Milan cytology reporting

MILAN SYSTEM OF SALIVARY GLAND CYTOLOGY REPORTING

1. Milan’s system of reporting salivary gland cytology Presenter: Dr.Argha Baruah Moderator: Dr.ML Harendra Kumar

2. Introduction: Salivary gland fine-needle aspiration (FNA) cytology has become an accepted method of evaluating salivary gland tumors preoperatively FNA of salivary gland tumors was shown to have a high specificity in differentiating benign and malignant lesions (97%) FNA falls flat in terms of sensitivity (80%)

3. Why we need a uniform reporting system? Because of the wide diversity of tumors arising in the salivary glands along with significant morphologic overlap . Most pathologists report these specimens by employing heterogeneous diagnostic terminology, specifically for indeterminate diagnoses, and that clinician’s act variably based upon these reports. Inconsistencies in reporting of salivary gland FNA specimens can have an effect on the correlation between cytologic interpretation and surgical outcome and finally has an impact on patient care

4. The Bethesda system for reporting was created to address the inconsistencies and the shortcomings of the terminology used for reporting FNA specimens. A few authors have suggested that a similar classification is needed for reporting of salivary gland FNA specimens. Griffith et al. proposed a four category scheme that effectively stratified salivary gland FNA specimens by overall risk of malignancy and risk of high grade malignancy.The scheme was comprised of the following diagnostic categories: benign, neoplasm of uncertain malignant potential (NUMP), suspicious for malignancy and positive for malignancy; the overall risk of malignancy for each category was 2%, 18%, 75.8%, and 100%, respectively.

5. Rossi et al. based on the experience of two academic centres with 709 salivary gland FNA specimens, stratified their cytologic diagnosis into the following diagnostic categories with associated risk of malignancy: nondiagnostic /inadequate—17%, benign—16%, neoplasm—6%, atypical—53%,suspicious for malignancy/malignant—94%.

6. This led a group of experienced cytopathologists and histopathologists to attempt to create a uniform cytological reporting scheme. The proposed system is based on key principles developed for standardized terminology systems adopted for other body sites ( ie , uterine cervix, pancreas,thyroid , and urinary system)

7. The standardization effort started in September 2015 at the European Congress of Cytology, which was held in Milan, Italy, under the umbrella of the American Society of Cytopathology (ASC) and the International Academy of Cytology (IAC). Subsequently, an international panel of 49 cytopathologists and histopathologists (the Milan group) was organized to establish a unified effort under the title of “The Milan System for Reporting Salivary Gland Cytopathology.” Before starting the task of constructing a taxonomy, the Milan group invited the international cytology and histology communities to answer a series of questions .Questions were generated in accord with the current literature and experience of the authors in the core group. The preliminary version was presented by Dr. William Faquin at  USCAP  2016 in Seattle

8. THE BENEFITS OF A UNIFORM REPORTING SYSTEM FOR SALIVARY GLAND CYTOPATHOLOGY: 1. Improve communication between pathologists and clinicians 2. Improve patient care 3.Facilitate cytologic-histologic correlation 4.Promote research into the epidemiology, molecular biology, pathology 5.Foster sharing of data from different laboratories for collaborative studies

9. The Milan System for Reporting Salivary Gland Cytopathology 1) Non diagnostic 2) Non-Neoplastic 3) Atypia of undetermined significance (AUS) 4) Neoplastic: a) Benign b) Uncertain malignant potential (SUMP) 5) Suspicious for Malignancy 6) Malignant

10. Sample adequacy and evaluation: Minimum number of lesional and nonlesional cells that cytopathologist require to consider a aspirate as benign vs nondiagnostic /unsatisfactory was not established.

11. Category I:Non-Diagnostic: 1)Insufficient quantitative and/or qualitative cellular material to make a cytologic diagnosis 2)Includes aspirates with benign elements only 3)Includes non-mucinous cyst contents 4)Aspirate smears with cyst contents only ( ie . granular debris and histiocytes and few to no epithelial cells)

12. Benign salivary gland elements only

13. For aspirates containing only normal salivary gland elements, a cautionary note is recommended. Note: Clinical and radiologic correlations are recommended to ensure that the aspirate is representative of the lesion; the findings in this aspirate do not explain the presence of a salivary gland mass.

14. Non-mucinous cyst contents DDX: Ductal cyst, pseudocyst, cystic neoplasm Absence of an epithelial component

15. Category II: Non-Neoplastic: Specimens lacking evidence of a neoplastic process: 1)Inflammatory, metaplastic, and reactive( i.e acute, chronic, and granulomatous sialadenitis,sialadenosis , etc…) 2)Reactive lymph nodes (flow cytometry is needed) Note: Clinico -radiological correlation is essential to ensure that the specimen is representative of the lesion

16. Reactive Lymph Node

17. REACTIVE PROCESS VS LYMPHOMA IMMUNOPHENOTYPING combined with cytomorphology is the key to diagnosing and subtyping reactive conditions vs lymphoma. NOTE: For negative lymph nodes, caution is warranted: A note suggesting repeat FNA or tissue biopsy if lymphadenopathy persists

18. Chronic Sialadenitis Hypocellular, cohesive basaloid groups, inflammation

19. Granulomatous Sialadenitis

20. Category III: Atypia of Undetermined Significance (AUS): Cannot entirely exclude a neoplasm. Heterogeneous category A majority will be reactive atypia or poorly sampled neoplasms Specimens are often compromised ( eg , air-drying, blood clot) Should be used rarely (<10 % of all salivary gland FNAs)

21. The diagnosis of AUS can be used in the following scenarios: •Squamous, oncocytic , or other metaplastic changes indefinite for a neoplasm •Low cellularity specimens that are suggestive of, but not diagnostic of a neoplasm •Specimens with preparation artifacts hampering distinction between a non-neoplastic and neoplastic process •Mucinous cystic lesions with an absent or very scant epithelial component •Salivary gland lymph nodes or lymphoid lesions which are indefinite for a lymphoproliferative disorder •Reactive and reparative atypia indefinite for a neoplasm

22. Mucinous Cyst Contents Only- Cannot exclude MEC

23. Oncocytic metaplasia vs Neoplasm

24. Reactive vs basaloid neoplasm

25. Category IV: NEOPLASM Diagnostic category reserved for benign neoplasms diagnosed based on established cytomorphologic criteria BENIGN NEOPLASM ENTITIES: Pleomorphic Adenoma Warthin Tumor Oncocytoma Soft Tissue Tumors Lipoma Schwannoma Lymphangioma Hemangioma Benign SUMP

26. Warthin Tumor Oncocytes, chronic inflammation, and cystic debris

27. Pleomorphic Adenoma Matrix-rich types of PA are the easiest.

28. SUMP(Salivary gland neoplasm of uncertain malignant potential) Reserved for: Diagnostic of a neoplasm; however, a diagnosis of a specific entity cannot be made.Amalignant neoplasm cannot be excluded. SUMP ENTITIES: Cellular Basaloid Neoplasm Oncocytoid Neoplasm Neoplasm with Granular and/or Vacuolated or clear cells

29. Basal Cell Neoplasm- DDX basal cell adenoma, AdCC

30. Oncocytoid neoplasm

31. Pleomorphic Adenoma With Atypia or Metaplasia

32. The inability to separate these tumor types with greater accuracy preoperatively is made more frustrating by the fact that the surgical approach can be quite different. The application of a monomorphic cellular basaloid neoplasm with fibrillary stroma was meant to capture pleomorphic adenomas . The finding of hyaline stroma was predicted to identify those neoplasms of higher risk, specifically adenoid cystic carcinoma

33. Category V: Suspicious for Malignancy Aspirates which are highly suggestive of malignancy but not definitive.Atypia concerns malignancy but sample falls short for clear diagnosis. Often high grade carcinomas with limited sampling or other limitation Markedly atypical cells with poor smear preparation, poor cell preservation, fixation artifact , or obscuring inflammation and blood Presence of limited cytologic features of a specific malignant lesion (e.g. adenoid cystic carcinoma, mucoepidermoid carcinoma, acinic cell carcinoma) in an otherwise sparsely cellular aspirate

34. Presence of markedly atypical and/or suspicious cytologic features in a subset of cells but admixed with features of a benign salivary gland lesion. Atypical features can include prominent nucleoli or macronucleoli , anisonucleosis , increased nuclear to cytoplasmic ratio, nuclear molding , prominent nuclear pleomorphism, atypical mitosis, and clumped, coarse chromatin

35. Malignancy: Aspirates which are diagnostic of malignancy Sub-classify into specific types and grades of carcinoma: e.g. low grade vs high grade "Other" malignancies such as lymphomas, sarcomas and metastases are also included in this category and should be specifically designated.

36. Mucoepidermoid Carcinoma

37. HG B-Cell Lymphoma

38. Ancillary Studies: Immunocytochemistry LBC Smears Cell block FISH RT-PCR Next Generation Sequencing

39. Rarely there was enough material on slides or in cell blocks to perform ancillary studies. The use of p63/calponin for myoepithelial cells, mucicarmine/D-PAS for MEC, and CD117/DOG-1 have been shown to have some usefulness in differentiating ACC from polymorphous adenocarcinoma and PA. Greater than 90% of the ancillary studies are performed on cell block material and very less are performed directly on cytologic preparations.

40. Ancillary studies useful in: Basaloid neoplasm Oncocytic neoplasm Metastatic lesions Rule out lymphoma Subtype a high grade carcinoma Subtype a low grade carcinoma

41. t(6:9) MYB oncogene-NFIB transcription factor In salivary gland, this finding by FISH is specific for AdCC

42. Nuclear β catenin in basal cell adenoma:

43. ETV6-NTRK3 rearrangement for difficult cases

44. DOG1 and Acinic Cell Carcinoma SOX-10 and Acinic Cell Carcinoma

45. - Squamous cell carcinoma

46. Mucoepidermoid Carcinoma: IHC is non-specific t(11:19) translocation MECT1/MAML2 –FISH

47. Pitfalls in Milan’s It should be noted that the cumulative risk of malignancy for each diagnostic category may represent an unintended overestimation due to: institutional referral patterns (large academic and referral centers vs.community practice), surgical selection bias based on factors such as large size of the mass, high risk clinical radiologic features.

48. The category of atypia of undetermined significance (AUS) is not well defined. The cases we classified as AUS were those in which the differential was between a retention cyst ( ie , a nonneoplastic lesion) and a low-grade mucoepidermoid carcinoma ( ie , a malignant neoplastic lesion). Therefore, these cases were categorized as atypical because we were not sure even about the neoplastic nature of the lesion. Even members of the Milan group are concerned about the overuse of the term “AUS” as noted in other cytological systems. Still the categories of division are very subjective. Robust testing is still going on in terms of validity and reproducibility

49. Summary: Salivary gland cytology presents many diagnostic challenges The Milan System for Reporting Salivary Gland Cytopathology will help to produce a more uniform diagnostic structure. It is a practical classification system that is user friendly and can be internationally accepted with a useful format for clinicians. Improved communication between treating clinician and pathologist Improved patient care and help in multicentric collaborative study . Availability of IHC and molecular markers can greatly improve the accuracy of salivary gland FNA

50. Reference: Griffith CC, Pai RK, Schneider F, et al. Salivary gland tumor fineneedle aspiration cytology: a proposal for a risk stratification classification. Am J Clin Pathol . 2015;143:839-853 Rossi ED, Faquin WC ; Baloch Z , Barkan CA, Foschini MP,Pusztaszeri M, Vielh P, Daniel FI.The Milan System for Reporting Salivary Gland Cytopathology: Analysis and Suggestions of Initial Survey. Cancer Cytopathology.2017;1-10 Wei S,Lester J,Kathleen T,Zubair WB.Reporting of fine needle aspiration (FNA) specimens of salivary gland lesions: A comprehensive review. Diagnostic Cytopathology. 2017;1–8.

51. The Milan System for Reporting Salivary Gland Cytopathology  1st ed. 2018 Edition