Salivary glands
Cytopathology (Milan system)
Malignant

Editorial Board Member: Andrey Bychkov, M.D., Ph.D.
Jen-Fan Hang, M.D.

Topic Completed: 28 May 2020

Minor changes: 28 May 2020

Copyright: 2020, PathologyOutlines.com, Inc.

PubMed Search: Milan system malignant salivary

Jen-Fan Hang, M.D.
Page views in 2020 to date: 180
Cite this page: Hang JF, Bychkov A. Milan system - Malignant. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/salivaryglandsmilanmalignant.html. Accessed July 7th, 2020.
Definition / general
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)
  • Attempt should be made to grade the tumor as low, intermediate or high grade
  • Specific tumor type should be provided if possible
Epidemiology
Sites
  • Parotid gland: 65 - 80% of all salivary gland tumors (Kumar: Robbins and Cotran Pathologic Basis of Disease, 9th Edition, 2014)
    • 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
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
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
      • Ancillary testing (Diagn Cytopathol 2017;45:808):
        • Positive for SOX10 and DOG1 (complete membranous pattern) immunocytochemistry
    • 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 (Cancer Cytopathol 2018;126:627):
        • Positive for androgen receptor and GATA3 immunocytochemistry
    • 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 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 cytologic atypia and necrosis in cases with high grade transformation
      • Ancillary testing (Cancer Cytopathol 2018;126:627):
        • Positive for MYB and KIT immunocytochemistry
        • Positive for MYB or MYBL1 FISH
    • Carcinoma ex pleomorphic adenoma:
      • Approximately 7% of all pleomorphic adenomas
      • 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

Dr. Faquin on the Milan system - malignant category

Sample pathology report
  • Satisfactory for evaluation. Malignant. Low grade mucoepidermoid carcinoma.
  • Satisfactory for evaluation. Malignant. High grade carcinoma, consistent with salivary duct carcinoma.
  • Satisfactory for evaluation. Malignant. High grade carcinoma. Presence of scant chondromyxoid matrix, suggestive of carcinoma ex pleomorphic adenoma.
Differential diagnosis
Board review style question #1

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

  1. Acinic cell carcinoma
  2. Adenoid cystic carcinoma
  3. Mucoepidermoid carcinoma
  4. Secretory carcinoma
Board review 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.

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Reference: Milan system - Malignant
Board review style question #2

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

  1. Acinic cell carcinoma
  2. Adenoid cystic carcinoma
  3. Mucoepidermoid carcinoma
  4. Secretory carcinoma
Board review answer #2
B. Adenoid cystic carcinoma

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

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Reference: Milan system - Malignant
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