy:
- With surgical follow up only: 9.6% (6.8 - 12.4%) (Diagn Cytopathol 2020;48:880)
- Overall: 2.1% (Am J Clin Pathol 2019;151:613)
Management: clinical follow up and radiologic correlation

Atypia of undetermined significance (AUS) (category III)

< 10% of salivary gland FNA (Cancer Cytopathol 2020;128:348)
Diagnostic criteria:
- Limited cellular atypia
- Lacks qualitative or quantitative features for diagnosing a neoplasm
Common AUS conditions:
- Reactive or reparative atypia
- Metaplastic changes indefinite for a neoplasm (ex: squamous, oncocytic, etc.)
- Mucinous cystic lesions with an absent or a very limited epithelial component
- Nonmucinous cystic lesions with atypical epithelial cells
- Low cellularity FNA suggestive but not diagnostic of a neoplasm
- Lymphoid lesions indefinite for lymphoproliferative disorder
Estimated risk of malignancy: 20%
Real world risk of malignancy:
- With surgical follow up only: 36.9% (25.6 - 48.2%) (Diagn Cytopathol 2020;48:880)
- Overall: 25.0% (Am J Clin Pathol 2019;151:613)
Management: repeat FNA or surgery

Neoplasm: benign (category IVA)

30 - 40% of salivary gland FNA (Cancer Cytopathol 2020;128:348)
Diagnostic criteria:
- Characteristic cytomorphologic features of a specific benign neoplasm
Common benign tumors diagnosed:
- Epithelial: pleomorphic adenoma (60 - 70%), Warthin tumor (20 - 30%), oncocytoma, etc.
- Mesenchymal: schwannoma, lipoma, hemangioma, etc.
Conditions better classified as salivary gland neoplasm of uncertain malignant potential (SUMP):
- Matrix producing carcinomas with basaloid cells falsely interpreted as pleomorphic or basal cell adenoma (ex: adenoid cystic carcinoma, basal cell adenocarcinoma → SUMP with basaloid features)
- Carcinomas with oncocytic / oncocytoid cells or prominent lymphocytic infiltrates falsely interpreted as Warthin tumor or oncocytoma (ex: Warthin-like variant of mucoepidermoid carcinoma, mucoepidermoid carcinoma with lymphoid cuffing, acinic cell carcinoma with / without lymphoid infiltrates, secretory carcinoma → SUMP with oncocytic / oncocytoid features)
- Carcinomas with bland myoepithelial-like morphology falsely interpreted as pleomorphic adenoma or myoepithelioma (ex: myoepithelial carcinoma, epithelial myoepithelial carcinoma, secretory carcinoma → SUMP, not otherwise specified, with myoepithelial features)
- Basal cell adenoma, myoepithelioma and cystadenoma due to overlapping cytomorphology with other malignant tumors
Estimated risk of malignancy: < 5%
Real world risk of malignancy:
- With surgical follow up only: 2.4% (1.8 - 3.0%) (Diagn Cytopathol 2020;48:880)
- Overall: 1.5% (Am J Clin Pathol 2019;151:613)
Management: surgery or clinical and radiological follow up

Neoplasm: salivary gland neoplasm of uncertain malignant potential (SUMP) (category IVB)

< 10% of salivary gland FNA (Cancer Cytopathol 2020;128:348)
Diagnostic criteria:
- Cytomorphologic features diagnostic of a neoplasm but indefinite for a specific tumor type to further distinguish between benign or malignant
Common SUMP conditions:
- Cellular benign neoplasm (ex: cellular pleomorphic adenoma)
- Neoplasm with atypical features
  - Cellular neoplasm with basaloid features (ex: pleomorphic adenoma, basal cell adenoma / adenocarcinoma, adenoid cystic carcinoma, epithelial myoepithelial carcinoma, polymorphous adenocarcinoma, etc.)
  - Cellular neoplasm with oncocytic / oncocytoid features (ex: Warthin tumor, oncocytoma, mucoepidermoid carcinoma, acinic cell carcinoma, secretory carcinoma, etc.)
  - Cellular neoplasm with clear cell features (ex: myoepithelioma, epithelial myoepithelial carcinoma, acinic cell carcinoma, secretory carcinoma, mucoepidermoid carcinoma, etc.)
- Low grade carcinoma (ex: low grade mucoepidermoid carcinoma)
SUMP subclassifications proposed by different authors:
- Cellular basaloid neoplasm, cellular oncocytic / oncocytoid neoplasm, cellular neoplasm with clear cell features (Faquin: The Milan System for Reporting Salivary Gland Cytopathology, 1st Edition, 2018)
- Basaloid neoplasm (risk of malignancy: 27.6%), salivary gland neoplasm with predominant oncocytic cells (risk of malignancy: 20.0%) (Cancer Cytopathol 2018;126:490)
- Oncocytic / squamoid subtype (risk of malignancy: 61.1%), basaloid subtype (risk of malignancy: 40.0%) and myoepithelial subtype (risk of malignancy: 18.8%) (Cancer Cytopathol 2018;126:924)
- Basaloid features (risk of malignancy: 38.5%), oncocytic features (risk of malignancy: 7.7%), unspecified features (risk of malignancy: 41%) (Cancer Cytopathol 2019;127:377)
- Monomorphic basaloid SUMP (risk of malignancy: 23.5%), monomorphic oncocytic SUMP (risk of malignancy: 58.8%) (Cancer Cytopathol 2021 Mar 31 [Epub ahead of print])
Estimated risk of malignancy: 35%
Real world risk of malignancy:
- With surgical follow up only: 37.2% (30.5 - 44.0%) (Diagn Cytopathol 2020;48:880)
- Overall: 27.7% (Am J Clin Pathol 2019;151:613)
Management: surgery

Suspicious for malignancy (SM) (category V)

< 5% of salivary gland FNA (Cancer Cytopathol 2020;128:348)
Diagnostic criteria:
- Features that are highly suggestive of but not unequivocal for malignancy
Common SM conditions:
- Markedly atypical cells with poor preparation or obscuring factors
- Limited cytologic features of a specific malignancy (ex: adenoid cystic carcinoma with limited cellular atypia or hyaline globules, mucoepidermoid carcinoma with limited mucus cells or extracellular mucin, secretory carcinoma with limited cytoplasmic vacuolization or papillary formations)
- Suspicious cytologic features in a subset of cells but admixed with predominant features of a benign lesion (ex: carcinoma ex pleomorphic adenoma)
- Monomorphic population of small lymphocytes suspicious for a low grade lymphoma
- Scant large atypical lymphocytes suspicious for a high grade lymphoma or Hodgkin lymphoma
Estimated risk of malignancy: 60%
Real world risk of malignancy: 80.6% (70.6 - 85.7%) (Diagn Cytopathol 2020;48:880)
Management: surgery

Malignant (category VI)

10 - 15% of salivary gland FNA (Cancer Cytopathol 2020;128:348)
Diagnostic criteria:
- FNA showing diagnostic features of malignancy
Common malignant conditions:
- Low grade carcinoma (ex: acinic carcinoma, secretory carcinoma, etc.)
- High grade carcinoma (ex: salivary duct carcinoma, lymphoepithelial carcinoma, tumor with high grade transformation, etc.)
- Carcinoma with intermediate or multiple grades (ex: mucoepidermoid carcinoma, adenoid cystic carcinoma, myoepithelial carcinoma, etc.)
- Other malignancy: lymphoma, sarcoma, metastasis, etc.
Common false positive conditions:
- Pleomorphic or basal cell adenoma with prominent hyaline globules falsely interpreted as adenoid cystic carcinoma → better classified as SUMP with basaloid features
- Benign tumor or nonneoplastic lesion with squamous or mucinous metaplasia falsely interpreted as mucoepidermoid carcinoma (ex: pleomorphic adenoma, Warthin tumor, chronic sialadenitis → better classified as AUS or SUMP)
Diagnostic tip:
- An attempt should be made to subclassify these aspirates into different grades and specific types of carcinoma if possible
Estimated risk of malignancy: 90%
Real world risk of malignancy: 97.4% (96.4 - 98.5%) (Diagn Cytopathol 2020;48:880)
Management: surgery

Diagrams / tables

Images hosted on other servers:

Milan system

Cytology description

See above

Cytology images

Contributed by Jen-Fan Hang, M.D.

Nondiagnostic

Nonneoplastic acinar cells

Benign skeletal muscle

Cystic fluid only

Atypia of undetermined significance (AUS)

Mucinous cyst

Atypical lymphoid proliferation

Neoplasm: benign

Pleomorphic adenoma (PA): fibrillary extracellular matrix

PA: plasmacytoid
myoepithelial cells

PA with squamous metaplasia

Warthin tumor

Oncocytoma

Neoplasm: salivary gland neoplasm of uncertain malignant potential (SUMP)

With oncocytic / oncocytoid features

With basaloid features

Malignant

Mucoepidermoid carcinoma

Acinic cell carcinoma

Salivary duct carcinoma

Adenoid cystic carcinoma

Secretory carcinoma

Videos

Milan system

Algorithmic approach to everyday salivary gland cytology

Differential diagnosis

See above

Additional references

J Am Soc Cytopathol 2018;7:111, Adv Anat Pathol 2019;26:84, Laryngoscope 2020;130:80, Cancer Cytopathol 2021 Apr 28 [Epub ahead of print]

Board review style question #1

A 62 year old man presents with a 3.6 cm left parotid nodule. The fine needle aspiration shows a cellular smear, which is composed of fragments of bland looking, basaloid cells intermingled with magenta colored hyaline globules. What is the best diagnosis according to the Milan System for Reporting Salivary Gland Cytopathology?

Category III: atypia of undetermined significance
Category IVA: benign neoplasm, pleomorphic adenoma
Category IVB: salivary gland neoplasm of uncertain malignant potential, with basaloid features
Category VI: malignant, adenoid cystic carcinoma

Board review style answer #1

C. Category IVB: salivary gland neoplasm of uncertain malignant potential, with basaloid features

Basaloid neoplasms showing overlapping morphology of bland basal cells and acellular metachromatic matrix are better classified as salivary gland neoplasm of uncertain malignant potential, with basaloid features. The final pathology of the same case showed a basal cell adenoma with prominent hyaline globules.

Comment Here

Reference: Milan system

Board review style question #2

A 39 year old woman presents with multiple submandibular nodules. A 2.3 cm intrasubmandibular gland nodule undergoes ultrasound guided fine needle aspiration. The cytology shows a proliferation of monotonous small lymphocytes and scattered tingible body macrophages. What is the best diagnosis according to the MSRSGC?

Category I: nondiagnostic
Category II: nonneoplastic
Category III: atypia of undetermined significance
Category VI: malignant, lymphoma

Board review style answer #2

C. Category III: atypia of undetermined significance

Bland lymphocytic aspirates showing any evidence of monomorphic population are better classified as atypia of undetermined significance. The subsequent excision of a lymph node adjacent to submandibular gland showed a follicular lymphoma.

Comment Here

Reference: Milan system

Mucinous adenocarcinoma (pending)

[Pending]

Mucocele / ranula

Table of Contents

Definition / general

Nonneoplastic cyst-like, mucus accumulation of the salivary gland (Acta Cytol 2022;66:359)

Essential features

Mucocele, sialocele and ranula are extravasation of mucin (Otolaryngol Clin North Am 2021;54:543)
Pseudocysts with no epithelial lining (Otolaryngol Clin North Am 2021;54:543)
Cyst-like structure surrounded by granulation tissue and no cyst lining epithelium
Abundant mucin with scattered macrophages and rare inflammatory cells on cytology

Terminology

Mucocele, sialocele, ranula (Otolaryngol Clin North Am 2021;54:543)

ICD coding

ICD-10: K11.6 - mucocele of salivary gland

Epidemiology

Mainly young adults and children (Otolaryngol Clin North Am 2021;54:543)
Slight female prevalence (M:F = 1:1.3) (Am J Otolaryngol 2015;36:114)

Sites

Minor salivary glands located in the lower lip, tongue, floor of mouth and buccal mucosa, uncommon in major salivary glands like parotid, submandibular or submaxillary (J Pharm Bioallied Sci 2012;4:S180, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;89:159)

Pathophysiology

Ruptured salivary gland duct and subsequent leakage of the mucin into the soft tissue surrounding salivary gland (J Oral Maxillofac Surg 2002;60:237, Med Oral Patol Oral Cir Bucal 2005;10:180)

Etiology

History of trauma to the mouth or face
Habit of biting the lip
History of previous sialolith removal (Am J Otolaryngol 2015;36:114)
Obstruction of the salivary ducts (Am J Otolaryngol 2015;36:114)

Diagrams / tables

N/A

Clinical features

Painless, gradually increasing in size, unilateral mass near or within the salivary gland

Diagnosis

Nontender, solitary, well defined, dome shaped, fluctuant nodule of buccal mucosa (J Pharm Bioallied Sci 2012;4:S180)

Laboratory

Increased protein content and amylase in aspirated material by chemical analysis (J Pharm Bioallied Sci 2012;4:S180)

Radiology description

Well defined, hypoechogenic cystic mass with sharp borders and no echoes within the mass (J Pharm Bioallied Sci 2012;4:S180)
Hourglass shaped cystic mass on CT scan (Am J Otolaryngol 2015;36:114)
Tail sign, diagnostic of sublingual ranula, communication between the sublingual and submandibular components of the cystic mass located behind the posterior free edge of the mylohyoid muscle (Am J Otolaryngol 2015;36:114)

Radiology images

Contributed by Ulrike Hamper, M.D., M.B.A.

Ultrasound, cyst

Prognostic factors

Excellent
Low to null recurrence rate (Am J Otolaryngol 2015;36:114)

Case reports

3 year old girl with an intraparotid mucocele (Br J Oral Maxillofac Surg 2020;58:1049)
5 year old boy presented with a gradual neck swelling (J Indian Assoc Pediatr Surg 2023;28:253)
23 year old man presented with left submandibular swelling (Ear Nose Throat J 2022 Feb 18 [Epub ahead of print])
25 year old man with a soft tumor mass located in the right submaxillary region (Med Oral Patol Oral Cir Bucal 2005;10:180)
39 year old woman with huge left submandibular mucocele (J Craniofac Surg 2022;33:e784)

Treatment

Surgical excision such as cystectomy, en bloc removal of the cyst and the submandibular gland, or en bloc removal of the mass, marsupialization or uproofing the large lesions to prevent significant loss of tissue, laser ablation, electrocautery, sclerotherapy and cryosurgery (J Pharm Bioallied Sci 2012;4:S180, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;89:159, Am J Otolaryngol 2015;36:114)

Clinical images

Image not free to access

Gross description

Grossly abundant glary transparent to white to blood tinged, viscous, sticky, thick mucoid material on fine needle aspiration (Diagn Cytopathol 2002;27:197, J Pharm Bioallied Sci 2012;4:S180)
Cystic structure containing viscous fluid

Gross images

Image not free to access

Frozen section description

Fibroconnective tissue and chronic inflammation

Frozen section images

N/A

Microscopic (histologic) description

Pseudocyst with a fibrous tissue wall (Am J Otolaryngol 2015;36:114)

Microscopic (histologic) images

Contributed by Zahra Maleki, M.D.

Cystic lined cavity

Virtual slides

N/A

Cytology description

Predominantly mucin and scattered macrophages and lack of epithelial cells (Acta Cytol 2022;66:359, Diagn Cytopathol 2002;27:197)

Cytology images

Contributed by Zahra Maleki, M.D.

Fine needle aspiration

Immunofluorescence description

N/A

Immunofluorescence images

N/A

Positive stains

CD68 highlights scattered macrophages
Mucicarmine stains the mucin

Negative stains

AE1 / AE3

Electron microscopy description

N/A

Electron microscopy images

N/A

Molecular / cytogenetics description

N/A

Molecular / cytogenetics images

N/A

Videos

N/A

Sample pathology report

Surgical pathology
- Parotid mass, right, resection:
  - Fragments of fibroconnective tissue with fibrosis and chronic inflammation consistent with mucocele; no epithelial component identified (see comment)
  - Comment: The imaging of the mass showed a well defined cystic mass.
Cytopathology
- Parotid, left, fine needle aspiration:
  - The Milan System for Reporting Salivary Gland Cytopathology: atypia of undetermined significance (AUS) (see comment) (Cancer Cytopathol 2021;129:214)
  - Comment: The specimen consists of predominantly mucin and rare macrophages. The differential diagnosis includes mucocele, low grade mucoepidermoid carcinoma, Warthin tumor and less likely, pleomorphic adenoma.
  - Recommend: Clinical and radiographic correlation.

Differential diagnosis

Low grade mucoepidermoid carcinoma:
- Abundant mucin
- Rare mucin containing epithelial cells
- Rare clusters of malignant epithelial cells (Acta Cytol 2022;66:359, J Oral Maxillofac Surg 2010;68:2146)
Retention cyst:
- Mucinous cystic contents
- Lacks the extensive surrounding chronic inflammation
- Surrounded by epithelial lining (J Pharm Bioallied Sci 2012;4:S180)
Warthin tumor:
- Double layer of oncocytic epithelium
- Dense lymphoid aggregate underneath the epithelium

Differential diagnosis in cytology

Warthin tumor:
- Polymorphous lymphocytes and fragments of oncocytic epithelium in a dirty mucoid background (Diagn Cytopathol 2002;27:197)
Low grade mucoepidermoid carcinoma:
- Fragments of malignant epithelial cells and scattered squamous cells in a background of abundant mucin (Diagn Cytopathol 2002;27:197)
Pleomorphic adenoma:
- Cystic change and abundant mucoid / myxoid background or dilated ducts (Diagn Cytopathol 2002;27:197)

Additional references

Int J Pediatr Otorhinolaryngol 2023;166:111481, Minerva Dent Oral Sci 2021;70:263, J Investig Clin Dent 2019;10:e12410, Orv Hetil 2018;159:1516

Board review style question #1

Fine needle aspirate (FNA) of a cystic sublingual mass in a 23 year old woman is shown above. The patient noticed a small bump 2 weeks ago. The aspirated material looks like the image shown. What is the most likely diagnosis?

Mucocele
Mucoepidermoid carcinoma
Squamous cell carcinoma
Warthin tumor

Board review style answer #1

A. Mucocele. Mucocele consists of mucin and scattered macrophages. Answer B is incorrect because there are no atypical epithelial cells or mucin producing cells. Mucoepidermoid carcinoma is more cellular than the above case. Answer C is incorrect because there are no malignant squamous cells. Squamous cell carcinoma consists of malignant squamous cells with variable degree of maturation and intracellular keratin. Anisonucleaosis and pleomorphism are common features of squamous cell carcinoma in cytology specimens. Answer D is incorrect because there are no oncocytes or lymphocytes. Warthin tumor consists of fragments of oncocytes and lymphocytes in a cystic background.

Comment Here

Reference: Mucocele / ranula

Board review style question #2

Fine needle aspirate (FNA) of a submandibular gland is shown above. 2 passes were performed and all slides displayed the same cytomorphology. The mass completely disappeared after the aspiration. What is the most correct diagnosis when applying the Milan System for Reporting Salivary Gland Cytology?

Atypia of undetermined significance
Malignant
Nondiagnostic
Nonneoplastic

Board review style answer #2

A. Atypia of undetermined significance. Abundant mucin even without any epithelial cells is considered atypical in the Milan system due to a risk of malignancy and potential overlap with low grade mucoepidermoid carcinoma. Answer C is incorrect because there is abundant mucin in the background. Answer D is incorrect because there is no salivary gland epithelium and there are no salivary gland acini. Answer B is incorrect because there is no epithelial component indicating a malignant process such as acinic cell carcinoma.

Comment Here

Reference: Mucocele / ranula

Mucocele / ranula (pending)

[Pending]

Mucoepidermoid carcinoma

Table of Contents

Definition / general

Malignant glandular epithelial neoplasm characterized by mucous, intermediate and epidermoid cells, with columnar, clear cell or oncocytoid features

Essential features

Malignant epithelial neoplasm
Characterized by mucous, intermediate and epidermoid cells, with columnar, clear cell or oncocytoid features
Most common malignant salivary gland neoplasm in both adults and children
Prognosis influenced by tumor stage, tumor site, surgical margins (WHO 2017)
Associated with a specific translocation t(11;19)(q14-21;p12-13) with CRTC1(MECT1)-MAML2 fusion

Terminology

Mucoepidermoid carcinoma (MEC)
Not recommended: mucoepidermoid tumor

ICD coding

ICD-O: 8430/3 - mucoepidermoid carcinoma
ICD-10 (depends on site):
- C08.0 - malignant neoplasm of submandibular gland
- D48.7 - neoplasm of uncertain behavior of other specified sites
- C07 - malignant neoplasm of parotid gland
- C08.9 - malignant neoplasm of major salivary gland, unspecified

Epidemiology

Most common malignant salivary gland tumor (adults and children) (Br J Oral Maxillofac Surg 2013;51:399)
Represents 10 - 15% of all salivary gland tumors (Br J Oral Maxillofac Surg 2013;51:399)
Adults: wide age range (15 - 86 years, median 49 years) (Am J Surg Pathol 2001;25:835)
Children: 11 - 15 years (median 13 years) (Int J Pediatr Otorhinolaryngol 2019;120:93)
F > M (slight predominance) (Br J Oral Maxillofac Surg 2013;51:399)

Sites

Occurs in major and minor salivary glands (predominance of major > minor) (Eur J Surg Oncol 2021;47:1376)
Major: parotid > submandibular > sublingual (Eur J Surg Oncol 2021;47:1376)
Minor: palate, buccal mucosa, retromolar region (Indian J Pathol Microbiol 2018;61:397)
Rarely occurs in sinonasal tract, nasopharynx, lungs and intraosseous mandible (Int Forum Allergy Rhinol 2019;9:1046, Expert Rev Respir Med 2018;12:249, Case Rep Dent 2018;2018:9348540)

Etiology

Possible association with ionizing radiation (Indian J Pathol Microbiol 2018;61:397)

Clinical features

In one study, 33% of patients are asymptomatic; however, varies with tumor site and size (J Stomatol Oral Maxillofac Surg 2020;121:713)
Most common presentation is painless swelling with pressure and discomfort
Can be variably fixed, rubbery or soft mass (J Stomatol Oral Maxillofac Surg 2020;121:713)

Diagnosis

Preoperative assessment (radiology) may consist of:
- Ultrasonography (USG) for small tumors in major salivary glands
- Larger recurrent tumors: CT imaging for bone involvement, MRI for soft tissue delineation (Semin Radiat Oncol 2012;22:245)
- Evidence of (18)-fluorodeoxyglucose positron emission tomography CT in locoregionally advanced tumors (Nucl Med Commun 2013;34:211)
Preoperative assessment (fine needle aspiration)

Radiology description

Influenced by tumor size, location and possibly tumor grade
Ultrasonography:
- Typically a well circumscribed hypoechoic lesion, with a partial or completely cystic appearance against a relatively hyperechoic normal parotid gland
CT:
- Lower grade tumors are well circumscribed with cystic component (see Radiology images)
- Enhancing solid component and calcifications occasionally seen
- Higher grade tumors are solid and show poorly defined, infiltrative margins
MRI:
- Low grade tumors are similar in appearance to a pleomorphic adenoma
- Higher grade tumors are solid, with a lower signal on T2 and poorly defined margins
Reference: Radiopaedia: Mucoepidermoid Carcinoma of Salivary Glands [Accessed 8 January 2021]

Radiology images

Images hosted on other servers:

Parotid mucoepidermoid carcinoma, CT

Prognostic factors

Adults:
- Excellent prognosis, with approximately 98.8% 5 year survival rate in low grade and 97.4% in intermediate grade tumors
- About 67% 5 year survival rate for high grade tumors
Children:
- 5 year survival of 98%, as they predominantly present with low to intermediate grade tumors
Negative prognostic variables
- Tumor arising in the submandibular gland: lymph node metastases common
- Positive surgical margins
- Extraparenchymal extension
- Nodal / distant metastases
- Increased expression of MUC1
References: J Stomatol Oral Maxillofac Surg 2020;121:713, Wenig: Atlas of Head and Neck Pathology, 3rd Edition, 2016

Case reports

16 year old boy with a mandibular radiolucent lesion (Case Rep Dent 2018;2018:9348540)
36 year old man with a left parotid gland mass (Anticancer Res 2019;39:3213)
69 year old woman with a right submental mass (Eur Ann Otorhinolaryngol Head Neck Dis 2017;134:355)

Treatment

Complete surgical resection
- Conservative approach for stage I and stage II tumors
- Wide excision with wide margin for high grade tumors or tumors with positive margins
Neck lymph node dissection (depends on nodal status and histologic grade)
Adjuvant radiotherapy and chemotherapy might be considered for higher grade tumors
Reference: J Stomatol Oral Maxillofac Surg 2020;121:713

Gross description

Incompletely encapsulated or unencapsulated
Well circumscribed
Low grade: often cystic
High grade: often solid, necrotic, tan-pink
References: J Stomatol Oral Maxillofac Surg 2020;121:713, Wenig: Atlas of Head and Neck Pathology, 3rd Edition, 2016

Gross images

Contributed by Kelly Magliocca D.D.S., M.P.H.

Cut surface, high grade

Frozen section description

Higher grade tumors can be mistaken for squamous cell carcinoma, a pitfall (Cancer 2004;100:1876)

Frozen section images

Contributed by Rema A. Rao, M.D. and Saeed Asiry, M.D.

Positive margin for tumor

Microscopic (histologic) description

Solid, cystic or mixed growth patterns
Can show papillary or glandular growth pattern
Areas suggesting a capsule can be seen in low grade mucoepidermoid carcinoma
Varying proportions of epidermoid cells, intermediate cells and mucocytes
Solid nests, sheets or cords of epidermoid cells
Overt keratinization is rare
Mucous cells embedded in epidermoid cell nests or lining cystic spaces
Intermediate cells found within epidermoid cell nests or forming separate nests
Background stromal sclerosis
Luminal or extracellular pools of mucin may be present
Mitosis, necrosis and pleomorphism more commonly seen in high grade tumors
Limited number of mucocytes and cystic spaces in high grade tumors
Perineural and lymphovascular invasion possible (Wenig: Atlas of Head and Neck Pathology, 3rd Edition, 2016)
Focal clear cell changes can occur due to accumulation of glycogen
Histologic variants: clear cell, oncocytic, sclerosing, Warthin-like, ciliated, spindle cell and mucoacinar (Am J Surg Pathol 2015;39:1479, Am J Surg Pathol 2018;42:130, Int J Surg Pathol 2017;25:705, Am J Surg Pathol 2021;45:1028, Am J Surg Pathol 1999;23:523)
Reference: J Stomatol Oral Maxillofac Surg 2020;121:713

Histopathologic grading:

4 histologic grading systems (2 quantitative and 2 qualitative)
2 different morphologic quantitative point systems, although histologic grading using any grading system appears to be inconsistent (Am J Surg Pathol 2019;43:885)
Significant grading disparity between pathologists (Am J Surg Pathol 2019;43:885)
Armed Forces Institute of Pathology (AFIP) grading scheme (quantitative) (Am J Surg Pathol 2019;43:885)
- Criteria:
  - Intracystic component less than 20% (2)
  - Neural invasion (2)
  - Necrosis (3)
  - 4 or more mitoses (3)
  - Anaplasia (4)
- Grade:
  - Low grade (0 - 4)
  - Intermediate grade (5 - 6)
  - High grade (7 or more)
Brandwein et al. grading scheme (quantitative) (Am J Surg Pathol 2001;25:835)
- Criteria:
  - Intracystic component less than 25% (2)
  - Tumor front invades in small nests and islands (2)
  - Pronounced nuclear atypia (2)
  - Lymphovascular invasion (3)
  - Bony invasion (3)
  - 4 or more mitoses (3)
  - Perineural invasion (3)
  - Necrosis (3)
- Grade:
  - Low grade (0)
  - Intermediate grade (2 - 3)
  - High grade (4 or more)
Modified Healy grading system (qualitative)
- Low grade
  - Macro and microcysts
  - Rare intermediate cells
  - Rare mitotic figures
  - Absent or minimal nuclear pleomorphism
  - Well circumscribed tumor with broad edges
  - Extravasated mucin and fibrotic stroma present
- Intermediate grade
  - Microcysts and solid component
  - More intermediate cells
  - Few mitotic figures
  - Slight nuclear pleomorphism
  - Uncircumscribed tumor
  - Fibrotic stroma separating tumor nests
- High grade
  - Predominantly solid, with or without microcysts
  - Perineural invasion present
  - Lymphovascular invasion present
  - Surrounding soft tissue invasion present
  - Many mitotic figures
  - Nuclear pleomorphism, including presence of prominent nucleoli
  - Predominance of intermediate cells
  - Desmoplastic stoma
Memorial Sloan Kettering Cancer Center (MSKCC) grading system (qualitative)
- Low grade
  - Predominantly cystic growth pattern (> 80%)
  - 0 - 1 mitotic figures/10 high power fields (HPF)
  - Well circumscribed
  - No necrosis
- Intermediate grade
  - Predominantly solid growth pattern
  - 2 - 3 mitotic figures/10 high power fields (HPF)
  - Well circumscribed or infiltrative
  - No necrosis
- High grade
  - Any growth pattern but usually solid
  - ≥ 4 mitotic figures/10 high power fields (HPF)
  - Usually infiltrative
  - Necrosis is present

Microscopic (histologic) images

Contributed by Rema A. Rao, M.D. and Saeed Asiry, M.D.

Tumor architecture

Tumor cell types

Epidermoid cells

Mucus cells

Intermediate cells

Clear cell changes

Case #346

4 year old boy

Ki67

Mucicarmine

Virtual slides

Images hosted on other servers:

Low grade mucoepidermoid carcinoma

Cytology description

Most often graded as low grade or high grade on FNA
Low to intermediate grade:
- Can be acellular or hypocellular smears
- Extracellular mucin may be the prominent feature
- Cystic background
- Aggregates of epidermoid cells, intermediate cells and mucocytes
- Epidermoid cells appear as bland cohesive flat sheets with squamoid / dense cytoplasm and well defined cellular borders
- Predominantly mucus cells floating in extracellular mucin (low grade)
- No keratinization seen
- Lympocytes present in about 20% of cases and are abundant
High grade:
- Highly cellular aspirates
- High grade nuclear features with pleomorphic nuclei, prominent nucleoli
- Intermediate cells and mucous cells are rare
- Increased mitosis
- Necrotic background
References: J Clin Diagn Res 2017;11:ER04, Cibas: Cytology - Diagnostic Principles and Clinical Correlates, 5th Edition, 2020

Cytology images

Contributed by Rema A. Rao, M.D. and Saeed Asiry, M.D.

Background mucin

Neoplastic cells

Mucus cells

Neoplastic cells in sheets

Keratinizing cells

Single keratinizing cells

Crowded squamous cells

Images hosted on other servers:

Low grade and oncocytic tumors

Positive stains

Pancytokeratin, CK5/6, p63, p40, EMA, CK7, CK14
Membrane bound mucins: MUC1, MUC2, MUC4, MUC5AC and MUC5B
Mucocytes: mucin positive for mucicarmine and PASD (diastase resistant) stains
Reference: J Stomatol Oral Maxillofac Surg 2020;121:713

Negative stains

S100, GFAP, calponin, muscle specific actin, androgen receptor, HER2, DOG1, CK20 (Arch Pathol Lab Med 2015;139:55)
SOX10: rare cases may be positive (Hum Pathol 2016;56:134)
Mammaglobin: some cases may show positive cells (Hum Pathol 2016;56:134)
GATA3: occasional cells may be positive (Hum Pathol 2016;56:134)

Electron microscopy description

Epidermoid cells attached to each other with desmosomes and mucus cells showing mucous globules with stellate mucoid material (Oral Surg Oral Med Oral Pathol 1979;47:247)

Molecular / cytogenetics description

t(11;19)(q14-21;p12-13) with CRTC1(MECT1)-MAML2 fusion (Nat Genet 2003;33:208)
- Present in 80% of mucoepidermoid carcinoma (Am J Surg Pathol 2016;40:1151)
- Low to intermediate grade (78%), high grade (84%) (Am J Surg Pathol 2016;40:1151)
- Detected by fluorescence in situ hybridization (FISH) or RT-PCR (Am J Surg Pathol 2019;43:885)

Molecular / cytogenetics images

Images hosted on other servers:

FISH analysis of MAML2

Sample pathology report

Parotid gland, right, parotidectomy:
- Mucoepidermoid carcinoma, intermediate grade (2.3 cm)
- The tumor is confined to the parotid gland.
- No lymphovascular or perineural invasion is identified.
- Three lymph nodes, negative for carcinoma (0/3).
- Surgical margins negative for carcinoma.
- Carcinoma 0.3 cm of closest margin, medial.
- See synoptic report.

Differential diagnosis

For low to intermediate grade tumors:
- Necrotizing sialometaplasia (Acta Otorrinolaringol Esp 2020;71:328):
  - Lobular pattern, lacks cystic pattern, no intermediate cells
- Pleomorphic adenoma with squamous and mucinous cell metaplasia (J Oral Maxillofac Pathol 2018;22:S69):
  - Composed of epithelial and myoepithelial cells and extracellular matrix material
- Warthin tumor with squamous metaplasia (J Med Case Rep 2019;13:12):
  - Lacks the translocations seen in mucoepidermoid carcinoma
  - Shows bilayered oncocytic epithelium
- Acinic cell carcinoma (Eur Arch Otorhinolaryngol 2016;273:3511):
  - DOG1 and SOX10 positive
- Mammary analogue secretory carcinoma (MASC) (Bosn J Basic Med Sci 2016;16:237):
  - S100 positive
For high grade tumors:
- Squamous cell carcinoma (primary or secondary) (J Cancer Res Ther 2015;11:664):
  - Shows keratinization and intercellular bridges
  - Lacks intermediate cells and mucocytes
- Salivary duct carcinoma (Head Neck Pathol 2017;11:288):
  - GATA3, HER2 and androgen receptor positive
  - Shows a Roman bridge pattern, comedonecrosis

Additional references

Goldblum: Rosai and Ackerman's Surgical Pathology, 11th Edition, 2017, El-Naggar: WHO Classification of Head and Neck Tumours, 4th Edition, 2017

Board review style question #1

Which of the following is true about mucoepidermoid carcinoma?

Associated with t(12;15)(p12;q25) and ETV6-NTRK3 gene fusion
Highly associated with smoking
Most common malignant salivary tumor in children
Positive for HER2 and AR by immunohistochemistry
Prognosis is poor regardlesss of histologic grade

Board review style answer #1

C. Most common malignant salivary tumor in children

Comment Here

Reference: Mucoepidermoid carcinoma

Board review style question #2

Which of the following histologic features is more commonly seen in low to intermediate grade mucoepidermoid carcinoma?

4 or more mitoses
Bone invasion
Intracystic component more than 30%
Necrosis
Perineural invasion

Board review style answer #2

C. Intracystic component more than 30%

Comment Here

Reference: Mucoepidermoid carcinoma

Board review style question #3

The focal clear cell change seen in this mucoepidermoid carcinoma case is due to

Accumulation of glycogen
Accumulation of mucin
Degradation of neoplastic cells
Fixation artifact
High grade transformation

Board review style answer #3

A. Accumulation of glycogen

Comment Here

Reference: Mucoepidermoid carcinoma

Myoepithelial carcinoma

Table of Contents

Definition / general

Myoepithelial carcinoma of the salivary gland is a carcinoma that is composed exclusively or near exclusively of myoepithelial cells
May arise de novo or ex pleomorphic adenoma

Essential features

Carcinoma composed entirely of myoepithelial cells showing invasive growth
Subclassified as de novo or ex pleomorphic adenoma (ex PA)
Over 50% shows PLAG1 fusion

Terminology

Malignant myoepithelioma (not recommended)

ICD coding

ICD-O: 8430/3 - mucoepidermoid carcinoma
ICD-11: 2B67.Y - other specified malignant neoplasms of parotid gland

Epidemiology

May affect patients of a wide age range: the reported median age of presentation is 59 years (range: 14 - 90) (Am J Surg Pathol 2015;39:931, Arch Otolaryngol Head Neck Surg 2010;136:702)
No obvious gender predilection
May occur in pediatric population (Hum Pathol 2017;67:37)
Accounts for approximately 4% of salivary gland neoplasms (Arch Otolaryngol Head Neck Surg 2010;136:702)
Frequency may be underestimated, as myoepithelial carcinoma is generally underrecognized (Surg Pathol Clin 2021;14:67, Am J Surg Pathol 2019;43:601)

Sites

Parotid gland is the most common site of involvement, accounting for 24 - 73% of cases (J Oral Maxillofac Surg 2015;73:1938, Am J Surg Pathol 2015;39:931, Arch Otolaryngol Head Neck Surg 2010;136:702)
Sites of involvement in a descending frequency are the parotid gland, minor salivary glands (especially those from the palate) and the submandibular gland (J Oral Maxillofac Surg 2015;73:1938, Am J Surg Pathol 2015;39:931, Arch Otolaryngol Head Neck Surg 2010;136:702)

Clinical features

Nonspecific; the most commonly presentation is a painless mass (Arch Otolaryngol Head Neck Surg 2010;136:702)

Diagnosis

Definite diagnosis can only be rendered in resection specimen by demonstrating invasiveness and (near) pure myoepithelial population within the tumor

Radiology description

CT shows a solitary, lobulated or multinodular, heterogeneously enhancing mass with a partial ill defined border (Oral Surg Oral Med Oral Pathol Oral Radiol 2017;123:e182)

Radiology images

Images hosted on other servers:

Multinodular parotid mass (arrows)

Prognostic factors

Relatively aggressive clinically: 15 - 27% develops distant metastasis and over 33% have local recurrence (Arch Otolaryngol Head Neck Surg 2010;136:702, J Oral Maxillofac Surg 2015;73:1938, Am J Surg Pathol 2015;39:931, Am J Surg Pathol 2000;24:761, Arch Biochem Biophys 1989;269:272)
Higher propensity for distant rather than regional metastasis
Reported adverse prognostic factors include myoepithelial carcinoma ex pleomorphic adenoma, necrosis, high mitotic index (> 4 per 10 high power fields) and positive margin status (Am J Surg Pathol 2015;39:931, Arch Otolaryngol Head Neck Surg 2010;136:702)

Case reports

28 year old woman with a 4.0 cm parotid mass (Case Rep Otolaryngol 2020;2020:8325374)
64 year old patient present with a large mass in the maxillary sinus (Head Neck Pathol 2021 Jan 4 [Epub ahead of print])
65 year old African American man with a painless hard palate mass metastasizing to lung and spine (Case Rep Pathol 2019;2019:3863270)

Treatment

Surgical resection with negative margin is considered the standard of care

Gross description

Gross appearance is nonspecific
Tumor is often present as an expansile, lobulated to multinodular, beige to white mass, sometimes with ill defined / infiltrative border

Gross images

Contributed by Abeer Salama, M.D. and Bin Xu, M.D., Ph.D.

Lobulated parotid mass

Microscopic (histologic) description

Invasiveness is typically demonstrated as expansile invasive multinodular growth: myoepithelial carcinoma rarely shows infiltration of single cells / small clusters or desmoplastic reaction
Nodules often have a hypocellular center with hyalinized stroma or bland necrosis surrounded by a hypercellular peripheral zone
Tumor necrosis can be seen within the hypercellular central zone of a tumor nodule
Currently, there is no well defined, widely accepted grading system: presence of tumor necrosis is considered by some as a feature of high grade myoepithelial carcinoma (Am J Surg Pathol 2015;39:931)
Composed (near) entirely of myoepithelial cells showing various cytologic features, including clear cell, epithelioid, plasmacytoid or spindle cell morphology
Hyalinized, myxoid or myxochondroid stroma may be seen in myoepithelial carcinoma de novo and ex PA
Common architectural patterns include solid, trabeculae, cords, nests and single cells
Presence of pre-existing / residual pleomorphic adenoma component can be seen in myoepithelial carcinoma ex PA

Microscopic (histologic) images

Contributed by Abeer Salama, M.D. and Bin Xu, M.D., Ph.D.

Multinodular invasive growth

Expansile lobulated growth

Necrotic hypocellular central zone

Myoepithelial carcinoma ex PA

Epithelioid features

Plasmacytoid features

Clear cell features

Spindle cell features

S100 immunostain

CAM5.2 immunostain

Calponin immunostain

Cytology description

Hypercellular specimen composed entirely of myoepithelial cells
Myoepithelial cells shows a mixture of plasmacytoid, epithelioid or spindle morphology arranges as small groups or single cells (Cancer 2002;96:32, Kokyu To Junkan 1985;33:533)
Scant amount of metachromatic stroma, mitotic figures and nuclear pleomorphism may be present

Cytology images

Images hosted on other servers:

Diff-Quik stain

Positive stains

Cytokeratins (e.g. AE1 / AE3 and CAM 5.2)
Myoepithelial markers: S100, calponin, SMA and GFAP
p63 and p40
SOX10
PLAG1
While there should be positivity for myoepithelial markers, not all may be positive in a single case
Reference: Surg Pathol Clin 2021;14:67

Negative stains

Melanocytic markers, such as HMB45 and MelanA (Surg Pathol Clin 2021;14:67)

Molecular / cytogenetics description

PLAG1 fusion is the most common molecular event, being detected in approximately 50% of myoepithelial carcinoma de novo and ex PA (Nat Commun 2017;8:1197, Am J Surg Pathol 2021;45:1)
- Fusion partners include FGFR1, TGFBR3, ND4 and others
Clear cell myoepithelial carcinoma may additionally show EWSR1 fusion (Am J Surg Pathol 2015;39:338, Am J Surg Pathol 2021;45:1, Nat Commun 2017;8:1197)
Despite EWSR1 rearrangements by FISH, corresponding fusion transcripts have not been identified in most cases and the significance is unclear
Small proportion has HMGA2 fusion (Nat Commun 2017;8:1197)

Molecular / cytogenetics images

Images hosted on other servers:

Molecular signature (oncoprint)

Sample pathology report

Parotid gland, left; superficial parotidectomy:
- Myoepithelial carcinoma, high grade, 3.5 cm (see comment and synoptic report)
- Comment: The tumor shows a mitotic index of 8 per 10 high power fields. Tumor necrosis is noted. Immunohistochemistry studies show that the tumor is positive for S100, calponin and CAM5.2, whereas negative for HMB45. The morphologic and immunohistochemical features are most consistent with myoepithelial carcinoma.

Differential diagnosis

Myoepithelioma:
- Benign counterpart of myoepithelial carcinoma
- Encapsulated without evidence of invasion (being capsular, vascular and perineural)
Pleomorphic adenoma:
- Similarity:
  - Pleomorphic adenoma can be myoepithelial rich and may contain areas with pure myoepithelial cells
  - Pleomorphic adenoma may have pseudopod(s) protruding outside of tumor capsule
- Difference:
  - Pleomorphic adenoma lacks the multinodular / lobulated invasive growth of myoepithelial carcinoma and contains areas typical of pleomorphic adenoma with ductal, myoepithelial and stromal component
Polymorphous adenocarcinoma:
- Both tumors contained one cell type and are positive for S100
- Other myoepithelial markers, e.g. calponin and SMA, are typically negative or very focally positive in polymorphous adenocarcinoma
- Polymorphous adenocarcinoma shows architectural diversity with single filing, trabecular, cribriform, papillary and solid growth pattern, whereas myoepithelial carcinoma usually has cord and solid architecture
- Myxoid stromal component may be seen in polymorphous adenocarcinoma but is usually focal
- Polymorphous adenocarcinoma shows mutations or fusion involving PRKD 1 / PRKD 2 / PRKD 3 genes, whereas myoepithelial carcinoma has frequent PLAG1 fusion
Myoepithelial tumor of the soft tissue:
- Myoepithelial tumors arising from salivary glands or soft tissue are indistinguishable on histology and immunohistochemistry level (Head Neck Pathol 2020;14:121)
- EWSR1 fusions with POU5F1, PBX1, ZNF444, KLF17 and PBX3 seem restricted to soft tissue myoepithelial tumors (Head Neck Pathol 2020;14:121)
- Radiological correlation is essential to determine the site of origin

Additional references

El-Naggar: WHO Classfication of Head and Neck Tumours, 4th Edition, 2017

Board review style question #1

A parotid tumor is resected from a 46 year old man. The tumor is positive for S100, cytokeratin AE1 / AE3 and calponin, whereas negative for AR. What is the diagnosis?

Adenoid cystic carcinoma
Myoepithelial carcinoma
Pleomorphic adenoma
Salivary duct carcinoma

Board review style answer #1

B. The low power H&E clearly shows invasion, which supports a diagnosis of carcinoma and excludes benign entities, such as pleomorphic adenoma. At high power, the tumor contains one type of tumor cells, which exclude all carcinoma with biphasic patterns (e.g. adenoid cystic carcinoma). The immunohistochemical profile is consistent with myoepithelial phenotype. Therefore, the correct diagnosis is myoepithelial carcinoma.

Comment Here

Reference: Myoepithelial carcinoma

Board review style question #2

Which of the following statement about the myoepithelial carcinoma of the salivary gland is true?

It harbors PRKD1 fusion
It has negligible risk of distant metastasis
It is biphasic, composed of epithelial (ductal) and myoepithelial elements
It may arise de novo or ex pleomorphic adenoma

Board review style answer #2

D. Myoepithelial carcinoma contains only one cell type (myoepithelial cells) and does not contain epithelial (ductal) cells. PRKD1 fusion is seen in polymorphous adenocarcinoma / cribriform adenocarcinoma. Myoepithelial carcinoma is relatively aggressive, with approximately 20% risk of distant metastasis. It may arise de novo or ex pleomorphic adenoma.

Comment Here

Reference: Myoepithelial carcinoma

Myoepithelioma

Table of Contents

Definition / general

Rare, benign tumor composed almost exclusively of myoepithelial cells

Essential features

Epithelial component should be less than 5% (some consider even focal epithelial differentiation sufficient to label the tumor as pleomorphic adenoma) (J Oral Maxillofac Pathol 2013;17:257)
Monomorphic histology and rare or absent ductal structures in myoepithelioma differentiate it from pleomorphic adenoma

Terminology

Formerly considered a variant of pleomorphic adenoma; recognized as a distinct entity by WHO in 1991 (Clin Pract 2014;4:628, Pathol Res Pract 1990;186:555)
Not recommended: myoepithelial cell tumor, myoepithelial adenoma

ICD coding

ICD-O: 8982/0 - myoepithelioma
ICD-10: D11.0 - benign neoplasm of parotid gland

Epidemiology

1% of all salivary gland neoplasms (Case Rep Oncol 2014;7:310)
2.2% of major and 5.7% of minor salivary gland neoplasms, respectively (Case Rep Oncol 2014;7:310)
No sex predilection (Clin Pract 2014;4:628)
Myoepithelioma of parotid occurs in older people and is composed more often of spindle and epithelial cells (Am J Surg Pathol 2003;27:1183, Histopathology 1995;27:1)
Myoepithelioma of minor glands occurs in slightly younger individuals and is composed of plasmacytoid cells (Am J Surg Pathol 2003;27:1183, Histopathology 1995;27:1)

Sites

Affects the parotid gland (~40%) and minor salivary gland sites (palate) (~21%) (Case Rep Oncol 2014;7:310, Arch Otolaryngol Head Neck Surg 2003;129:359)

Pathophysiology

Arising from neoplastic myoepithelial cells located between the basement membrane and the basal plasma membrane of acinar or ductal / luminal cells
Accumulation of p53 and overexpression of KIT receptor have been implicated in malignant progression (J Clin Pathol 1998;51:552, Cancer Lett 2000;154:107)

Etiology

Myoepithelial cells are contractile cells originating from the ectoderm, found in normal tissues with secretory function that aids in excreting glandular secretions (Ear Nose Throat J 2011;90:E9, Clin Pract 2014;4:628)
Common stem cell with a bidirectional differentiation into epithelial or myoepithelial cell is hypothesized to be the cell of origin; the varied histological types (spindle, plasmacytoid, epithelioid, clear and oncocytic) exhibited by myoepitheliomas can be attributed to the various stages in the differentiation from a cell that has the potential to differentiate into epithelial cells (J Clin Diagn Res 2013;7:1165)
Myoepitheliomas and pleomorphic adenomas are hypothesized to exist along a continuum, with a shared chromosome 12q cytogenetic abnormality (Cancer Genet Cytogenet 1999;113:49)

Clinical features

No distinctive clinical features
1% of salivary gland tumors, more common in parotid (40%) and minor salivary gland (21%) (Case Rep Oncol 2014;7:310, Arch Otolaryngol Head Neck Surg 2003;129:359)
Usual age of presentation is 40 - 50 years (range: 9 - 85 years)
No sex predilection (Clin Pract 2014;4:628)
Slow growing, painless, well circumscribed mass
Recurs locally if incomplete removal (Semin Diagn Pathol 1997;14:203)
Clear cell variant may have unpredictable clinical course despite being histologically benign (Rosai: Ackerman's Surgical Pathology, 8th Edition, 1996)

Diagnosis

Diagnosis is often rendered in resection specimen

Radiology description

Located chiefly in the superficial lobe and abutted on the capsule of the gland
CT: well circumscribed, enhancing mass lesion with smooth or lobulated margins (AJNR Am J Neuroradiol 2008;29:1372)
May contain enhancing nodules and nonenhancing areas of linear bands, slit-like shaped or of cystic configuration
MRI: well circumscribed, lobulated, inhomogeneous enhancement, apparent diffusion coefficient, different from Warthin tumor and similar to pleomorphic adenoma (AJNR Am J Neuroradiol 2009;30:591)

Prognostic factors

Malignant transformation to myoepithelial carcinoma has been reported but seems to be extremely rare (Ultrastruct Pathol 1996;20:145, Am J Surg Pathol 2000;24:761)

Case reports

29 year old woman with plasmacytoid myoepithelioma of palate (Head Neck Pathol 2011;5:154)
41 year old woman with myoepithelioma as a palatine nodule (J Oral Med Oral Surg 2018;24:81)
80 year old man with cystic clear cell myoepithelioma of parotid gland (Oral Maxillofac Surg 2009;13:45)
86 year old woman with a mucinous myoepithelioma (SAGE Open Med Case Rep 2020;8:2050313X20940567, Head Neck Pathol 2013;7:S85)
3 cases of myoepithelioma in minor salivary glands (J Oral Maxillofac Pathol 2013;17:257)
Oncocytic myoepithelioma of salivary gland (Virchows Arch 1999;434:537)

Treatment

Complete surgical excision with free margin recommended (Clin Pract 2014;4:628)
Regular follow up to evaluate for local recurrence

Clinical images

Images hosted on other servers:

Plasmacytoid myoepithelioma of minor salivary glands

Gross description

Up to 5 cm; encapsulated, may have cystic change
Absence of grossly myxoid or chondroid areas
Solid, tan or yellow-tan glistening cut surface
Usually encapsulated in parotid gland and no capsule for those in minor salivary glands (Ear Nose Throat J 2001;80:155)

Frozen section description

Nonspecific, may show atypical cells, usually need to defer to permanent for further characterization

Microscopic (histologic) description

Spindled, epithelioid, plasmacytoid, clear or oncocytic cells; most tumors are composed of a single cell type but combinations may occur (Clin Pract 2014;4:628)
Well circumscribed or encapsulated with a thin capsule
Stroma, when present, may be hyalinized, fibrous, myxoid or mucoid; lipomatous stroma may rarely been seen.
Encapsulation uncommon in minor salivary gland tumors
Architectural pattern: solid (non-myxoid), myxoid, reticular (canalicular-like) or mixed patterns of myoepithelial cells with no ductal differentiation
Mucinous myoepithelioma is rarely reported; contains abundant intracellular mucin material, which may be mistaken for signet ring cell adenocarcinoma of salivary gland with positive myoepithelial markers and should be distinguished from secretory myoepithelial carcinoma (Head Neck Pathol 2013;7:S85)

Microscopic (histologic) images

Contributed by Xiaofeng Zhao, M.D., Ph.D. and Shuanzeng Wei, M.D., Ph.D.

Spindle cell type

Epithelioid type

Nest / trabecular pattern

Cytology description

Monotonous spindle cell, plasmacytoid cells or epithelioid cells (J Oral Maxillofac Pathol 2014;18:131)
No glandular / ductal cells
Can have nuclear grooves, intranuclear cytoplasmic inclusions, no marked pleomorphism, no mitoses

Cytology images

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

Cellular specimen

Monotonous epithelioid cells

Positive stains

GFAP, S100, SMA, calponin, HHF35 / muscle specific actin, CD10, CK14, CEA (variable), p63 (J Cell Biol 1980;84:633, Acta Histochem Cytochem 2012;45:269)

Negative stains

Plasmacytoid variant may be negative for all myoepithelial markers

Electron microscopy description

Composed of a single cell population characterized by numerous cytoplasmic filaments, duplication of basement membrane material and characteristic cytoplasmic appearance of myoepithelial cells (Arch Pathol 1974;98:312, Oral Oncology Extra 2005;41;104)

Molecular / cytogenetics description

Clear cell myoepithelial carcinoma can have EWSR1 rearrangement (Am J Surg Pathol 2015;39:338)
NTF3-PLAG1, FBXO32-PLAG1 and GEM-PLAG1 fusions have been detected in oncocytic myoepithelioma (Hum Pathol 2020;103:52)
Detection of PLAG1 rearrangement by cytogenetics or other methods can be helpful (Ann Diagn Pathol 2017;28:19, Hum Pathol 2020;103:52)

Sample pathology report

Parotid, right, parotidectomy:
- Myoepithelioma, 3.6 cm, completely excised

Differential diagnosis

Myoepithelial carcinoma:
- Invasive growth pattern
- Low recurrence rate
- For palatal myoepitheliomas, encapsulation is not a reliable criterion
- High cell proliferative activity (i.e. 7 mitosis instances per 10 high power fields or a Ki67 labeling index > 10%) may indicate malignancy (Cancer 1998;83:1292)
- Spindle morphologic characteristics were observed with nodal and distant metastasis (Arch Otolaryngol Head Neck Surg 2010;136:702)
Basal cell adenoma:
- Ductal (epithelial) cells present
Pleomorphic adenoma:
- Fibromyxoid stroma and ductal structure present
Spindle cell soft tissue neoplasm, nerve sheath tumor, fibrous histiocytoma, nodular fasciitis, synovial sarcoma, leiomyoma, leiomyosarcoma and hemangiopericytoma:
- Keratin negative
Plasmacytoma:
- Perinuclear clearing (hof)
- Positive for plasma cell markers, such as CD138

Board review style question #1

A 46 year old man presents with swelling close to his right ear. Imaging reveals a well circumscribed 1.8 cm nodule in the parotid gland. Biopsy findings are shown in the picture above. Which of the following statements about this tumor is true?

Monomorphic tumor cells and absence of ducts help to differentiate myoepithelioma from pleomorphic adenoma
Mucinous features should rule out this entity
Sometimes the epithelial component can be as high as 30%
This lesion is most common in minor salivary glands of palate
This tumor is completely benign and no malignant transformation has been reported

Board review style answer #1

A. Monomorphic tumor cells and absence of chondromyxoid stroma and ducts help to differentiate myoepithelioma from pleomorphic adenoma. The presence of chondromyxoid stroma is consistent with pleomorphic adenoma rather than myoepithelioma.

Comment Here

Reference: Myoepithelioma

Board review style question #2

Which of the following is correct about myoepithelioma?

Negative for keratin
Negative for nuclear beta catenin
Negative for S100
Negative for SMA and HHF35
Positive for PLAG1 translocation

Board review style answer #2

E. Positive for PLAG1 abnormalities. Detection of PLAG1 rearrangement by cytogenetics or other methods can be helpful. NTF3-PLAG1, FBXO32-PLAG1 and GEM-PLAG1 fusions have been detected in oncocytic myoepithelioma (Ann Diagn Pathol 2017;28:19, Hum Pathol 2020;103:52).

Comment Here

Reference: Myoepithelioma

Necrotizing sialometaplasia

Table of Contents

Definition / general

Reactive, self resolving inflammatory condition of the salivary glands that most often affects the palate and is known to mimic malignancy both clinically and histopathologically

Essential features

Classically begins as a swelling that evolves into a crater-like ulceration, which resolves within 3 - 12 weeks
Most commonly affects the palate
Necrosis or disruption of salivary acini with squamous metaplasia of ductal structures
Etiology is thought to be a reaction to trauma or smoking in a setting of vascular compromise / tissue ischemia
Mimics malignancy both clinically and histopathologically

Terminology

Not recommended: adenometaplasia

ICD coding

ICD-10: K11.8 - other diseases of salivary glands
ICD-11: DA04 - diseases of salivary glands

Epidemiology

Slight female predominance, although older studies cite a male prominence (Dermatol Online J 2020;26:13030, Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:577)
Wide age range; mean age of 35 (Dermatol Online J 2020;26:13030)

Sites

Hard palate is the most common site
Other sites include buccal mucosa, floor of mouth, nasal cavity, trachea, parotid gland, sublingual gland, submandibular gland, larynx, maxillary sinus, tongue, tonsil and retromolar trigone (Arch Pathol Lab Med 2009;133:692)

Pathophysiology

Unknown pathogenesis; thought to be caused by vascular ischemia that interrupts the blood supply to the underlying salivary glands (Stomatologija 2022;24:56)

Etiology

Smoking / vaping
Trauma, including
- Nonspecific mechanical trauma
- Trauma from dental procedures or anesthetic, especially with vasoconstrictors
- Trauma from an ill fitting denture or orthodontic appliances
- Trauma from intubation or extubation (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:577)
Bulimia or frequent episodes of vomiting may be an underreported cause (Arch Pathol Lab Med 2009;133:692, Quintessence Int 2016;47:147, Stomatologija 2022;24:56)
Alcohol, anabolic steroid and cocaine use (Stomatologija 2022;24:56)

Clinical features

Acute onset, erythematous or mucosal colored swelling often precedes development of crater-like ulceration, which measures 1 - 3 cm (Arch Pathol Lab Med 2009;133:692)
- Borders of the ulcer may be raised
- Swelling may be fluctuant, mimicking an abscess (Arch Pathol Lab Med 2009;133:692)
Pain and rapid progression are almost universal (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:577)
- Sensations of itching, burning and paresthesia have also been reported (Oral Surg Oral Med Oral Pathol 1991;72:317, Dermatol Online J 2020;26:13030, Cureus 2023;15:e42825, Autops Case Rep 2021;11:e2021244)
Often unilateral but bilateral and metachronous cases are seen
May be mistaken for malignancy (Arch Pathol Lab Med 2009;133:692)
Typically heals within 3 - 12 weeks (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:577)
Uncommon; < 1% of oral biopsies (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:577)

Diagnosis

Abrupt, rapidly progressing swelling with subsequent formation of a crateriform ulceration and spontaneous healing over a span of 3 - 12 weeks is clinically diagnostic for necrotizing sialometaplasia (NSM); however, the aggressive clinical behavior / appearance may prompt biopsy to rule out malignancy prior to regression (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:577)
Close clinical follow up is imperative; if lesional tissue does not heal, biopsy is advised to rule out neoplasia
- NSM has been reported to occur alongside malignancies (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:577)
Biopsies of lesional tissue should be ample and should avoid particularly necrotic areas (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:577)

Radiology description

Absent radiologic findings or rare bony erosion (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:577, Cureus 2023;15:e42825)

Radiology images

Images hosted on other servers:

Rare bony erosion

Prognostic factors

Heals spontaneously within 3 - 12 weeks, although uncommon cases persist for up to 6 months (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:577, Dermatol Online J 2020;26:13030)

Case reports

26 year old man presented with an ulcer on the palate (Clin Case Rep 2021;9:2019)
27 year old woman presented with severe pain and a swelling on the palate (Dermatol Online J 2020;26:13030)
32 year old man presented with a 1 month history of palatal swelling (Autops Case Rep 2021;11:e2021244)
50 year old woman presented with bony erosion and swelling of the palate (Cureus 2023;15:e42825)

Treatment

Self resolving within 3 - 12 weeks, although surgical debridement with fabrication of a palatal guard may be considered in abnormally slow healing lesions (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:577, Arch Pathol Lab Med 2009;133:692)
Diagnostic biopsy or rebiopsy is recommended in nonhealing lesions

Clinical images

Contributed by Douglas Damm, D.D.S., Ashley Clark, D.D.S.,
Eric Mencarelli, M.D., D.D.S. and Molly Housley Smith, D.M.D.

Palatal ulceration and erythema

Midline palatal ulceration

Bilateral palatal ulcerations

Microscopic (histologic) description

Squamous metaplasia of ductal structures and acini with preservation of the salivary lobular architecture is an essential feature, according to World Health Organization (see WHO classification-oral cavity & oropharynx)
Necrosis / infarction of acini characterized by loss of nuclei and cell borders with or without zones of spilled mucin
Pseudoepitheliomatous hyperplasia with generally bland cytology or keratinocytic regenerative atypia
Reactive, myxocollagenous background stroma
Surface ulceration, granulation tissue and subacute inflammation may be present
Has been conceptualized by 5 histologic stages of development and evolution: infarction, sequestration, ulceration, repair and healing (Int J Oral Surg 1982;11:283)

Microscopic (histologic) images

Contributed by Kelly Magliocca, D.D.S., M.P.H. (Case #497) and Molly Housley Smith, D.M.D.

Metaplasia of residual salivary ducts

Pseudoepitheliomatous
hyperplasia

Bland cytology

Spilled mucin

Surface ulceration

Glandular necrosis

Acute inflammation

Healing stage

Positive stains

Immunohistochemistry is often not necessary for diagnosis
- Generally low p53 and Ki67 index (Dermatol Online J 2020;26:13030)
- Epithelial (CK5, CK6, CK7, CAM5.2, etc.) and myoepithelial (SMA, calponin, p63, S100, etc.) markers may be used to highlight metaplastic ductal epithelium / lobular architecture (Dermatol Online J 2020;26:13030, Arch Pathol Lab Med 2009;133:692)

Sample pathology report

Hard palate, incisional biopsy:
- Necrotizing sialometaplasia (see comment)
- Comment: The microscopic sections show ulcerated mucosa with zones of pseudoepitheliomatous hyperplasia without prominent cytologic atypia. Squamous metaplasia of ductal structures with preservation of lobular architecture is appreciated along with necrosis of salivary acini and extravasated mucin. No evidence of a neoplasm is identified upon review of multiple deeper levels. Clinical follow up to ensure complete resolution of the lesional tissue is recommended.

Differential diagnosis

Although the clinical differential diagnosis for an ulceration or swelling on the palate may include a variety of entities (e.g., salivary gland neoplasm, T cell lymphoma, granulomatosis with polyangiitis, deep fungal or bacterial infection), the main histopathological differential diagnosis includes mucoepidermoid carcinoma, squamous cell carcinoma or subacute necrotizing sialadenitis
Mucoepidermoid carcinoma (MEC):
- Can be challenging to differentiate NSM from MEC on fragmented biopsies or in the later stages of NSM (Head Neck Pathol 2022;16:54)
- Lobular architecture is not preserved
- S100 negative
- Depending on the grade of MEC, the following features may be seen in MEC but not in NSM (Arch Pathol Lab Med 2009;133:692)
  - Cystic spaces
  - Cellular pleomorphism / atypical mitotic figures
  - Presence of perineural / lymphovascular invasion
  - Proliferation of apparently neoplastic goblet cells
  - Lack of intact lobular architecture
- May show t(11;19)(q14-21;p12-13) with CRTC1(MECT1)::MAML2 fusion
Squamous cell carcinoma (SCCa):
- Exhibits pleomorphism / abnormal mitotic figures, as compared with NSM which often shows pseudoepitheliomatous hyperplasia with bland cytology (Head Neck Pathol 2022;16:54)
- Myoepithelial markers (e.g., p63, SMA, calponin, S100, etc.) should be absent in SCCa (Arch Pathol Lab Med 2009;133:692)
- SCCa is usually negative for CK7 (Arch Pathol Lab Med 2009;133:692)
Subacute necrotizing sialadenitis (SNS):
- Debate exists on whether SNS should be considered a separate entity from NSM (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:577)
- Rapid onset of a painful swelling, typically on the palate, which is characterized by necrosis of salivary glands and mixed inflammation but lacks surface ulceration and shows minimal to no squamous metaplasia of ductal epithelium (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:577)
- Heals within 2 - 3 weeks

Additional references

Neville: Oral and Maxillofacial Pathology, 5th Edition, 2023

Board review style question #1

Necrotizing sialometaplasia most commonly affects what site?

Minor salivary glands of the lip
Minor salivary glands of the palate
Parotid
Submandibular gland

Board review style answer #1

B. Minor salivary glands of the palate. Although necrotizing sialometaplasia can affect any of the given answer choices, it classically involves the minor salivary glands of the hard palate. Answers A, C and D are incorrect because necrotizing sialometaplasia occurs at these sites less frequently than in the minor salivary glands of the palate.

Comment Here

Reference: Necrotizing sialometaplasia

Board review style question #2

A patient presents to clinic with severe pain and an ulceration on the hard palate. She states that the lesion began after a dental procedure as a swelling that rapidly progressed to an ulceration over the course of a couple weeks. What is the diagnosis?

Mucoepidermoid carcinoma
Necrotizing sialometaplasia
Squamous cell carcinoma
T cell lymphoma

Board review style answer #2

B. Necrotizing sialometaplasia. The patient presented with the classic clinical history of acute onset of a rapidly progressing lesion on the hard palate, which began as a swelling that subsequently ulcerated. Biopsy revealed large zones of pseudoepitheliomatous hyperplasia, squamous metaplasia of ducts, lack of overt pleomorphism and areas of acinar necrosis and mucin spillage. Answer A (mucoepidermoid carcinoma) is incorrect because the lobular architecture of the gland is preserved and there is no proliferation of cystic spaces or neoplastic goblet cells. Although T cell lymphomas classically may affect the hard palate, answer D is incorrect because the biopsy did not show an atypical lymphoid infiltrate. Answer C (squamous cell carcinoma) is incorrect as the proliferation of squamous epithelium classically forms the pseudoepitheliomatous hyperplasia type pattern and lacks cellular pleomorphism.

Comment Here

Reference: Necrotizing sialometaplasia

Neoplasm-benign

Table of Contents

Definition / general

Fine needle aspiration (FNA) shows characteristic cytomorphologic features of a specific benign neoplasm of the salivary gland (Faquin: The Milan System for Reporting Salivary Gland Cytopathology, 1st Edition, 2018)

Essential features

Salivary gland FNA diagnostic of a benign neoplasm (pleomorphic adenoma 60 - 70%, Warthin tumor 20 - 30%, other tumors 10%)
30 - 40% of all salivary gland FNA
Estimated risk of malignancy (ROM) by the Milan system: < 5%

Terminology

Neoplasm: benign (category IVA)
Specific diagnosis of a benign neoplasm should be provided in this category

Epidemiology

Salivary gland tumors are uncommon and represent < 2% of all human tumors (Kumar: Robbins & Cotran Pathologic Basis of Disease, 10th Edition, 2020)
Epithelial tumors account for 80 - 90% and approximately 60% are benign

CPT coding

88172 - determination of adequacy of specimen
88173 - FNA interpretation

Sites

Parotid gland: 65 - 80% of all salivary gland tumors, 70 - 85% are benign (Kumar: Robbins & Cotran Pathologic Basis of Disease, 10th Edition, 2020)
Submandibular gland: 10% of all salivary gland tumors, 55 - 60% are benign
Minor salivary glands (including sublingual glands and seromucinous glands of the upper aerodigestive tract): 20% of all salivary gland tumors, 10 - 30% of sublingual gland tumors and 50% of minor salivary gland tumors are benign

Clinical features

Frequency among all the Milan system categories: 30 - 40%
Resection rate: 43.5 - 61.4% (Cancer Cytopathol 2020;128:348)
Risk of neoplasm: > 99% (J Oral Maxillofac Surg 2010;68:2146)
Real world risk of malignancy:
- With surgical follow up only: 2.4% (1.8 - 3.0%) (Diagn Cytopathol 2020;48:880)
- Overall: 1.5% (Am J Clin Pathol 2019;151:613)

Radiology description

On ultrasound, benign salivary gland tumors are usually well defined and hypoechoic (Eur J Radiol 2008;66:419)

Case reports

12 year old boy with a parotid juvenile sclerosing polycystic adenosis, cytologically mimicking a Warthin tumor (Diagn Cytopathol 2019;47:1208)
41 year old woman with a glandular schwannoma at submandibular region, cytologically mimicking a pleomorphic adenoma (Diagn Cytopathol 2015;43:395)
53 year old women with Warthin-like variant of mucoepidermoid carcinoma of parotid glands, cytologically mimicking a Warthin tumor (Diagn Cytopathol 2017;45:1132)
61 year old man with an epithelioid schwannoma of the facial nerve, cytologically mimicking a parotid pleomorphic adenoma (Diagn Cytopathol 2014;42:58)
70 year old man with a cystic pleomorphic adenoma of parotid gland, cytologically mimicking a mucoepidermoid carcinoma (Diagn Cytopathol 2005;32:229)
78 year old woman with a pleomorphic adenoma at hard palate, showing predominant plasmocytoid myoepithelial cells and cytologically mimicking a poorly differentiated carcinoma (Diagn Cytopathol 2009;37:56)

Treatment

Surgery or clinical and radiological follow up

Cytology description

Pleomorphic adenoma: 60 - 70% of all benign salivary gland FNA
- Mixture of myoepithelial cells, ductal cells and extracellular stroma
- Myoepithelial cells are usually the predominant cell type with various cytomorphology, including round, polygonal, plasmacytoid, spindle, etc.
- Ductal cells show bland cytologic features with organized honeycombing or ductal arrangement
- Extracellular matrix shows characteristic feathery / fibrillary borders and bright magenta color on Romanowsky type stain and gray-green chondromyxoid features on Papanicolaou stain
Warthin tumor: 20 - 30% of all benign salivary gland FNA
- Sheets of oncocytes and mixed population of lymphocytes in a characteristic dirty proteinaceous background
- Oncocytic sheets show an organized honeycombing or papillary arrangement and are typically cyanophilic at the periphery and bright orange at the center on Papanicolaou stain
- Oncocytes show densely granular cytoplasm, centrally located nuclei and small nucleoli
- Lymphocytes are mostly small mature cells
Oncocytoma:
- Cellular oncocytic aspirates with very clean background
- Oncocytes show abundant finely granular cytoplasm, centrally placed or eccentric nuclei and occasional distinct nucleoli
- Cellular arrangement can be irregular sheets, small clusters or single cells
Most FNA of basal cell adenoma, myoepithelioma and cystadenoma should be better classified as salivary gland neoplasm of uncertain malignant potential (SUMP) due to overlapping cytomorphology with other malignant tumors
Other benign mesenchymal neoplasms:
- Schwannoma: spindle shaped cells with wavy nuclei and bipolar cytoplasmic processes in syncytium-like fragments
- Lipoma: fragments of benign adipocytes with clear cytoplasm and small nuclei
- Hemangioma: bloody aspirates with few groups of bland spindle shaped endothelial cells

Cytology images

Contributed by Jen-Fan Hang, M.D.

Pleomorphic adenoma (PA): fibrillary extracellular matrix

PA: plasmacytoid
myoepithelial cells

PA with squamous metaplasia

Warthin tumor

Oncocytoma

Videos

Benign neoplasm 1

Benign neoplasm 2

Sample pathology report

Submandibular gland, right, fine needle aspiration:
- Satisfactory for evaluation
- Neoplasm: benign
- Pleomorphic adenoma
Parotid gland, right, fine needle aspiration:
- Satisfactory for evaluation
- Neoplasm: benign
- Warthin tumor
Parotid gland, left, fine needle aspiration:
- Satisfactory for evaluation
- Neoplasm: benign
- Oncocytoma

Differential diagnosis

Pleomorphic adenoma:
- Pleomorphic adenoma with squamous or mucinous metaplasia can be falsely interpreted as mucoepidermoid carcinoma
- Pleomorphic adenoma with prominent hyaline globules can be falsely interpreted as adenoid cystic carcinoma
- False negative rate: 3% (25/840) (Cancer Cytopathol 2021;129:43)
  - Carcinoma ex pleomorphic adenoma (36%, 9/25)
  - Adenoid cystic carcinoma (24%, 6/25)
  - Mucoepidermoid carcinoma (12%, 3/25)
  - Epithelial myoepithelial carcinoma (8%, 2/25)
  - Salivary duct carcinoma (4%, 1/25)
  - Malignant peripheral nerve sheath tumor (4%, 1/25)
  - Large B cell lymphoma (4%, 1/25)
Warthin tumor:
- FNA with predominant dirty granular background material and scant epithelial component can be falsely interpreted as necrosis
- Warthin tumor with squamous or mucinous metaplasia can be falsely interpreted as mucoepidermoid carcinoma
- False negative rate: 1.3% (4/304) (Cancer Cytopathol 2021;129:43)
  - Mucoepidermoid carcinoma (50%, 2/4)
  - Acinic cell carcinoma (50%, 2/4)
Oncocytoma:
- Low grade carcinomas with oncocytoid features, e.g. acinic cell carcinoma and secretory carcinoma, usually show zymogen granules or secretory globules instead of the mitochondria type fine granules in the cytoplasm

Additional references

Laryngoscope 2013;123:3056, Diagn Cytopathol 2019;47:617

Board review style question #1

A 45 year old man presented with a 2.8 cm, slow growing mass at left parotid region. He underwent ultrasound guided FNA for evaluation. What is the best diagnosis?

Basal cell adenoma
Oncocytoma
Pleomorphic adenoma
Warthin tumor

Board review style answer #1

C. Pleomorphic adenoma. Magenta colored extracellular matrix with feathery / fibrillary borders and intermingled bland myoepithelial cells are characteristic features of a pleomorphic adenoma.

Comment Here

Reference: Neoplasm-benign

Board review style question #2

Which salivary gland tumor below should be reported on FNA as "salivary gland neoplasm of uncertain malignant potential (SUMP)"?

Basal cell adenoma
Oncocytoma
Pleomorphic adenoma
Warthin tumor

Board review style answer #2

A. Basal cell adenoma. Basal cell adenoma shows overlapping morphological features with basal cell adenocarcinoma in FNA. The distinction between these 2 tumors depends on the histological examination to demonstrate tumor invasion. Moreover, pleomorphic adenoma with predominant basal cells and solid / tubular variant of adenoid cystic carcinoma can also cytologically mimic a basal cell adenoma. Therefore, it is recommended to report FNA with basal cell features as SUMP with basaloid features in the Milan system.

Comment Here

Reference: Neoplasm-benign

Neoplasm-salivary gland neoplasm of uncertain malignant potential (SUMP)

Table of Contents

Definition / general

Fine needle aspiration (FNA) result with cytomorphologic features diagnostic of a neoplasm but because a specific entity cannot be ascertained, a malignant neoplasm cannot be excluded
7.2% of all salivary gland FNA (Cancer Cytopathol 2022;130:800)
Estimated risk of malignancy (ROM) by the Milan system: 35%
Real world ROM: 42.1% (FNA with surgical follow up), 29.8% (overall) (Cancer Cytopathol 2022;130:511)
Risk of neoplasm (RON): 96% (Cancer Cytopathol 2022;130:511)

Essential features

Cellular benign neoplasm (e.g., cellular pleomorphic adenoma [PA])
Neoplasm with atypical features
- Cellular neoplasm with basaloid features (e.g., pleomorphic adenoma, basal cell adenoma / adenocarcinoma, adenoid cystic carcinoma, epithelial myoepithelial carcinoma, polymorphous adenocarcinoma)
- Cellular neoplasm with oncocytic / oncocytoid features (e.g., Warthin tumor, oncocytoma, mucoepidermoid carcinoma, acinic cell carcinoma, secretory carcinoma)
- Cellular neoplasm with clear cell features (e.g., myoepithelioma, epithelial myoepithelial carcinoma, acinic cell carcinoma, secretory carcinoma, mucoepidermoid carcinoma)
Low grade carcinoma (e.g., low grade mucoepidermoid carcinoma)

Terminology

Neoplasm: salivary gland neoplasm of uncertain malignant potential (SUMP) (category IVB)

Diagrams / tables

Contributed by Jen-Fan Hang, M.D.

SUMP subcategories

Treatment

Due to the high risk of neoplasm, complete surgical excision is usually the standard treatment for symptomatic patients with an FNA result of SUMP
Imaging evaluation of the tumor border can provide further information regarding the extent of surgery

Cytology description

SUMP subcategorization
- Recommended by the Milan system (Faquin: The Milan System for Reporting Salivary Gland Cytopathology, 1st Edition, 2018)
  - Cellular basaloid neoplasm
    - FNA with a predominant population of cells with scant cytoplasm that confers a basaloid cytomorphology
  - Cellular oncocytic / oncocytoid neoplasm
    - FNA with oncocytic or oncocytoid features that cannot be classified further
  - Cellular neoplasm with clear cell features
    - FNA with lesional cells with clear, foamy, granular, vacuolated cytoplasm or any combination thereof
    - Uncommon and variably overlapping with the oncocytic / oncocytoid features
- Modified scheme for subcategorizing SUMP proposed by Hang, et al. (Cancer Cytopathol 2022;130:511)
  - Basaloid SUMP
    - FNA with monotonous basaloid tumor cells with scant cytoplasm and without a purely fibrillary extracellular matrix
    - 47.7% of all SUMP FNA
    - ROM: 36.5%; RON: 98.1%
    - Histology correlation
      - Benign neoplasm: pleomorphic adenoma (32.7%) > basal cell adenoma (25%)
      - Malignancy: adenoid cystic carcinoma (16%) > basal cell adenocarcinoma (5.8%)
  - Oncocytic / oncocytoid SUMP
    - FNA with monotonous epithelioid tumor cells with moderate to abundant amounts of cytoplasm showing oncocytic or oncocytoid features
    - Cases with coarsely granular, foamy, vacuolated or so called clear cytoplasm are considered within the spectrum of oncocytic / oncocytoid features
    - 30.7% of all SUMP FNA
    - ROM: 52.5%; RON: 91.1%
    - Histology correlation
      - Benign neoplasm: Warthin tumor (22.8%) > oncocytoma (10.9%)
      - Malignancy: mucoepidermoid carcinoma (22.8%) > acinic cell carcinoma (14.9%)
  - SUMP, not otherwise specified (NOS)
    - SUMP cases that could not be comfortably placed in either basaloid or oncocytic / oncocytoid subcategory
    - Common scenarios
      - FNA with focal atypical features in a tumor otherwise favoring a benign neoplasm (e.g., cellular pleomorphic adenoma or pleomorphic adenoma with anisonucleosis that are indefinite for benign)
      - FNA with a predominance of an unclassified cell type (e.g., plasmacytoid, spindle, mixed, etc.)
    - 21.9% of all SUMP FNA
    - ROM: 31.9%; RON: 98.6%
    - Histology correlation (mostly myoepithelial cell rich tumors)
      - Benign neoplasm: pleomorphic adenoma (47.2%) > myoepithelioma (6.9%)
      - Malignancy: carcinoma ex pleomorphic adenoma (9.7%) > myoepithelial carcinoma (6.9%)

Cytology images

Contributed by Jen-Fan Hang, M.D.

Basaloid SUMP

Oncocytic / oncocytoid SUMP

Spindle cell features

Squamoid features

Molecular / cytogenetics description

Immunocytochemical surrogates for molecular alterations
- Basaloid SUMP
  - Pleomorphic adenoma (including carcinoma ex pleomorphic adenoma) (Cancer Cytopathol 2016;124:397)
    - PLAG1 or HMGA2 (+)
    - Sensitivity: 85%; specificity: 92%
  - Adenoid cystic carcinoma (Cancer Cytopathol 2014;122:257)
    - MYB (+)
    - Sensitivity: 80%; specificity: 100%
- Oncocytic / oncocytoid SUMP
  - Acinic cell carcinoma (Cancer Cytopathol 2022;130:949)
    - NR4A3 (+)
    - Sensitivity: 100%; specificity: 97%
  - Secretory carcinoma (Diagn Cytopathol 2021;49:E329)
    - Pan TRK (+)
Gene rearrangement testing (by FISH or next generation sequencing [NGS]) (J Am Soc Cytopathol 2019;8:157)
- Basaloid SUMP
  - Pleomorphic adenoma: PLAG1 or HMGA2 rearrangement
  - Adenoid cystic carcinoma: MYB or MYBL1 rearrangement
- Oncocytic / oncocytoid SUMP
  - Mucoepidermoid carcinoma: MAML2::CRTC1 / 3
  - Acinic cell carcinoma: NR4A3 rearrangement
  - Secretory carcinoma: ETV6::NTRK3
  - Hyalinizing clear cell carcinoma: EWSR1::AFT1
Gene mutation testing (by PCR or NGS)
- Basaloid SUMP
  - Basal cell adenoma: CTNNB1 mutation
  - Adenoid cystic carcinoma: NOTCH1 mutation in a subset
  - Polymorphous adenocarcinoma: PRKD1 E710D

Sample pathology report

Parotid gland, right, fine needle aspiration:
- Neoplasm: salivary gland neoplasm of uncertain malignant potential (SUMP)
- Cellular basaloid neoplasm (see comment)
- Comment: The specimen shows monotonous basaloid cells with minimal nuclear atypia and scattered hyaline globules. There are no high grade features, such as mitoses or necrosis. The differential diagnosis includes basal cell adenoma / adenocarcinoma, pleomorphic adenoma and adenoid cystic carcinoma. Suggest correlation with clinical and radiologic findings.

Parotid gland, left, fine needle aspiration:
- Neoplasm: salivary gland neoplasm of uncertain malignant potential (SUMP)
- Cellular oncocytic / oncocytoid neoplasm (see comment)
- Comment: The specimen shows monotonous oncocytic / oncocytoid cells with minimal nuclear atypia in a lymphoplasmacytic background. Scattered mucinous extracellular materials are noted but no mucous cells are present. The differential diagnosis includes Warthin tumor with mucinous metaplasia and low grade mucoepidermoid carcinoma with oncocytic change. Suggest correlation with clinical and radiologic findings.

Differential diagnosis

SUMP category is only reserved for cases with a predominance of monomorphic cytomorphology and cases with pleomorphic tumor cells are recommended to be classified as either suspicious for malignancy (category V) or malignant (category VI)
Basaloid SUMP cases with a purely fibrillary extracellular matrix are compatible with a pleomorphic adenoma and are recommended to be classified as benign neoplasm (category IVA)

Additional references

Cancer Cytopathol 2018;126:627, Acta Cytol 2020;64:92

Board review style question #1

Category III: atypia of undetermined significance
Category IVA: benign neoplasm, pleomorphic adenoma
Category IVB: salivary gland neoplasm of uncertain malignant potential, with basaloid features
Category VI: malignant, adenoid cystic carcinoma

Board review style answer #1

C. Category IVB: salivary gland neoplasm of uncertain malignant potential, with basaloid features. Basaloid neoplasms showing overlapping morphology of bland basal cells and extracellular nonfibrillary matrix are better classified as salivary gland neoplasm of uncertain malignant potential, with basaloid features. The final pathology of the same case showed a basal cell adenoma with prominent hyaline globules.

Comment Here

Reference: Neoplasm-salivary gland neoplasm of uncertain malignant potential (SUMP)

Board review style question #2

A 49 year old woman presents with a 2.5 cm right parotid nodule. Fine needle aspiration cytology is performed and the result is shown in the figure. What would be the most likely diagnosis if the patient receives surgical excision?

Basal cell adenoma
Mucoepidermoid carcinoma
Secretory carcinoma
Warthin tumor

Board review style answer #2

A. Basal cell adenoma. The figure shows a proliferation of basaloid cells admixed with extracellular matrix. It is consistent with the cytologic diagnosis of SUMP with basaloid features. The differential diagnosis includes matrix producing tumors with basaloid cells, such as basal cell adenoma / adenocarcinoma and adenoid cystic carcinoma. Answers B - D are incorrect because Warthin tumor, mucoepidermoid carcinoma and secretory carcinoma are the less likely options since they usually present with neoplastic cells harboring more abundant cytoplasm and often would be interpreted as SUMP with oncocytic / oncocytoid features.

Comment Here

Reference: Neoplasm-salivary gland neoplasm of uncertain malignant potential (SUMP)

Neuroendocrine carcinoma

Table of Contents

Definition / general

Salivary neuroendocrine carcinomas are exceedingly rare (Am J Surg Pathol 2019;43:682)
Divided into small cell carcinoma and large cell neuroendocrine carcinoma (Head Neck Pathol 2018;12:13, Head Neck Pathol 2013;7:295)
Metastases, especially from the skin, are much more common than primary tumors (Am J Surg Pathol 2019;43:682)
Many previously reported cases likely represent occult metastatic Merkel cell carcinoma of cutaneous origin (Am J Surg Pathol 2019;43:682)

Essential features

Rare tumor type found predominantly in parotid gland
2 morphologies: small cell neuroendocrine carcinoma and large cell neuroendocrine carcinoma
Positive for neuroendocrine IHC markers; also frequently CK20 positive (Am J Surg Pathol 1997;21:226)
Can be difficult to distinguish from metastatic Merkel cell carcinoma (Am J Surg Pathol 2019;43:682)

Terminology

Small cell neuroendocrine carcinoma of the salivary gland
Large cell neuroendocrine carcinoma of the salivary gland

ICD coding

ICD-10: C08.9 - malignant neoplasm of major salivary gland, unspecified

Epidemiology

Adults

Sites

Majority occur in the parotid gland, followed by the submandibular gland

Pathophysiology

At least some arise as high grade transformation from a lower grade salivary tumor, such as pleomorphic adenoma and acinic cell carcinoma (Head Neck Pathol 2012;6:502, Head Neck Pathol 2016;10:152)

Etiology

Unknown at this time

Clinical features

Most common clinical presentation: rapidly growing neck mass

Diagnosis

Fine needle aspiration or core biopsy of mass

Radiology images

Images hosted on other servers:

Parotid mass

Prognostic factors

Unknown

Case reports

48 year old woman with a right cheek mass (small cell carcinoma ex pleomorphic adenoma) (Head Neck Pathol 2012;6:502)
1 patient in a series of 25 acinic cell carcinomas with high grade transformation had small cell carcinoma ex acinic cell carcinoma of the parotid gland (Head Neck Pathol 2016;10:152)

Treatment

Surgical: local resection and neck dissection
Majority receive adjuvant radiation
Subset receive chemotherapy
Reference: Head Neck Pathol 2018;12:13

Gross description

Mass lesion within the resected salivary gland
Solid cut surface
Areas of necrosis may be noted

Microscopic (histologic) description

Small cell neuroendocrine carcinoma (Head Neck Pathol 2018;12:13):
- Sheets, trabeculae or nests of small, blue tumor cells
- High nuclear to cytoplasmic ratios with scant cytoplasm
- Hyperchromatic, finely granular chromatin
- Nuclear molding and crush artifact are common
- Occasional rosettes
- Brisk mitotic activity (> 10 mitoses / 10 HPF)
- Apoptotic debris and areas of geographic necrosis may be present
Large cell neuroendocrine carcinoma (Head Neck Pathol 2018;12:13):
- More abundant cytoplasm
- Larger nuclei with course chromatin and often prominent nucleoli
- Palisading may be seen at the periphery of tumor nests
- Occasional rosettes
- Brisk mitotic activity (> 10 mitoses / 10 HPF)
- Apoptotic debris and areas of geographic necrosis may be present

Microscopic (histologic) images

Contributed by Lulu Sun, M.D., Ph.D. and Rebecca Chernock, M.D.

Small cell neuroendocrine carcinoma

Infiltration of salivary parenchyma

Necrosis

Nuclear features

Chromogranin

Synaptophysin

Cytokeratin 5/6

MCPyV IHC

Large cell neuroendocrine carcinoma

Nested architecture

Necrosis

Cytologic features

Cytology description

Small cell neuroendocrine carcinoma (J Cytol 2016;33:34):
- Tumor cell clusters and single cells
- High nuclear to cytoplasmic ratios with scant cytoplasm
- Nuclear molding and crush artifact are common
- Granular salt and pepper chromatin with inconspicuous nucleoli
- Nuclear breakdown or apoptotic bodies / necrotic background
Large cell neuroendocrine carcinoma (Auris Nasus Larynx 2005;32:89):
- Tumor cell clusters and single cells
- Larger cells with more abundant cytoplasm
- Granular salt and pepper chromatin with inconspicuous nucleoli
- Nuclear breakdown or apoptotic bodies / necrotic background

Positive stains

Neuroendocrine markers (may not stain with every antibody, recommend panel of neuroendocrine markers): synaptophysin, chromogranin, CD56
CK20 (perinuclear dot-like pattern, some cases)

Negative stains

TTF1 (occasionally positive)
CK7
Merkel cell polyomavirus (MCPyV)

Molecular / cytogenetics description

Absence of Merkel cell polyomavirus and UV signature mutations (Am J Surg Pathol 2011;35:1806, Am J Surg Pathol 2019;43:682, Head Neck Pathol 2018;12:13)

Sample pathology report

Salivary gland, right parotid, parotidectomy:
- Small cell neuroendocrine carcinoma (see comment)
- Comment: Histologic sections show a small cell neuroendocrine carcinoma involving the parotid gland. The tumor cells are positive for synaptophysin, chromogranin and cytokeratin 20. TTF1 is negative. Immunohistochemistry for Merkel cell polyomavirus (MCPyV) is also negative. The majority of high grade neuroendocrine carcinomas located in the parotid gland represent metastases, usually from the head and neck skin, rather than primary salivary carcinomas. Correlation with clinical history and physical exam findings is recommended to exclude a metastasis. Even in the absence of an identifiable cutaneous primary, occult metastatic Merkel cell carcinoma is still more likely. Mutational signature analysis from next generation sequencing assays may aid in determining tumor origin as a UV signature would favor a metastasis from a cutaneous primary.

Differential diagnosis

Metastatic neuroendocrine carcinoma:
- Parotid gland contains lymph nodes which are a favored site of metastasis from cutaneous head and neck cancer
Metastatic Merkel cell carcinoma:
- Clinical history is most useful; however, there may not be an identifiable skin tumor and primary tumor regression also possible (Am J Dermatopathol 2016;38:e154)
- Absence of associated low grade salivary tumor (other than Warthin tumor)
- Also CK20 positive in perinuclear, dot-like pattern
- Merkel cell polyomavirus or UV signature mutations present in most cases and not found in primary salivary tumors (Am J Surg Pathol 2009;33:1771, Am J Surg Pathol 2019;43:682, Head Neck Pathol 2018;12:13)
Metastatic lung neuroendocrine carcinoma:
- TTF1 positive
- CK20 negative
Lymphoma:
- CD45 positive
- Cytokeratin negative

Board review style question #1

A 70 year old man presented with an enlarging mass in the left cheek soft tissue. The mass was removed and shows the histology above. The tumor is positive for CK20 (dot-like) and synaptophysin and is negative for CK7. Which of the following features would favor a salivary primary over a metastasis from an occult cutaneous primary tumor?

Adjacent pleomorphic adenoma
History of multiple head and neck skin cancers
Molecular analysis showing a UV signature
Positive immunohistochemistry for MCPyV

Board review style answer #1

A. Adjacent pleomorphic adenoma

Comment Here

Reference: Neuroendocrine carcinoma

Board review style question #2

Which of the following is true about primary neuroendocrine carcinomas of the salivary gland?

The most common site is in the sublingual gland
They do not stain with classical neuroendocrine markers (synaptophysin and chromogranin)
They have low grade morphology
They often stain positively with CK20 in a perinuclear dot-like pattern

Board review style answer #2

D. They often stain positively with CK20 in a perinuclear dot-like pattern

Comment Here

Reference: Neuroendocrine carcinoma

Nodular oncocytic hyperplasia

Table of Contents

Definition / general

Either parotid cysts lined by oncocytes or well defined clusters of oncocytes (mm to cm)
First reported by Schwartz (Cancer 1969;23:636)
Also called multinodular oncocytoma, multifocal adenomatous oncocytic hyperplasia

Clinical features

Benign, multifocal / nodular or diffuse proliferation of oncocytic cells, usually in parotid gland
May be bilateral

Case reports

68 year old man with 6 cm parotid swelling (J Cytol 2012;29:80)
78 year old man (Laryngorhinootologie 2004;83:185)

Microscopic (histologic) description

Either parotid cysts lined by oncocytes or well defined clusters of oncocytes (mm to cm)
Oncocytes (oxyphilic cells) are large ductal epithelial cells with eosinophilic granular cytoplasm

Microscopic (histologic) images

Images hosted on other servers:

Parotid gland specimen

Cytology description

Oncocytic cells

Cytology images

Images hosted on other servers:

Various images

Electron microscopy description

Numerous mitochondria

Differential diagnosis

Normal aging: increased oncocytes
Oncocytoma: distinct mass
Rhabdomyoma: may resemble at intraoperative frozen section; positive for skeletal muscle markers; different morphology on permanent section (Arch Pathol Lab Med 1983;107:638)
Sialadenosis: may resemble diffuse oncocytosis (Laryngol Rhinol Otol (Stuttg) 1982;61:691)
Warthin tumor: double layer of epithelial cells resting on dense lymphoid stroma with variable germinal centers

Nondiagnostic

Table of Contents

Definition / general

Fine needle aspiration (FNA) with insufficient diagnostic material to provide an informative interpretation
18.2% of all salivary gland FNA (Cancer Cytopathol 2022;130:800)
Estimated risk of malignancy (ROM) by the Milan system: 25% (Faquin: The Milan System for Reporting Salivary Gland Cytopathology, 1st Edition, 2018)
Real world risk of malignancy: 15.7% (FNA with surgical follow up), 4.1% (overall) (Cancer Cytopathol 2022;130:800)

Essential features

FNA with insufficient amount of lesional cells to provide an informative interpretation (ideally > 60 lesional cells for adequate evaluation)
Poorly prepared slides with artifacts (e.g., air drying, obscuring blood and poor staining) that preclude the evaluation of the cellular component
Normal nonneoplastic salivary gland elements in the setting of a clinically or radiologically defined mass
Nonmucinous cyst fluid without an epithelial component

Terminology

Nondiagnostic
Nondiagnostic, cystic fluid only for nonmucinous cyst fluid without an epithelial component

Etiology

Palpation guidance without ultrasound, inadequate sampling determined by rapid on site evaluation and lesions with cystic, vascular or diffuse nature are significantly associated with nondiagnostic results (Cancer Cytopathol 2022;130:609)

Treatment

Clinical / radiologic follow up only (56%), direct surgery (19%) and repeat FNA (19%) (Cancer Cytopathol 2022;130:609)

Cytology description

FNA with < 60 lesional cells, although specific criteria have not been established
Poorly prepared slides with artifacts (e.g., air drying, obscuring blood and poor staining) that preclude the evaluation of the cellular component
Normal nonneoplastic salivary gland elements in the setting of a clinically or radiologically defined mass
Nonmucinous cyst fluid without an epithelial component
Exclusion criteria
- FNA with scant cellularity but significant cytologic atypia → at least atypia of undetermined significance (AUS)
- Mucinous cyst fluid contents without an epithelial component → atypia of undetermined significance
- Abundant inflammatory cells without an epithelial component → nonneoplastic
- Acellular FNA with a matrix component suggestive of a pleomorphic adenoma → neoplasm: benign
Reference: Faquin: The Milan System for Reporting Salivary Gland Cytopathology, 1st Edition, 2018

Cytology images

Contributed by Jen-Fan Hang, M.D.

Nonneoplastic acinar cells

Benign skeletal muscle

Cystic fluid only

Sample pathology report

Parotid gland, right, fine needle aspiration:
- Nondiagnostic (see comment)
- Comment: Insufficient cellularity for diagnosis.

Submandibular gland, left, fine needle aspiration:
- Nondiagnostic (see comment)
- Nonneoplastic benign salivary gland elements only
- Comment: The finding of nonneoplastic salivary gland elements only does not explain the presence of a clinically or radiologically defined mass. Repeat fine needle aspiration under radiologic guidance is recommended if clinically indicated.

Parotid gland, left, fine needle aspiration:
- Nondiagnostic (see comment)
- Comment: Cystic fluid only.

Board review style question #1

A 45 year old woman presents with a 2.8 cm right parotid nodule. Ultrasound demonstrates a well defined nodule with heterogeneous echogenicity. Fine needle aspiration is performed. What is the best diagnosis according to the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC)?

Atypia of undetermined significance
Benign neoplasm, pleomorphic adenoma
Nondiagnostic
Nonneoplastic

Board review style answer #1

C. Nondiagnostic. The presence of normal nonneoplastic salivary gland acinar cells only in the setting of a clinically and radiologically defined mass should be diagnosed as nondiagnostic. The FNA sample is not considered representative of the lesion detected on clinical and radiologic examination. Repeat FNA under radiologic guidance is recommended if clinically indicated.

Comment Here

Reference: Nondiagnostic

Board review style question #2

A 38 year old man presents with a 3.0 cm right parotid mass. Ultrasound demonstrates a mixed solid and cystic tumor. Fine needle aspiration is performed. What is the best diagnosis according to the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC)?

Atypia of undetermined significance, mucinous cystic lesion
Malignant, low grade mucoepidermoid carcinoma
Nondiagnostic, cyst fluid only
Nonneoplastic, compatible with mucocele

Board review style answer #2

A. Atypia of undetermined significance, mucinous cystic lesion. This FNA contains abundant mucin without any epithelial cells. The differential diagnosis includes a benign mucinous cyst; however, a low grade mucoepidermoid carcinoma cannot be excluded. Based on the MSRSGC, the most appropriate diagnosis would be atypia of undetermined significance. Clinical and radiological correlations are needed. Aspiration of a residual mass, if present, may help to achieve a more specific diagnosis.

Comment Here

Reference: Nondiagnostic

Nonneoplastic

Table of Contents

Definition / general

Lacking cytomorphologic evidence of a neoplastic process
Includes inflammatory, metaplastic, infectious and reactive changes

Essential features

The Milan System for Reporting Salivary Gland Cytopathology provides a standardized system for reporting results (Faquin: The Milan System for Reporting Salivary Gland Cytopathology, 1st Edition, 2018)
Nonneoplastic category includes inflammatory, metaplastic, infectious and reactive changes without cytomorphologic evidence of neoplasia
Estimated risk of malignancy (ROM) is expected to be low (~10%) (Diagn Cytopathol 2017;45:820)
Sialadenitis (acute, chronic and granulomatous) is the most common nonneoplastic lesion (J Am Soc Cytopathol 2021;10:349)
Usual management involves clinical follow up with radiologic correlation

CPT coding

88172 - determination of adequacy of specimen
88173 - FNA interpretation
88305 - cell block preparation

Sites

Major salivary glands (parotid, submandibular, sublingual), less frequent in minor salivary glands

Laboratory

Flow cytometry for lymphoid rich samples

Radiology description

Sialadenitis
- Enlarged, hypoechoic with heterogeneous echotexture (Br J Radiol 2003;76:271)
- Fat stranding and thickening of the superficial fascia and platysma muscles (J Clin Imaging Sci 2018;8:47)
Sialolithiasis
- Sialoliths can be detected using ultrasound (usually the initial examination imaging) or unenhanced computed tomography (Br J Radiol 2003;76:271)
- Magnetic resonance sialography or conventional sialography can be performed in case of high suspicion for a nonradiopaque calculus (J Clin Imaging Sci 2018;8:47)
Tumor-like lesions
- Some inflammatory conditions can produce salivary gland enlargement with homogeneous enhancement, mimicking neoplasia (e.g., chronic sclerosing sialadenitis) (J Clin Imaging Sci 2018;8:47)
Simple cysts
- Round / oval mass with well delineated borders, anechoic center and clear posterior acoustic enhancement
- May represent benign entities (reactive lymph nodes, salivary duct cyst, lymphoepithelial cyst) but it is noteworthy that benign and malignant neoplasms may also present standard features of a simple cyst (J Ultrason 2016;16:191)
- Intracystic attenuation or signal intensity are due to viscosity or increased protein concentration of the cystic fluid content (Jpn J Radiol 2019;37:627)
HIV associated lymphoepithelial lesion
- Numerous entirely cystic, combined cystic and solid or entirely solid lesions, which are typically bilateral (Jpn J Radiol 2019;37:627)

Radiology images

Contributed by Jose Manuel Gutierrez Amezcua, M.D. and Tamar C. Brandler, M.D., M.S.

Deep parotid lobe nodule

Solid and cystic parotid lesion

Parotid solid enhancing lesion

Enlarged periparotid lymph node

Case reports

51 year old woman, 59 year old man, 67 year old woman and 88 year old man with chronic sclerosing sialadenitis (Küttner tumor) misinterpreted as neoplastic in the context of previous head and neck malignancy (Head Neck Pathol 2016;10:389)
54 year old woman with hydatid cyst of the parotid gland (Turk Patoloji Derg 2017;33:171)
57 year old man with unilateral cysticercosis of the parotid gland (Case Rep Otolaryngol 2021;2021:9999441)
68 year old man with left submandibular sialadenitis and abundant amylase crystalloids (Indian J Otolaryngol Head Neck Surg 2014;66:348)
71 year old woman with multifocal adenomatous oncocytic hyperplasia of the parotid gland (Case Rep Oncol 2014;7:819)

Cytology description

Acute sialadenitis:
- Frequency: parotid > submandibular > sublingual glands
- Acute inflammation (neutrophils) with or without bacteria and background debris
- Rarely sampled since it is usually a clinical diagnosis
Chronic sialadenitis:
- Frequency: submandibular > parotid > sublingual glands
- Hypocellular aspirate with basaloid (atrophic) or metaplastic ductal cells and few / absent acinar cells
- Chronic inflammation (lymphocytes and plasma cells)
- Fragments of fibrotic stroma
- With or without amylase crystalloids (rectangular or rhomboid nonbirefringent structures) (Cancer Cytopathol 2021;129:432)
- Chronic sclerosing sialadenitis (also known as Küttner tumor) is an IgG4 related disease that can present as firm mass simulating neoplasia
Sialolithiasis:
- Frequency: submandibular > parotid > sublingual glands
- Hypocellular aspirate with scant acinar cells and benign ductal cells
- Ductal cells may exhibit squamous and mucinous metaplasia
- Calcifications (liths) in an (usually chronic) inflammatory background
Granulomatous sialadenitis:
- Hypocellular aspirate with groups of epithelioid histiocytes with or without multinucleated giant cells
- Variable inflammatory and necrotic debris background
- Differential diagnosis: mucin extravasation (most common), infectious (tuberculosis, actinomycosis, cat scratch, tularemia), systemic disease (e.g., sarcoidosis)
Reactive lymph node hyperplasia:
- Almost exclusively in the parotid (intra or periparotid lymph nodes)
- Cellular aspirates with characteristics similar to a reactive lymph node:
  - Mixed, heterogeneous population of mature lymphocytes and background lymphoglandular bodies
  - Tingible body macrophages
  - Lymphohistiocytic aggregates (fragments of germinal center)
- Collect material for flow cytometry whenever lymphoma is in the differential diagnosis
Lymphoepithelial cyst:
- Associated with autoimmune disease (e.g., Sjögren syndrome) or young HIV+ individuals (usually multiple and bilateral) (Diagn Cytopathol 2012;40:684)
- Proteinaceous and keratin debris with squamous cells (without significant atypia), lymphocytes and lymphohistiocytic aggregates
- May see glandular (columnar / ciliated) cyst lining
Lymphoepithelial sialadenitis (LESA):
- More common in parotid gland (~90% of cases), in women and associated with autoimmune conditions like Sjögren syndrome
- Cellular aspirate with large sheets of reactive ductal cells with or without squamous metaplasia and percolating mature lymphocytes
- Ductal cells have enlarged nuclei with distinct nucleoli but lack significant pleomorphism or atypia
- Mixed population of mature lymphocytes, dendritic cells and tingible body macrophages
Sialadenosis or sialosis:
- Frequency: parotid (often bilaterally) > submandibular glands
- Infrequent cause of enlargement of salivary glands associated with systemic metabolic conditions (e.g., diabetes, metabolic syndrome, hypothyroidism, alcohol abuse, malnutrition, liver disease, etc.)
- Cellular aspirate with hypertrophic acinar cells without cytologic or architectural alterations
- Clinicoradiological correlation is essential for diagnosis (no discrete mass)
Salivary duct cyst:
- Also known as salivary retention cyst, mucus retention cyst, sialocyst
- Frequency: minor salivary glands > parotid gland (particularly superficial lobe) (J Clin Imaging Sci 2013;3:3)
- Reactive lesion to salivary gland duct obstruction and buildup of salivary contents that results in duct ectasia
- Acellular or paucicellular aspirate of benign acinar / ductal cells, background debris containing macrophages (cyst contents), with or without inflammatory cells and amylase crystalloids
- Presence of mucin precludes classification as nonneoplastic (Diagn Cytopathol 2002;27:197)

Cytology images

Contributed by Jose Manuel Gutierrez Amezcua, M.D., Pascale G. Levine, M.D. and Tamar C. Brandler, M.D., M.S.

Amylase crystalloids

Cyst contents

Cyst with lymphoid and squamous cells

Benign epithelial cells and lymphocytes

Lymphoepithelial cyst excision

Granulomatous sialadenitis

Giant cell

Acute sialadenitis

Chronic sialadenitis

Reactive lymph node

Sample pathology report

Nonneoplastic:
- Granulomatous sialadenitis (see comment)
- Comment: Smears show predominantly benign salivary gland acinar cells, chronic inflammation, epithelioid histiocytes forming granulomas and scattered multinucleated giant cells. These findings may be related to chronic sialadenitis, duct obstruction or sarcoidosis. Clinical and radiologic correlation is recommended.

Nonneoplastic:
- Reactive intraparotid lymph node (see comment)
- Comment: Smears show a mixed lymphoid population with a predominance of mature lymphocytes, scattered tingible body macrophages and germinal center fragments (lymphohistiocytic aggregates). Please correlate with concurrent flow cytometry.

Nonneoplastic:
- Consistent with salivary duct cyst (see comment)
- Comment: Smears show groups of ciliated respiratory type columnar cells, abundant amylase crystals, scattered macrophages, few groups of oncocytic metaplastic cells, benign salivary acinar cells and some background inflammation and debris. No atypia, mucin or malignancy is seen. These cytologic findings are compatible with a nonneoplastic cyst.

Differential diagnosis

Cystic salivary gland lesions:
- Interpretation is challenging due to overall low cellularity and not well established diagnostic criteria
- ~45% will fall under the nonneoplastic category of the Milan system (Cancer Cytopathol 2021;129:214)
- Specimens containing nonmucinous cystic fluid only are best classified as nondiagnostic
- Specimens containing benign acinar or ductal epithelial components, background debris with macrophages (cyst contents) with or without inflammatory cells and amylase crystals are best classified as nonneoplastic (Cancer Cytopathol 2021;129:214)
- Specimens containing abundant mucin with or without epithelial cells are best classified as atypia of undetermined significance (AUS) due to the possibility of underlying mucoepidermoid carcinoma (Head Neck Pathol 2018;12:548)
Lymphoma:
- Lymphomas originating from the salivary glands are rare, accounting for ~3% of all malignant tumors which more commonly affect the parotid glands (World J Clin Cases 2020;8:2717)
- Risk factors include certain viral infections (HIV, EBV), immunosuppression and autoimmunity, particularly Sjögren syndrome
- Usually presents with a unilateral asymptomatic mass that enlarges over a period of time, with or without cervical lymphadenopathy
- Whenever non-Hodgkin lymphoma is in the differential, additional passes for flow cytometry evaluation are recommended
- Reassuring features of benignity in specimens with abundant lymphoid tissue include:
  - Mixed, heterogeneous population of mature lymphocytes and background lymphoglandular bodies
  - Tingible body macrophages
  - Lymphohistiocytic aggregates (fragments of germinal center)

Board review style question #1

A 40 year old patient undergoes ultrasound guided fine needle aspiration (FNA) of a 2.1 cm cystic lesion in the inferior aspect of the parotid gland. The aspirate smear stained with Diff-Quik is shown above. Which of the following would be the appropriate way to characterize this lesion?

Atypia of undetermined significance
Nondiagnostic
Nonneoplastic
Salivary gland neoplasm of uncertain malignant potential
Suspicious for malignancy

Board review style answer #1

C. Nonneoplastic

Comment Here

Reference: Nonneoplastic

Board review style question #2

Which of the following findings on fine needle aspiration (FNA) would preclude classification of a salivary gland lesion as nonneoplastic?

Abundant mucin with or without epithelial cells
Granulomas and scattered multinucleated giant cells
Heterogeneous lymphocytes with tingible body macrophages
Metaplastic ductal cells with calcification and chronic inflammation
Nonmucinous background debris with macrophages

Board review style answer #2

A. Abundant mucin with or without epithelial cells

Comment Here

Reference: Nonneoplastic

Oncocytoma

Table of Contents

Definition / general

Benign tumor composed of oncocytes
Also called oxyphilic adenoma
1 - 2% of salivary gland neoplasms; more frequent than oncocytosis and oncocytic carcinoma

Clinical features

Usually parotid gland mass, also submandibular gland or minor salivary glands
Mean age 60 years
20% associated with radiation therapy or radiation exposure
Rarely bilateral, multiple
Rarely synchronous with Warthin tumor or carcinoma ex pleomorphic adenoma
May occur in trisomy 7 or in BHD syndrome

Radiology description

Specific MRI features: T1 hypointense, isointense to normal gland on fat saturated T2 and postcontrast T1; CT features: enhancing tumor and nonenhancing cystic component (AJNR Am J Neuroradiol 2011;32:1703, AJNR Am J Neuroradiol 2010;31:1413)

Case reports

68 year old man with parotid mass (J Cytol 2012;29:80)
79 year old woman with parotid tumor with multinodular oncocytic hyperplasia (Arch Pathol Lab Med 2003;127:e53)

Treatment

Local excision
Excellent prognosis but may have late recurrence

Gross description

Well circumscribed with fibrous capsule, solid, tan-red-brown, lobulated, often small, may have cystic spaces

Microscopic (histologic) description

Eosinophilic or clear cell (glycogen) with sheets, trabeculae, acini or follicular patterns of monotonous large polygonal cells with well defined cell borders, deeply eosinophilic, granular cytoplasm, small round nuclei
Vascular stroma, may have clear cell change, background of oncocytic nodular hyperplasia, psammoma bodies, tyrosine rich crystals
No mitotic figures, no elastosis

Microscopic (histologic) images

Images hosted on other servers:

Various images

Cytology description

Cellular oncocytic aspirates with very clean background
Oncocytes show abundant finely granular cytoplasm, centrally placed or eccentric nuclei and occasional distinct nucleoli
Cellular arrangement can be irregular sheets, small clusters or single cells

Cytology images

Contributed by Jen-Fan Hang, M.D.

Clean background

Bland oncocytes

Positive stains

PTAH, CK5 / 6, CK8 / 18, CK10 / 13, EMA, Ki67, p63 (Head Neck Pathol 2007;1:123)
Also antimitochondrial antibody, CK7+ / CK20-
High viral load of high risk HPV (Int J Biol Markers 2007;22:239), CEA, GFAP, variable S100

Negative stains

Myoepithelial markers (alpha smooth muscle actin, smooth muscle myosin heavy chain, calponin, Arch Pathol Lab Med 1999;123:801), CEA, GFAP

Electron microscopy description

Packed with mitochondria with partitions

Differential diagnosis

Metastases: prostate carcinoma is PSA+, renal cell carcinoma is p63+, CD10+, CK20+
Oncocytic carcinoma: malignant features, invasive, high Ki67, regional nodal or distant metastases
Oncocytic metaplasia: no mass
Oncocytoid artifact: electrocautery
Oncocytosis
Warthin tumor: FNA has lymphoid component, mucus, necrosis

Oncocytosis (pending)

[Pending]

Pleomorphic adenoma

Table of Contents

Definition / general

Benign triphasic salivary gland neoplasm composed of epithelial (ductal) cells, myoepithelial cells and chondromyxoid stroma

Essential features

Triphasic salivary gland tumors with ductal cells, myoepithelial cells and stromal component
Most common salivary gland neoplasm

Terminology

Benign mixed tumor

ICD coding

ICD-O: 8940/0 - pleomorphic adenoma
ICD-10: D11.0 - benign neoplasm of parotid gland

Epidemiology

Most common salivary gland tumor in both children and adults (Hum Pathol 2018;73:194, El-Naggar: WHO Classification of Head and Neck Tumours, 4th Edition, 2017)
Affects patients of all ages, most commonly in 30s - 60s
F > M (2:1)

Sites

Most commonly affected site is the parotid gland (84% of cases)
May also occur in other major salivary glands (submandibular and sublingual glands), lacrimal gland and minor salivary glands of upper aerodigestive tract (El-Naggar: WHO Classification of Head and Neck Tumours, 4th Edition, 2017)

Etiology

Prior radiation increases the risk of developing pleomorphic adenoma

Clinical features

Slow growing, painless, well circumscribed mass involving salivary gland

Diagnosis

Diagnosis can be rendered on preoperative cytology or biopsy, showing typical metachromatic fibrillary stroma (in cytology) or triphasic growth pattern (on biopsy)

Benign metastasizing mixed tumors

Rare, controversial clinical entity with late metastasis (6 - 52 years) after tumor excision
- Metastatic sites include bone, CNS, kidney, liver, lung, lymph nodes, maxilla, pharynx, skin, sphenoid sinus
Benign morphology in original and metastatic tumor
Associated with incomplete pleomorphic adenoma surgery / local recurrence, post cardiac transplant patient / immunosuppression (Mod Pathol 1998;11:1142)

Radiology description

Mass with well defined or bosselated border, hyperintense on T2 MRI

Radiology images

Images hosted on other servers:

MRI parotid tumor

Prognostic factors

Benign tumor: surgical resection with negative margin is considered curative
Enucleation is associated with 15 - 25% risk of local recurrence
Recurrences are usually within 18 months but can be up to 50 years later (Arch Pathol Lab Med 2008;132:1445)
Risk of malignant transformation is ~5%
Risk factors for malignant transformation: multiple recurrences, submandibular location, older age, larger size, prominent hyalinization, increased mitotic rate (if present, sample tumor more thoroughly), radiation exposure

Case reports

6 year old girl with pleomorphic adenoma of the parotid gland (Children (Basel) 2018;5:E127)
28 year old man with submandibular mass (Case #243)
54 year old man with painless swelling over left half of upper lip for past 10 years (Case #392)
84 year old man, a former smoker, with enlarging parotid gland lesion (Case #404)
Metastasizing pleomorphic adenoma with recurrent PLAG1 or HMGA2 fusion (Am J Surg Pathol 2019;43:1145)

Treatment

Complete surgical resection with negative margin is the mainstream treatment
Enucleation is not advocated given the high risk of local recurrence
Radiation therapy may be considered in symptomatic recurrent cases not amenable to surgical treatment (El-Naggar: WHO Classification of Head and Neck Tumours, 4th Edition, 2017)

Clinical images

Images hosted on other servers:

Minor salivary gland tumor

Mass over mandible

Parotid tumor

Large submandibular mass

Parotid tumor

Gross description

Primary tumor: well demarcated, bosselated gray-white myxoid mass
Recurrent tumor: numerous myxoid to fibrotic nodules of various size, giving a shotgun bullet appearance

Gross images

Contributed by Bin Xu, M.D., Ph.D. and Kelly Magliocca D.D.S., M.P.H.

Primary pleomorphic adenoma

Recurrent pleomorphic adenoma

Pleomorphic adenoma

Case #392

External surface

Cut surface

Microscopic (histologic) description

Bosselated outer surface, often with tongue-like protrusions (pseudopods)
Typically has 3 components:
- Epithelial (ductal) component forming the inner layer of cysts and tubules
- Myoepithelial cells as the outer layer of cysts and tubules and scattered within the myxoid stroma
  - Cytology of myoepithelial cells can be plasmacytoid, spindled, epithelioid, clear or stellate shaped
- Stromal component is typically myxoid, chondroid or myxochondroid
  - It can also be hyalinized or fibrotic
Metaplastic changes may be seen, e.g. adipose metaplasia, osseous metaplasia, squamous metaplasia (sometimes with keratinization), sebaceous metaplasia and mucinous metaplasia
Intravascular permeation has been reported in a small percentage of cases and does not increase the risk of recurrence or distant metastasis
- It is proposed to be a phenomenon associated with surgical manipulation (Am J Surg Pathol 2012;36:1674)
Other features that may be seen in pleomorphic adenoma include
- Tyrosine crystal: dense amorphous eosinophilic floret shaped crystal
- Increased cellularity: so called cellular pleomorphic adenoma
- Increased mitotic activity
- Myoepithelial rich area or tumor

Microscopic (histologic) images

Contributed by Bin Xu, M.D., Ph.D. and Andrey Bychkov, M.D., Ph.D.

Encapsulated mass

Bosselated interface

Pseudopods

Recurrent pleomorphic adenoma

Triphasic tumor

Clear myoepithelial cells

Plasmacytoid myoepithelial cells

Spindle myoepithelial cells

Squamous and mucinous metaplasia

Adipose and osseous metaplasia

Tyrosine crystals

Biphasic population

Case #404

Pleomorphic adenoma

Myoepithelial cells

Chondroid stroma

Myoepithelial cells

Virtual slides

Contributed by Andrey Bychkov, M.D., Ph.D.

Pleomorphic adenoma

Cytology description

Matrix containing tumor
Typical feature is its unique fibrillary stroma
Mixture of myoepithelial cells, ductal cells and extracellular stroma
Myoepithelial cells are usually the predominant cell type with various cytomorphology, including round, polygonal, plasmacytoid, spindle, etc.
Ductal cells show bland cytologic features with organized honeycombing or ductal arrangement
Extracellular matrix shows characteristic feathery / fibrillary borders and bright magenta color on Romanowsky type stain and gray-green chondromyxoid features on Papanicolaou stain

Cytology images

Contributed by Bin Xu, M.D., Ph.D. and Jen-Fan Hang, M.D.

Diff-Quik smear

Papanicolaou stain

Fibrillary extracellular matrix

Plasmacytoid
myoepithelial cells

Squamous metaplasia

Positive stains

Ductal (epithelial) cells are typically positive for cytokeratins (e.g. AE1 / AE3, CAM5.2 and CK7)
Myoepithelial cells are positive for GFAP, S100, SOX10, actin - alpha smooth muscle, calponin, p40 and p63
PLAG1 and HMGA2 can be used as surrogate immunohistochemical markers for underlying PLAG1 or HMGA2 fusion (Histopathology 2018;72:285, Histopathology 2017;71:511)

Negative stains

Melanoma markers, e.g. MelanA, HMB45

Molecular / cytogenetics description

PLAG1 fusion (chromosome 8q12) or HMGA2 fusion (chromosome 12q14-15) is present in ~70% of pleomorphic adenomas (Oncogene 1998;16:1409, Cancer Res 1997;57:13)

Molecular / cytogenetics images

Images hosted on other servers:

FISH for PLAG1

Sample pathology report

Parotid, left, parotidectomy:
- Pleomorphic adenoma, 2.0 cm, margins negative for tumor

Differential diagnosis

Carcinoma ex pleomorphic adenoma (malignant mixed tumor):
- Demonstrates frank evidence of malignancy, e.g. marked nuclear pleomorphism, frank necrosis, invasion beyond pre-existing capsule, perineural or lymphovascular invasion
- Both may contain PLAG1 or HMGA2 fusion (Hum Pathol 2015;46:26)
Myoepithelioma and myoepithelial carcinoma:
- Contain (nearly) exclusively myoepithelial cells
- Ductal (epithelial) component is scant or absent
Other salivary gland neoplasms (adenoid cystic carcinoma, polymorphous adenocarcinoma, epithelial myoepithelial carcinoma):
- Pleomorphic adenoma may show various architectural and cytologic features that resemble other salivary tumors
- Identifying areas typical of pleomorphic adenoma with triphasic ductal, myoepithelial and stromal components is helpful to establish the diagnosis
Squamous cell carcinoma:
- Both may contain squamous epithelium with keratinization and may be difficult to differentiate in small biopsy or cytology material
- Is not triphasic; identification of ductal, epithelial and stromal components typical of pleomorphic adenoma rules out squamous cell carcinoma

Board review style question #1

A 2.5 cm parotid tumor is resected. The most common molecular alteration of this tumor is

ETV6-NTRK3 fusion
MYB-NFIB fusion
PLAG1 fusion
PRKD1 mutation

Board review style answer #1

C. PLAG1 fusion (this is a pleomorphic adenoma)

Comment Here

Reference: Pleomorphic adenoma

Board review style question #2

Which of the following statements regarding pleomorphic adenoma is true?

Carries nearly zero risk of recurrence or malignant transformation
Characterized by architectural diversity and is composed of one single type of cells
Is the most common salivary gland neoplasm
Typically treated with enucleation

Board review style answer #2

C. Pleomorphic adenoma is the most common salivary gland neoplasm

Comment Here

Reference: Pleomorphic adenoma

Board review style question #3

A 45 year old man presented with a 2.8 cm, slow growing mass at left parotid region. He underwent ultrasound guided FNA for evaluation. What is the best diagnosis?

Basal cell adenoma
Oncocytoma
Pleomorphic adenoma
Warthin tumor

Board review style answer #3

C. Pleomorphic adenoma

Magenta colored extracellular matrix with feathery / fibrillary borders and intermingled bland myoepithelial cells are characteristic features for a pleomorphic adenoma.

Comment Here

Reference: Pleomorphic adenoma

Polymorphous adenocarcinoma

Table of Contents

Definition / general

Polymorphous adenocarcinoma is an indolent salivary gland carcinoma characterized by cytologic uniformity and architectural diversity, predominantly affecting minor salivary glands, in particular the hard and soft palate

Essential features

Occurs in minor salivary glands predominantly, in particular the palate in approximately 60% of cases
- May occur in major salivary gland in less than 5% of cases (Am J Surg Pathol 2016;40:1526)
Composed entirely of one cell type with pale nuclei and open chromatin
The term polymorphous refers to the architectural diversity, i.e. the tumors contains multiple architectural patterns
Characterized by molecular alteration of PRKD genes, in particular PRKD1 E710D hotspot mutations (Nat Genet 2014;46:1166, Mod Pathol 2020;33:65)

Terminology

Terminal duct carcinoma, lobular carcinoma, low grade papillary adenocarcinoma, cribriform adenocarcinoma of (minor) salivary gland, polymorphous low grade adenocarcinoma

ICD coding

ICD-O: 8525/3 - Terminal duct adenocarcinoma
ICD-10: C05.9 - Malignant neoplasm of palate, unspecified

Epidemiology

F:M = ~2:1 (Am J Surg Pathol 2016;40:1526, Cancer 1999;86:207, Arch Otolaryngol Head Neck Surg 2010;136:385)
Mean age of diagnosis in the 50 - 60s (range: 16 - 90) (Am J Surg Pathol 2016;40:1526, Cancer 1999;86:207, Arch Otolaryngol Head Neck Surg 2010;136:385)
Second most common salivary gland carcinoma of palate and of oral cavity

Sites

Most frequently occurs in the palate (in 49 - 87% of cases) (Am J Surg Pathol 2016;40:1526, Cancer 1999;86:207, Arch Otolaryngol Head Neck Surg 2010;136:385)
Other possible primary sites are minor salivary glands of upper aerodigestive tract, including oral cavity (e.g. floor of mouth, retromolar trigone, lip and lateral tongue), oropharynx (e.g. base of tongue and tonsil), sinonasal tract and nasopharyx
May occur in major salivary gland, in particular the parotid gland, in less than 5% of cases

Clinical features

Commonly presents with palpable mass

Diagnosis

Typically rendered in biopsy or resection specimens

Radiology description

No specific radiologic findings
CT and MRI are used preoperatively to establish the extent of disease and the presence of bone invasion

Radiology images

Images hosted on other servers:

Prognostic factors

Excellent prognosis with a 10 year disease specific survival of 94 - 99% and 10 year recurrence free survival of 83 - 88% (Oral Oncol 2016;55:6, Laryngoscope 2015;125:1644, Oral Oncol 2019;95:52)
The presence of at least 10% of papillary or at least 30% of cribriform architecture is an independent adverse prognostic factor (Am J Surg Pathol 2016;40:1526)
Cribriform adenocarcinoma of salivary gland, currently considered by WHO classification as a variant of polymorphous adenocarcinoma, is associated with higher frequency (7 - 100%) of lymph nodal metastasis (El-Naggar: WHO Classification of Head and Neck Tumours, 4th Edition, 2017, Histopathology 1999;35:495, Mod Pathol 2020;33:65, Oral Oncol 2019;95:52, Am J Surg Pathol 2011;35:1168)
Tumors harboring PRKD1, PRKD2 or PRKD3 fusion incur 50% risk of lymph node metastasis (Mod Pathol 2020;33:65)
Other adverse pathologic prognostic factors reported include larger tumor size, advanced stage, lymphovascular invasion, bone invasion, perineural invasion of large nerve and tumor necrosis (Eur Arch Otorhinolaryngol 2018;275:1681)

Case reports

43 year old Japanese man with palate polymorphous adenocarcinoma with high grade transformation (Head Neck Pathol 2019;13:131)
50 year old woman with a slow growing mass involving the hard palate and alveolar ridge (J Oral Maxillofac Pathol 2018;22:S60)
60 year old woman with a large tumor of maxillary sinus (Dentomaxillofac Radiol 2013;42:14804843)
70 year old woman with a tonsillar mass and neck lymph node metastasis (Diagn Cytopathol 2017;45:468)

Treatment

Surgical resection with appropriative margin is the primary curative treatment (Eur Arch Otorhinolaryngol 2018;275:1681)
Neck lymph node dissection may be performed for patients with a diagnosis of cribriform adenocarcinoma or with clinically positive lymph node(s)
Postoperative radiation therapy may be considered on an individual basis, especially for tumors with positive margins or perineurial invasion (Eur Arch Otorhinolaryngol 2018;275:1681)
Chemotherapy is in general reserved for patients with distant metastasis or nonoperable disease (Eur Arch Otorhinolaryngol 2018;275:1681)

Clinical images

Images hosted on other servers:

Submucosal mass involving maxilla

Palate nodule

Gross description

Typically presents as a submucosal white to beige, firm, lobulated nodule or mass with infiltrative border

Gross images

Contributed by Bin Xu, M.D., Ph.D.

Macroscopic appearance

Microscopic (histologic) description

Diagnostic criteria:
- Cytologic uniformity: the tumor is composed entirely of one type of tumor cells characterized by monotonous pale nuclei with marked chromatin clearing resembling that of papillary thyroid carcinoma
- Architectural diversity: showing highly variable architectural patterns of different proportions, including single filing arrangement, trabecular, tubular, reticular, papillary, solid and cribriform pattern
Targetoid arrangement and streaming of tumor cells and nests around nerves and vessels are common
Perineurial invasion is frequent, being seen in 60 - 75% of cases (Oral Surg Oral Med Oral Pathol 1991;71:469, Am J Surg Pathol 2016;40:1526)
Uncommon histologic features include: microcalcification, oncocytic changes, mucocytes and high grade transformation (defined as marked nuclear atypia, prominent mitotic activity and tumor necrosis) (Head Neck Pathol 2019;13:131)
Cribriform adenocarcinoma of salivary gland
- Cribriform adenocarcinoma is currently considered by WHO classification as a variant of polymorphous adenocarcinoma (Chan: WHO Classification of Head and Neck Tumours, 4th Edition, 2017)
- First described as a tumor with a high propensity to base of tongue/posterior tongue location and a high risk of nodal metastasis (Histopathology 1999;35:495)
- Later reported in minor salivary glands outside of base of tongue and even major salivary gland (Am J Surg Pathol 2011;35:1168, Am J Surg Pathol 2016;40:1526, Mod Pathol 2020;33:65)
- Shares the same cytologic features of optic clearing pale nuclei and immunohistochemistry profile as polymorphous adenocarcinoma
- Characterized by lobulated architecture separated by fibrous septa and relatively uniformed solid, cribriform or microcystic architecture
  - Peripheral palisading, peripheral clefting and glomeruloid structures are common

Microscopic (histologic) images

Contributed by Bin Xu, M.D., Ph.D.

Infiltrative mass

Optical clearing of nuclei

Targetoid arrangement and perineural invasion

Papillary architecture

Cribriform architecture

Reticular pattern

Solid pattern

Oncocytic changes

Cribriform adenocarcinoma of salivary gland

S100

CK7

Virtual slides

Images hosted on other servers:

Polymorphous adenocarcinoma

Cytology description

Given that most tumors are located intraorally, fine needle aspiration cytology is rarely used for the diagnosis
Case reports show that this tumor typically contains uniform tumors cells with ground glass nuclei, scattered nuclear grooves and inconspicuous nucleoli

Cytology images

Images hosted on other servers:

Papanicolaou stain

Positive stains

S100, CK7 and SOX10: diffusely and strongly positive
p63: variably positive (78 - 100%) (Am J Surg Pathol 2016;40:1526, Head Neck Pathol 2015;9:79, Asian Pac J Cancer Prev 2019;20:2917)

Negative stains

p40 (Am J Surg Pathol 2016;40:1526, Head Neck Pathol 2015;9:79, Asian Pac J Cancer Prev 2019;20:2917)
EMA, SMA, MSA, GFAP and GATA3: positive in ~ 10 - 20% (Head Neck Pathol 2019 Jun 20 [Epub ahead of print])

Molecular / cytogenetics description

Polymorphous adenocarcinoma:
- 73 - 89% harbor PRKD1 E710D hotspot mutation (Nat Genet 2014;46:1166, Mod Pathol 2020;33:65, Am J Surg Pathol 2020;44:545)
- 6 - 11% contain fusions involving PRKD1, PRKD2 or PRKD3 genes, with the fusion partners being ARID1A or DDX3X (Genes Chromosomes Cancer 2014;53:845, Mod Pathol 2020;33:65, Am J Surg Pathol 2020;44:545)
Cribriform adenocarcinoma of salivary gland:
- 70 - 94% have PRKD1, PRKD2 or PRKD3 fusions, whereas 0 - 20% show PRKD1 E710D mutation

Molecular / cytogenetics images

Images hosted on other servers:

PRKD mutations and fusions

Sample pathology report

Palate, right, partial maxillectomy:
- Polymorphous adenocarcinoma, 2.3 cm, margin uninvolved by carcinoma (see synoptic report)

Differential diagnosis

Adenoid cystic carcinoma:
- Biphasic with both ductal and myoepithelial elements
- Both tumors can have tubular, cribriform and solid architecture
- Dark angulated basaloid nuclei
- Typically p63+ / p40+ in adenoid cystic carcinoma (versus p63+ / p40- in polymorphous adenocarcinoma) (Head Neck Pathol 2015;9:79)
Secretory carcinoma:
- Both may have papillary or solid architecture
- Both tumors are diffusely S100+
- GCDFP-15+ / mammaglobulin+
- ETV6-NTRK3 fusion
Myoepithelial carcinoma:
- Both contain a single type of tumor cells and trabecular or solid growth pattern
- Lacks alteration in PRKD genes
- Both may be S100+ / GFAP+ / SMA+ / MSA+

Board review style question #1

EWSR1-ATF1 fusion
MYB-NFIB fusion
PLAG1 fusion
PRKD1 E710D hotspot mutation

Board review style answer #1

D. PRKD1 E710D hotspot mutation. This is a polymorphous adenocarcinoma.

Comment Here

Reference: Polymorphous adenocarcinoma

Board review style question #2

It is a biphasic salivary gland carcinoma showing ductal (epithelial) and myoepithelial differentiation
It is the most common salivary gland carcinoma originated from the palate
It is the most common salivary gland neoplasm originated from the palate
It most frequently occurs in the palate

Board review style answer #2

D. It most frequently occurs in the palate

Comment Here

Reference: Polymorphous adenocarcinoma

Primary salivary gland neoplasms-general

Table of Contents

Definition / general | Sites | Poor prognostic factors | Treatment

Definition / general

Risk factors: radiation exposure (atomic bomb survivors, radiation therapy, chemoradiation therapy) with mean latency after low dose radiation exposure of 11 years for malignant tumors and 21 years for benign tumors
- Alcohol and tobacco are NOT risk factors except for Warthin tumor (associated with smoking)
Benign: pleomorphic adenoma (50%), Warthin tumor (5%), oncocytoma, basal cell adenoma, ductal papilloma
Malignant: mucoepidermoid carcinoma (15%), polymorphous low grade adenocarcinoma (10%), acinic cell carcinoma, adenoid cystic carcinoma, malignant mixed tumor, squamous cell carcinoma (1%)
Bilateral tumors: Warthin tumor is most common, also pleomorphic adenoma and acinic cell carcinoma
15% of parotid tumors are malignant, 40% elsewhere
Children: pleomorphic adenoma most common but more often malignant; most common malignant tumors are mucoepidermoid carcinoma, adenoid cystic carcinoma, acinic cell carcinoma
Regional lymph nodes: nodal metastases usually evident on initial clinical evaluation
- Low grade tumors rarely metastasize to regional nodes, high grade tumors often do; nodal involvement tends to be orderly from intraglandular to adjacent nodes to upper and midjugular nodes and occasionally to retropharyngeal nodes
- Bilateral nodal involvement is rare
Metastases: usually to lungs

Sites

> 90% arise in parotid gland, 5% in submandibular gland
Deep parotid tumors may present as intraoral masses
Sublingual tumors are rare and may be difficult to distinguish from minor salivary gland primary tumors of anterior floor of mouth
Minor salivary gland tumors usually in hard palate (site with most glandular tissue); may arise in lymph nodes around salivary glands

Poor prognostic factors

Postoperative recurrence, submandibular gland site, facial nerve paralysis, high grade tumor

Treatment

Parotid gland tumors: superficial lobe tumors are treated with superficial / partial parotidectomy with preservation of facial nerve
- Total parotidectomy with sacrifice of facial nerve may be necessary if high grade or advanced tumor
- Neck dissection necessary if nodal involvement
Submandibular tumors: total excision; often recur because of difficulty of getting good margins due to closeness of mandible
Radiation therapy: for inoperable tumors

Salivary duct carcinoma

Table of Contents

Definition / general

First described by Kleinsasser in 1968 (Arch Klin Exp Ohren Nasen Kehlkopfheilkd 1968;192:100)
High grade malignant salivary gland neoplasm with in situ and invasive components
Morphologically resembles invasive ductal carcinoma of the breast

Essential features

High grade salivary gland malignancy
Histology is similar to invasive ductal carcinoma of the breast (specifically luminal androgen receptor [AR]+ subtype)
In situ areas frequently have comedo necrosis
Nearly all cases (> 90%) are AR positive
Poor prognosis

Terminology

Also known as high grade ductal carcinoma

ICD coding

ICD-O: 8500/3 - infiltrating duct adenocarcinoma, salivary glands
ICD-10: C07 - C08 - malignant neoplasm of salivary gland

Epidemiology

Patients are usually in their sixth to seventh decade of life
- Mean age: 67.4 years
- Range: 33 - 92 years (Am J Surg Pathol 2015;39:705)
M:F = 2.4:1 (AMA Otolaryngol Head Neck Surg 2016;142:489, Am J Surg Pathol 2015;39:705)
Represents ~10% of all salivary glands malignancies

Sites

Most commonly affects the parotid gland
Other sites include the submandibular gland and minor salivary glands

Pathophysiology

Several tumor suppressor genes may play a role in development, including TP53, HRAS, PIK3CA, PTEN and BRAF (Cancer Cytopathol 2020;128:693)

Etiology

Unknown
May arise de novo (60%) or from ex pleomorphic adenoma (40%) (Am J Surg Pathol 2015;39:705)

Clinical features

Rapidly growing neck mass, typically in the vicinity of the parotid gland
Facial pain
Facial weakness or paralysis
Regional or distant metastasis (lung, bone, brain or other sites)
References: Cancer Cytopathol 2020;128:693, Oral Oncol 2017;74:40, Zhonghua Kou Qiang Yi Xue Za Zhi 2019;54:416

Diagnosis

Neck mass that typically leads to imaging studies and fine needle aspiration
Patients may have a long standing history of pleomorphic adenoma that suddenly started to grow rapidly
References: Head Neck Pathol 2017;11:288, Ear Nose Throat J 2012;91:356

Radiology description

CT (Neuroradiology 2012;54:631):
- Typically shows a mass with heterogonous enhancement
- Can show foci of calcifications
MRI (AJNR Am J Neuroradiol 2005;26:1201):
- Invasive or ill defined margins
- Can appear well circumscribed in a minority of cases (~15%) (Neuroradiology 2012;54:631)
- On T1 weighted images, tumors appear hypointense compared with the surrounding salivary gland and isointense compared with the skeletal muscle
- On T2 weighted images, tumors are hyperintense compared with contralateral parotid
- Cellular components of the tumor enhance early with a high washout ratio
- Fibrotic and cellular poor areas show gradual upward enhancement
- Cellular areas with necrosis enhance early and poorly washout

Radiology images

Contributed by Jalal B. Jalaly, M.B.B.S., M.S.

CT cross sectional view

CT coronal view

Prognostic factors

Prognosis is poor, with overall survival rate of ~35%
Median overall survival is 3.1 years (AMA Otolaryngol Head Neck Surg 2016;142:489)
Poor prognostic factors:
- Higher tumor stage (especially nodal category N2 or higher), 5 year survival rates for stage I is 42% and 23% for stage IV (Cancer 2005;103:2526)
- Perineural invasion (especially if the facial nerve is involved and is sacrificed during surgery)
- Extranodal extension
- 50 years or older (Head Neck 2014;36:694)

Case reports

39 year old man complaining of decreased mobility of lower left eyelid and painless swelling of the left preauricular area (Folia Histochem Cytobiol 2015;53:342)
45 year old man with cytology and followup surgical pathology (J Cytol 2017;34:107)
50 year old patient with progressive facial paralysis and left parotid mass (Mod Pathol 2012;25:919)
59 year old man with progressive difficulty in swallowing and a muffled voice for 2 months (Medicine (Baltimore) 2018;97:e0095)
60 year old patient with salivary duct carcinoma of the sinonasal cavity (Head Neck 2016;38:E2464)

Treatment

Total parotidectomy with neck dissection
Adjuvant radiotherapy should be considered, as salivary duct carcinoma is high grade by definition (NCCN: NCCN Guidelines - Head and Neck Cancers [Accessed 7 June 2021])
Chemotherapy (antiandrogens, trastuzumab, anti-BRAF and anti-PIK3CA) for advanced disease as indicated

Clinical images

Images hosted on other servers:

Nasopharyngoscopy

Gross description

Mean gross greatest dimension is 3.2 cm and ranges from 0.5 - 9 cm (Am J Surg Pathol 2015;39:705)
Tumors typically have ill defined borders but may appear well circumscribed
Cut surface is heterogeneous and can show gross evidence of necrosis
Regional lymphadenopathy is common

Gross images

Contributed by Jalal B. Jalaly, M.B.B.S., M.S.

Enlarged intraparotid lymph nodes

Frozen section description

Typically not indicated as cytology is usually diagnostic of a high grade malignancy
High grade malignancy with necrosis and cellular pleomorphism

Microscopic (histologic) description

Invasive tumor cells with ample eosinophilic (oncocytic) cytoplasm forming cords, nests and cribriform glands in a desmoplastic stroma
Nuclear cytology is high grade with nuclear pleomorphism
In situ component frequently shows central necrosis
Secondary salivary duct carcinomas show pleomorphic adenoma intimately associated with the malignant component (~40% of salivary duct carcinomas are secondary) (Am J Surg Pathol 2015;39:705)
Histological variants show at least focal areas with conventional histology (Head Neck Pathol 2017;11:288)
- Mucin rich (Am J Surg Pathol 2003;27:1070)
- Micropapillary (Am J Surg Pathol 2004;28:319, Oral Surg Oral Med Oral Pathol Oral Radiol 2016;121:e162)
- Sarcomatoid (Am J Clin Pathol 2004;122:222)
- Rhabdoid (Histopathology 2017;70:164)
- Basal-like (Histopathology 2012;61:629, Am J Surg Pathol 2015;39:705)

Microscopic (histologic) images

Contributed by Jalal B. Jalaly, M.B.B.S., M.S.

Infiltrating nests and glands

Eosinophilic cytoplasm

Comedo necrosis

High grade nuclear cytology

Pleomorphic nuclei

AR+

Carcinoma ex pleomorphic adenoma

AR+

HER2+

Intracytoplasmic mucin

Mucicarmine+

AR+

Virtual slides

Images hosted on other servers:

Salivary duct carcinoma

Cytology description

Cellular smears with dirty necrotic background
Clusters of epithelial cells with high grade pleomorphic nuclei and ample cytoplasm
Mitotic figures and apoptotic debris
Immunohistochemical stains can be done on cell block slides to confirm the diagnosis (AR positive) and rule out metastasis / other primary high grade neoplasms of the salivary gland (see IHC section)
Reference: Cancer Cytopathol 2020;128:693

Cytology images

Contributed by Jalal B. Jalaly, M.B.B.S., M.S. and Jen-Fan Hang, M.D.

Diff-Quik

Pap stain

ThinPrep

Prominent nucleoli

Hyperchromasia

Immunofluorescence description

HER2 amplification by FISH analysis may be necessary for 2+ cases by HER2 immunohistochemistry (as defined by the American Society of Clinical Oncology / College of American Pathologists (ASCO / CAP) guidelines for breast cancer) (Arch Pathol Lab Med 2018;142:1364)
Samples are considered to be amplified when the average copy number ratio (HER2 / CEP17) is ≥ 2.0 (Oncotarget 2017;8:59023)

Immunofluorescence images

Images hosted on other servers:

HER2 amplification by FISH

Positive stains

Nearly all are positive for AR (> 90%), GATA3, AE1 / AE3, CK7, 34βE12 and EMA (Arch Pathol Lab Med 2015;139:55)
Most (~80%) are positive for GCDFP-15 (Am J Surg Pathol 2015;39:705, Am J Clin Pathol 1998;109:75)
PSA positive in ~57% (Am J Surg Pathol 2000;24:579)
HER2 (3+) in 10 - 35% (Head Neck Pathol 2018;12:488, Head Neck Pathol 2014;8:133, Am J Clin Pathol 1998;109:75)
Mucicarmine in mucin rich variant

Negative stains

Multifocal S100 positivity in 41% (Am J Clin Pathol 1998;109:75)
DOG1 and SOX10 (Mod Pathol 2012;25:919, Mod Pathol 2013;26:1041)
Most are negative for p63, CK5/6, ER and PR (Head Neck Pathol 2018;12:488, Head Neck Pathol 2014;8:133, Am J Clin Pathol 1998;109:75)

Molecular / cytogenetics description

PLAG1, HMGA2, PIK3CA, HRAS, TP53, ERBB2, BRAF alterations may be present (Cancer 2016;122:3136)

Sample pathology report

Parotid, right, parotidectomy:
- Salivary duct carcinoma, 2 cm, with lymphatic, vascular and perineural invasion, within 0.1 cm from deep resection margin (see comment)
- Comment: Metastatic carcinoma in 5 of 40 lymph nodes (5/40), largest metastatic focus measures 2.3 cm, with extranodal extension.

Differential diagnosis

Metastatic adenocarcinoma:
- Breast invasive ductal carcinoma:
  - If ER and PR+, easy to differentiate; otherwise morphological, clinical and radiological correlations are necessary
- Lung adenocarcinoma:
  - TTF1 and napsin+
- Prostatic adenocarcinoma:
  - NKX3.1+; AR and PSA do not differentiate
  - Other sites should be ruled out, based on clinical, radiological and histological findings
- Metastatic squamous cell carcinoma:
  - Histologic overlap, especially if nonkeratinizing; p63 and CK5/6+, AR-
Primary salivary gland neoplasms with high grade transformation (well differentiated areas may be focal):
- High grade mucoepidermoid carcinoma:
  - Can be challenging to differentiate from mucinous variant
  - p63 and CK5/6 positivity favors mucoepidermoid carcinoma (Head Neck Pathol 2014;8:133)
- Epithelial myoepithelial carcinoma:
  - Dual population with myoepithelial component highlighted by p63
- Myoepithelial carcinoma:
  - Plasmacytoid morphology
  - Diffuse p63 and S100
- Adenoid cystic carcinoma:
  - Dual population and cribriform growth pattern in areas with conventional histology
- Adenosquamous carcinoma:
  - Diffuse p63 and CK5/6 positivity in squamous areas
- Intraductal carcinoma (cribriform cystadenocarcinoma):
  - Entirely in situ and usually has low grade cytology
  - Although AR can be positive, it is typically negative (Head Neck Pathol 2017;11:288, Histopathology 2018;73:314, Head Neck Pathol 2013;7:S59)

Additional references

El-Naggar: WHO Classification of Head and Neck Tumors, 4th Edition, 2017

Board review style question #1

Which of the following immunohistochemical stains is characteristic of salivary duct carcinoma?

Androgen receptor
DOG1
Estrogen receptor
GATA3
SOX10

Board review style answer #1

A. Androgen receptor. Although GATA3 is frequently positive in salivary duct carcinoma, it is also positive in other salivary and nonsalivary gland malignancies. DOG1, SOX10 and estrogen receptor are usually negative.

Comment Here

Reference: Salivary duct carcinoma

Board review style question #2

What percentage of salivary duct carcinomas arise from preexisting pleomorphic adenoma (i.e., carcinoma ex pleomorphic adenoma) as seen in the photomicrograph?

10 - 20%
40 - 50%
60 - 70%
80 - 90%

Board review style answer #2

B. 40 - 50%

Comment Here

Reference: Salivary duct carcinoma

Sclerosing microcystic adenocarcinoma

Table of Contents

Definition / general

Sclerosing microcystic adenocarcinoma (SMA) is an exceedingly rare tumor of presumed minor salivary gland origin that closely resembles cutaneous microcystic adnexal carcinoma (MAC)
It arises in mucosal sites in the head and neck region
SMA is made up of deeply infiltrative, variably sized bland ducts, tubules, cords and nests that contain a biphasic population of myoepithelial cells and cuboidal cells within an abundant, densely sclerotic stroma (Head Neck Pathol 2019;13:215, Surg Pathol Clin 2021;14:137)

Essential features

Sclerosing microcystic adenocarcinoma (SMA) is a unique and rare tumor of presumed salivary origin in the head and neck region that shows significant morphologic overlap with microcystic adnexal carcinoma (MAC) of the skin (Surg Pathol Clin 2021;14:137, Diagnostics (Basel) 2022;12:1288)
It is composed of a biphasic population of inner cuboidal and outer myoepithelial cells that form highly infiltrative and variably sized ducts, tubules, cords and nests within a dense collagenous stroma; perineural invasion and skeletal muscle involvement is prominent
Myoepithelial cells are often attenuated but are occasionally clear while the cuboidal component is relatively monomorphic with eosinophilic cytoplasm and round nuclei with even chromatin, occasional nucleoli and no increase in mitosis
Although follow up data are limited, patients with SMA have had uniformly good outcomes without locoregional recurrence or distant metastases (Surg Pathol Clin 2021;14:137)

Terminology

Microcystic adnexal (sclerosing sweat duct) carcinoma of intraoral minor salivary gland origin (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;112:284)
Primary minor salivary gland tumors with microscopic features ascribed to MAC, also referred to as sclerosing sweat duct or syringomatous carcinoma (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;112:284)
Adenocarcinoma, not otherwise specified (Hum Pathol Rep 2021;26:300577)

ICD coding

ICD-O:
- 8000/3 - salivary gland neoplasm, malignant
- 8140/3 - salivary gland adenocarcinoma, NOS

Epidemiology

Exceedingly rare tumor
Average patient age of 52.6 years (range: 41 - 73 years) (Head Neck Pathol 2016;10:501, Ann Diagn Pathol 2021;54:151806)
Predilection for women (F:M = 4:1) (Head Neck Pathol 2016;10:501)
Immunosuppression may play a role in its pathogenesis (Ann Diagn Pathol 2021;54:151806)

Sites

Most commonly arises from minor salivary glands in the intraoral cavity, including the tongue, lip mucosa, floor of mouth and buccal mucosa, as well as the nasopharynx (Surg Pathol Clin 2021;14:137, Head Neck Pathol 2016;10:501)
Has also been reported to arise from within the parotid gland (Ann Diagn Pathol 2021;54:151806, Hum Pathol Rep 2021;26:300577)

Pathophysiology

Pathophysiology is still under investigation
SMA may show morphologic overlap with cutaneous MAC because normal intraoral minor salivary glands have morphologic and functional overlap with normal eccrine sweat glands
Recently, whole exome sequencing of a single case revealed a moderate tumor mutational burden, a putative loss of function mutation in CDK11B and no molecular overlap with mutations previously identified in MAC, though more work needs to be done (Anticancer Res 2020;40:6375)

Etiology

Like MAC, immunosuppression may play a role in the pathogenesis of SMA (several of the cases described have had a history of immunosuppressive therapy for autoimmune disorders, chemotherapy or radiation)

Clinical features

Typically painless, slow growing mass or submucosal lump (Oral Surg Oral Med Oral Pathol Oral Radiol 2018;125:e94)
Both SMA and MAC exhibit an infiltrative growth pattern and a highly aggressive local behavior with perineural invasion that can cause numbness (Hum Pathol Rep 2021;26:300577)
Due to extensive perineural invasion, clear surgical margins may be difficult; patients with positive margins are recommended to undergo adjuvant radiation therapy

Diagnosis

Tumors may be visualized or palpated on the physical exam while imaging, such as CT and MRI, can be utilized to examine the extent of disease
Definitive diagnosis will typically be made on an excisional biopsy specimen

Radiology description

Irregular and amorphous FDG avid lesion with infiltrative pattern that may obscure fat planes (Hum Pathol Rep 2021;26:300577, Ann Diagn Pathol 2021;54:151806, Head Neck Pathol 2019;13:215)

Radiology images

Images hosted on other servers:

Tongue tumor

Floor of mouth mass and enlarged lymph node

Prognostic factors

SMA appears to have an indolent clinical course with no documented lymph node involvement or distant metastatic disease, despite the concerning infiltrative histologic appearance (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;112:284)
Patients with positive surgical margins are recommended to receive adjuvant radiation therapy
Although follow up data are limited, patients with SMA have had uniformly good outcomes without locoregional recurrence or distant metastases (follow up durations ranging from 21 to 60 months) (Ann Diagn Pathol 2021;54:151806, Surg Pathol Clin 2021;14:137)

Case reports

48 year old man with sclerosing microcystic adenocarcinoma of the tongue (Diagnostics (Basel) 2022;12:1288)
52 year old woman with an ulcerated palatal nodule of 6 months duration (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;112:284)
55 year old woman with left floor of mouth fullness and history of multiple sclerosis on immunotherapy (Head Neck Pathol 2019;13:215)
59 year old woman with an induration on her tongue (AJSP: Reviews & Reports 2021;26:329)
67 year old man with slowly enlarging right parotid mass of 2 years duration (Hum Pathol Rep 2021;26:300577)
73 year old man with a history of nasopharyngeal carcinoma treated with radiotherapy, presented with an ulcerating left tonsillar tumor (Ann Diagn Pathol 2021;54:151806)
5 case series of tumors closely resembling MAC occurring in the mucosal surfaces of the head and neck (Head Neck Pathol 2016;10:501)

Treatment

Wide, local excision with selective neck dissection, though lack of lymph node metastasis in the reported literature may favor against a neck dissection (Hum Pathol Rep 2021;26:300577)
Adjuvant radiation therapy for patients with positive margins (Head Neck Pathol 2019;13:215)
Adjuvant radiation therapy because of perineural invasion (AJSP: Reviews & Reports 2021;26:329)
Due to a lack of data on long term outcomes, prolonged follow up (Oral Surg Oral Med Oral Pathol Oral Radiol 2018;125:e94)

Clinical images

Images hosted on other servers:

Ulcerated palate tumor

Gross description

Ill defined, white-tan-gray, firm mass that may show gross extension into adjacent skeletal muscle or adipose tissue (Head Neck Pathol 2019;13:215, Ann Diagn Pathol 2021;54:151806, Hum Pathol Rep 2021;26:300577, AJSP: Reviews & Reports 2021;26:329, Diagnostics (Basel) 2022;12:1288)

Gross images

Images hosted on other servers:

Tongue tumor

Frozen section description

Assessment of surgical margins, especially during intraoperative evaluation, is extremely challenging if not impossible due to the paucicellular and low grade nature of the tumor (Head Neck Pathol 2019;13:215)

Microscopic (histologic) description

SMA has a distinctive low power appearance of a relatively paucicellular tumor with clearly invasive variably sized ducts, tubules, cords and nests within densely sclerotic or desmoplastic stroma
Invasive component is composed of a biphasic population of inner cuboidal and outer myoepithelial cells
Myoepithelial cells are often attenuated and flattened but are occasionally more prominent and clear
Cuboidal cells are relatively monomorphic with eosinophilic cytoplasm and round nuclei with even chromatin, occasional nucleoli and no increase in mitosis
No significant nuclear atypia or necrosis (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;112:284)
No dysplasia is noted in the overlying mucosa (Diagnostics (Basel) 2022;12:1288)
Ducts and tubules are frequently filled with eosinophilic secretions that stain positively with mucicarmine (Surg Pathol Clin 2021;14:137)
Tumor infiltrates skeletal muscle (Head Neck Pathol 2019;13:215)
Perineural invasion is common (AJSP: Reviews & Reports 2021;26:329)

Microscopic (histologic) images

Contributed by Marc Pusztaszeri, M.D.

Infiltrative tubules and poorly formed glands

Perineural invasion

CK7 and p63

CK5/6 and p40

CK AE1 / AE3 and SOX10

Cytology description

Distinct population of basaloid epithelial cells arranged in branching sheets and clusters with minimal nuclear pleomorphism
Biphasic appearance is apparent
Some of the cell clusters are bordered by a layer of flattened cells with ovoid bland nuclei
Occasional intranuclear inclusions are seen
Hyaline globular matrix, fibrillary metachromatic stroma and mucin are not identified
Mitotic activity, significant nuclear atypia and necrosis are absent (Ann Diagn Pathol 2021;54:151806)

Positive stains

Epithelial cells: positive for CK7, carcinoembryogenic antigen (CEA), epithelial membrane antigen (EMA), AE1 / AE3, CAM5.2, CK5/6 (Surg Pathol Clin 2021;14:137, Head Neck Pathol 2019;13:215, AJSP: Reviews & Reports 2021;26:329)
Myoepithelial cells: typically positive for myoepithelial markers, such as p40, p63, S100 and SMA (Surg Pathol Clin 2021;14:137, Head Neck Pathol 2019;13:215, AJSP: Reviews & Reports 2021;26:329)
Luminal secretions are positive for mucicarmine (Surg Pathol Clin 2021;14:137)
Ki67 proliferation index is low (< 5%) (Diagnostics (Basel) 2022;12:1288, Oral Surg Oral Med Oral Pathol Oral Radiol 2018;125:e94)
Overall, the tumor cells show a similar staining pattern to MAC (Head Neck Pathol 2019;13:215)

Negative stains

CD117, SOX10, MYB, estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR) (Oral Surg Oral Med Oral Pathol Oral Radiol 2018;125:e94, Diagnostics (Basel) 2022;12:1288)

Molecular / cytogenetics description

Recently, whole exome sequencing of a single case revealed a moderate tumor mutational burden, a putative loss of function mutation in CDK11B and no molecular overlap with mutations previously identified in MAC (Anticancer Res 2020;40:6375)
However, the molecular landscape of SMA is largely unknown at this point in time

Sample pathology report

Tongue, partial glossectomy:
- Sclerosing microcystic adenocarcinoma (2.4 cm), margins uninvolved by carcinoma (see synoptic report and comment)
- Comment: Sections show deeply infiltrative nests, cords and tubules of tumor cells embedded in prominent desmoplastic to densely collagenous stroma. The tumor is composed of a biphasic population of peripheral, flattened myoepithelial cells with central, bland cuboidal ductal cells with round nuclei, evenly dispersed chromatin and occasional nucleoli. Significant atypia and necrosis are not identified and mitotic figures are not conspicuous. Lumens of various sizes containing occasional dense, globular eosinophilic secretory material are present. The tumor infiltrated into skeletal muscles and multiple foci of perineural invasion are identified. On immunohistochemistry, the outer myoepithelial population stains positively for p63 and SMA while the inner cuboidal ductal cells stain positively for CK7. This immunohistochemical staining pattern supports the diagnosis.

Differential diagnosis

Squamous cell carcinoma (SCC):
- Single cell population
- Presence of overt keratinization or associated squamous dysplasia (Surg Pathol Clin 2021;14:137)
- High grade and significantly more cytologic atypia (Surg Pathol Clin 2021;14:137)
- Prominent mitotic figures (Surg Pathol Clin 2021;14:137)
Tubular variant of adenoid cystic carcinoma:
- Cribriform architecture (Ann Diagn Pathol 2021;54:151806)
- Hyalinized / myxoid globules (Ann Diagn Pathol 2021;54:151806)
- CD117 is expressed by the luminal cells in virtually all cases of tubular adenoid cystic carcinoma but is consistently negative in SMA (Ann Diagn Pathol 2021;54:151806)
- More pronounced cytologic atypia with hyperchromatic, angulated nuclei (Surg Pathol Clin 2021;14:137)
- Detection of MYB or MYBL1 rearrangements can also confirm the diagnosis of adenoid cystic carcinoma in 50 - 80% of cases (Surg Pathol Clin 2021;14:137)
Epithelial myoepithelial carcinoma:
- Biphasic phenotype with a bilayered nature and arranged in tubular structures
- EMC is usually multinodular and surrounded by a thick capsule
- Characteristic abluminal myoepithelial cells with abundant clear cytoplasm
- Infiltration and perineural invasion that is usually accompanied by high grade transformation or dedifferentiation (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;112:284)
- Lacks the characteristic sclerotic / hyalinized stroma observed in SMA
Cribriform adenocarcinoma of the tongue and minor salivary glands:
- Consists of variably solid and cribriform areas containing bland, overlapping, pale nuclei with a distinct similarity to papillary thyroid carcinoma
- Lesion can have a fibromyxoid stroma and a tubular architecture
- Tubules have a single cell layer
- Margin of the tumor may be infiltrative and lymphovascular invasion may be present
- Positivity with antibodies to S100, cytokeratins and KIT has been recorded (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;112:284)
Polymorphous adenocarcinoma:
- Greater architectural variability, including tubules, fascicles and solid, cribriform and small papillary areas
- Most typical diagnostic features are concentric layers or whirl-like structures of neoplastic cells around the central nidus
- Lacks the densely sclerotic stroma and bilayered ducts of SMA
- Typically takes the form of a cellular solid, unencapsulated neoplasm that is infiltrative at the periphery
- Uniform positivity with antibodies to S100 (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;112:284, Diagnostics (Basel) 2022;12:1288)
- PRKD1, PRKD2 or PRKD3 gene rearrangements as well as PRKD1 point mutations can help confirm the diagnosis (Nat Genet 2014;46:1166, Genes Chromosomes Cancer 2014;53:845)
Low grade mucoepidermoid carcinoma:
- Cystic with admixture of intermediate cells, epidermoid cells and scattered mucocytes or nests of mucocytes in varying proportions
- Lacks the characteristic sclerotic / hyalinized stroma observed in SMA
  - One exception is an uncommon eosinophilic variant of MEC with areas of hyalinization
  - However, this rare variant manifests in major salivary glands, mainly the parotid gland and prominent eosinophilia is not observed in SMA (Diagnostics (Basel) 2022;12:1288)
- Detection of MAML2 gene fusions can confirm the diagnosis
Mammary analog secretory carcinoma:
- Cells of the microcysts are dramatically different from those of SMA, showing abundant foamy cytoplasm
- They are much more richly cellular than SMA without a considerable stromal contribution
- ETV6 fusions can confirm the diagnosis (ETV6::NTRK3 most common) (Head Neck Pathol 2016;10:501)
Low grade adenocarcinoma, nonintestinal type:
- Tumors are composed of tubules lined by bland cuboidal to columnar cells
- They can be fairly mitotically quiescent
- Cytoplasm often contains pale basophilic mucinous material
- Lack the dense hyalinized stroma, instead showing more crowded glandular configurations
- Perineural invasion is rare (Head Neck Pathol 2016;10:501)
Chronic sclerosing sialadenitis (Küttner tumor):
- Extensive periductal and perivascular fibrosis and sclerosis
- Foci of hyalinosis
- Infiltration by mononuclear cells (mostly lymphocytes and plasma cells)
- Acinar atrophy and obliterative phlebitis (Clin Case Rep 2019;7:1600)
- Lacks perineural invasion
Sclerosing sialometaplasia:
- Benign, reactive lesion
- Lacks the diffusely infiltrative growths beyond the extent of minor salivary glands
- Lobular configuration without perineural invasion (Diagnostics (Basel) 2022;12:1288)

Additional references

Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;109:e28, WHO Classification of Tumours Editorial Board: Head and Neck Tumours, 5th Edition, 2022

Board review style question #1

Which of the following immunohistochemical staining patterns support a diagnosis of sclerosing microcystic adenocarcinoma?

CK7 in central ductal / epithelial component; p63 in peripheral myoepithelial cell population
p63 in central ductal / epithelial component; CK7 in peripheral myoepithelial cell population
S100 in central ductal / epithelial component; pancytokeratin in peripheral myoepithelial cell population
SMA in central ductal / epithelial component; pancytokeratin in peripheral myoepithelial cell population

Board review style answer #1

A. CK7 in central ductal / epithelial component; p63 in peripheral myoepithelial cell population. The central ductal component showing positivity for pancytokeratin and CK7 and the peripheral myoepithelial cell population expressing smooth muscle actin, S100, p63 and p40 (Surg Pathol Clin 2021;14:137). Answers B - D are incorrect because these are not the immunohistochemical staining patterns for sclerosing microcystic adenocarcinoma.

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Reference: Sclerosing microcystic adenocarcinoma

Board review style question #2

Sclerosing microcystic adenocarcinoma (SMA) has been seen in association with which of the following?

Alcohol
HPV infection
Immunosuppression
Smoking

Board review style answer #2

C. Immunosuppression. SMA frequently arises in the context of immunosuppression (Anticancer Res 2020;40:6375). Answers A, B and D are incorrect because alcohol, HPV infection and smoking have not been reported as associations with this tumor.

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Reference: Sclerosing microcystic adenocarcinoma

Sclerosing polycystic adenoma

Table of Contents

Definition / general

Rare salivary gland disorder, first described in 1996 (Am J Surg Pathol 1996;20:161)
Resembles fibrocystic changes and sclerosing adenosis of the breast (Head Neck Pathol 2020;14:630)
Exact nature of the disease is unknown but recent evidence suggests that it is neoplastic (Am J Surg Pathol 2017;41:e33)

Essential features

Resembles fibrocystic changes and sclerosing adenosis of the breast (Head Neck Pathol 2020;14:630)
Composed of irregularly distributed bilayered ducts and acini within a sclerotic stroma (Head Neck Pathol 2020;14:630)

Terminology

Sclerosing polycystic adenosis
Sclerosing adenosis
Polycystic adenosis
Sclerosing polycystic sialadenopathy

ICD coding

ICD-10: K11.8 - Other diseases of salivary glands

Epidemiology

Occurs over a wide age range (9 - 84 years); mean: 40 years
Slight female predominance (F:M = 3:2) (Am J Surg Pathol 2017;41:e33)

Sites

Parotid gland (around 70%), occasional examples in the submandibular glands and oral cavity (Am J Surg Pathol 2017;41:e33)

Pathophysiology

Originally believed to be a reactive, nonneoplastic process resembling fibrocystic changes of the breast but evidence suggests it is likely neoplastic (Head Neck Pathol 2020;14:630)
- Recurrence rate of up to 30% (Am J Surg Pathol 2006;30:939)
- Demonstration of clonality in 6 cases using the human androgen receptor assay (HUMARA) (Am J Surg Pathol 2006;30:939)
- Targeted next generation sequencing demonstrated mutations in genes that are well established to be drivers in human neoplasms (Head Neck Pathol 2020;14:630)

Etiology

Unknown

Clinical features

Slow growing mass, may have pain or altered sensation (Am J Surg Pathol 2017;41:e33)

Diagnosis

Best made on histologic examination of excisional material

Radiology description

Limited published descriptions
T2 weighted MRI: small cystic areas show high signal intensity
Ultrasound: hypoechoic, well circumscribed with microcysts (Head Neck Pathol 2012;6:247)

Radiology images

Images hosted on other servers:

Parotid lesion

Prognostic factors

Local recurrence rate up to 30% (Am J Surg Pathol 2006;30:939)
Solitary case of an invasive component arising following multiple recurrences over decades (Virchows Arch 2014;464:621)

Case reports

7 and 33 year old sisters present with firm nodules of the right parotid gland (Pathol Res Pract 2014;210:342)
49 year old man with left palatal swelling (Contemp Clin Dent 2019;10:676)
79 year old woman with a sinonasal mass (Hum Pathol 2013;44:1937)

Treatment

Complete, conservative local resection followed by prolonged surveillance (Am J Surg Pathol 2017;41:e33)

Clinical images

Images hosted on other servers:

Palate lesion

Gross description

Well delineated, pale, firm, rubbery nodules embedded within normal salivary gland
May be multinodular (Am J Surg Pathol 1996;20:161)

Frozen section description

Well circumscribed proliferation of scattered dilated, variably sized ducts lined by hyperplastic epithelium in a vague nodular pattern
Foci of apocrine change
Dense stroma
Because a definitive diagnosis may not be possible at the time of frozen section, a descriptive interpretation such as "sclerotic fibrous material with benign appearing glandular elements" could be rendered (Pathology 2016;48:93)

Microscopic (histologic) description

Circumscribed with preservation of lobular architecture (Am J Surg Pathol 2006;30:939)
Composed of irregularly distributed bilayered ducts and acini within a sclerotic stroma (Head Neck Pathol 2020;14:630)
Ducts range from small tubules to ectatic spaces; may contain secretory material or foamy macrophages (Head Neck Pathol 2020;14:630)
- Ductal cells can have vacuolated, foamy, apocrine and mucous appearances (Am J Surg Pathol 2006;30:939)
- Hyperplastic ductal epithelium forming solid, microcystic and cribriform structures (Am J Surg Pathol 2017;41:e33)
- Small eosinophilic globules of basement membrane-like material in some cribriform areas (i.e. collagenous spherulosis) (Am J Surg Pathol 1996;20:161)
Acini contain numerous, coarse eosinophilic, periodic acid-Schiff positive, intracytoplasmic granules (Am J Surg Pathol 2006;30:939)

Microscopic (histologic) images

Contributed by Jiancong Liang, M.D.

Preservation of lobular architecture

Variably sized ducts

Hyperplastic intraluminal epithelium

Acini with eosinophilic granules

Cytology description

Interpretation is challenging and frequently misdiagnosed
Cohesive sheets and aggregates of cells
Moderate to abundant finely granular eosinophilic cytoplasm
Round to oval nuclei
Evenly distributed chromatin with indistinct nucleoli (Diagn Cytopathol 2017;45:640)

Positive stains

Epithelial cells:
- Cytokeratin (AE1 / AE3 and CAM5.2) (Am J Surg Pathol 2006;30:939)
- PR: 80% (Virchows Arch 2002;440:29)
Myoepithelial cells:
- SMA, p63 and calponin (Am J Surg Pathol 2017;41:e33)
Acinar cells with coarse eosinophilic cytoplasm
- Periodic acid-Schiff (PAS), diastase resistant
- GCDFP-15 (Am J Surg Pathol 2006;30:939)

Negative stains

Epithelial cells:
- CEA and HER2 / neu (Am J Surg Pathol 2006;30:939)

Electron microscopy description

Cells have abundant cytoplasm filled by electron dense granules of various sizes consistent with zymogen granules (Virchows Arch 2002;440:29)

Molecular / cytogenetics description

Genetic alterations in PI3K pathway
- PTEN mutations, PIK3CA mutations and PIK3R1 alterations (Head Neck Pathol 2020;14:630)

Sample pathology report

Parotid, right, excision:
- Sclerosing polycystic adenoma (see comment)
- Comment: Sections show a well demarcated nodule of densely collagenized stroma intermingling among a proliferation of acini and tubules. The latter are lined by cells which vary from vacuolated to foamy to apocrine to mucinous. Some ducts possess a hyperplastic epithelium with atypia reminiscent of ductal carcinoma in situ. Acini are remarkable for prominent eosinophilic intracytoplasmic granules which are highlighted upon PAS stain. No invasive growth is recognized.

Differential diagnosis

Chronic sclerosing sialadenitis:
- Submandibular gland
- Fibrosis is not nodular
- Dense lymphoplasmacytic infiltrate with lymphoid follicles (Pathology 2016;48:93)
- Atrophic parenchyma without ductal hyperplasia or acinar cells with coarse PAS+ zymogen-like granules (Am J Surg Pathol 2017;41:e33)
Polycystic (dysgenetic) disease:
- Bilateral
- Composed of a honeycombed lattice network of cysts replacing the entire parenchyma (Am J Surg Pathol 2006;30:154)
- No acinar proliferation and little fibrosis
- Characteristic congophilic laminated spheroliths (Histopathology 1987;11:953)
- Lacks recurrences
Pleomorphic adenoma:
- Chondromyxoid stroma and prominent myoepithelial component
- Lacks acinar cells and definitive lobular growth pattern (Am J Surg Pathol 2017;41:e33)
Mucoepidermoid carcinoma:
- Invasive growth pattern
- Lacks scar-like hyalinized fibrous sclerosis
- Absence of acinar cells with prominent brightly eosinophilic granules
- More numerous mucous cells
- Lacks a myoepithelial cell layer (Am J Surg Pathol 2017;41:e33)
Acinic cell carcinoma:
- Loss of lobular architecture
- Smaller PAS+ eosinophilic granules
- Less varied architecture and cell population
- Lacks a myoepithelial cell layer (Am J Surg Pathol 2017;41:e33)
Intraductal carcinoma (low grade salivary duct carcinoma / low grade cribriform cystadenocarcinoma):
- More complex cystic pattern
- May have invasive growth (Am J Surg Pathol 2006;30:154)
- Lacks acinar cells with PAS+ granules (Am J Surg Pathol 2017;41:e33)
- Ductal cells lack foamy, vacuolated, mucous, clear, squamous and columnar cytomorphology (Am J Surg Pathol 2017;41:e33)

Board review style question #1

A 50 year old woman presents with a slow growing parotid mass. Calponin and p63 immunostains highlighted a subset of the cells. Elsewhere in the lesion, acini containing large, brightly eosinophilic, periodic acid-Schiff positive, intracytoplasmic granules were identified. What is the most likely diagnosis?

Acinic cell carcinoma
Sclerosing polycystic adenoma
Chronic sclerosing sialadenitis
Pleomorphic adenoma

Board review style answer #1

B. Sclerosing polycystic adenoma

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Reference: Sclerosing polycystic adenoma

Board review style question #2

Which of the following immunohistochemical patterns support a diagnosis of sclerosing polycystic adenoma?

p63+ in epithelial and myoepithelial cells; HER2 / neu+ and PR- in epithelial cells
p63+ in myoepithelial cells; HER2 / neu- and PR+ in epithelial cells
p63+ in epithelial and myoepithelial cells; HER2 / neu- and PR-
p63+ in myoepithelial cells; HER2 / neu+ and PR+ in epithelial cells

Board review style answer #2

B. p63+ in myoepithelial cells; HER2 / neu- and PR+ in epithelial cells

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Reference: Sclerosing polycystic adenoma

Sebaceous adenocarcinoma (pending)

Secretory carcinoma

Table of Contents

Definition / general

Rare primary salivary gland tumor that harbors specific ETV6 genetic rearrangement, most commonly ETV6-NTRK3 translocation t(12;15)(q13;q25) (Am J Surg Pathol 2010;34:599)
Similar morphological, immunohistochemical and molecular features as secretory carcinoma of the breast (Am J Surg Pathol 2010;34:599)

Essential features

Rare primary salivary gland carcinoma characterized by ETV6 gene rearrangement (Am J Surg Pathol 2010;34:599, Am J Surg Pathol 2020;44:1295, Am J Surg Pathol 2018;42:1121)
Predominantly (76%) occurs in parotid, minor salivary glands of oral cavity and submandibular gland
- Also described in nasal cavity, skin and thyroid (Am J Surg Pathol 2020;44:1295)
Predominantly adults, wide age range (5 - 87 years) (Am J Surg Pathol 2020;44:1295, Histopathology 2012;61:387)
Various histological growth patterns, including cystic, solid, tubular, papillary cystic and lobular
- Cysts with intraluminal colloid-like secretions (Am J Surg Pathol 2010;34:599)
Cells with bubbly cytoplasm and relatively monotonous round nuclei with small but distinct nucleoli (Am J Surg Pathol 2010;34:599, Histopathology 2012;61:387, Pathology 2015;47:659)
Immunohistochemical expression of GATA3, S100, NTRK3, MUC4, mammaglobin (Pathology 2015;47:659, Head Neck Pathol 2013;7:311, Histopathology 2020;76:375)
Generally low grade with indolent clinical behavior; however, local lymph node metastases may be seen in up to 22% (Histopathology 2012;61:387)
- Rare high grade transformation with aggressive clinical behavior, including distant metastasis (Pathol Res Pract 2017;213:1112, Int J Surg Pathol 2017;25:613, Ann Oncol 2016;27:920)

Terminology

Previously known as mammary analogue secretory carcinoma (MASC)

ICD coding

ICD-10: C07 - Malignant neoplasm of parotid gland

Epidemiology

Slight male predominance (M:F = 1.4:1) (Histopathology 2012;61:387)
Wide age range (5 - 87 years) (Oral Surg Oral Med Oral Pathol Oral Radiol 2020 May 31 [Epub ahead of print])
Mean age 49.9 (Am J Surg Pathol 2020;44:1295)

Sites

Parotid (76%), minor salivary glands of oral cavity and submandibular gland (Am J Surg Pathol 2020;44:1295)
Rare sites include
- Nasal cavity, skin and thyroid (Am J Surg Pathol 2020;44:1295)
- Lung (Hum Pathol 2018;74:109)
- Vulva (Int J Gynecol Pathol 2019;38:283)
- Lacrimal gland (Am J Ophthalmol 2018;193:178)

Etiology

Unknown

Clinical features

Slow growing painless mass; mean duration: 1 year (Head Neck 2019;41:1227, Oral Oncol 2018;82:29)
Low T stage at diagnosis (almost always T1 or T2) (Oral Oncol 2018;82:29, Pathology 2015;47:659)
Generally indolent clinical course with recurrence rates of < 10% and 10 year overall survival of 95% after macroscopically complete resection (Head Neck 2019;41:1227)
Local lymph node involvement at diagnosis in a minority (5 - 22%) (JAMA Otolaryngol Head Neck Surg 2019;145:91, Histopathology 2012;61:387)
- Distant metastases in < 5% (JAMA Otolaryngol Head Neck Surg 2019;145:91, Head Neck 2019;41:1227)
Locally aggressive behavior and poor outcomes have been reported if incompletely resected (Head Neck 2019;41:1227, Pathology 2015;47:659)
High grade transformation with aggressive clinical behavior including distant metastasis has been reported (Pathol Res Pract 2017;213:1112, Int J Surg Pathol 2017;25:613)

Diagnosis

Imaging modalities for workup of salivary gland neoplasms include ultrasonography, CT and MRI (Otolaryngol Head Neck Surg 2021;164:27)
Cytologic diagnosis requires awareness / high degree of suspicion and cell block for immunohistochemistry (Acta Cytol 2017;61:469)

Radiology description

Imaging features are nonspecific; tumors often have a cystic component (Dentomaxillofac Radiol 2018;47:20170218)

Prognostic factors

pT stage of 3 or 4 and high grade features appear most strongly associated with poor clinical outcomes (Head Neck 2019;41:1227, Pathology 2015;47:659)
While definite thresholds are not yet described, nuclear pleomorphism, easily identified mitotic activity or presence of comedonecrosis have been described to confer poor prognosis (Int J Clin Exp Pathol 2014;7:9008)
Rare high grade transformation with aggressive clinical behavior including distant metastasis has been reported (Am J Surg Pathol 2014;38:23, Am J Surg Pathol 2018;42:1121, Pathol Res Pract 2017;213:1112, Int J Surg Pathol 2017;25:613)

Case reports

15 year old girl with slow growing painless parotid mass (Am J Otolaryngol 2015;36:741)
44 year old man with painless buccal mass showing high grade transformation on histology developed pleural metastases within months of diagnosis (Int J Surg Pathol 2017;25:613)
59 year old woman with metastatic high grade secretory carcinoma with ETV6-RET rearrangement (Am J Surg Pathol 2018;42:1121)
74 year old man with cervical lymph node involvement with no evident primary site of disease (Case Rep Oncol 2017;10:192)

Treatment

Primary resection
Neck dissection or adjuvant radiotherapy if adverse prognostic features or evidence of lymph node metastases present (JAMA Otolaryngol Head Neck Surg 2019;145:91, Pathol Res Pract 2017;213:1112, Otolaryngol Head Neck Surg 2021;164:27)
TRK inhibitors have shown promise in phase 1 and 2 trials for ETV6-NTRK3 rearranged tumors but efficacy is not established (N Engl J Med 2018;378:731)
- Cases of initial response followed by acquired resistance have been reported in advanced disease (Ann Oncol 2016;27:920, Int J Surg Pathol 2017;25:613)

Gross description

Generally well circumscribed unencapsulated lesions, solid or cystic (Pathology 2015;47:659)
Size range 6 - 30 mm, median 20 mm in a series of 22 cases (Head Neck 2019;41:1227)
- Tumors as large as 70 mm have been reported (Pathol Res Pract 2017;213:1112)

Gross images

Contributed by Ruta Gupta, M.B.B.S., M.D.

Cystic tumor

Solid tumor

Microscopic (histologic) description

Circumscribed or infiltrative edge
Lobulated architecture
Variable arrangements, including macrocystic, microcystic, solid, tubular, follicular and papillary cystic patterns (Am J Surg Pathol 2010;34:599, Am J Surg Pathol 2019;43:1483)
Pale eosinophilic colloid-like intraluminal secretions; secretions are periodic acid-Schiff (PAS) reagent positive and diastase resistant (Am J Surg Pathol 2010;34:599)
Tumor cells have eosinophilic or vacuolated cytoplasm and monomorphic round vesicular nuclei with small but distinctive nucleoli
Occasional lymphovascular invasion and perineural invasion are seen (Head Neck 2019;41:1227)
High grade transformation has been reported with a distinct population of tumor cells exhibiting solid or trabecular growth, infiltrative margins, desmoplastic stromal reaction, comedo-like necrosis, nuclear pleomorphism, increased mitotic rate, loss of secretory activity and perineural invasion
- A distinct low grade (conventional) carcinomatous component is also present (Pathol Res Pract 2017;213:1112)

Microscopic (histologic) images

Contributed by Ruta Gupta, M.B.B.S., M.D.

Solid architecture

Solid and cystic architecture

Solid architecture

Macrocystic lesion

Papilliform architecture

Colloid-like secretions

Intraluminal secretions

Cytological features

Macrocystic lesion

Diastase resistant secretions

S100

MUC4

Pan-TRK

Virtual slides

Images hosted on other servers:

42M secretory carcinoma parotid

33F secretory carcinoma parotid

Cytology description

Cytology is variable and nonspecific and requires high index of suspicion / awareness and cell block preparation
Difficult to distinguish from benign entities and other low grade malignancies (APMIS 2019;127:491, Acta Cytol 2017;61:469)
Cohesive clusters or sheets of epithelial cells with variable eosinophilic, granular to vacuolated cytoplasm and uniform nuclei with single nucleoli (APMIS 2019;127:491)
Papillary fragments and acinar arrangements commonly seen; cystic lesions may show cystic debris in the background (APMIS 2019;127:491, Diagn Cytopathol 2015;43:287)
Cell block preparation for immunohistochemistry with S100, GATA3, pan-TRK is useful (APMIS 2019;127:491, Cancer Cytopathol 2018;126:627)

Cytology images

Contributed by Ruta Gupta, M.B.B.S., M.D.

Cell block

Contributed by Jeffrey Krane, M.D., Ph.D. and Jen-Fan Hang, M.D.

Sheets and clusters cells

Nuclei are uniform

Papillary pattern

Vacuolated cytoplasm

Papillary and secretory

Images hosted on other servers:

FNA cytology of secretory carcinoma

Positive stains

CK7: 100% sensitive, nonspecific when compared with acinic cell carcinoma (Am J Surg Pathol 2010;34:599)
GATA3: 100% sensitive; useful to distinguish from histologic mimic acinic cell carcinoma but nonspecific (53%) when the differential diagnoses include a variety of other salivary gland neoplasms (Head Neck Pathol 2013;7:311)
S100: 100% sensitive, 67% specific when compared with acinic cell carcinoma (Am J Surg Pathol 2010;34:599)
SOX10: 100% sensitive (Hum Pathol 2016;56:134)
- Not specific, as a variety of salivary gland tumors including acinic cell carcinoma can show staining
MUC4: 91% sensitivity, 100% specificity (Histopathology 2020 Sep 15 [Epub ahead of print])
- May also be seen in mucoepidermoid carcinoma
Mammaglobin: 83% sensitive but lacks specificity in diagnostic context as it is expressed in intraductal carcinoma (86%) and polymorphous adenocarcinoma (37%) (Histopathology 2020 Sep 15 [Epub ahead of print])
Pan-TRK: nuclear staining is 64% sensitive and reported specificities range from 92% to 100% (Histopathology 2020;76:375, Histopathology 2019;75:54)
- NB: cytoplasmic pan-TRK staining is extremely nonspecific and should be disregarded (Histopathology 2019;75:54)
- Pan-TRK will not stain tumors with other fusion partners for ETV6 (Histopathology 2019;75:54, Am J Surg Pathol 2020;44:962)

Electron microscopy description

Not used in routine practice
Cells show features of intercalated / striated duct cell differentiation (Head Neck Pathol 2017;11:419)

Molecular / cytogenetics description

Recurrent translocation t(12;15)(p13;q24), resulting in fusion of ETV6 on chromosome 12 and NTRK3 on chromosome 15 (Am J Surg Pathol 2010;34:599)
Alternate fusion partners have been identified, including ETV6-RET and ETV6-MET (Am J Surg Pathol 2020;44:1295, Hum Pathol 2019;83:50, Am J Surg Pathol 2018;42:1121)
Potential role of other non-ETV6 translocations according to recent reports: VIM-RET and CTNNA1-ALK (Am J Surg Pathol 2020;44:1295, Am J Surg Pathol 2020;44:962)

Molecular / cytogenetics images

Contributed by Ruta Gupta, M.B.B.S., M.D.

ETV6 rearrangement by FISH

NTRK3 rearrangement by FISH

Videos

Salivary gland neoplasms characterized by gene fusions

Case presentations of various salivary gland pathologies

Sample pathology report

Left parotid, excision:
- Secretory carcinoma (see comment)
- Comment: There is a well demarcated but focally infiltrative parotid neoplasm with lobulated growth, macrocystic and microcystic areas. The cysts are lined by relatively monomorphic epithelioid cells with moderate amounts of vacuolated eosinophilic cytoplasm and a central round nucleus with a small but distinctive nucleolus. The microcysts contain colloid-like eosinophilic secretions. Immunohistochemistry shows tumor cells to be positive for S100, MUC4, pan-TRK and GATA3 and negative for DOG1. The combined morphological and immunohistochemical features strongly support the diagnosis of secretory carcinoma, a primary salivary gland malignancy. This is further confirmed by fluorescent in situ hybridization using ETV6 break apart probe demonstrating ETV6 rearrangement. Lymphovascular or perineural involvement is not seen. The tumor is 2 mm from the closest margin of resection.
- Secretory carcinoma generally demonstrates indolent behavior. However, it has a propensity to recur unless completely excised. Local lymph node metastasis occurs in up to 22% of patients and distant metastasis, while rare, has been reported in a subset of cases

Differential diagnosis

Acinic cell carcinoma:
- Rare in nonparotid locations
- Cytoplasmic PAS diastase resistant zymogen granules
- NR4A3+, DOG1+ (Am J Surg Pathol 2019;43:1264, Eur Arch Otorhinolaryngol 2016;273:3511)
- GATA3-, MUC4-, mammaglobin-, pan-TRK- (Histopathology 2020 Sep 15 [Epub ahead of print], Head Neck Pathol 2013;7:311, Histopathology 2019;75:54)
Intraductal carcinoma:
- Cystic structures with intracystic epithelial proliferation resembling ductal carcinoma in situ of the breast, including Roman bridge formations
- Similar immunohistochemical profile but myoepithelial markers positive in the peripheral myoepithelial cell layer and MUC4- in tumor cells (Histopathology 2020 Sep 15 [Epub ahead of print], APMIS 2020;128:191)
- RET rearrangements in the majority of tumors (APMIS 2020;128:191)
Polymorphous adenocarcinoma:
- Tumor of minor salivary glands, rare in major salivary glands
- Multiple varying architectural patterns, lacking secretions
- p63+, SMA+ (Eur Arch Otorhinolaryngol 2018;275:1681)
- GATA3-, pan-TRK- nuclear (may have cytoplasmic staining), mammaglobin variable (Histopathology 2020 Sep 15 [Epub ahead of print], Head Neck Pathol 2013;7:311 Histopathology 2020;76:375)
Mucoepidermoid carcinoma:
- Goblet cells with intracytoplasmic mucin among squamoid intermediate cells
- p63+, CK5/6+ (Head Neck Pathol 2014;8:133)
- S100-, mammaglobin-
- MAML2-CRTC1 translocations in the majority of tumors (Ann Surg Oncol 2002;9:688)

Board review style question #1

A 48 year old man has a parotid nodule for 9 - 12 months. Which of the following is true?

It is characterized by PAS diastase resistant cytoplasmic zymogenic granules and immunohistochemically by positivity for DOG1 and S100
It is characterized by PAS diastase resistant cytoplasmic zymogenic granules and immunohistochemically by positivity for ER and PR
It is characterized histologically by PAS diastase resistant intraluminal secretions and immunohistochemically by positivity for androgen receptor and p63
It is characterized histologically by PAS diastase resistant intraluminal secretions and immunohistochemically by positivity for pan-TRK, S100 and mammaglobin
It is generally a highly aggressive malignancy with most patients showing distant solid organ metastases at presentation

Board review style answer #1

D. It is characterized histologically by PAS diastase resistant intraluminal secretions and immunohistochemically by positivity for pan-TRK, S100 and mammaglobin. The image shows a secretory carcinoma with abundant secretions.

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Reference: Secretory carcinoma

Board review style question #2

A 49 year old woman has a lesion on the floor of the mouth with metastases to lymph nodes. The tumor cells show strong staining with S100 and MUC4. Which of the following genetic changes are likely to be found in this tumor?

ETV6-NTRK3 translocation
HER2 amplification
MAML2-CRTC1 translocation
MYB-NFIB translocation
PLAG1 translocation

Board review style answer #2

A. ETV6-NTRK3 translocation. The image shows a secretory carcinoma with papilliform architecture.

Comment Here

Reference: Secretory carcinoma

Sialadenitis-infectious

Table of Contents

Definition / general

Infection / inflammation of the salivary glands of either bacterial (acute suppurative sialadenitis) or viral origin
- Paramyxovirus (mumps) is the best known cause of viral sialadenitis

Essential features

Acute suppurative sialadenitis
- Results from ascending bacterial contamination from the oral cavity in a setting of impaired salivary flow
- Staphylococcus aureus is the most common cause
- Usually affects parotid of either preterm infants or the elderly
Viral sialadenitis
- Causative agents include paramyxovirus (mumps), cytomegalovirus, coxsackievirus, herpes simplex virus, influenza A, parainfluenza and adenovirus
- Viral sialadenitis due to mumps
  - Occurs mainly in those less than 15 years old (85%)
  - Affects the parotid bilaterally with epididymo-orchitis occurring in 20 - 30% of postpubertal males (Am J Hyg 1959;69:91)
  - Peaks in late winter / early spring for those in temperate climates

Terminology

Acute suppurative sialadenitis is also known as acute sialadenitis or bacterial sialadenitis
Viral sialadenitis (mumps)

ICD coding

ICD-10: K11.20 - Sialoadenitis, unspecified
ICD-10: K11.21 - Acute sialoadenitis

Epidemiology

Acute suppurative sialadenitis is most common in preterm infants and the elderly (J Craniofac Surg 2003;14:37)
- Predisposing factors include dehydration, obstruction (sialolithiasis), malnourishment, immunosuppression, chronic illness, certain medications (i.e. anticholinergics) and diabetes mellitus (Am Fam Physician 2014;89:882)
Viral sialadenitis caused by mumps peaks in late winter / early spring for those in temperate climates
- 85% occur in those less than 15 years old
- Risk factors include compromised immunity, international travel and lack of vaccination (StatPearls: Mumps [Accessed 1 September 2020])
- While immunization has reduced the frequency of paramyxovirus (mumps), there were 150 outbreaks and 9,000 cases in the United States between 2015 and 2017 (JAMA 2019;322:1022)

Sites

Both affect the parotid; however, mumps is typically bilateral
- Parotid is more prone to acute suppurative sialadenitis because serous saliva is less able to protect against bacterial infection than the mucoid rich content of saliva from the sublingual and submandibular glands (Oral Maxillofac Surg Clin North Am 2009;21:353)

Etiology

Acute suppurative sialadenitis is due to retrograde bacterial contamination from the oral cavity in a setting of impaired salivary flow
- Staphylococcus aureus is the most common cause; Streptococcal species and Haemophilus influenza are also common (Ann Surg 1962;156:251)
Viral sialadenitis results from systemic infection by a virus rather than direct infection (Otolaryngol Clin North Am 2014;47:763)

Clinical features

Patients present with tender enlargement of the salivary glands
- Epididymo-orchitis occurs in 20 - 30% of postpubertal males affected by mumps (Am J Hyg 1959;69:91)

Diagnosis

Diagnosis of mumps is made on symptoms and physical exam and is supported by serology or reverse transcription PCR (RT-PCR) (J Virol Methods 2020;277:113817)
Based on clinical examination with culture of purulent discharge

Case reports

10 month old infant with unilateral parotiditis (J Craniofac Surg 2016;27:e233)
9 year old boy with parotid swelling (Arch Otolaryngol Head Neck Surg 1995;121:1426)
14 year old girl presents with facial swelling after orthodontic treatment (J Orthod 2012;39:314)
50 year old woman develops parotid swelling after endoscopic retrograde cholangiopancreatography (Gastrointest Endosc 2011;74:199)

Treatment

Acute suppurative sialadenitis is managed by antimicrobial therapy based on culture result with surgical drainage if abscess develops
Mumps is self limited

Microscopic (histologic) description

Diagnoses of both acute suppurative and viral sialadenitis are usually reached on clinical grounds, although rarely biopsied
- Acute suppurative sialadenitis is associated with edema, hyperemia and acute inflammation
- Viral sialadenitis shows diffuse interstitial edema, intense hyperemia and a dense lymphohistiocytic infiltrate (Am J Pathol 1949;25:1105)

Sample pathology report

Parotid, right, biopsy:
- Acute suppurative sialadenitis (see comment)
- Comment: There is edema, hyperemia, bacteria and increased numbers of neutrophils. Neutrophils surround and infiltrate ducts and focally is associated with duct destruction. If clinically indicated, correlation with culture results would be helpful in directing appropriate antibiotic therapy.

Differential diagnosis

Diagnosis of infectious sialadenitis is usually made clinically and thus microscopic evaluation is rare
- Cytomegalovirus:
  - Intranuclear "owl’s eye" viral inclusions in ducts and acini
  - Lacks acute inflammation
- Tuberculosis:
  - Usually within an intraparotid or periparotid lymph node
  - Necrotizing granulomas
  - Acid fast bacilli on Ziehl-Nielson stain
  - Lacks acute inflammation

Board review style question #1

What is the most common bacterial cause of acute suppurative sialadenitis?

Actinomyces
Escherichia coli
Haemophilus influenzae
Peptostreptococcus species
Staphylococcus aureus

Board review style answer #1

E. Staphylococcus aureus

Comment Here

Reference: Sialadenitis-infectious

Board review style question #2

Acute suppurative sialadenitis most often affects the

Minor salivary glands
Parotid gland
Sublingual gland
Submandibular gland

Board review style answer #2

B. Parotid gland

Comment Here

Reference: Sialadenitis-infectious

Board review style question #3

Which of the following is true about mumps?

Has been eradicated since the introduction of the mumps vaccine
Is caused by double stranded DNA paramyxovirus
Most commonly presents as epididymo-orchitis
Usually affects those less than 15 years old

Board review style answer #3

D. Usually affects those less than 15 years old

Comment Here

Reference: Sialadenitis-infectious

Sialadenoma papilliferum

Table of Contents

Definition / general

Rare benign biphasic tumor with exophytic squamous component and endophytic glandular component
Well differentiated papillary hyperplastic squamous epithelium covering ductal component of cleft-like cystic spaces lined by cuboidal or columnar epithelium with occasional goblet cells
First described by Abrams in 1969 (Cancer 1969;24:1057)

Clinical features

Usually hard palate (Arch Pathol Lab Med 2001;125:1595) or parotid gland of men over 40 years; also children (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:e51)
Painless
Tends to recur after excision

Case reports

65 year old man with parotid tumor (Head Neck 2013;35:E74)
79 year old woman with malignant transformation of sialadenoma papilliferum of the palate (Virchows Arch 2004;445:641)
82 year old woman with mucoepidermoid carcinoma arising in a background of sialadenoma papilliferum (Head Neck Pathol 2009;3:59)
Recurrence in buccal mucosa 3 years after excision (J Laryngol Otol 1995;109:787)

Gross description

Well circumscribed, round / oval, papillary tumor of mucosal surface

Microscopic (histologic) description

Biphasic, with well differentiated papillary hyperplastic squamous epithelium covering ductal component of cleft-like cystic spaces lined by cuboidal or columnar epithelium with occasional goblet cells
Variable oncocytes and squamous metaplasia, dysplasia and in situ carcinoma in exophytic component (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;104:e27)
Has malignant counterpart or evolves to mucoepidermoid carcinoma or epithelial myoepithelial carcinoma with high grade carcinoma

Microscopic (histologic) images

Images hosted on other servers:

Floor of mouth tumor

Mucoepidermoid carcinoma arising in a background of sialadenoma papilliferum

Positive stains

Squamous epithelium and ductal structures: CK7, AE1 / AE3, CEA, EMA
Ductal structures: also CAM 5.2, S100
Also CK8, CK19 (Int J Oral Maxillofac Surg 2004;33:621)
One study identified 2 subsets of basally located cells:
1. Positive for CK14, S100, GFAP, vimentin and smooth muscle actin - similar to myoepithelial cells
2. CK13+ and CK14+ only (J Oral Pathol Med 1996;25:336)

Negative stains

CK20, desmin, muscle specific actin, HPV (J Cutan Pathol 1999;26:259)

Electron microscopy description

Oncocyte is predominant cell; contains numerous mitochondria, parallel filaments within cell cytoplasm attached by desmosomes (Arch Pathol Lab Med 1986;110:523)

Differential diagnosis

Sialoblastoma

Table of Contents

Definition / general

Rare malignant tumor, diagnosed at or near birth, resembling epithelial anlage of salivary glands but in arrested state of differentiation (Ann Otol Rhinol Laryngol 1992;101:958, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;109:109)

Clinical features

Childhood epithelial salivary gland tumor; common among the perinatal tumors
Occurs in submandibular, parotid or minor salivary glands; also ectopic salivary gland tissue
Uni or multinodular, 2 - 7 cm, rapid growth
May recur locally or involve regional lymph nodes; also lung metastases

Case reports

Girl infant with tumor arising in ectopic salivary gland tissue in cheek (J Plast Reconstr Aesthet Surg 2009;62:e241)
Boy infant with congenital tumor arising in minor salivary gland of buccal mucosa (Fetal Pediatr Pathol 2011;30:32)
3 month old boy with submandibular swelling of insidious onset (J Pediatr Surg 2008;43:e11)
3 month old girl with recurrent and metastatic tumor (Rare Tumors 2011;3:e13)
18 month old girl with parotid gland tumor (Pediatr Blood Cancer 2010;55:1427)
2 year old with 2 cm mass in parotid gland with increasing anaplasia (Am J Surg Pathol 1999;23:342)
6 year old girl with recurrent tumor (Acta Cytol 2003;47:1123)

Treatment

Excision; chemotherapy if cannot completely excise (Pediatr Blood Cancer 2010;55:374); possibly brachytherapy

Microscopic (histologic) description

Ductules and solid organoid nests of basaloid cells with fine chromatin and cuboidal epithelial cells
2 histological patterns: favorable pattern with semiencapsulation of benign basaloid cells with intervening stroma; unfavorable pattern with anaplastic basaloid cells, broad pushing to infiltrative periphery and minimal stroma (Ann Diagn Pathol 2006;10:320)
Variable necrosis, variable mitotic activity, variable nuclear atypia, no perineurial invasion

Microscopic (histologic) images

Images hosted on other servers:

Recurrent and metastatic tumor

Nests of basaloid cells

Cytology description

Tight, solid clusters of atypical basaloid cells plus dispersed epithelial and myoepithelial cells with metachromatic magenta hyaline globular material

Positive stains

Cytokeratin (ductal structures), S100, smooth muscle actin, calponin, p63
Also AFP, cytoplasmic HER2, p53; Ki67 index increases with recurrence and may predict behavior (Pediatr Dev Pathol 2010;13:32)

Differential diagnosis

Adenoid cystic carcinoma
Basal cell adenoma
Pleomorphic adenoma: may have embryonal structures
Teratoma

Sjögren syndrome

Table of Contents

Definition / general

Chronic autoimmune disorder of the salivary and lacrimal exocrine glands
Primary etiological events remain unknown (CMAJ 2014;186:E579)
Characterized by lymphocytic infiltrates of the affected glands with subsequent dysfunction of these glands and the clinical picture of sicca syndrome
Considered primary if not associated with other systemic disease or secondary if it occurs in association with another underlying autoimmune condition (Clin Exp Med 2022;22:9)

Essential features

Chronic autoimmune disorder of uncertain etiology
Characterized by focal lymphocytic sialadenitis with subsequent clinical sequela including keratoconjunctivitis sicca (dry eyes) and xerostomia (dry mouth)
Diagnosed using a combination of subjective and objective measures as determined by the 2016 American College of Rheumatology / European League Against Rheumatism (ACR / EULAR) classification
Salivary gland biopsy findings consistent with diagnosis are focal lymphocytic sialadenitis with a focus score (FS) ≥ 1

Terminology

Not recommended: Mikulicz disease (Lancet 2005;366:321)

ICD coding

ICD-10: M35.0 - Sjögren syndrome
ICD-11: 4A43.2 - Sjögren syndrome

Epidemiology

One of the 3 most common autoimmune disorders (Lancet 2005;366:321)
F:M = 9:1 (Clin Exp Med 2022;22:9)
Bimodal distribution
- Third and fourth decade
- Sixth decade (Lancet 2005;366:321)
Incidence of 6.92 per 100,000 person-years (person-years is defined as the estimate of the actual time at risk in years that all persons contributed to a study) (95% confidence interval, 4.98 - 8.86)
Prevalence of 60.82 cases per 100,000 inhabitants (Europe, South America, Asia) (95% confidence interval, 43.69 - 77.94) (Ann Rheum Dis 2015;74:1983)

Sites

Exocrine glands
- Notably lacrimal and salivary glands (Eur J Oral Sci 2018;126:37)

Pathophysiology

Pathological basis of the disease remains unknown
Numerous theories have been proposed; however, a consensus has not been established (Immunol Lett 2011;141:1)

Etiology

Etiology is unknown
- Likely multifactorial with potential genetic, environmental and hormonal factors suggested; however, no causal associations have been demonstrated (Clin Exp Rheumatol 2022;40:2211)
Primary Sjögren syndrome
- 90% of patients with high anti-Ro and anti-La antibody titers are HLA DR3 positive (Clin Med (Lond) 2007;7:53)
Secondary Sjögren syndrome
- Sjögren syndrome associated with rheumatoid arthritis has a different genetic background (HLA DR4) (Lancet 2005;366:321)

Diagrams / tables

Images hosted on other servers:

ACR / EULAR
classification criteria
for primary Sjögren
syndrome

Clinical features

Keratoconjunctivitis sicca (dry eyes)
Xerostomia (dry mouth)
Enlarged salivary glands
Extraglandular manifestations include
- Musculoskeletal
  - Myalgia, arthralgia and morning stiffness
- Dermatological
  - Xerosis
- Respiratory tract
  - Rhinosinusitis
  - Vocal hoarseness
  - Chronic cough (Clin Exp Med 2022;22:9)

Diagnosis

2016 ACR / EULAR classification system
- Score ≥ 4 is compatible with a diagnosis of primary Sjögren syndrome in patients experiencing ocular or oral dryness or with clinical suspicion due to systemic features (Arthritis Rheumatol 2017;69:35)
Factors assessed include
- Labial salivary gland biopsy with lymphocytic sialadenitis and focus score ≥ 1 (3 points)
- Anti-SSA (Ro) positive serology (3 points)
- Ocular staining score ≥ 5 (1 point)
- Schirmer test ≤ 5 mm / 5 min (1 point)
- Unstimulated whole saliva flow rate ≤ 1 mL/min (1 point)
Exclusion criteria
- History of head and neck radiation treatment
- Active hepatitis C infection
- Sarcoidosis, amyloidosis
- IgG4 related disease
- Graft versus host disease
- Acquired immunodeficiency syndrome (Arthritis Rheumatol 2017;69:35)

Laboratory

Positive anti-SSA (Ro) antibodies and anti-SSB (La) antibodies
Emerging potential biomarkers: muscarinic type 3 receptor (M3R), salivary calprotectin and carbamylated proteins (homocitrulline) (Eur J Oral Sci 2018;126:37)

Radiology description

Sialography
- Serial Xray projections taken following injection of contrast medium
  - Imaging with computed tomography (CT) and magnetic resonance imaging (MRI) has also been developed producing 3 dimensional images of the ductal system
- Dilatation of ducts and punctate collections of contrast medium (sialectasis)
- Sparsity of ductal branching
- Less commonly used (J Clin Med 2020;9:2492)
MRI
- Heterogeneous signal intensity distribution on T1 and T2 weighted images conveying a salt and pepper appearance
- Cystic changes in advanced disease (J Clin Med 2020;9:2492)
Ultrasound
- Hypoechogenic areas, hyperechogenic reflections and poorly defined salivary gland borders (J Clin Med 2020;9:2492)
- Ultrasound findings may be incorporated in the diagnostic features in the future; however, these require further validation (Clin Exp Rheumatol 2018;36:159)

Radiology images

Images hosted on other servers:

Sialography findings: normal versus Sjögren

Ultrasound findings
suggestive of
primary Sjögren
syndrome

Prognostic factors

High focus score predicts greater decline in unstimulated salivary flow over time (Ann Rheum Dis 2008;67:949)
Overall increased risk of lymphoma with an estimated risk of 5 - 15% of patients (Presse Med 2012;41:e511)
- Risk of lymphoma thought to be 40 times greater than the general population (Ann Intern Med 1978;89:888)
Most commonly low grade non-Hodgkin lymphoma, specifically extranodal marginal zone of mucosa associated lymphoid tissue (MALT) lymphoma
Features thought to be associated with increased risk of transformation to lymphoma include
- High focus score
  - Particularly focus score ≥ 3 has a positive predictive value of 16% and negative predictive value of 98% for non-Hodgkin lymphoma (Ann Rheum Dis 2014;73:1537)
- Detection of ectopic germinal centers, although some studies did not find these a predictive factor for MALT lymphoma (Rheumatology (Oxford) 2013;52:276)
  - Usually correlate with a higher focus score (Ann Rheum Dis 2014;73:1537)

Case reports

22 year old woman with a diagnosis of ranula preceding a diagnosis of primary Sjögren syndrome (World J Clin Cases 2021;9:5701)
41 year old woman with a varied clinical presentation of primary Sjögren syndrome (BMJ Case Rep 2019;12:e231802)
55 year old woman with bilateral parotid gland enlargement and Sjögren syndrome (J Int Oral Health 2015;7:72)
60 year old woman with cutaneous mucosa associated lymphoid tissue lymphoma complicating Sjögren syndrome (World J Clin Cases 2022;10:4509)

Treatment

Primarily symptomatic treatment, including
- Artificial tears
- Saliva replacement
- NSAIDs for musculoskeletal symptoms (Clin Med (Lond) 2007;7:53)

Clinical images

Images hosted on other servers:

Bilateral parotid gland enlargement

Microscopic (histologic) description

Historically minor salivary gland biopsy has been assessed
- In a limited study, parotid gland biopsy was shown to have similar diagnostic sensitivity and specificity (Rheumatology (Oxford) 2007;46:335)
Focal lymphocytic sialadenitis is the histological hallmark
- 1 or more dense aggregates with 50 or more lymphocytes
- Usually in perivascular or periductal areas
- Cannot be attributed if dominated by features of nonspecific chronic sialadenitis or chronic sclerosing sialadenitis (Reumatismo 2018;70:146)
Other features are nonspecific and include
- Nonspecific chronic sialadenitis and chronic sclerosing sialadenitis
  - Mild to diffuse lymphocytic infiltrates
  - Progressive atrophy of normal salivary gland acini
  - Duct dilatation
  - Variable parenchymal fibrosis
- Lymphoepithelial lesions (seen in ~50% of patients with primary Sjögren syndrome) (Clin Exp Rheumatol 2022;40:2434)
  - Lymphocytic infiltrate of ducts and basal cell hyperplasia
- Ectopic germinal centers
  - Recommended that these always be reported if present (Ann Rheum Dis 2017;76:1161)
- Granulomatous inflammation
- Adiposis (Autoimmun Rev 2020;19:102690, Reumatismo 2018;70:146)
ACR / EULAR classification criteria for labial salivary gland biopsy
- Focal lymphocytic sialadenitis
  - If identified, a focus score should be recorded, with a focus score ≥ 1 suggestive of Sjögren syndrome (Arthritis Rheumatol 2017;69:35)
  - Focus score 1 = 1 focus of 50 lymphocytes per 4 mm² (Arthritis Rheum 2011;63:2021)
  - Recommended at least 4 labial salivary glands with a surface area of at least 8 mm² to allow for adequate assessment and focus scoring (Ann Rheum Dis 2017;76:1161)

Microscopic (histologic) images

Contributed by Alice Ormandy, M.B.B.S., M.P.H. and Salman Marvi, M.D.

Multiple nodular lymphocytic aggregates

Lymphocytic aggregates with germinal centers

Nodular lymphocytic aggregate

Core biopsy parotid

Germinal center

Submandibular gland lymphoid aggregates

Submandibular gland germinal centre

Cytology description

Nonspecific findings
May find benign myoepithelial and ductal epithelial cells interspersed with a lymphocytic infiltrate
There may be macrophages in the background (Prog Health Sci 2013;3:178)

Cytology images

Contributed by Alice Ormandy, M.B.B.S., M.P.H.

Lymphoid clusters

Lymphocytic infiltrate

Positive stains

BCL6 highlight germinal center B cells
CD21 / CD23 can highlight follicular dendritic cells in germinal centers (Reumatismo 2018;70:146)

Sample pathology report

Salivary gland, biopsy
- Focal lymphocytic sialadenitis with associated mild atrophy of the salivary acini (see comment)
- Comment: There is a single nodular lymphocytic aggregate (1 cluster of > 50 lymphocytes per 4 mm², focus score = 1). There is no germinal center formation and no features to suggest malignancy. The finding of focal chronic sialadenitis with a focus score of 1 is compatible with the diagnosis of Sjögren syndrome in the correct clinical context. Correlation with clinical history, radiology, serology and flow cytometry is recommended.

Differential diagnosis

Nonspecific chronic sialadenitis:
- Clinical pathological correlation required
IgG4 disease:
- Plasma cell rich inflammatory infiltrate
- Increased ratio of IgG4 to IgG plasma cells

Board review style question #1

What features on the salivary gland biopsy shown from a patient with Sjögren syndrome are associated with an increased risk of lymphoma?

Atrophy
Fat infiltration
Fibrosis
Focus score ≥ 3

Board review style answer #1

D. Focus score ≥ 3. A high focus score, particularly ≥ 3, has a positive predictive value of 16% and negative predictive value of 98% for non-Hodgkin lymphoma (Ann Rheum Dis 2014;73:1537). Answers A, B and C are incorrect because fat infiltration and fibrosis are all features that can be present in salivary gland biopsies of patients with Sjögren syndrome; however, they have not been associated with increased risk of lymphoma in these patients.

Comment Here

Reference: Sjögren syndrome

Board review style question #2

What is the most common salivary gland lymphoma occurring in patients with primary Sjögren syndrome?

Diffuse large B cell lymphoma
Extranodal marginal zone of mucosa associated lymphoid tissue (MALT) lymphoma
Follicular lymphoma
Hodgkin lymphoma

Board review style answer #2

B. Extranodal marginal zone of mucosa associated lymphoid tissue (MALT) lymphoma. Answers A and C are incorrect because diffuse large B cell lymphoma and follicular lymphoma have been reported in salivary glands; however, they are not the most common lymphoma in this site. Answer D is incorrect because Hodgkin lymphoma is rare in salivary glands (Rheumatology (Oxford) 2022;61:3818).

Comment Here

Reference: Sjögren syndrome

Squamous cell carcinoma

Table of Contents

Definition / general

True salivary gland primaries of squamous cell carcinoma are very rare; most squamous cell carcinomas are metastases to intraparotid lymph nodes from primaries in oral cavity, upper aerodigestive tract or skin
Squamous cell carcinomas represent 16 - 54% of malignant salivary gland tumors, about 11% of malignant tumors of major salivary glands

Clinical features

Squamous cell carcinomas (primary or secondary) are most frequent parotid malignant tumor (30 - 37%), represent 4% of submandibular gland tumors
Usually men (when considering major salivary gland tumors); also associated with AIDS
May occur in Stensen duct
Rapid painless growth with infiltration of surrounding structures, regardless of origin; may cause acute facial paralysis
Aggressive behavior, with 50% 5 year survival (Arch Pathol Lab Med 2001;125:740)

Treatment

Radical surgery, radiation therapy

Gross description

Large, poorly encapsulated mass

Microscopic (histologic) description

Classic features of squamous cell carcinoma
May have perineural invasion, clear cell change
Often component or coexisting with other tumors: carcinosarcoma, epidermoid cyst, epithelial myoepithelial carcinoma, malignant mixed tumor, mucoepidermoid carcinoma, sarcomatoid carcinoma, salivary duct carcinoma, sebaceous lymphadenoma, Warthin tumor (Mod Pathol 2002;15:724)

Positive stains

CK7 (variable, Mod Pathol 2004;17:407), CK13, CK14, CK19; also vimentin, p53, cyclin D1, MDM2, p63 diffuse (basaloid type)

Negative stains

CK20, COX2, CK8, factor XIIIa, p16, CDK4, Rb, E2F1
Loss of E-cadherin

Differential diagnosis

Adenoid cystic carcinoma: p63+, resembles basaloid squamous cell carcinoma (Mod Pathol 2005;18:645)
High grade mucoepidermoid carcinoma: intermediate cells, mucus cells, COX2+

Staging

Table of Contents

Definition / general

Staging of definitive resections for primary salivary gland carcinoma and neuroendocrine carcinoma of the parotid, submandibular or sublingual gland should use this system
On occasion it may be difficult to distinguish a sublingual salivary gland primary with certainty from a salivary gland tumor arising from minor salivary glands in the anterior floor of mouth

Essential features

AJCC 7th edition staging was sunset on December 31, 2017; as of January 1, 2018, use of the 8th edition is mandatory
There are no significant changes to pT classification
- Carcinomas for which the pTis designation may be applied include some intracapsular carcinomas ex pleomorphic adenomas and intraductal carcinomas
pN classification now incorporates extranodal extension
Use of the CAP protocol is not required for recurrent tumors or for metastatic tumors that are resected at a different time than the primary tumor
- Use of this protocol is also not required for pathology reviews performed at a second institution (i.e. secondary consultation, second opinion or review of outside case at second institution)
CAP staging protocol: CAP: Protocol for the Examination of Specimens From Patients With Cancers of the Larynx [Accessed 17 September 2018]
Alternatively for providers practicing in different geographic regions, there may be interest in the International Collaboration on Cancer Reporting (ICCR) guidelines: ICCR: Carcinomas of the Major Salivary Glands (TNM8) [Accessed 17 September 2018]

ICD coding

C07.9: Parotid gland
C08.0: Submandibular gland
C08.1: Sublingual gland
C08.8: Overlapping lesion of major salivary glands
C08.9: Major salivary gland, NOS

Primary tumor (pT)

pTX: Primary tumor cannot be assessed
pT0: No evidence of primary tumor
pTis: Carcinoma in situ
pT1: Tumor ≤ 2 cm without extraparenchymal extension
pT2: Tumor > 2 cm but ≤ 4 cm without extraparenchymal extension
pT3: Tumor > 4 cm or tumor with extraparenchymal extension
pT4a: Tumor of any size invading skin, mandible, ear canal or facial nerve
pT4b: Tumor of any size invading skull base or pterygoid plates or encases carotid artery

Notes:

Extraparenchymal extension is clinical or macroscopic evidence of invasion of soft tissues
Microscopic evidence alone does not constitute extraparenchymal extension for classification purposes

Regional lymph nodes (pN)

pNX: Regional lymph nodes cannot be assessed
pN0: No regional lymph node metastasis
pN1: Metastasis in a single ipsilateral lymph node ≤ 3 cm without extranodal extension
pN2a: Single ipsilateral lymph node metastasis ≤ 3 cm with extranodal extension or > 3 cm but ≤ 6 cm without extranodal extension
pN2b: Metastasis in multiple ipsilateral lymph nodes ≤ 6 cm without extranodal extension
pN2c: Metastasis in bilateral or contralateral lymph node(s) ≤ 6 cm without extranodal extension
pN3a: Metastasis in a lymph node > 6 cm without extranodal extension
pN3b: Extranodal extension in a single ipsilateral lymph node > 3 cm or single contralateral node or multiple nodes with metastases, any with extranodal extension

Notes:

A selective neck dissection will include 10+ lymph nodes and a comprehensive neck dissection (radical or modified radical neck dissection) will include 15+ lymph nodes
Negative pathologic examination of a smaller number of nodes still mandates a pN0 designation
Midline nodes are considered ipsilateral nodes
Measurement of tumor metastasis:
- Cross sectional diameter of the largest lymph node metastatic deposit (not the lymph node itself) is measured in the gross specimen at the time of macroscopic examination or if necessary, using the histologic slide
Extranodal extension (ENE):
- AJCC 8th edition introduces the use of ENE in pN categorization
- Must be clearly defined as tumor present within the confines of the lymph node and extending through the lymph node capsule into the surrounding connective tissue, with or without associated stromal reaction

Distant metastasis (pM)

pM0: No distant metastasis
pM1: Distant metastasis

AJCC prognostic stage grouping

Stage 0:	Tis	N0	M0
Stage I:	T1	N0	M0
Stage II:	T2	N0	M0
Stage III:	T3	N0	M0
	T0 - 3	N1	M0
Stage IVA:	T4a	N0 - 1	M0
	T0 - 4a	N2	M0
Stage IVB:	Any T	N3	M0
	T4b	Any N	M0
Stage IVC:	Any T	Any N	M1

Registry data collection variables

Extranodal extension clinical (present versus absent)
Extranodal extension pathological (present versus absent)
Extent of microscopic extranodal extension (distance of extension from the native lymph node capsule to the farthest point of invasion in extranodal tissue)
Perineural invasion
Lymphovascular invasion
p16 / HPV status
Performance status
Tobacco use and pack years
Alcohol use
Depression diagnosis

Histopathologic type

Mucoepidermoid carcinoma
Adenoid cystic carcinoma
Acinic cell carcinoma
Polymorphous adenocarcinoma
(Mammary analogue) secretory carcinoma
Salivary duct carcinoma
Carcinoma ex pleomorphic adenoma
Epithelial myoepithelial carcinoma
(Hyalinizing) clear cell carcinoma
Adenocarcinoma, not otherwise specified
- Includes cystadenocarcinoma, intestinal type adenocarcinoma and mucinous adenocarcinoma
Basal cell adenocarcinoma
Carcinosarcoma
Intraductal carcinoma
Lymphoepithelial carcinoma
Myoepithelial carcinoma
Oncocytic carcinoma
Poorly differentiated carcinoma
- Large cell neuroendocrine carcinoma
- Small cell neuroendocrine carcinoma
- Undifferentiated carcinoma
Sebaceous adenocarcinoma
Squamous cell carcinoma

Notes:

In this current classification, sialoblastoma is designated as a tumor of uncertain malignant potential
Metastasizing pleomorphic adenoma has been collapsed under pleomorphic adenoma
Since the biologic behavior of these still overlaps with the other malignant tumors, these can be reported under "other"

Board review style question #1

Regarding the following parotid gland primary salivary gland adenocarcinoma, which of the pT category criteria in the 8th edition AJCC staging guide is satisfied by the examination of this gross resection specimen photograph?

pT1 by depth of invasion
pT2 by tumor size
pT3 by presence of necrosis
pT3 by extraparenchymal extension

Board review style answer #1

D. pT3 by extraparenchymal extension (white arrows point to border of skeletal muscle, yellow arrows point to border of malignancy, black arrow points to tumor invading skeletal muscle)

Comment Here

Reference: Pathologic TNM staging of major salivary glands (AJCC 8th edition)

Striated duct adenoma (pending)

[Pending]

Suspicious for malignancy

Table of Contents

Definition / general

FNA that shows features highly suggestive of but not unequivocal for malignancy (Faquin: The Milan System for Reporting Salivary Gland Cytopathology, 2nd Edition, 2023)

Essential features

FNA that shows cytologic features suggestive of malignancy and meets some but not all of the criteria for malignancy
FNA should be subcategorized if possible (e.g., suspicious for a primary salivary gland malignancy, suspicious for metastasis, suspicious for lymphoma)

Terminology

Suspicious for malignancy (category V)

CPT coding

88172 - determination of adequacy of specimen
88173 - FNA interpretation

Sites

Salivary gland malignancies represent 0.3% of cancers of all body sites (Int J Cancer 2021 Apr 5 [Epub ahead of print], CA Cancer J Clin 2021;71:209)
15 - 35% of parotid gland, 41 - 45% of submandibular and 70 - 90% of sublingual glands tumors are malignant (Head Neck Pathol 2022;16:1043)
In comparison, more than half of minor gland tumors (including palate, tongue, the floor of the mouth, retromolar region and lips) are likely to be malignant (Head Neck Pathol 2022;16:1043)

Clinical features

Frequency among all the Milan system categories: 4%
Risk of malignancy (ROM) is 83% in the 2nd edition of Milan System, with a large study demonstrating a ROM of 83.3% (Cancer Cytopathol 2018;126:94)

Laboratory

For FNAs of suspicious for malignancy (SM), ancillary studies can help to refine the differential diagnosis and place the specimen into a more definitive diagnostic category
Low grade carcinomas
- Acinic cell carcinoma (Cancer Cytopathol 2021;129:104)
  - Positive for NR4A3 (nuclear stain): highly specific; negative in normal acinar cells
  - Positive for DOG1 (complete membranous) and SOX10 immunocytochemistry
  - Positive FISH for NR4A3 rearrangements
- Secretory carcinoma (J Oral Pathol Med 2023;52:255, Sci Rep 2021;11:22639)
  - Positive for pan-TRK, S100, mammaglobin, GATA3 and GCDFP-15 immunocytochemistry
  - Positive FISH for ETV6 rearrangements
Carcinomas with intermediate or multiple grades
- Adenoid cystic carcinoma (Mod Pathol 2018;31:934, Pak J Med Sci 2017;33:1376)
  - Positive for MYB (nuclear stain) and KIT immunocytochemistry
  - Positive FISH or NGS for MYB or MYBL1 rearrangements
- Mucoepidermoid carcinoma (Cancer Cytopathol 2018;126:627, Am J Surg Pathol 2018;42:e11)
  - Positive for mucicarmine stain in mucus cells
  - Positive for p63 and p40 immunocytochemistry
  - Positive FISH for MAML2 rearrangements
High grade carcinomas
- Salivary duct carcinoma (Cancer Cytopathol 2020;128:693)
  - Positive for androgen receptor (AR) and GATA3 immunocytochemistry
  - Evaluation for AR and HER2 status for targeted therapy
- Metastasis: squamous cell carcinoma, melanoma (Head Neck Pathol 2021;15:843, Case Rep Oncol 2021;14:957)
Lymphoma
- Flow cytometry (AJSP Rev Rep 2020;25:249, Cytopathology 2014;25:231)

Radiology description

There is overlap in the imaging appearance of benign and malignant tumors; however, some features suggestive of malignancy include (Radiology 2000;216:19, AJNR Am J Neuroradiol 2011;32:1202)
- Ill defined margins
- Invasion of adjacent fat, muscle or bone
- Infiltration of the overlying skin
- Perineural spread of tumor and facial nerve palsy
- Regional adenopathy
Infectious and inflammatory pathologies may also demonstrate ill defined borders and small malignancies may feature smooth borders (AJNR Am J Neuroradiol 2011;32:1202, Semin Ultrasound CT MR 2013;34:196)
Pathologic lymph nodes in the drainage territory of a mass are suggestive of malignancy (Radiographics 2006;26:745)

Cytology description

FNA should be subcategorized if possible (e.g., suspicious for a primary salivary gland malignancy, suspicious for a metastasis, suspicious for lymphoma) (Diagn Cytopathol 2017;45:820)
Significant proportion will be suboptimal samples of a high grade carcinoma
Reasons that a salivary gland FNA leads to an interpretation of suspicious for malignancy include
- Presence of markedly atypical cells with poor smear preparation, cell preservation, fixation artifact or obscuring blood or inflammation
- Presence of limited cytologic features of a specific type of malignancy
- Scant cellularity but presence of markedly atypical or suspicious cytologic features (prominent nucleoli, anisonucleosis, increased N:C ratio, nuclear molding, prominent nuclear pleomorphism, atypical mitoses and coarse chromatin)
- Scant sample with features suggestive of a neuroendocrine neoplasm
- Scant sample with features suggestive of a metastatic lesion
Many of the aspirates of lymphoma classified as suspicious for malignancy lack sufficient material for ancillary studies; some of the cytomorphologic features suggestive of lymphoma include
- Prominent population of large atypical lymphocytes with coarse chromatin and prominent nucleoli, seen in large cell lymphomas
- Monomorphic population of small to intermediate sized lymphocytes, seen in follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma
- Heterogeneous lymphoid population with atypical forms, seen in extranodal marginal zone lymphomas (EMZL), in particular in patients with history of Sjögren syndrome

Cytology images

Contributed by Manish Mahadeorao Bundele, M.B.B.S., M.D. and Rebecca Tian Mei Au, M.B.B.S.

Suspicious for acinic cell carcinoma

Suspicious for adenoid cystic carcinoma

Suspicious for mucoepidermoid carcinoma

Suspicious for large cell lymphoma

Suspicious for metastatic carcinoma

Suspicious for high grade basal cell adenocarcinoma

Suspicious for high grade basal cell adenocarcinoma

Sample pathology report

Parotid, right, fine needle aspiration smears:
- Satisfactory for evaluation
- Suspicious for malignancy
- Rare markedly atypical cell clusters, suspicious for high grade carcinoma

Parotid, right, fine needle aspiration smears:
- Satisfactory for evaluation
- Suspicious for malignancy
- Atypical cell clusters in a mucinous background, suspicious for low grade mucoepidermoid carcinoma

Parotid, right, fine needle aspiration smears:
- Satisfactory for evaluation
- Suspicious for malignancy
- Monomorphic population of small lymphoid cells, suspicious for non-Hodgkin lymphoma (see comment)
- Comment: Additional tissue sampling either by repeat FNA or other tissue biopsy is recommended for further evaluation with ancillary studies, including flow cytometry.

Parotid, right, fine needle aspiration smears:
- Evaluation limited by low yield of well preserved cells
- Suspicious for malignancy
- Cyst contents with atypical squamous cells with enlarged hyperchromatic nuclei / dyskeratotic cells, suspicious for metastatic keratinizing squamous cell carcinoma

Differential diagnosis

Aspirates with scant cellularity but presence of markedly atypical cells:
- Benign
  - Reactive and reparative atypia
  - Squamous, oncocytic or other metaplastic changes
- Malignant
  - Salivary duct carcinoma:
    - Highly cellular with 3 dimensional clusters and single discohesive cells in a dirty / necrotic background and with overtly malignant cytologic features with abundant finely granular cytoplasm, nuclear pleomorphism, prominent nucleoli and frequent mitoses
  - Metastasis:
    - Metastatic cystic keratinizing squamous cell carcinoma:
      - Cyst contents with atypical squamous cells and dyskeratotic cells
  - Melanoma:
    - Wide range of cytomorphologic appearances; classically shows discohesive pleomorphic cells with eccentric nuclei, prominent nucleoli and fine to coarsely granular cytoplasmic melanin pigment

Lymphoid rich aspirates:

Benign
- Chronic sialadenitis, including IgG4 related disease:
  - Hypocellular smears with chronic inflammation (including lymphocytes and plasma cells)
  - Small groups of ductal cells (may be basaloid or metaplastic)
  - Absent or scant acinar cells
  - Fibrotic stromal fragments
- Reactive lymph node hyperplasia:
  - Mixed population of lymphocytes with predominance of small mature forms
  - Tingible body macrophages
  - Lymphohistiocytic aggregates / germinal centers
- Benign lymphoepithelial lesion / lymphoepithelial sialadenitis (LESA):
  - Cellular aspirate with lymphoepithelial lesions (cohesive sheets of ductal cells and small mature lymphocytes percolating through the epithelial sheets)
  - Mixed population of lymphocytes, dendritic cells and tingible body macrophages with predominance of small mature lymphocytes
  - Lymphohistiocytic aggregates
- Warthin tumor:
  - Tripartite appearance with dirty proteinaceous background, small lymphocytes and sheets of uniform oncocytes
Malignant
- Heterogeneous lymphoid population with atypical forms (extranodal marginal zone lymphomas [EMZL])
- Monomorphic lymphoid population with small / intermediate lymphocytes (follicular lymphoma; mantle cell lymphoma; small lymphocytic lymphoma)
- Large atypical lymphocytes (large cell lymphomas)

Cellular aspirates with oncocytic / oncocytoid cells or vacuolated cells:

Benign
- Oncocytosis:
  - Acinar and ductal cells with abundant granular, eosinophilic cytoplasm; normal cytoarchitectural arrangement of acini and ductal cells
- Oncocytoma:
  - Irregular sheets and clusters of large polygonal cells with abundant homogeneous granular cytoplasm, well defined cytoplasmic borders and enlarged, round nuclei with distinct nucleoli
  - Clean background or with red blood cells
  - No nuclear pleomorphism and mitotic figures
- Warthin tumor:
  - Tripartite appearance with dirty proteinaceous background, small lymphocytes and sheets of uniform oncocytes
Malignant
- Oncocytic variants of tumors (e.g., mucoepidermoid carcinoma oncocytic variant)
- Aspirates with cells containing granular (usually coarse) / vacuolated cytoplasm (secretory carcinoma; acinic cell carcinoma; metastatic renal cell carcinoma)
- Aspirates with cells containing appreciable focal nuclear atypia (salivary duct carcinoma, high grade mucoepidermoid carcinoma, oncocytic carcinoma, high grade oncocytic epithelial myoepithelial carcinoma, metastatic carcinoma)

Cellular aspirates with basaloid cells:

Benign
- Cellular Pleomorphic adenoma:
  - Cellular basaloid neoplasm with absent to scant fibrillary matrix
- Basal cell adenoma:
  - Cellular basaloid neoplasm with absent to scant hyaline stroma
  - Nonspecific cytomorphologic features; will need histological evaluation to exclude invasive features
- Myoepithelioma:
  - Cellular basaloid neoplasm with minimal to no matrix
  - Nonspecific cytomorphologic features; will need histological evaluation to exclude invasive features
Malignant
- Adenoid cystic carcinoma:
  - Monotonous, small basaloid cells with dark angulated nuclei and indistinct cytoplasm
  - Arranged in sheets or tubular pattern
  - Homogenous acellular nonfibrillary and intensely metachromatic matrix
- Carcinoma ex pleomorphic adenoma:
  - Focal component of classic pleomorphic adenoma may be seen
  - Carcinomatous component most often salivary duct carcinoma or high grade adenocarcinoma, NOS
- Epithelial myoepithelial carcinoma:
  - Variable proportions of ductal and myoepithelial cells
  - Predominant population of clear myoepithelial cells
  - Laminated acellular stromal cores
- Myoepithelial carcinoma:
  - Cells with myoepithelial differentiation with cell types including plasmacytoid, spindled, clear and epithelioid forms
  - Metachromatic stromal material
  - Will need histological evaluation to demonstrate invasive features
- Basal cell adenocarcinoma:
  - Cellular basaloid neoplasm with absent to scant hyaline stroma
  - Nonspecific cytomorphologic features; will need histological evaluation to demonstrate invasive features
- Polymorphous adenocarcinoma:
  - Cytomorphologic features which lack specificity for a definitive diagnosis
  - Ductal phenotype with cellular monotony and architectural heterogeneity

Mucin containing aspirates:

Benign
- Mucocele / mucus retention cyst:
  - Pooled mucin surrounded by a simple cyst lined by an intact, attenuated, cuboidal, columnar or squamous epithelium lining
- Warthin tumor with focal mucinous metaplastic change:
  - Mucinous background with sheets of oncocytes and small lymphocytes
Malignant
- Mucoepidermoid carcinoma:
  - Admixture of goblet type mucus cells, intermediate and epidermoid cells

Additional references

Cancer Cytopathol 2018;126:756, Cancer Cytopathol 2018;126:541

Board review style question #1

What is the risk of malignancy on excision if a diagnosis of suspicious for malignancy is given on a fine needle aspiration (FNA) of the parotid?

< 20%
~40%
~60%
> 80%

Board review style answer #1

D. > 80%. The risk of malignancy is 83%, as per the Milan System for Reporting Salivary Gland Cytopathology. Answers A - C are incorrect because the risk on excision is higher than 80% if reported as suspicious for malignancy on FNA.

Comment Here

Reference: Suspicious for malignancy

Board review style question #2

This is a representative image from a parotid gland fine needle aspiration. On cell block immunostaining, the epithelial cell clusters are positive for GATA3, AR and negative for DOG1, while the spindle cells are positive for p63 and SOX10. What category should this aspirate be placed in according to the Milan System for Reporting Salivary Gland Cytopathology?

Atypia of undetermined significance
Benign neoplasm
Malignant
Suspicious for malignancy

Board review style answer #2

D. Suspicious for malignancy. As mentioned above, on cell block immunostaining the atypical epithelial cell clusters are positive for GATA3, AR and negative for DOG1. These features raise the possibility of carcinoma with oncocytoid / apocrine features, such as salivary duct carcinoma. The background bland spindle myoepithelial cells are positive for p63 and SOX10 suggests a pleomorphic adenoma component. Given the limited cluster of cells with carcinoma morphology and admixed with bland myoepithelial cells, the correct answer is suspicious for malignancy. Answer B is incorrect because atypical cells are seen. Answer A is incorrect because the degree of atypia seen in these few atypical cell clusters is of high grade and is generally beyond this category. Answer C is incorrect because qualitative and quantitative features of atypical cells are insufficient for this category.

Comment Here

Reference: Suspicious for malignancy

Warthin tumor

Table of Contents

Definition / general

Benign salivary gland tumor that is composed of oncocytic epithelial cells lining papillary and cystic structures in a lymphoid stroma
Second most frequent benign tumor of the parotid gland (after pleomorphic adenoma) (Head Neck Pathol 2020;14:412)
Infarcted / metaplastic subtype may occur following FNA biopsy (Clin Otolaryngol Allied Sci 1989;14:205)

Essential features

Benign salivary gland tumor
Bilayered papillae and cysts lined by oncocytic cells and flattened basal cells
Lymphoid stroma

Terminology

Papillary cystadenoma lymphomatosum, adenolymphoma, cystadenolymphoma

ICD coding

ICD-10: D11.9 - benign neoplasm of major salivary gland, unspecified

Epidemiology

Accounts for 5 - 20% of all salivary tumors (J Clin Exp Dent 2013;5:e218)
Mean age at diagnosis is 62 years (range: 12 - 92 years) (Laryngoscope 1983;93:695)
M ≈ F
- Historically M > F (Oral Surg Oral Med Oral Pathol 1986;61:256)
More common in smokers (Am J Epidemiol 1996;144:183)

Sites

Almost exclusively involves the parotid gland, especially the inferior pole and periparotid lymph nodes (Br J Oral Maxillofac Surg 1998;36:52, Br J Oral Maxillofac Surg 1993;31:43)
Multifocality is detected in 12 - 20% of patients with bilaterality in 5 - 17% of patients (Oral Oncol 2002;38:35, Acta Otolaryngol 2006;126:1213)

Pathophysiology

Probably arises from salivary ductal inclusions in parotid lymph nodes (Head Neck Pathol 2014;8:73, Head Neck Pathol 2021;15:438)
Clonality studies have suggested a nonneoplastic nature (Hum Pathol 2000;31:1377, Mod Pathol 2005;18:964)

Etiology

Strong link to cigarette smoking (especially when bilateral) (Am J Epidemiol 1996;144:183)
Other suggested risk factors include radiation exposure in atomic bomb survivors and autoimmune diseases (especially thyroiditis) (Cancer 1997;79:1465, Acta Otolaryngol 1997;117:623, J Craniomaxillofac Surg 2015;43:427)

Clinical features

Presents with a painless, slow growing and fluctuant mass in the lower pole of the parotid gland (Oral Surg Oral Med Oral Pathol 1986;61:256)
Glucose avid on PET and often incidentally detected during PET work up (Am J Otolaryngol 2015;36:259)

Radiology description

Parotid tail location
Cystic change, multifocality
Avidity on PET CT (Am J Otolaryngol 2015;36:259)

Prognostic factors

Favorable prognosis (Diagn Interv Imaging 2016;97:37)
Recurrence is usually due to inadequate excision (Int J Oral Maxillofac Surg 2008;37:831)
Malignant transformation has rarely been reported but is increasingly thought to represent Warthin-like carcinomas rather than true Warthin tumors (J Oral Pathol Med 1994;23:330, Am J Surg Pathol 2015;39:1479)

Case reports

50 year old man presented with painless swelling over the right lower side of the face (J Clin Diagn Res 2014;8:ZD37)
69 year old man presented with right parotid tumor of 1 year duration (J Med Case Rep 2019;13:12)
71 year old man with left parotid mass, slowly growing over a period of 12 years (Surgeries 2020;1:46)

Treatment

Surgical excision with adequate margins is usually curative (Diagn Interv Imaging 2016;97:37)

Gross description

Most are well circumscribed oval masses, 20 - 50 mm in diameter (Indian J Otolaryngol Head Neck Surg 2019;71:839)
Solid areas and multiple cysts with papillary projections are apparent on the cut surface

Gross images

Contributed by Sapna Balgobind, M.B.B.Ch.

Cut surface

Microscopic (histologic) description

Varying proportions of papillary cystic structures lined by bilayered oncocytic epithelial cells and surrounded by a lymphoid stroma including germinal centers
Epithelial component is comprised of inner columnar and outer cuboidal cells
Limited foci of squamous, mucous, ciliated and sebaceous cells can be present
Infarcted / metaplastic subtype (Am J Surg Pathol 2013;37:1743, Histopathology 1999;35:432):
- Bilayered epithelium is replaced by squamous metaplastic epithelium with no atypia
- Mucinous metaplasia may also be present
- Biopsy site reaction may be present with necrosis, squamous metaplasia and a stromal reaction (including granuloma formation)
Stroma poor tumors have bilayered oncocytic lining but minimal lymphoid stroma (Oral Oncol 2002;38:163)

Microscopic (histologic) images

Contributed by Sapna Balgobind, M.B.B.Ch. and @AnaPath10 on Twitter

Parotid gland with
circumscribed
tumor

Bilayered oncocytic epithelium with lymphoid background

Mucinous metaplasia

Squamous metaplasia

Warthin tumor

p40 staining

p63 staining

Cytology description

Small cohesive sheets of oncocytes with abundant granular cytoplasm
Central round nucleus with prominent nucleolus
Numerous lymphocytes with granular debris in the background
Reference: Cibas: Cytology - Diagnostic Principles and Clinical Correlates, 5th Edition, 2020

Cytology images

Contributed by Sapna Balgobind, M.B.B.Ch.

Oncocytic cells in groups

Oncocytic cells

Proteinaceous debris

Oncocytic cells with dense cytoplasm

Positive stains

All epithelial cells are positive for pancytokeratin
- CK7, CK8 / CK18 and EMA are positive in luminal (or inner) epithelial cells
- p63 and p40 show heterogenous nuclear staining of the basal cells (see Microscopic (histologic) images) (Interv Med Appl Sci 2016;8:41)
Lymphoid cells are positive for: B cell markers (CD20) and T cell markers (CD3, CD4, CD8)

Negative stains

S100, calponin, actin, GFAP

Electron microscopy description

Oncocytic epithelial cells show cytoplasm filled with mitochondria on electron microscopy (Acta Otorhinolaryngol Ital 2005;25:150)

Molecular / cytogenetics description

Absent MAML2 fusion (positive in mucoepidermoid carcinoma)

Sample pathology report

Salivary gland, parotidectomy:
- Warthin tumor (see comment)
- Comment: Sections show a well circumscribed tumor with a papillary architecture. The papillae are lined by bilayered oncocytic epithelial cells with a surrounding lymphoid stroma, containing germinal centers.

Differential diagnosis

Lymphoepithelial cyst:
- Dilated cystic structure lined by squamous / columnar epithelium with lymphoid follicles in the cyst wall
- Lacks papillary architecture
Mucoepidermoid carcinoma:
- Critical consideration in Warthin tumors with metaplastic squamous or mucinous cells
- Mucoepidermoid carcinoma can show Warthin-like variant (Am J Surg Pathol 2015;39:1479)
- p63 and CK5/6 are diffusely positive in mucoepidermoid carcinoma (Head Neck Pathol 2013;7:64)
- S100 is negative in mucoepidermoid carcinoma
- MAML2 fusions are present in mucoepidermoid carcinoma, absent in Warthin tumor
- Warthin-like mucoepidermoid carcinoma lacks the classic oncocytic bilayer of Warthin tumor and tends to show more complex epithelial organization (Am J Surg Pathol 2015;39:1479, Am J Surg Pathol 2018;42:130)

Additional references

WHO Classification of Tumours Editorial Board: Head and Neck Tumours, 5th Edition, 2024

Board review style question #1

A 49 year old man presents with bilateral, slow growing parotid masses. An H&E section of the tumor is pictured above. What is the most likely diagnosis?

Classic Warthin tumor
Lymphoepithelial cyst
Oncocytoma
Warthin-like variant of mucoepidermoid carcinoma

Board review style answer #1

A. Classic Warthin tumor. The photograph shows features of a classic Warthin tumor with papillary structures lined by bilayered oncocytic epithelium. The other entities on the list do not match the entity shown on the H&E photograph provided.

Comment Here

Reference: Warthin tumor

Board review style question #2

Which of the following is a risk factor for developing a Warthin tumor?

Alcohol abuse
Cigarette smoking
Intravenous drug use
MAML2 translocation

Board review style answer #2

B. Cigarette smoking. The other risk factors listed have not been proven to be associated with Warthin tumor.

Comment Here

Reference: Warthin tumor

WHO classification (pending)

[Pending]

Recent Salivary glands Pathology books

Bishop: 2021

Cardesa: 2016

Carlson: 2015

Faquin: 2023

Franchi: 2020

García : 2019

Gnepp: 2021

IARC: 2024

Jiang: 2023

Mody: 2022

Neville: 2023

Stelow: 2020

Thompson: 2022

VandenBussche: 2017

Wenig: 2017

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Home > Salivary glands

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