Salivary glands
Cytology
Milan system
Malignant
Author: Jen-Fan Hang, M.D.
Editorial Board Member: Marc Pusztaszeri, M.D.
Deputy Editor-in-Chief: Andrey Bychkov, M.D., Ph.D.
Last author update: 9 August 2021
Last staff update: 11 May 2022
Copyright: 2021-2023, PathologyOutlines.com, Inc.
PubMed Search: Malignant[TIAB] salivary gland cytopathology Milan system
Table of Contents
Definition / general | Essential features | Terminology | CPT coding | Epidemiology | Sites | Clinical features | Radiology description | Case reports | Treatment | Cytology description | Cytology images | Videos | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Hang JF. Malignant. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/salivaryglandsmalignant.html. Accessed June 1st, 2023.
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
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
- Acinic cell carcinoma
- 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
- Salivary duct carcinoma
- 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
- Mucoepidermoid carcinoma
- 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
- Nonneoplastic acinar cells:
- 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
- Pleomorphic adenoma:
- Acinic cell carcinoma versus
- 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.)
- High grade mucoepidermoid carcinoma:
- Salivary duct carcinoma versus
- 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)
- Mucocele and mucin extravasation:
- 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)
- Pleomorphic adenoma:
- Mucoepidermoid carcinoma versus
- 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.)
- Sialoadenitis or intrasalivary gland lymph node:
Additional references
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
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
Comment Here
Reference: Malignant
