[Salivary gland tumors: 2022 WHO blue book and beyond]. / Tumeurs des glandes salivaires : OMS 2022 et au-delà.

In 2022, the 5th edition of the WHO classification of Head and Neck tumors was published online. In the salivary gland chapter, a new benign entity, the keratocystoma, was introduced. The sclerosing polycystic adenosis has been recognized as tumoral and is now termed sclerosing polycystic adenoma. The striated duct adenoma now has its own dedicated chapter. Additionally, a new variant of pleomorphic adenoma, termed "canalicular adenoma-like," has been incorporated. Regarding malignant tumors of the salivary glands, significant doubts now exist regarding the actual existence of oncocytic carcinoma, which has been reclassified among emerging entities. Two new malignant entities have also emerged: microsecretory adenocarcinoma and microcystic sclerosing adenocarcinoma. Finally, primary mucinous adenocarcinoma of the salivary glands has been acknowledged as a distinct entity.

[Changes of the World Health Organization 2022 classification (5th edition) of salivary glands tumors].

Pathological diagnosis of salivary gland tumors is one of the most challenging areas in all head and neck surgical pathology. The classification of salivary gland tumors was updated in the 5th edition of the World Health Organization Classification of Head and Neck Tumours, most of which were based on their molecular pathological characteristerics. This new classification features a description of several new entitiesamong benign and malignant neoplasms, salivary gland tumors with updated naming or diagnostic criteria, and lesions deleted from this section, etc.This present review focuses on the updates and changes in the new classification of salivary gland tumors, and provides some reference for head and neck surgeons and pathologists.

Utility of the Milan system for reporting salivary gland cytopathology during rapid on-site evaluation (ROSE) of salivary gland aspirates.

OBJECTIVE: Rapid on-site evaluation (ROSE) is a fine needle aspiration (FNA) technique for ensuring sampling adequacy and triaging samples. The Milan system for reporting salivary gland cytopathology (MSRSGC) is a standardised reporting system which aims to improve risk stratification. There is scant literature on the diagnostic value and agreement of MSRSGC on ROSE with final cytological diagnosis in salivary gland FNAs. We aimed to assess the concordance of MSRSCG categorisation and diagnosis on ROSE with final cytological and histological diagnosis. METHODS: This prospective study included consecutive salivary gland FNAs for which ROSE was performed over a six-month period. MSRSGC category and diagnosis on ROSE were compared with the final cytological diagnosis and MSRSGC category, and histopathological diagnosis, where available. RESULTS: Sixty salivary gland aspirates were included. The adequacy rate with ROSE was 100%. Using the MSRSGC classification during ROSE, 26 (43.2%) samples were categorised as benign neoplasm, 21 (35%) as malignant neoplasm, 9 (15%) as non-neoplastic, and one each (1.7%) belonged to the remaining four categories. MSRSGC categorisation on ROSE concurred with final the cytological diagnosis in 58/60 cases (96.7%). Discrepancies in MSRSGC categories on ROSE included one atypia of undetermined significance with final report as non-neoplastic, and one non-diagnostic as suspicious for malignancy. Good correlation of MSRSGC categories on ROSE with final histopathological diagnosis (88.9% concordance) was also noted. CONCLUSIONS: MSRSGC on ROSE shows good concordance with final cytology and histopathology diagnosis, indicating that categorisation according to MSRSGC has utility in ensuring that adequate material is obtained and triaged appropriately for the diagnosis of salivary gland aspirates.

Whole-Genome Sequencing of Common Salivary Gland Carcinomas: Subtype-Restricted and Shared Genetic Alterations.

PURPOSE: Salivary gland carcinomas (SGCs) are pathologically classified into several widely diverse subtypes, of which adenoid cystic carcinoma (ACC), mucoepidermoid carcinoma (MEC), and salivary duct carcinoma (SDC) are the most commonly encountered. A comparative genetic analysis of these subtypes provides detailed information on the genetic alterations that are associated with their tumorigenesis and may lead to the identification of biomarkers to guide tumor-specific clinical trials. EXPERIMENTAL DESIGN: Whole-genome sequencing of 58 common SGCs (20 ACCs, 20 SDCs, and 18 MECs) was performed to catalog structural variations, copy number, rearrangements, and driver mutations. Data were bioinformatically analyzed and correlated with clinicopathologic parameters, and selected targets were validated. RESULTS: Novel and recurrent type-specific and shared genetic alterations were identified within and among 3 subtypes. Mutually exclusive canonical fusion and nonfusion genomic alterations were identified in both ACC and MEC. In ACCs, loss of chromosome 12q was dominant in MYB or MYBL1 fusion-positive tumors and mutations of NOTCH pathway were more common in these fusion negatives. In MECs, CRTC1-MAML2 fusion-positive tumors showed frequent BAP1 mutation, and tumors lacking this fusion were enriched with LRFN1 mutation. SDCs displayed considerable genetic instability, lacked recurrent chromosomal rearrangements, and demonstrated nonoverlapping TP53 mutation and ERBB2 amplification in a subset of tumors. Limited genetic alterations, including focal amplifications of 8q21-q23, were shared by all subtypes and were associated with poor survival. CONCLUSIONS: This study delineates type-specific and shared genetic alterations that are associated with early phenotypic commitment and the biologic progression of common SGCs. These alterations, upon validation, could serve as biomarkers in tumor-specific clinical trials.

Salivary Mucinous Adenocarcinoma Is a Histologically Diverse Single Entity With Recurrent AKT1 E17K Mutations: Clinicopathologic and Molecular Characterization With Proposal for a Unified Classification.

Mucin-producing salivary adenocarcinomas were historically divided into separate colloid carcinoma, papillary cystadenocarcinoma, and signet ring cell carcinoma diagnoses based on histologic pattern, but have recently been grouped together in the adenocarcinoma not otherwise specified category. It is currently unclear if these tumors represent 1 or more distinct entities and how they are related to well-circumscribed papillary mucinous lesions with recurrent AKT1 E17K mutations that were recently described as salivary intraductal papillary mucinous neoplasm. Here, we sought to evaluate the clinicopathologic and molecular features of salivary mucinous adenocarcinomas to clarify their classification. We identified 17 invasive mucin-producing salivary adenocarcinomas, 10 with a single histologic pattern, and 7 with mixed patterns. While most tumors demonstrated papillary growth (n=15), it was frequently intermixed with colloid (n=6) and signet ring (n=3) architecture with obvious transitions between patterns. All were cytokeratin 7 positive (100%) and cytokeratin 20 negative (0%). Next-generation sequencing performed on a subset demonstrated recurrent AKT1 E17K mutations in 8 cases (100%) and TP53 alterations in 7 cases (88%). Of 12 cases with clinical follow-up (median: 17 mo), 4 developed cervical lymph node metastases, all of which had colloid or signet ring components. Overall, overlapping histologic and immunohistochemical features coupled with recurrent AKT1 E17K mutations across patterns suggests that mucin-producing salivary adenocarcinomas represent a histologically diverse single entity that is closely related to tumors described as salivary intraductal papillary mucinous neoplasm. We propose a unified mucinous adenocarcinoma category subdivided into papillary, colloid, signet ring, and mixed subtypes to facilitate better recognition and classification of these tumors.

Intraductal Carcinomas of the Salivary Gland.

Intraductal carcinoma of the salivary gland is a rare tumor characterized by intracystic proliferations of papillary, cribriform, and solid architecture of small uniform epithelial cells, reminiscent of ductal carcinoma in situ of the breast. Recent literature has identified 4 distinctive subtypes: the intercalated duct type, apocrine type, mixed/hybrid type, and oncocytic type, all with corresponding immunohistochemical and molecular findings. Although these tumors are typically in situ, as evidenced by a retained myoepithelial layer, they can demonstrate minimal invasion or, rarely, widespread invasive growth. Their overall prognosis is favorable, with few reported cases of recurrences and nodal metastases but no evidence of distant metastases.

Genomic Analysis of Salivary Gland Cancer and Treatment of Salivary Gland Cancers.

Salivary gland cancer is a heterogenous group of tumors that presents challenges with both diagnosis and therapy. Recent advances in the classification of salivary gland cancers have led to distinct histologic and genomic criteria that successfully differentiate between cancers with similar clinical behavior and appearance. Genomic abnormalities have led to the emergence of targeted therapies being used in their therapy with drastic improvements in outcomes as well as reductions in treatment-related toxicity. Dramatic results seen with molecular targets, such as HER2, TRK, and others, indicate that this approach has the potential to yield even better treatments for the future.

Sialadenoma Papilliferum.

Sialadenoma papilliferum (SP) is a rare, benign salivary gland neoplasm sharing similar histopathologic features and harboring the same genetic alterations, BRAF V600E or HRAS mutations, with syringocystadenoma papilliferum. SP most commonly occurs in the hard palate and in older adults. Clinically, SP is most likely to be diagnosed as a squamous papilloma. Microscopically, SP shows an exophytic papillary epithelial proliferation and a contiguously endophytic ductal proliferation. Two distinct subtypes are identified: classic SP and oncocytic SP. Conservative surgical treatment seems to be adequate with a low recurrence. SOX10 immunohistochemistry and BRAF analysis may be useful in differential diagnosis.

Contribution of small tissue biopsy and flow cytometry to preoperative cytological categorization of salivary gland fine needle aspirates according to the Milan System: Single center experience on 287 cases.

BACKGROUND: Milan system for reporting salivary gland cytopathology (MSRSGC) was proposed to provide a standardized reporting system for salivary gland fine needle aspiration biopsies. Modified Menghini type semi-automatic aspiration biopsy needles provide small tissue fragments (STFs), as well as cellular smears, and immunohistochemical and molecular studies can be performed using the STFs. AIMS: We aimed to evaluate the contribution of STFs and ancillary techniques to pre-operative diagnosis of salivary gland lesions. MATERIALS AND METHODS: In this study, smears of 287 cases with histopathological correlation were re-reviewed and assigned to one of the MSRSGC categories. In the second step, histopathological and immunohistochemical findings in STFs were evaluated together with cytological findings. Final diagnoses were obtained with the inclusion of flow cytometry (FC) results when available. Risk of malignancy (ROM) was calculated for each diagnostic category. RESULTS: In the evaluation based on smears, a specific diagnosis could be obtained in 64.8% of the cases. ROMs were 0% for nondiagnostic (ND), 5.6% for non-neoplastic (NN), 55% for atypia of undetermined significance (AUS), 0.6% for benign neoplasm (BN), 27.8% for salivary gland neoplasm of uncertain malignant potential (SUMP), and 100% for suspicious for malignancy (SFM) and malignant (M) categories. With the addition of histopathological and immunohistochemical findings and FC results, a specific diagnosis could be obtained in 75.2% of the cases. ROMs were 0% for ND, 4.5% for NN, 53.8% for AUS, 0.6% for BN, 0% for SUMP, and 100% for SFM/M categories. CONCLUSIONS: STFs contribute correct categorization of salivary gland lesions. The major contribution of ancillary methods is in the SUMP category.

Utility of the Milan system for reporting salivary gland cytopathology: A retrospective 5 years study.

BACKGROUND: Fine-needle aspiration cytology (FNAC) is an established technique for preoperative diagnosis of salivary gland lesions; however, lack of a uniform reporting system has been a handicap. The main aims of this study were to evaluate the utility of the - "The Milan System for Reporting Salivary Gland Cytopathology" (MSRSGC) and ascertain the risk of malignancy (ROM) for each category. METHODS: All salivary gland FNACs over 5 years (January 2014-December 2018) were reviewed and assigned a diagnostic category from the MSRSGC. Clinical data were taken from Cytology records. Cytodiagnosis was correlated with histopathology wherever available and ROM was calculated. RESULTS: A total of 120 salivary gland FNACs were studied. Age ranged between 5 and 85 years, male:female ratio was 2:1 and parotid was the commonest gland aspirated. Cases were reclassified as I non-diagnostic (2.5%), II non-neoplastic (15%), III atypia of uncertain significance-AUS (1.7%), IV A neoplasm benign (50%), IV B neoplasm of uncertain malignant potential (12.5%), V suspicious for malignancy (5%), and VI malignant (13.3%). Follow-up was available in 70 (58.3%) cases. The sensitivity, specificity, negative predictive value, and positive predictive value were 92.3%, 100%, 100%, and 98.27% respectively. ROM was non-neoplastic (0%), AUS (50%), neoplasm benign (0%), neoplasm of uncertain malignant potential (28.6%), suspicious for malignancy (100%), and malignant (100%). CONCLUSION: Salivary gland FNAC is a reliable diagnostic tool and the "Milan system" will further increase FNA reliability, help risk stratification, and improve patient care.

Prediction of Minor Salivary Gland Carcinoma: A Novel Nomogram and Risk Classification System for Overall Survival and Cancer-Specific Survival.

OBJECTIVE: Minor salivary gland carcinoma (MiSGC) is rare, and the understanding of this disease is insufficient. This study aimed to identify independent risk factors and develop a nomogram for evaluating the overall survival (OS) and cancer-specific survival (CSS) of patients with MiSGC. STUDY DESIGN: Retrospective cohort study. SETTING: SEER database (Surveillance, Epidemiology, and End Results). SUBJECTS AND METHODS: We collected data from patients diagnosed with MiSGC between 2004 and 2015 from the SEER database. According to patient registration, all patients were randomly allocated to training sets and validation sets (2:1). Then, Kaplan-Meier product limit curves and Cox proportional hazard regressions were performed to estimate the prognostic effect of variables. Nomograms based on Cox proportional hazard regressions were established to estimate 3- and 5-year OS and CSS. Finally, the nomogram was developed by the training set, and validation was performed with the concordance index, calibration curves, and decision curve analyses. RESULTS: In total, 1787 MiSGC cases were registered in SEER. The concordance index for internal validation of OS and CSS prediction was 0.842 and 0.816; that of external validation was 0.871 and 0.831. The calibration plots showed good consistency between nomogram prediction and actual survival. The decision curve analysis showed substantial net benefits of the new predictive model. CONCLUSIONS: We constructed nomograms and a corresponding risk classification system predicting the OS and CSS of patients with MiSGC. These tools can generate simple-to-use clinical risk grouping and determine the relationship between adjuvant therapy and active surveillance.

The impact of nodal status in major salivary gland carcinoma: A multicenter experience and proposal of a novel N-classification.

OBJECTIVES: Despite differences in oncological behavior, the 8th edition of AJCC TNM staging currently proposes the same N-classification for major salivary glands (MSG) carcinoma and squamous cell carcinoma of the upper aerodigestive tract. The present study aims to investigate a more reliable definition of N-categories for MSG carcinoma. MATERIALS AND METHODS: A retrospective multicenter study was performed, including 307 patients treated for primary MSG carcinoma from 1995 to 2019. Outcome measures included overall survival (OS), disease specific survival, and local, regional, and distant recurrence. Survival analysis was performed using log-rank test and Cox proportional-hazards model. Overall number (ON) and largest diameter (LD) of nodal metastases, including intra-parotid metastases, were considered to develop three novel proposals of N-classification; their performance were compared with the current TNM staging using Akaike information criterion (AIC), Bayesian information criterion (BIC), and Nagelkerke pseudo-R2. RESULTS: Intra-parotid nodes, ON and LD of nodal metastases emerged as major prognosticators for OS, while extra-nodal extension did not impact on any survival. The current N-classification did not show a satisfactory OS stratification. Three novel N-classifications were developed according to number of metastatic nodes (0 vs 1-3 vs ≥ 4) and/or their maximum diameter (<20 mm vs ≥ 20 mm). They all showed better accuracy in OS stratification, and achieved better AIC, BIC and Nagelkerke pseudo-R2 indices when compared to current N-classification. CONCLUSION: All the proposed N-classifications improved OS stratification and could help in defining a specific N-classification for MSG carcinoma. Their validation and assessment in an external cohort is needed.

The Decline of Salivary Adenocarcinoma Not Otherwise Specified as a Tumor Entity: Reclassification Using Contemporary Immunohistochemical Profiling and Diagnostic Criteria.

The classification of salivary gland carcinomas has become increasingly specific over the last decade with the definition of new tumor types, documentation of novel molecular and immunohistochemical findings, and development of more refined diagnostic criteria. In this setting, it is unclear how many salivary tumors still cannot be easily categorized-and whether such tumors represent undifferentiated malignancies or include additional definable entities. Relying largely on current classification schemes and contemporary immunohistochemical panels, we reassessed salivary tumors previously diagnosed as adenocarcinoma, not otherwise specified (ACA NOS) from 2 large academic medical centers. Fifty-seven ACA NOS (72%) could be reclassified as more specific entities including 31 salivary duct carcinomas (39%), 7 polymorphous adenocarcinomas (9%), 5 epithelial-myoepithelial carcinomas (6%), 4 myoepithelial carcinomas (5%), 4 secretory carcinomas (5%), 1 acinic cell carcinoma (1%), 1 basal cell adenocarcinoma (1%), 1 intraductal carcinoma (1%), and 1 clear cell carcinoma (1%) as well as 2 metastatic squamous cell carcinomas (3%). Of reclassified cases, 21 (37%) represented variant histologies within these categories. ACA NOS comprised 11% of salivary malignancies before reclassification, but only 4% after reclassification. The remaining 22 ACA NOS demonstrated heterogeneous features, with an association between histologic grade and clinical outcome. In effect, ACA NOS is becoming a bygone entity as modern classification schemes and ancillary techniques now permit more specific typing of a majority of these tumors, potentially facilitating more specific prognostication and treatment. Additional distinctive entities such as mucinous adenocarcinoma may still be definable within the ACA NOS category.

A novel clinically-oriented classification of fine-needle aspiration cytology for salivary gland tumors: a 20-year retrospective analysis of 1175 patients.

BACKGROUND: When determining treatment strategy for a salivary gland tumor, assessing histology and malignancy grade before surgery is essential. Several new diagnostic classification systems for salivary gland cytology have recently been proposed. However, none incorporate histology and grade of malignancy. METHODS: We developed a new cytology classification system that incorporates histology and grade of malignancy of salivary gland tumors (OMC classification), consisting of 11 categories. Our OMC classification was applied to 1175 patients who had preoperative cytology and confirmed final pathological diagnosis available from the past 20 years at our hospital (benign tumor: 981 patients, malignant tumor: 194 patients). RESULTS: Based on the cytology, 729 patients (62.0%) had benign histology (Category 4-1), and 87 patients (7.4%) were diagnosed with grade of malignancy (Category 6-3 + 6-4). Based on the final pathological diagnosis, the accuracy rate of Category 4-1 and Category 6-3 + 6-4 of our classification system was 93.4% and 88.5%, respectively. CONCLUSION: Based on the correct diagnosis rate, the inclusion of histology and grade of malignancy in the salivary gland cytology classification was considered feasible. Thus, the OMC classification system is considered a useful tool when determining the treatment strategy for a salivary gland tumor.

Putting morphology to the test: An established classification scheme reliably stratifies salivary gland cytology by risk of malignancy with substantial interobserver agreement.

BACKGROUND: The Milan System for Reporting Salivary Gland Cytopathology describes several salivary gland fine-needle aspiration cytology (SGFNAC) morphologies developed by Griffith et al. Basaloid neoplasms are pleomorphic (PB) or monomorphic with fibrillary (MBFib), hyaline (MBHy), or other (MBOther) matrix. Oncocytoid neoplasms can be pleomorphic (PO), demonstrate granular and/or vacuolated cytoplasm (OGV), or be monomorphic with mucinous (MOMuc), cystic (MOCyst), or other (MOOther) background. In the current study, the authors explore interobserver agreement (IOA) and risk of malignancy (ROM) for these subcategories. METHODS: The study included 169 SGFNAC cases with surgical follow-up. Four reviewers categorized these cases using the criteria of Griffith et al. with consensus determined by majority. For all morphologic categories, IOA (using the Fleiss kappa) and ROM were calculated. RESULTS: ROMs for basaloid categories were: PB: 100% (1 of 1 case); MBHy: 71.4% (5 of 7 cases); MBFib: 50.0% (3 of 6 cases); and MBOther: 47.4% (9 of 19 cases). ROMs for oncocytoid neoplasms were: OGV: 100% (10 of 10 cases); MOMuc: 92.3% (12 of 13 cases); PO: 88.9% (8 of 9 cases); MOOther: 33.3% (5 of 15 cases); and MOCyst: 0 (0 of 1 case). The system demonstrated substantial agreement overall (κ = 0.69). For basaloid neoplasms, the IOA results were: MBHy: κ = 0.59; MBFib: κ = 0.41; MBOther: κ = 0.41; and PB: κ = 0.11. For oncocytoid neoplasms, the IOA results were: MOMuc: κ = 0.88; OGV: κ = 0.67; PO: κ = 0.63; MOOther: κ = 0.57; and MOCyst: κ = 0.18. CONCLUSIONS: The SGFNAC scheme proposed by Griffith et al. and incorporated into the Milan System for Reporting Salivary Gland Cytopathology demonstrated substantial agreement overall, with particularly high agreement for the MOMuc, OGV, PO, and MBHy categories. The PB and MOCyst categories demonstrated slight agreement and may be improved by revised criteria. The PB, PO, MOMuc, and OGV categories demonstrated high ROM, and the latter 2 categories might best be classified as suspicious for malignancy.

Application of the Milan System for Reporting Salivary Gland Cytopathology: A 10-Year Experience in a Single Japanese Institution.

OBJECTIVE: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) is a recently published evidence-based categorization system for salivary gland fine-needle aspiration (FNA). We applied MSRSGC to Japanese cases and evaluated its utility. STUDY DESIGN: A total of 480 FNA cases were reviewed. We recategorized each case into one of the MSRSGC categories. The risk of neoplasm (RON) and the risk of malignancy (ROM) for each diagnostic category in MSRSGC, and the sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) for malignancy and for neoplasms were calculated for cases with histological follow-up. In addition, the overall ROM (O-ROM) was calculated for all FNA cases. RESULTS: RON, ROM, and O-ROM rates were as follows - non-diagnostic: 51.3, 5.1, and 1.0%; non-neoplastic: 0, 0, and 0%; atypia of undetermined significance: 83.9, 12.9, and 7.3%; neoplasm, benign: 100, 0, and 0%; salivary gland neoplasm of uncertain malignant potential: 100, 32.1, and 23.7%; suspicious for malignancy: 100, 85.7, and 60%; and malignant: 100, 100, 81.8%. The sensitivity, specificity, and accuracy with (without) indeterminate cases for malignancy were 65 (100), 99 (99), 92% (99%) and PPV and NPV were 96 and 100%, respectively, and those for neoplasms were 84 (100), 100 (100), 85% (100%), and PPV and NPV were 100 and 100%, respectively. CONCLUSIONS: The MSRSGC is useful for stratification of ROM and for promoting the performance of salivary gland FNA. The MSRSGC could be easily introduced in Japan and may improve the Japanese salivary gland FNA status.

Interobserver variability between cytopathologists and cytotechnologists upon application and characterization of the indeterminate category in the Milan System for Reporting Salivary Gland Cytopathology.

BACKGROUND: The indeterminate categories in the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) are diagnostically challenging because of inherent heterogeneity and complexity, with wide interobserver variability (IOV). Herein, the authors explore the concordance rate (CR) between cytopathologists (CPs) and cytotechnologists (CTs) in interpreting indeterminate salivary gland lesions using the MSRSGC. METHODS: Between 2011 and 2016, 86 indeterminate fine-needle aspirations had slides available for review, of which 48 had follow-up. Four CPs and 2 CTs performed an independent, blinded review of these slides and categorized them according to the MSRSGC. The CRs between CTs and CPs with the final sign-out cytopathologist (FCP) were assessed, and interobserver agreement was categorized into uniform, majority, divided, minimal, or no agreement. RESULTS: The overall CR with the FCP ranged from 48.8% to 60.5% for CPs and from 22.1% to 36% for CTs. IOV κ scores for the entire group were 0.314 and, with the FCP as the reference, ranged from 0.403 to 0.539 for CPs and from 0.091 to 0.254 for CTs. Uniform, majority, divided, minimal, and no agreement was noted in 12.8%, 31.4%, 38.4%, 10.5%, and 6.9%, respectively, of all cases and in 16.7%, 35.4%, 31.3%, 8.3%, and 6.3%, respectively, of the cases with follow-up. Diagnostic challenges included distinguishing lymphoma from a reactive process and distinguishing mucin from mucin-like material. CONCLUSIONS: CPs had modestly higher CRs compared with CTs; and, although the variable CRs highlight indeterminate IOV, the MSRSGC enables reproducibility. Characterizing larger cohorts in the indeterminate categories will further improve MSRSGC criteria. Moreover, education on the MSRSGC should include CTs and CPs to improve overall diagnostic accuracy.

[Salivary gland cytopathology: Milan system 2018]. / Cytopathologie des glandes salivaires : le système de Milan 2018.

The salivary glands cytology is one of the most challenging area in cytopathology because of the wide diversity of benign and malignant tumors also because of their heterogeneity. However, fine needle aspiration cytology, with magnetic resonance imaging, represents a first-line examination to guide a possible surgical procedure and its extent. An accurate diagnosis of a specific tumor is sometimes difficult to assess in cytology. Also, as for gynecological, thyroid or urinary cytologies, a panel of experts met to develop a cytological classification of salivary gland lesions associated with a risk of malignancy and management proposals. The Milan System for Reporting Salivary Gland Cytopathology was published in 2018. The French Society of Clinical Cytology (SFCC) offers here an official summarized French version oh this terminology and recommends its use.

Histologic Classification and Molecular Signature of Polymorphous Adenocarcinoma (PAC) and Cribriform Adenocarcinoma of Salivary Gland (CASG): An International Interobserver Study.

Polymorphous adenocarcinoma (PAC) shows histologic diversity with streaming and targetoid features whereas cribriform adenocarcinoma of salivary gland (CASG) demonstrates predominantly cribriform and solid patterns with glomeruloid structures and optically clear nuclei. Opinions diverge on whether CASG represents a separate entity or a variant of PAC. We aimed to assess the level of agreement among 25 expert Head and Neck pathologists in classifying these tumors. Digital slides of 48 cases were reviewed and classified as: PAC, CASG, tumors with ≥50% of papillary architecture (PAP), and tumors with indeterminate features (IND). The consensus diagnoses were correlated with a previously reported molecular alteration. The consensus diagnoses were PAC in 18/48, CASG in16/48, PAP in 3/48, and IND in 11/48. There was a fair interobserver agreement in classifying the tumors (κ=0.370). The full consensus was achieved in 3 (6%) cases, all of which were classified as PAC. A moderate agreement was reached for PAC (κ=0.504) and PAP (κ=0.561), and a fair agreement was reached for CASG (κ=0.390). IND had only slight diagnostic concordance (κ=0.091). PAC predominantly harbored PRKD1 hotspot mutation, whereas CASG was associated with fusion involving PRKD1, PRKD2, or PRKD3. However, such molecular events were not exclusive as 7% of PAC had fusion and 13% of CASG had mutation. In conclusion, a fair to moderate interobserver agreement can be achieved in classifying PAC and CASG. However, a subset (23%) showed indeterminate features and was difficult to place along the morphologic spectrum of PAC/CASG among expert pathologists. This may explain the controversy in classifying these tumors.

Histopathological evaluation of minor salivary gland papillary-cystic tumours: focus on genetic alterations in sialadenoma papilliferum and intraductal papillary mucinous neoplasm.

AIMS: Minor salivary gland tumours showing a predominant papillary-cystic structure are rare, and constitute a mixture of various types of neoplasm; thus, the histopathological assessment of these tumours poses a significant diagnostic challenge. We aimed to delineate the histological characteristics of these tumours and further mutational aspects with a particular focus on sialadenoma papilliferum (SP) and intraductal papillary mucinous neoplasm (IPMN). METHODS AND RESULTS: We retrieved 28 papillary-cystic tumours of the minor salivary glands, and performed histological re-evaluation and mutation analyses of several key oncogenes. The histological classifications were as follows: SP (n = 10), SP-like intraductal papillary tumour (SP-IPT) (n = 2), IPMN (n = 9), intraductal papilloma, cystadenoma, and cystadenocarcinoma (two, three and two respectively). Whereas SP typically consisted of a combination of exophytic squamous epithelium and endophytic intraductal papillary infoldings, SP-IPT lacked the exophytic component. SP and SP-IPT frequently harboured BRAF V600E mutations (75.0%), which were identified in both squamous and ductal components. IPMN was characterised by a well-demarcated cystic lesion filled exclusively with a papillary proliferation of mucinous cells and a high rate of AKT1 E17K mutations (88.9%). Intraductal papillomas were unilocular cystic lesions with intraluminal papillary growth of bland columnar cells. In contrast, both cystadenomas and cystadenocarcinomas showed a multicystic appearance with a papillary configuration. Cystadenocarcinomas invaded the surrounding tissue and were composed of markedly atypical tumour cells. CONCLUSION: The appropriate interpretation of histological findings and specific genetic alterations (e.g. BRAF V600E and AKT1 E17K in SP and IPMN) would be useful for the correct diagnosis of minor salivary gland papillary-cystic tumours.