Rare Salivary Gland Research Articles

Identifying potential immuno-oncology targets in salivary gland mucoepidermoid carcinoma based on inflammatory status and treatment response.

Mucoepidermoid carcinoma is a rare salivary gland malignant tumour. This study aimed to investigate inflammatory and immune signatures of mucoepidermoid carcinoma by identifying potential proteo-transcriptomic biomarkers towards the development of precision immuno-oncology treatment strategies. A total of 30 biopsies obtained from patients diagnosed with mucoepidermoid carcinoma between 2013 and 2022 were analysed after H&E staining for scoring of histological inflammatory stroma subtypes and inflammatory hotspots with QuPath. Multiplex immunofluorescence staining and NanoString nCounter PanCancer IO 360™ panel were used to assess stroma and tumour inflammation signatures in high grade mucoepidermoid carcinoma cases in the tumour microenvironment via proteomics and transcriptomics, respectively. Inflammatory cells within the histological inflammatory stroma inflammatory (HIS-INF/hot) tumour neighbourhoods were greater compared to the histological inflammatory stroma-immune desert (HIS-ID/cold) (p = 0.001). A similar trend was observed between treatment non-responders and responders in stroma neighbourhoods (p = 0.0625) and in stroma-to-interface inflammatory hotspots (p = 0.0081), indicating an augmented inflammatory response in hot tumours and non-responders. Furthermore, there were striking differences in the expression of pan-immune leukocyte marker CD45 between responders and non responders particularly in the tumour neighbourhoods (p = 0.0341), but such were not robust for PD-1 and macrophage fractions. Additionally, transcriptomic analysis revealed key differences in leukocyte activation profiles between responders and non-responders. This preliminary report unveils the importance of assessing immune leukocyte cellular fractions and pathways for future prognostic biomarker discoveries in mucoepidermoid carcinoma as per the involvement of CD45-driven inflammatory and immune mediators in high grade mucoepidermoid carcinoma in non-responders to treatment. These findings will potentially contribute to the development of novel personalised immunotherapies.

Utility of Wnt family member 9b (Wnt9b) immunohistochemistry inthe cytologic diagnosis of metastatic breast carcinoma.

Wnt family member 9b (Wnt9b) has been demonstrated as a valuable marker for breast cancer diagnosis in surgical pathology. In this study, we examined the utility of Wnt9bin diagnosing metastatic breast carcinomaincytologysamples. Cell blocks from fine needle aspirations (FNA) and fluid specimens of 96 metastatic breast carcinomasand 123 primary and metastatic non-breast neoplasms from various organ systems were evaluated by Wnt9band GATA3 immunohistochemistry (IHC). Wnt9b and GATA3 were positive in 81.3%and 92.7%ofmetastaticbreast carcinomas, respectively. Conversely, 93.5%and 90.0%of non-breast, non-urothelial carcinomas were negative for Wnt9b and GATA3, respectively. Wnt9b expression was positive in rare gastrointestinal, gynecological, lung, pancreas, and salivary gland tumors. All twenty-eight urothelial carcinomas were negative for Wnt9b, while twenty-six (92.9%) were positive for GATA3. Wnt9b was slightly less sensitive but more specific than GATA3 in diagnosing metastatic breast cancer in cytology samples. Particularly, Wnt9b shows higher specificity in differentiating breast and urothelial primaries. The combined use of Wnt9b and GATA3 may increase diagnostic accuracy.

Mucoepidermod carcinoma of palate- A rare case report and management

Mucoepidermoid carcinoma is a rare salivary gland tumor affecting minor salivary gland. This case report discusses the clinical features, diagnosis and management and rehabilitation of patient of mucoepidermoid carcinoma of palate. A 32-year old female reported with the chief complain of painless swelling and ulceration on right side of hard palate since 6 months. Then proper clinical, radiological and histopathological investigations and analysis were done to come to diagnosis and based on the incisional biopsy report the diagnosis was confirmed to be mucoepidermoid carcinoma of intermediate grade. This case report depicts timely and accurate diagnosis and decision on treatment plan based on all investigation can not only lead to treatment but also rehabilitation of patient.

Abstract PO-071: Pseudonormal morphology of adenoid cystic carcinoma cells subverts the antitumor reactivity of immune cells

Abstract Objectives: Adenoid cystic carcinoma (ACC) is a rare salivary gland cancer most frequently arising in the head and neck region. The ACC microenvironment exhibits low immunogenicity (low tumor infiltrating lymphocytes and dendritic cells). This scenario favours immune evasion and partially explains poor prognosis because of the activation of immune inhibitory proteins. Gipie is a hook-related protein, that is involved in protein trafficking. Gipie (HkRP3, encoded by CCDC88B) is associated with T cell maturation and inflammatory functions and target cell killing in natural killer (NK) cells. Gipie is present in ACC patient samples and cells. Therefore, we investigated proliferation, apoptosis, and morphologic changes caused by Gipie in oral and salivary gland cancer cells in presence of immune cells. Methods: We assayed UM-HACC-2A (adenoid cystic carcinoma), A-253 (mucoepidermoid carcinoma, MEC), SCC4, SCC9, SCC25, CAL27 (oral squamous cell carcinoma, OSCC), OKF6 (normal oral) cells cocultured with, NK-92 (natural killer), and Jurkat, Clone E6-1 (acute T cell leukemia) cells, to construct multiple salivary gland and oral cancer-immune cell co-culture models. Gipie silenced cancer cells (silencing maintained for 48 hours) in the cancer immune coculture models were compared with their unaltered subsets. Cancer-immune cells interactions were maintained for 16 hours. Overall three hundred thirty-six (336) co-culture models were used to determine apoptosis, immune activation, morphology, transmigration, and protein expression. Additionally, we performed targeted mass spectrometry analysis to identify changes in protein profiles. Results: ACC cells exhibited Pseudonormal morphology after interacting with immune cells in the 3D coculture model. Gipie-silenced ACC cells in coculture model transformed to “lymphoblast-like” morphology. Gipie-silenced ACC cells in co-culture model (n = 24) showed significant increase of apoptotic cells compared to unaltered ACC cells, lowering of T regulatory cells (FoxP3+/IL-2Rα+/CD25+) (n = 24), and increase of activated NK cells (NKp30+/IFN-γ+) (n = 24) with significantly higher release of granzyme (n = 12) and perforin (n = 12). Increased activation of immune cells (transmigration and fluorescence intensity) via 3D-z-stack images were observed in Gipie-silenced subsets (n = 24). MEC cells responses were significantly less compared to ACC in co-culture models followed by silencing of Gipie, while OSCC and OKF6 cell responses were negligible, under identical conditions. Conclusions: The presence of Gipie confers pseudonormal morphology to ACC cells thereby reducing immune attack. Thus, trafficking proteins may impact ACC cancer-immune cell interaction during conventional chemotherapy or monoclonal immunotherapy. Citation Format: Rajdeep Chakraborty, Charbel Darido, Giuseppe Palmisano, Arthur Chien, Aidan Tay, Thiri Zaw, Shoba Ranganathan. Pseudonormal morphology of adenoid cystic carcinoma cells subverts the antitumor reactivity of immune cells [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-071.

Molecular Factors in Carcinoma Ex Pleomorphic Adenoma: Systematic Review and Meta-Analysis.

Carcinoma ex pleomorphic adenoma (CXPA) is a rare malignant salivary gland tumor. Although multiple reviews have been published on salivary gland malignancies, it has been a decade since the last dedicated systematic review pertaining to CXPA alone was published. This study examines molecular factors in CXPA diagnosis. MEDLINE, CINAHL, Embase, Scopus, Web of Science (BIOSIS), Cochrane CENTRAL, Health Collection (Informit), OpenDOAR, and GreyNet International. Systematic review and meta-analysis from inception to October 31, 2022 for all English language studies pertaining to "carcinoma ex pleomorphic adenoma." Predicted incidence of each biomarker was calculated with meta-analysis. Comparison against pleomorphic adenoma (PA) and salivary duct carcinoma (SDC) when reported within the same study are performed. Risk of bias performed with JBI tool for prevalence studies. Of 19151 unique studies undergoing abstract screening, 55 studies (n = 1322 patients) underwent data analysis. Biomarkers with >3 studies were p53, HER2, AR, EGFR, PLAG1, ERBB, ER, PR, HMGA2, p16, p63, a-SMA, RAS, PTEN, PDL1, BRAF, PIK3CA, and c-kit. Highest incidence was seen in AR, EGFR, p16, and p53. Significant differences were demonstrated compared with PA and SDC. There was high heterogeneity and overall high risk of bias within studies. Molecular factors are an area of interest in the diagnosis of CXPA. Our study results support examining CXPA as a discrete cohort in future targeted therapy trials. Laryngoscope, 134:1042-1053, 2024.

Mammary analogue secretory carcinoma (MASC) of parotid gland- A case report

Mammary analogue secretory carcinoma is a rare salivary gland carcinoma which shares morphologic and immunohistochemical features with the secretory carcinoma of breast and was first proposed by Skalova in 2010 with translocation of (q13; q25), t (12; 15), subsequently giving ETV6-NTRK3 gene rearrangement. Usually, it is a benign tumor that affects the parotid gland, with slight predilection for males. The present article report a case of secretory carcinoma of right parotid gland with special emphasis on histological feature and immunohistochemistry for diagnostic purpose and its management. Differential diagnosis includes AciCC, ADC-NOS and MEC. In a review by Chiosa et al (2012) in 337 cases of salivary gland malignancy included AciCC, ADC-NOS, MEC, LGCC, non-ITAC, signet ring adenocarcinoma, PLGA and most common malignancy reclassified as MASC were AciCC (11/89), ADC-NOS (14/37), MEC (1/165). Management for MASC includes surgical excision of the lesion (either superficial or total parotidectomy) for local, less aggressive disease like for low-grade malignant salivary gland neoplasms. For more invasive, metastatic disease and positive margins- neck dissection, radiotherapy and chemotherapy are reserved. There is no standard multidisciplinary treatment protocol established due to scarcity of this disease.

A pilot study of volumetric and density tumor analysis of ACC patients treated with vorinostat in a phase II clinical trial

Rationale and objectivesAdenoid cystic carcinoma (ACC) is a rare salivary gland cancer. The vast majority of clinical trials evaluating systemic therapy efficacy in solid tumors use the Response Evaluation Criteria in Solid Tumors (RECIST) to measure response that is limited to 2 dimensional only evaluations, not taking volume or density into account. The indolent behavior ACC represents a challenge toward an appropriate evaluation of therapy response. Objectives: 1) To describe and contrast volumetric and density changes at each time-point, including changes noted from baseline to best response, to currently used 2 dimensional-only criteria (RECIST) and 2) To report the coefficient of variation in volume measurement among three reviewers on a subset of ACC patients. Materials and methodsWe retrospectively assessed a cohort of 18 prospectively treated patients with ACC in a phase 2 trial with vorinostat using a volumetric (viable tumor volume, VTV) and density criteria. Three independent and blinded observers segmented target lesions across a sample of randomly selected computed tomography (CT) exams to examine inter-observer variation. ResultsWe found that the average coefficient of variation among observers for all target lesions was 16.1%, with lung lesions displaying a smaller variation at 14.0% (p-value >0.17). We describe examples of decrease in volume and density in several lesions despite stable disease by RECIST. ConclusionThis pilot study demonstrates that two-dimensional criteria such as RECIST may not be the best criteria to assess response to therapy, especially with evolving tools within picture archiving and communication system (PACS) that can assess volumetric size, density and texture, however, this should be prospectively studied.

Canalicular adenoma of parotid gland: A case report and review of literature

Canalicular adenoma is a rare benign salivary gland neoplasm affecting predominantly the minor salivary gland. We present a case of a 55 year female who presented with a mucosal nodule in the left cheek and was diagnosed as Canalicular adenoma based on the morphology and immunohistochemistry findings. Our case is rare in that, it is a case of Canalicular adenoma affecting the major salivary gland – Parotid gland, and is the 7 case reported in literature to the best of our knowledge.

Clinicopathological analysis of 18 cases of secretory carcinoma of the salivary glands

Background/purposeSecretory carcinoma (SC) is a rare salivary gland tumor that featured by ETV6::NTRK3 gene fusion, and was included in the WHO Classification of Head and Neck Tumors since 2017. Nevertheless, the description of SCs by WHO is still vague. This study examined 18 SC cases by using both histomorphology and molecular pathology for diagnostic determination, especially immunohistochemical features of SCs. Materials and methodsBased on WHO characteristics, 18 patients with SC admitted between 2001 and 2022 were included in this study. Main histomorphological patterns, FISH analyses of the ETV6::NTRK3 gene fusion, and immunohistochemical analyses of S100, mammaglobin, DOG1, ADFP, CA6 and Ki-67 were performed. ResultsAmong the 18 SC patients, the median age of onset was 39.22 years. Grossly, the average tumor size in 2.96 cm with various texture from soft to tough. The majority patients were positive for S100, mammaglobin, and negative for DOG1, except for one patient negative for S100 (Case 18). All patients were positive for ADFP, and the majority patients were negative for CA6, except for Case 9. Two cases were found recurrence, and the tumor were found both in parotid gland with local invasion. ConclusionCombined with the results of previous studies, we proposed that the combination of all five markers, S100, mammaglobin, DOG1, ADFP and CA6, could contribute more to differential diagnosis of SCs with other salivary carcinomas, especially with AciCC. The prognosis of SCs is optimistic in most cases, but larger patient cohort and long-term follow-up are still needed.

A phase II study of lenvatinib plus pembrolizumab in patients with progressive, recurrent/metastatic adenoid cystic carcinoma.

6048 Background: Recurrent/metastatic adenoid cystic carcinoma (R/M ACC) is a rare salivary gland cancer (SGC) without standard treatments. The multitargeted, antiangiogenic kinase inhibitor lenvatinib (len) has activity in R/M ACC, but immune checkpoint inhibitor (ICI) therapies lack efficacy. Hypothesizing that VEGFR inhibition can enhance ICI-induced responses, we conducted a phase II trial evaluating len plus the programmed death-1 (PD-1) inhibitor pembrolizumab (pem) in two R/M SGC cohorts: ACC and non-ACC. Here we report results from the completed ACC cohort. Methods: Patients (Pts) with R/M ACC were enrolled. RECIST v1.1 measurable disease and evidence of progression on imaging performed within 6 months of enrollment were required; any number of prior therapies was allowed. Pts were treated with len 20 mg orally daily and pem 200 mg intravenously every 3 weeks (21-day cycles). The primary objective was to evaluate best overall response rate (ORR), seeking an ORR improvement with len+pem from 15% (previously reported with len alone) to 35%. In the first stage, > 3 confirmed complete and partial responses (cCRs+ cPRs) were required among 17 pts to continue to the second stage; > 8 responses among 32 total pts would have been considered positive (1-sided alpha 0.1, power 0.9). Secondary objectives included evaluating progression-free survival (PFS) and safety/tolerability per CTCAE v5.0 criteria. Results: 17 R/M ACC pts were enrolled and evaluable for the primary objective. One pt had a cPR for an ORR of 6%, failing to meet the rule for progression to the second stage. Thirteen (76%) pts had stable disease and 2 (12%) progression of disease as best response; 1 pt did not have response assessed. Thirteen (76%) pts experienced some degree of regression in RECIST target lesions (TLs; -1.9% to –42.8%), including 5 (29%) with > -20% regression. Eleven (65%) pts were progression-free for > 24 weeks. Twelve (71%) pts experienced at least one > Grade 3 adverse event related to study treatment. Sixteen pts had at least one treatment interruption or len dose reduction; 2 pts received only 1 cycle of therapy. Five pts were treated beyond first progression without observation of subsequent response. Quality of life data and correlative tissue studies are ongoing. Conclusions: The trial failed to demonstrate that len+pem produces a greater ORR in patients with R/M ACC than what was previously reported with len alone. Further investigation into the biology mediating ICI-resistance and development of novel approaches to augment the efficacy of immune-based therapies in ACC are needed. (Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA provided lenvatinib and pembrolizumab for the study.) Clinical trial information: NCT04209660 .

Dr Jekyll and Mr Hyde’ of exocrine gland carcinomas: Breast adenoid cystic carcinoma - A rare entity

Primary Adenoid Cystic Carcinoma of Breast (bACC) is an extremely rare salivary gland like tumor accounting for less than 0.1% of all breast tumors with excellent prognosis. These tumors are generally triple negative. There is limited data on optimal treatment and management.

Polymorphous adenocarcinoma of the buccal space—Rare, reported case from our institute

ABSTRACT Polymorphous adenocarcinoma (PAC) of head and neck tumors is a rare salivary gland neoplasm of indolent course. We reported a 63-year-old female who presented as an asymptomatic mass in buccal space. The patient, after metastatic workup, underwent complete excision of the lesion with a negative margin. Postoperative histopathology and immunohistochemistry (IHC) were suggestive of PAC. Presently patient is on follow-up as per a multidisciplinary team decision. To conclude, PAC diagnosis is challenging due to morphological diversity, which necessities IHC. In addition, presently treatment of choice as per the literature review is complete excision.

Uncommon case of cytopathological features of sialadenoma papilliferum.

Sialadenoma papilliferum, a benign and rare salivary gland neoplasm, accounts for 0.4%-1.2% of all salivary gland tumors and occurs primarily in minor salivary glands of the oral cavity. Here, we report a case of sialadenoma papilliferum and its associated cytological findings. A papillary tumor was incidentally detected on the palate of an 86-year-old Japanese man. Conventional oral exfoliative cytology was performed; the cytology smear exhibited epithelial clusters composed of atypical epithelial cells with a high nuclear/cytoplasm ratio and arranged in sheet or small papillary-like projections. Cytoplasmic vacuoles were also observed in the papillae. It was difficult to make a definitive diagnosis due to the presence of uncommon cytological features. The excisional biopsy specimen revealed histological features characteristic of sialadenoma papilliferum. Mutational analysis detected BRAFV600E mutation, which confirmed the diagnosis of sialadenoma papilliferum. To the best of our knowledge, no prior cytomorphological evaluations of sialadenoma papilliferum have been reported in detail. Oral exfoliative cytology specimens from salivary gland tumors can demonstrate uncommon cytomorphological features. A differential diagnosis of sialadenoma papilliferum can be based on the observation of mildly atypical epithelial cells that form small papillary-like structures.

Expression and localisation of MUC1 modified with sialylated core-2 O-glycans in mucoepidermoid carcinoma

Mucoepidermoid carcinoma (MEC) is the most frequent of the rare salivary gland malignancies. We previously reported high expression of Mucin 1 (MUC1) modified with sialylated core-2 O-glycans in MEC by using tissue homogenates. In this study, we characterised glycan structures of MEC and identified the localisation of cells expressing these distinctive glycans on MUC1. Mucins were extracted from the frozen tissues of three patients with MEC, and normal salivary glands (NSGs) extracted from seven patients, separated by supported molecular matrix electrophoresis (SMME) and the membranes stained with various lectins. In addition, formalin-fixed, paraffin-embedded sections from three patients with MEC were subjected to immunohistochemistry (IHC) with various monoclonal antibodies and analysed for C2GnT-1 expression by in situ hybridisation (ISH). Lectin blotting of the SMME membranes revealed that glycans on MUC1 from MEC samples contained α2,3-linked sialic acid. In IHC, MUC1 was diffusely detected at MEC-affected regions but was specifically detected at apical membranes in NSGs. ISH showed that C2GnT-1 was expressed at the MUC1-positive in MEC-affected regions but not in the NSG. MEC cells produced MUC1 modified with α2,3-linked sialic acid-containing core-2 O-glycans. MUC1 containing these glycans deserves further study as a new potential diagnostic marker of MEC.

Oncocytic Papillary Cystadenoma, an Unusual Variant Presenting as a Laryngeal Ventricular Cyst.

Cystadenoma arising from the larynx is a rare benign minor salivary gland tumor that can show mucinous or papillary morphology. The epithelial lining of the salivary gland tumor can present with oncocytic features, which is attributed to an increased number of mitochondria. We present a rare case of oncocytic papillary cystadenoma (OPC) of the larynx which has a combination of these features. The WHO defines OPC tumors as entities which closely resemble Warthin tumor, but lack its classic lymphoid component. The immunohistochemical profile and molecular genetic features are largely unknown. We present an 84-year-old female, former smoker, who presented with progressive dysphonia, dysphagia, and shortness of breath. Laryngoscopy revealed a large, smooth mass originating from the ventricle of the right vocal fold. Subsequent biopsy demonstrated cyst wall fragments lined by a bilayer of large columnar to cuboidal oncocytic cells that had granular eosinophilic cytoplasm, round to oval nuclei with finely dispersed chromatin, and small but distinct nucleoli. The surrounding stroma was slightly fibrotic with scant lymphoid elements. No nuclear pleomorphism, increased mitosis, or necrosis was identified. In the larynx, benign salivary gland tumors are rare and less frequent than malignant neoplasms. Awareness of rare benign entities like OPC help ensure proper management and aid in avoiding unnecessary therapy.

Loss of CDKN2A/B is a Molecular Marker of High-grade Histology and is Associated with Aggressive Behavior in Acinic Cell Carcinoma

Acinic cell carcinoma (AciCC) is a rare salivary gland cancer with excellent prognosis in most cases. However, a subset of patients will develop distant metastasis and die of disease. Recently, a 2-tiered grading scheme in AciCC was proposed to recognize patients at risk of poor outcome. We performed a genetic analysis of AciCC to explore the underlying molecular correlates of the tumor grade and examined programmed death ligand 1 (PD-L1) expression to identify potential candidates for immunotherapy. A retrospective cohort of 55 patients included 34 high-grade (HG) and 21 low-grade AciCCs. Forty-three cases were subjected to targeted exome sequencing by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets. PD-L1 immunohistochemistry was performed in 33 cases. Tumor mutation burden was low with a median of 1 and 2 mutations in low-grade and HG AciCCs, respectively. CDKN2A/B was the most frequently altered gene, and loss-of-function mutations were found only in HG but not in low-grade AciCCs (18/31 [58.1%] vs 0/12 [0%], P < .001). CDKN2A/B alterations were significantly associated with distant metastasis, which occurred in 16/18 (88.9%) CDKN2A/B mutants versus 11/25 (44%) wild-type cases (P = .004, Fisher exact test). Sequential profiling of multiple temporally distant samples from the same patient demonstrated intratumor heterogeneity, including the detection of CDKN2A/B deletion in the second, in HG metastasis only. ATM and PTEN mutations were detected in 6/31 (19.4%) and 5/31 (16.1%); ARID2, BIRC3, and FBXW7 mutations each in 4/31 (12.9%); and TP53, MTAP, and FAT1 each in 3/31 (9.7%) HG AciCC. PD-L1–positive labeling was more common in HG AciCC (9/17, 52.9% vs 3/16, 18.9%, P = .071). CDKN2A/B mutations in AciCC represent a molecular marker of HG histology and disease progression, providing a rationale for further studies to determine their prognostic and therapeutic significance in this salivary gland cancer. AciCC with ATM mutations may be amenable to targeted therapy. Immunotherapy can be considered to be a treatment option for a subset of patients with AciCC.

A Case of Myoepithelioma of the Soft Palate

Myoepithelioma is a relatively rare salivary gland tumor. Herein, we report a case of myoepithelioma of the soft palate. The patient was 48-year-old man who was found, during dental examination, to have a swelling on the left side of the soft palate, and was referred to a local clinic. Fine-needle aspiration cytology revealed ductal epithelial cells and myoepithelial cells, so that the initial diagnosis was pleomorphic adenoma. The patient was referred to our department, and we performed resection of the soft palate tumor. On histopathological examination, the tumor was found to be composed of plasmacytoid myoepithelial cells, and immunohistochemistry showed positive staining of the cells for AE1/AE3, S-100 protein, vimentin, and GEAP. The MIB-1 index, an indicator of malignant cell proliferation, was low (4%). The final diagnosis of the tumor was myoepithelioma, plasmacytoid cell type. Until the last follow-up, one year after the surgery, the patient showed no evidence of recurrence. Because several reports have suggested that myoepitheliomas could show malignant transformation, we propose to carefully follow-up our patient reported herein, with oral myoepithelioma.

Parotid Acinic Cell Carcinoma with Intracranial Metastasis: A Case Report and Literature Review

Acinic cell carcinoma is a rare salivary gland neoplasm frequently associated with local recurrence. While distal metastasis occurs in approximately 19% of cases, intracranial metastasis has been rarely reported in the literature and both preoperative patient characteristics and postoperative prognoses are not currently well-characterized.

Primary Pulmonary Hyalinizing Clear Cell Carcinoma: Case Series With Review of Literature.

Background: Hyalinizing clear cell carcinomas of tracheobronchial origin are very rare salivary gland type tumors accounting for less than 1% of lung tumors with only 13 cases reported to date. Their radiological features, morphological spectrum, and molecular features are not well described. Aim: To perform a clinicopathological analysis of primary pulmonary hyalinizing clear cell carcinomas. Method: A retrospective search of primary pulmonary hyalinizing clear cell carcinomas was conducted from authors' institutions and the clinicopathological features including details of molecular testing were analyzed. Results: Five primary pulmonary hyalinizing clear cell carcinomas were identified. The mean patient age at diagnosis was 48.2 years (range: 33-64 years). Three patients were women. All patients were nonsmokers and 3 were symptomatic; 2 were detected incidentally during health screening. The tumors were located in the main lobar bronchi ranging from 1.3 to 4.9 cm in maximum dimension. Microscopy showed cords and nests of at least, focally clear tumor cells. Mucin cysts lacking goblet cells were seen. All tumors were uniformly positive for p40, p63, AE1/AE3, keratin 7, and epithelial membrane antigen but negative for TTF1, KIT, neuroendocrine markers, and other myoepithelial markers. All cases showed Ewing sarcoma breakpoint region 1 (EWSR1) gene rearrangement. Perineural invasion and lymph node metastases were detected in patient 5. Two patients with available follow-up data were recurrence-free until 4 years (patient 1) and 9 months (patient 5) after resection. Conclusion: The present series adds to the scant available literature on primary pulmonary hyalinizing clear cell carcinomas highlighting the characteristic histomorphology, immunoprofiles, and benign outcomes of these rare tumors.

Recurrent IDH2 Mutations in Salivary Gland Striated Duct Adenoma Define an Expanded Histologic Spectrum Distinct From Canalicular Adenoma.

Striated duct adenoma (SDA) is a rare salivary gland neoplasm defined by histologic similarity to normal striated ducts. However, doubt persists about whether SDA represents a genuine entity distinct from canalicular adenoma and if a malignant counterpart exists. This study aims to evaluate the molecular underpinnings of SDA to clarify its pathogenesis and classification. We identified 10 SDA and 2 tumors called low-grade adenocarcinoma not otherwise specified that were retrospectively recognized to resemble SDA. All cases showed recurrent histologic features including (1) discrete monophasic tubules, (2) tall columnar eosinophilic cells, (3) monotonous oval nuclei, and (4) scant fibrous stroma, and most were positive for S100 protein (91%), SOX10 (80%), and CK7 (80%). Although 1 case was previously called adenocarcinoma based on interdigitation with normal acini, this pattern was also seen in some SDA, and likely does not indicate malignancy; the significance of growth surrounding nerve in 1 other case is less clear. Targeted sequencing identified IDH2 R172X mutations in all 8 cases with sufficient tissue, with positivity for IDH1/2 mutation-specific immunohistochemistry in 9 cases stained. In contrast, 5 canalicular adenomas lacked IDH2 mutations or other oncogenic alterations. Overall, IDH2 R172X mutations are a defining feature of SDA that, in combination with its recognizable pathologic profile, confirm it is a unique entity separate from canalicular adenoma. IDH1/2 mutation-specific immunohistochemistry may provide a convenient tool to facilitate diagnosis. Both morphology and IDH2 mutations raise parallels between SDA and breast tall cell carcinoma with reverse polarity.