Salivary glands
Cytopathology (Milan system)
Diagnostic categories

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

Topic Completed: 19 May 2020

Minor changes: 19 May 2020

Copyright: 2020, PathologyOutlines.com, Inc.

PubMed Search: Milan system diagnostic categories salivary

Jen-Fan Hang, M.D.
Page views in 2020 to date: 192
Cite this page: Hang JF, Bychkov A. Milan system - Diagnostic categories. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/salivaryglandsmilandiagnostic.html. Accessed May 24th, 2020.
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
  • MSRSGC 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
  • MSRSGC consists of 6 diagnostic categories, including nondiagnostic, nonneoplastic, atypia of undetermined significance (AUS), neoplasm (benign and salivary gland neoplasm of uncertain malignant potential [SUMP]), suspicious for malignancy (SM) and malignant
Terminology
  • 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:
      • Presence of any amount of cells with significant cytologic atypia should be classified as AUS
      • Mucinous cyst lesions with an absent or a very limited epithelial component should be classified as AUS
    • Estimated risk of malignancy by the MSRSGC: 25%
    • Real world risk of malignancy: 18.3% (with surgical follow up only), 4.4% (overall) (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:
      • Bland lymphocytic aspirates showing any evidence of monomorphic population should be better classified as AUS and considered for flow cytometry if necessary
    • Estimated risk of malignancy by the MSRSGC: 10%
    • Real world risk of malignancy: 8.9% (with surgical follow up only), 2.1% (overall) (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:
      • FNA showing limited cellular atypia
      • FNA lacking 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 by the MSRSGC: 20%
    • Real world risk of malignancy: 37.5% (FNA with surgical follow up), 25.0% (overall) (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:
      • FNA showing characteristic cytomorphologic features of a specific benign neoplasm
    • Common benign tumors diagnosed by FNA:
      • Epithelial: pleomorphic adenoma (60 - 70%), Warthin tumor (20 - 30%), oncocytoma, etc.
      • Mesenchymal: schwannoma, lipoma, hemangioma, etc.
    • Common false negative conditions:
      • Matrix producing carcinomas with basaloid cells falsely interpreted as pleomorphic or basal cell adenoma, ex: adenoid cystic carcinoma, basal cell adenocarcinoma → better classified as 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 → better classified as 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 → better classified as SUMP with myoepithelial features
      • Unrepresentative sampling, ex: carcinoma ex pleomorphic adenoma
    • Diagnostic tip:
      • Most FNA of basal cell adenoma, myoepithelioma and cystadenoma should be better classified as SUMP due to overlapping cytomorphology with other malignant tumors
    • Estimated risk of malignancy by the MSRSGC: < 5%
    • Real world risk of malignancy: 2.9% (FNA with surgical follow up), 1.5% (overall) (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:
      • FNA showing 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: basal cell adenoma / adenocarcinoma, adenoid cystic 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:
    • Estimated risk of malignancy by the MSRSGC: 35%
    • Real world risk of malignancy: 40.7% (FNA with surgical follow up), 27.7% (overall) (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:
      • FNA showing 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 by the MSRSGC: 60%
    • Real world risk of malignancy: 84.8% (Am J Clin Pathol 2019;151:613)
    • 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 by the MSRSGC: 90%
    • Real world risk of malignancy: 97.5% (Am J Clin Pathol 2019;151:613)
    • Management: surgery
Diagrams / tables

Images hosted on other servers:

Milan system

Cytology description
Cytology images

Contributed by Jen-Fan Hang, M.D.

Nondiagnostic

Nonneoplastic acinar cells

Benign skeletal muscles

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

Dr. Faquin on the Milan system

Differential diagnosis
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 MSRSGC?

  1. Category III: atypia of undetermined significance
  2. Category IVA: benign neoplasm, pleomorphic adenoma
  3. Category IVB: salivary gland neoplasm of uncertain malignant potential, with basaloid features
  4. Category VI: malignant, adenoid cystic carcinoma
Board review 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.

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Reference: Milan system - Diagnostic categories
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?

  1. Category I: nondiagnostic
  2. Category II: nonneoplastic
  3. Category III: atypia of undetermined significance
  4. Category VI: malignant, lymphoma
Board review 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.

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Reference: Milan system - Diagnostic categories
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