| Abstract|| |
Context: Many standard books, literatures, and internet described the characteristic lineament of each salivary gland lesion. Nevertheless, there are dozens of disarray, confusion, and unmanageable morphological features regarding proper reporting. To fight with these issues, Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) was introduced in 2018, but still the third category, Atypia of undetermined significance (AUS), poses difficulties for the pathologists and clinicians for a definite interpretation. Aim: The aim is to analyze the risk of neoplasia (RON) and risk of malignancy (ROM) of Milan's category III (AUS) by subdividing into six groups based on cytolomorphology. Settings and Design: The duration of study was from March 2018 to may 2021 with the focus on ROM and RON of all Milan's categories with especial attention on AUS. Methods and Material: Result of total 329 Fine Needle Aspiration Cytology of salivary glands was categorized according to MSRSGC. On the basis of cytomorphology, further subtyping of AUS and its cytohistopathology correlation was done. The ROM and RON of each subtype was analyzed. Statistical Analysis: All data were calculated by existing formulas. Results: Out of 329 aspirates, 24 (07.29%) cases belong to AUS with availability of histology in 13 (54.17%) cases. RON and ROM was 84.62% and 53.85%, respectively. Cases of lymphocytes with nuclear atypia (L-NA) was the most prevalent (29.17%). The RON were 60.00%, 68.57,% 84.62%, 94.87%, 87.50%, 100%, 100% and the ROM were 20.00%, 11.42%, 53.85%, 05.13%, 43.75%, 83.33% and 100% in each Milan's categories I, II, III, IVa, IVb, V, and VI, respectively. ROM was the highest in cystic fluid with nuclear atypia (C-NA) (100.0%), followed by basaloid cells (75%), L-NA (66.675), and SC (50%), but ROM was zero in NA and oncocytic cells. Conclusions: Subgrouping of AUS helps to dissipate the muddiness and provide more exact and reproducible diagnostic and prognostic tool.
Keywords: Atypia of undetermined significance (AUS), Milan system for reporting salivary gland cytopathology (MSRSGC), Risk of malignanacy (ROM), Risk of neoplasia (RON), subgroups
|How to cite this article:|
Karuna V, Vivek V, Singh R, Gupta P, Verma N. MSRSGC: A prospective study of heterogenous group atypia of undetermined significance. Indian J Pathol Microbiol 2022;65:630-6
|How to cite this URL:|
Karuna V, Vivek V, Singh R, Gupta P, Verma N. MSRSGC: A prospective study of heterogenous group atypia of undetermined significance. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 Aug 15];65:630-6. Available from: https://www.ijpmonline.org/text.asp?2022/65/3/630/351614
| Introduction|| |
Milan system (Six tier) was nominated by American Society of Cytopathology (ASC) and the International Academy of Cytology (IAC) in Italy, 2015, and finally published in 2018., Those 6 categories were as follows: category I – nondiagnostic (ND); category II – Non-Neoplastic (NN); category III – atypia of undetermined significance (AUS); category IV – neoplasm (N), subdivided into benign (IVa; B) and salivary gland neoplasm of uncertain malignant potential (IVb; SUMP); category V – suspicious of malignancy (SM); and category VI – malignant (M), respectively., Each category has an implied ROM and a usual scheme of management, though the actual management may depend upon factors other than fine-needle sampling results. The purpose of Milan system for reporting salivary gland cytopathology (MSRSGC) is to delineate patients who require surgical excision of salivary gland from patients who can be managed conservatively. There were several studies describing the usefulness of this system.,, Different ambiguous, inconsistent reporting criteria and nomenclature had been used by pathologists in the past; due to this reason, relevant results did not develop and created confusion among pathologists, surgeons, and radiologists. Present days, the third category (AUS) of Milan system possesses similar difficulties. According to Milan system this category includes <10% of all salivary gland FNACs. Basically, AUS category is a waste-basket of compromised morphology which show morphological overlap between non-neoplastic and neoplastic processes or atypical cytomorphologic feature that excludes the possibility of classifying it as “Non-Diagnostic.”,, The objectives of this study were to better characterize AUS cases by subtyping them based on different cytomorphology and to evaluate the clinical utility of this practice.
| Materials and Methods|| |
This case series was the study of 3.5 years, duration from March 2018 to May 2021, performed in the department of pathology. The study was approved by the ethical committee of institute. Patients referred to our department from various clinical departments and advised for FNAC, all gender, age groups, radiological diagnosed with salivary gland lesions, cooperative patients and fine needle aspirations interpreted as AUS were included, and patients those who had very tiny or ill defined swelling, took conservative treatment, referred to other hospitals, and morbid and physically ill patients were excluded from the study. After taking all needful information, written consents, local and systemic examination, and permission for FNAC from patients, needling procedure was done. No sedatives and local anesthesia were used during procedure. FNAC was performed using standard technique under aseptic precautions with the patients lying/sitting in a comfortable position and pillow under the head if needed. Three passes per case (total 329 cases) was performed using 10 ml syringe with 21-23G, ½, 1, and 1½ inch (according to the size of swelling) needle. No additional tissues/cells were removed from any patient, other than what was necessary for accurate cytological/histological diagnosis. Repeat needling was done in case of bloody material and cystic swelling. At least three smears were prepared on pre-cleaned slides using the standard one-step conventional methods; one for Leishmen and Giemsa (L&G) staining, one (95% ethyl alcohol fixed smear at least for 30 min) for Papanicolaou staining, and rest spare smears for other type of staining if needed. Smears were examined under microscope after mounted with DPX (dextrene polystyrene xylene) and reported according to MSRSGC. Category III (AUS) was further subdivided into six subgroups based on cytological findings: 1 – cases with nuclear atypia, designated NA; 2 – cases with basaloid cells, designated BC; 3 – cases with squamous cells, designated SC; 4 – cases with oncocytic cells, designated OC; 5 – cases of lymphocytes with nuclear atypia, designated L-NA; and 6 – cases of cystic fluid with nuclear atypia, designated C-NA. Received surgical tissue was processed as standard of protocol. Considering histopathology as a gold standard, RON and ROM of each category (resected cases only) and subgroup of AUS (resected cases only) were calculated. RON or ROM was determined by dividing the number of neoplastic cases (benign and malignant), or malignant cases, respectively, by a total number of histopathological follow-up available in the particular category.
| Results|| |
A total of 329 patients were included in this study. The fine needle aspirate result was categorized according to The Milan system by the pathologists. Among them, 158 (48.02%) were males and 171 (51.98%) were females with M:F ratio of 1:1.1. Minimum aged patients were noted in category I, II, and IVb (10–70 years each) and maximum aged patients were noted in category V (30–85 years) and VI (40–85 years). In this study, most of the patients were belonging in the Category IVa (N-152; 46.20%). Most commonly involved gland was parotid (65.05%) followed by submandibular (31.30%) and minor salivary gland (03.65) [Table 1].
Of the total of 329 cases, there were 08 cases (02.43%) of ND (I), 55 cases (16.72%) of NN (II), 29 cases (08.81%) of AUS (III), 152 cases (46.20%) of B (IVa), 35 cases (10.64%) of SUMP (IVb), 11 cases (03.34%) of SFM, and 39 cases (11.86%) of M. Surgical specimens were received in 132/329 (40.12%) cases. Cytohistopathological correlation exhibit concordance in 64/132 (48.48%) cases, whereas discordant in 68/132 (51.52%) cases. Out of later cases, 42 (31.82%) cases were as NN + B and 26 (19.70%) cases were as malignant. Overall, RON was 85.61% (113/132) and ROM was 33.33% (44/132) in resected lesions. The RON/ROM for each category was ND-60.00 (3/5)/20.00%(1/5), NN-68.57 (24/35)/11.43%(4/35), AUS-84.62 (11/13)/53.85%(7/13), B-94.87 (37/39)/05.13%(2/39), SUMP-87.50 (14/16)/43.75% (7/16), SFM-100% (6/6)/83.33%(5/6), and M-100% (18/18)/100%(18/18) [Table 2].
|Table 2: Representing concordant and discordant cases after histopathological diagnosis|
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AUS accounted for 08.82% (29/329) of the FNA diagnoses and 54.17% (13/29) cases underwent surgical procedure. Among these, 15.39% (2/13) were non-neoplastic lesions (Chronic sialadenitis); 30.78% (4/13) were benign neoplasms, including pleomorphic adenomas (2/4) and warthin tumor (2/4); and 53.83% (7/13) were malignant neoplasms including salivary duct carcinoma (SDCA; 1 case) [Figure 1]a and [Figure 1]b; Mucoepidermoid carcinoma (MEC; 3 cases) [Figure 1]c and [Figure 1]d; adenoid cystic carcimona (AdCC; 1 case) [Figure 2]a and [Figure 2]b; acinic cell carcimona (ACC; 1 case) [Figure 2]c and [Figure 2]d; and basal cell adenocarcinoma (BCadC; 1 case) [Figure 1] and [Figure 2]. In the category of AUS, most of the cases belonged to the subgroup L-NA (N-8/29; 27.59%) followed by BC (N-5/29; 20.69%), NA and SC (N-05/29; 17.24% each), C-NA (N-03/29; 10.34%) and OC (N-02/29;06.90%). The RON/ROM for each subgroup was NA-100/00.00%; BA-75/75%; SC-50/50%; OC-100/00.00%; L-NA-100/66.67%; and C-NA-100/100% [Table 3].
|Figure 1: (a and b) Subgroup BC: Case of mildly atypical basaloid like cells with nuclear crowding (Giemsa, x400) showing features of salivary duct carcinoma in histology (H and E, ×40) and (c and d) Subgroup SC: squamous cells with atypical morphology raises a differential diagnosis of squamous cell carcinoma (Giemsa, x400) histopathology of same case shows features of mucoepidermoid carcinoma (H & E, x100)|
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|Figure 2: (a and b) Subgroup BC: groups of basaloid-appearing cells with enlarged cells over a hyaline background indefinite for a neoplastic process (Giemsa, ×400) and histopathology of same case shows features of Adenoid cystic carcinoma (H and E, ×100); (c and d) Subgroup L,NA : Lymphoid cells with atypical features (Giemsa, x 100) diagnosed as acinic cell carcinoma in histology (H &E, x 100)|
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|Table 3: Subcategories of MSRSGC third category of atypia of undetermined significance (AUS)|
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| Discussion|| |
With its inception, The MSRSGC established a uniform, tiered reporting system for salivary gland FNA specimens. Using MSRSGC, the cytopathologist can communicate FNA interpretations to the referring physician in terms that are succinct, unambiguous, and clinically useful. But still, questions have arisen over the proper use of the diagnostic categories and the implied risks of malignancy. Present study also suffered to this issue as [Table 4] showed category III (AUS) and IVb (SUMP) have wide range of differences in ROM after cyto-histopathological reviews. However, categories I, II, Iva, and V demonstrated almost similarities to the actual ROM of the MSRSGC and other studies.,,,,,,
|Table 4: Details of risk of malignancy and comparison with Milan System for Reporting Salivary Gland Cytopathology and other studies|
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Category III (AUS) which is reserved for cases that lacks either qualitative or quantitative cytomorphologic features to be diagnosed with confidence as either non-neoplastic or neoplastic, for example, presence of Squamous, oncocytic, and other cell type with architectural and/or nuclear atypia. Several types of secondary alteration can be superimposed on a wide variety of salivary gland neoplasms. These include presence of lymphoid cells, cystic change, clear cell change, oncocytic alterations, sebaceous differentiation, mucin production, etc. These lesions are subjected to repeat FNA (Fine needle aspiration), biopsy, surgery, or molecular testing., Many situations like unavailability/abnormal molecular testing or inadequate repeat aspirates create difficulty in management due to lack of proper diagnosis. That also impacts mortality due to effect on malignancy rate. We searched many literatures showed wide range of differences in the ROM or RON ranging from 0.0% to 100%. In our study, the ROM for excise AUS nodules was 53.85%, while the standard proportion of patients with AUS is 20%. Comments on actual or various malignancy rates of this category are challenging. The reason behind this point might be overuse and minorities of cases undergo excision.,,,,,
To overcome limitations of this category, we tried to subcategorize AUS further using a six-tiered classification based on first impression of an aspirate. To the best of our knowledge, this is the first case study over AUS category of the Milan system for reporting salivary gland cytopathology, being reported.
The first group, designated as NA, cases of occasional cells has atypia that include mild nuclear enlargement, nuclear grooves, inclusions, or multi-nucleation. These features might be due to reactive changes, malignant transformation or metastatic tumors., In my research, 05/29 (17.24%) cases belong to this subcategory with the atypical features of increased cytoplasm and nuclear pleomorphism with prominent nucleoli. Out of 5 cases, two under went surgical resection and both were diagnosed as pleomorphic adenoma with 0% of ROM and 100% of RON.
Benign lesion with malignant component is the major reason of these atypical cells. As mentioned in many literatures, that epithelial malignancy in carcimona ex pleomorphic adenoma can originate in the form of mucoepidermoid carcinoma, squamous cell carcinoma, adenosquamous cell carcinoma, Adenoid cystic carcinoma, epithelial myoepithelial carcinoma, sarcomatoid carcinoma, acinic cell carcinoma, clear cell carcinoma, and myoepithelial carcinoma., In above scenario, histology is necessary to make actual diagnosis. In this study, two cases of first subcategory (NA) diagnosed as benign lesion denote the importance of histopathology. Pleomorphic adenoma is a benign tumor that has three main morphological features, which are as follows: capsule, parenchyma, and stroma. But malignant component designated as CAEXPA (carcinoma ex mixed tumour or pleomorphic adenoma) can be noted in 5% to 25% cases of all these glands.
Cases with basaloid cells were the second common subgroup in this study (20.69%). The basaloid cells described as small, uniform cells with little cytoplasm, have rounded nuclei located at the periphery. Presence of basaloid cells is a challenging point for the cytopathologists. These cells show their presence in many benign and malignant lesions, even in the non-neoplastic lesion. For examples: Pleomorphic adenoma, basal cell adenoma, basal cell adenocarcinoma, adenoid cystic carcinoma, basaloid squamous cell carcinoma, metastatic basal cell carcinoma, metastatic squamous carcinoma, and small cell carcinoma.,, So, all cytomorphological features for a particular lesion should be kept in mind to differentiate from basaloid neoplasma. In my research, 04/06 cases of this subgroup were correlated with histopathology and diagnosed as chronic sialadenitis, SDCA, AdCC, and BCAdC, respectively, with the rate of 75% malignancy. This finding has proven that basaloid cells might be present in both non-neoplastic and neoplastic lesions mainly in malignancy as resulted in this study.
Usually number of basaloid cells is less in chronic sialadenitis, but on cytology 01 case of this study shows atypical basaloid cells that made it difficult for categorization as non-neoplastic and neoplastic. Study of Prakesh et al. reported that one case of chronicsialadenitis showed features that cannot rule out malignancy., Salivary duct carcinoma is a rare tumor with incidence of 1% to 3% of all malignant salivary gland tumors. Diagnosis of this tumor is a challenge on FNAC because bland cytomorphologic features in some cases may lead to a false-negative interpretation., In my study, one case of AUS diagnosed as salivary duct tumor on histology had few atypical basaloid cells on cytology. Differentiation between basal cell adenoma and basal cell adenocarinoma are challenging as both tumor have basaloid cells with different morphologic features. Basal cell adenoma have monomorphic cell with fibrillary material, however, basal cell adenocarinoma have significant cytologic atypia, hyperchromasia, and high nuclear-to-cytoplasmic ratio. Basal cell adenoma can be also confused with adenoid cystic carcinoma as discussed in the case report of Arjun et al. The confusing point of that study was patient's age and hyaline globules around which basaloid cells were arranged that is the characteristic feature of adenoid cystic carcinoma.,
Third group is used for aspirates in which occasional atypical squamous cells was present. Aspirates with squamous cells may be noted in non-neoplastic, benign to malignant lesion such as necrotizing sialometaplasia, pleomorphic adenoma, warthin tumor, squamous cell carcinoma, mucoepidermoid carcinoma, etc. Two cases of this subgroup underwent surgery and reported as non-neoplastic (chronic sialadenitis) and neoplastic (Mucoepidermoid carcinoma) lesion, respectively. On review of literature, similar finding was also reported by other authors as well.,,,
Case with oncocytic cells is a smallest fourth subcategory of AUS. Oncocytic cells described as large, polygonal cells have small round central nucleus, indistinct nucleoli, and microgranular eosinophilic cytoplasm rich in mitochondria., In this study, only two cases belong to this subcategory. Low cellularity, epithelial cells morphology that mimicking oncocytic cell, and to reduce the rate of false positive cases, following situations were noted to categorize these cases as AUS. Out of 02 cases, one case reported as warthin's tumor histopathologically. The ROM is zero and RON (100%) was high in this group. Thereby, the presence of oncocytic cells indicated toward benign neoplasm in this study. Warthin's is a common benign tumor after pleomorphic adenoma and characterized by presence of oncocytic cells with lymphocytes cytolomorphogically. On histology, the unique features are bilayered oncocytic cells with columnar cells superficially and cuboidal cells basally.,, Presence of oncocytic cells also raise the possibility of parotid cyst, oncocytosis (oncocytic metaplasia), pleomorphic adenoma, sialadenosis, warthin's, basal cell adenoma, clear cell carcinoma, oncocytoma, acinic cell carcinoma, etc. as reported in many literatures.,,,,
Cases of lymphocytes with lymphoid and atypical epithelial cell were included in the fifth subgroup. Most of the cases of AUS belong to this subgroup. There were 08 (27.59%) cases. Three cases underwent surgery, out of which, one case was reported as warthin's tumor, second as mucoepidermoid carcinoma (MEC), and third as acinic cells carcinoma (ACC). The RON and ROM was 100% and 66.67%, respectively. Differential diagnosis of Lymphoid-Rich Epithelial Lesions of the Salivary Gland includes: Non-neoplastic: Chronic sialadenitis, Chronic sclerosing sialadenitis (Kuttner tumor), Lymphoepithelial sialadenitis (benign lymphoepithelial lesion), Benign lymphoepithelial cysts; Benign: Warthin tumor and Sebaceous lymphadenoma; Malignant: MEC, ACC, Sebaceous lymphadenocarcinoma, Lymphoepithelial-like carcinoma and Metastatic lesions.,,,,
FNAC findings of first two cases showed occasional atypical lymphoid cells and later one showed lymphoid cells with epithelial cell atypia that cannot rule out malignancy. In this study, the authors analyze that lymphoid cells with atypia can be present in neoplastic lesion, including benign and malignant. Mardi et al. reported a case that revealed uniform atypical cells over a background of mixed population of lymphoid cells on cytology and diagnosed as ACC histologically. Dhar et al. reported a case of papillary cystic ACC on histology, which was previously diagnosed as chronic sialadenitis on cytology. Both these studies indicate that on cytology presence of atypical cells with lymphocytes can be misinterpreted and histopathology is the gold standard for this type of cases. Presence of scattered bare tumor nuclei of damaged acinar cells are not to be mistaken for lymphocytes.
On FNAC, cystic fluid came out and smears prepared from centrifuged sediment showing few cells with nuclear atypia were included in the six subcategories. In C,NA subcategory of AUS, 01 out of 3 cases was reported as MEC on histology with the ROM 100%. Study of Geetha et al. reported that one case of low grade MEC was mistaken as mucus cyst on FNAC. Case report of Swathi et al. yielded straw colored fluid from right cheek swelling but on histology presence of clear and pleomorphic cells with hyperchromasia, different degrees of atypia highly was hightly suggestive of intermediate grade MEC. Cystic degenerative changes can be noted in non-neoplastic and neoplastic lesion including both benign and malignant as mentioned in previous publications. Cystic lesion comprises approximately 3% of all salivary gland tumors and at least one-third are neoplastic and difficult to diagnose on cytology due to low or sparse cellularity, lack of experience, and observer bias, later interpreted as false negative or false positive cases.,,,,,
Result of this study emphasizes that AUS is a robust diagnostic category that comprised 8.81% of the total cases of this study, which were comparable with the normal range (<10%) as mentioned in the MSRSGC. Subtyping of AUS cases demonstrated differential ROMs for the BC (75%), SC (50.0%), L-NA (66.67%), and C-NA (100%) with 00.00% in NA and OC subgroup, respectively. So, AUS requires further standardization and subgrouping in order to eliminate the diagnostic and prognostic variability associated with it. We have proposed one such system of subgrouping which may help dispel the confusion generated by an AUS report, to facilitates clinical stratification, and provide both pathologists and surgeons with a more exact and reproducible diagnostic and prognostic tool.
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Department of Orthopedics, Apusnova Hospital, Meerut, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]