The document discusses the development and benefits of the Milan System for Reporting Salivary Gland Cytopathology. It aims to standardize terminology for salivary gland FNA reports which previously lacked uniformity. The system categorizes specimens as non-diagnostic, non-neoplastic, atypia of undetermined significance, neoplastic (benign or uncertain malignant potential), suspicious for malignancy, or malignant. It is intended to improve communication between pathologists and clinicians, enhance patient care, and facilitate research by allowing standardized data collection across institutions. While validation is ongoing, the system provides a practical framework for uniform reporting of salivary gland cytology.

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

5.  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.

6.  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%.

7.  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)

8.  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

9. 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

10. 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

12. 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.

13. 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)

14. Benign salivary gland elements only

15.  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.

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

17. 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

18. Reactive Lymph Node

19. 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

20. Chronic Sialadenitis
Hypocellular, cohesive basaloid groups, inflammation

21. Granulomatous Sialadenitis

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

23. 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

24. Mucinous Cyst Contents Only- Cannot
exclude MEC

25. Oncocytic metaplasia vs Neoplasm

26. Reactive vs basaloid neoplasm

27. 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

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

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

30. 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

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

32. Oncocytoid neoplasm

33. Pleomorphic Adenoma With Atypia or
Metaplasia

34.  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

35. 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

36.  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

37. 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.

39. Mucoepidermoid Carcinoma

40. HG B-Cell Lymphoma

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

42.  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.

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

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

47. Nuclear β catenin in basal cell adenoma:

48. ETV6-NTRK3 rearrangement for difficult cases

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

50. - Squamous cell carcinoma

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

53. 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.

54.  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

55. 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


56. 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.

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