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Sclerosing polycystic adenoma (SPA) is a rare salivary gland neoplasm originally thought to represent a non-neoplastic lesion. Recently we have encountered an index case of apocrine intraductal carcinoma of parotid gland of 62-year-old man with invasive salivary duct carcinoma component arising from SPA, a combination of tumor entities that has never been published so far. Here, we further explore the nature of SPA by evaluating 36 cases that were identified from the authors' consultation files. The patients were 25 females and 11 males aged 11 to 79 years (mean, 47.8 y). All tumors originated from the parotid gland. Their size ranged from 11 to 70 mm (mean, 28 mm). Histologically, all cases revealed characteristic features of SPA, such as lobulated well-circumscribed growth, focal hyalinized sclerosis, presence of large acinar cells with abundant brightly eosinophilic intracytoplasmic granules, and ductal components with variable cytomorphologic characteristics, including foamy, vacuolated, apocrine, mucous, clear/ballooned, squamous, columnar and oncocyte-like cells. In all cases, there were foci of intraluminal solid and cribriform intercalated duct-like epithelial proliferations with variable dysplasia which were positive for S100 protein and SOX10, and fully enveloped by an intact layer of myoepithelial cells. In addition, 14/36 cases (39%) had focal intraductal cribriform and micropapillary apocrine-type dysplastic epithelial structures composed of cells positive for androgen receptors and negative for S100/SOX10. The intraductal proliferations of both types showed focal mild to severe dysplasia in 17 cases (17/36; 47%). Two cases showed overt malignant morphology ranging from high-grade intraductal carcinoma to invasive carcinoma with an apocrine ductal phenotype. Next generation sequencing using ArcherDX panel targeting RNA of 36 pan-cancer-related genes and/or a TruSight Oncology 170/500 Kit targeting a selection of DNA from 523 genes and RNA from 55 genes was performed. Tumor tissue was available for molecular analysis in 11 cases, and 9 (9/11; 82%) of them harbored genetic alterations in the PI3K pathway. Targeted sequencing revealed HRAS mutations c.37G>C, p.(Gly13Arg) (2 cases) and c.182A>G, p.(Gln61Arg) (2 cases), and PIK3CA mutations c.3140A>G, p.(His1047Arg) (3 cases), c.1633G>A, p.(Glu545Lys) (1 case), and c.1624G>A, p.(Glu542Lys) (1 case). Moreover, mutations in AKT1 c.49G>A, p.(Glu17Lys) and c.51dup, p.(Tyr18ValfsTer15); c.49_50delinsAG, p.(Glu17Arg) (as a double hit) were found (2 cases). In addition, germinal and somatic mutation of PTEN c.1003C>T, p.(Arg335Ter); c.445C>T, p.(Gln149Ter), respectively, were detected. Gene fusions were absent in all cases. These prevalent molecular alterations converging on one major cancer-related pathway support the notion that SPA is a true neoplasm with a significant potential to develop intraluminal epithelial proliferation with apocrine and/or intercalated duct-like phenotype. The name SPA more correctly reflects the true neoplastic nature of this enigmatic lesion., Competing Interests: Conflicts of Interest and Source of Funding: Supported in part by study grant SVV 22639 from the Ministry of Education, Czech Republic and the Finnish Cancer Society, Helsinki. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Salivary high-grade neuroendocrine carcinomas (NECs) are rare, occur predominantly in the parotid gland, and are difficult to differentiate from metastatic cutaneous Merkel cell carcinomas (MCCs), which have overlapping morphologic, immunophenotypic, and molecular profiles. Oncogenic Merkel cell polyomavirus (MCPyV), found in 70% to 80% of MCCs, has also been reported in a few salivary NECs, but this is controversial. A promising biomarker to distinguish the 2 tumor types are UV signature mutations. UV signature mutations indicate a sun damage-induced mechanism of pathogenesis and recently have been found to be highly prevalent in MCPyV-negative MCCs but would be inconsistent with salivary origin. Here, we examine UV signature mutations as a molecular marker to distinguish primary salivary high-grade NEC from MCC. Whole exome DNA sequencing was performed on matched tumor-normal tissue from 4 MCPyV-negative high-grade salivary NECs with no other primary source identified, as well as 3 melanomas and 3 lung NECs as positive and negative controls, respectively. UV signature mutations were found in all salivary NECs, when defined as ≥60% of total mutations being C-to-T transitions at dipyrimidine sites, and when compared with known human cancer-related mutational signatures. The presence of UV signature mutations in salivary high-grade NECs strongly favors these to be occult metastatic MCCs. True salivary primary NECs are likely exceedingly rare. When a high-grade NEC is encountered in the salivary gland, the presence of UV signature mutations or MCPyV may be useful to exclude occult unknown primary MCC.

NUT carcinoma (NC) represents a rare subset of highly aggressive poorly differentiated carcinomas characterized by rearrangement of the NUT (aka NUTM1, nuclear protein in testis) gene, most commonly fused to BRD4. Originally described as a mediastinal/thymic malignancy, NC has been reported at a variety of anatomic regions including the upper and lower aerodigestive tract. To date, only 7 NC cases of probable salivary gland origin have been reported. We herein describe 3 new cases (all affecting the parotid gland) in 2 women (39- and 55-y old) and 1 man (35-y old). Histologic examination showed poorly differentiated neoplasms composed of poorly cohesive small-sized to medium-sized cells with variable squamoid cell component that was focal and abrupt. Immunohistochemistry showed uniform expression of p63 and distinctive punctate expression of the NUT antigen in the tumor cell nuclei. Review of the reported salivary gland NC cases (total, 10) showed a male:female ratio of 1.5:1 and an age range of 12 to 55 years (median, 29 y). Site of the primary tumor was the parotid (7), sublingual (2), and submandibular (1) glands. All presented as rapidly growing masses treated by surgery followed by adjuvant radiotherapy/chemotherapy. Initial nodal status was positive in 8/10. At last follow-up (1 to 24 mo; median, 5 mo), 7/10 patients died of disease at a median of 5.5 months (1 to 24 mo) and only 2 were disease free at 7 and 14 months. Of 9 cases with genetic data, the fusion partner was BRD4 (n=7), non-BRD4/3 (n=1), or undetermined (n=1). None of 306 carcinomas spanning the spectrum of salivary carcinoma types screened by NUT immunohistochemistry was positive. This is the first small series on salivary NC highlighting the importance to include this rare disease in the differential diagnosis of poorly differentiated salivary gland carcinomas and in cases of presumable poorly differentiated carcinoma of unknown origin.

There has been some debate as to whether a subset of metaplastic Warthin tumors (mWTs) harbor the mucoepidermoid carcinoma (MEC)-associated CRTC1-MAML2 fusion. We analyzed 15 tumors originally diagnosed as mWT (mWT-like tumors), 2 of which had concurrent MECs. We looked for the CRTC1/3-MAML2 fusion transcripts and performed immunohistochemistry for p63 and fluorescence in situ hybridization (FISH) for the MAML2 split. To localize MAML2 split-positive cells at the cellular level, whole tumor tissue sections were digitalized (whole-slide imaging [WSI]). The CRTC1-MAML2, but not CRTC3-MAML2 was detected in 5/15 mWT-like tumors. FISH-WSI results showed that all epithelial cells harbored the MAML2 split in fusion-positive mWT-like tumors and were totally negative in fusion-negative mWT-like tumors. A review of the hematoxylin and eosin-stained slides showed that morphology of the "metaplastic" epithelium was virtually indistinguishable between fusion-positive and fusion-negative tumors. However, oncocytic bilayered tumor epithelium, characteristic to typical WT, was always found somewhere in the fusion-negative tumors but not in the fusion-positive tumors. This distinguishing histologic finding enabled 5 pathologists to easily differentiate the 2 tumor groups with 100% accuracy. The age and sex distribution of fusion-positive mWT-like tumor cases was similar to that of fusion-positive MEC cases and significantly different from those of fusion-negative mWT-like tumor and typical WT cases. In addition, only fusion-positive mWT-like tumors possessed concurrent low-grade MECs. In conclusion, a subset of mWT-like tumors were positive for the CRTC1-MAML2 fusion and had many features that are more in accord with MEC than with WT. The term Warthin-like MEC should be considered for fusion-positive mWT-like tumors.

Mammary analogue secretory carcinoma of salivary gland origin (MASC) is a recently described tumor resembling secretory carcinoma of the breast characterized by strong S-100 protein, mammaglobin, and vimentin immunoexpression and which harbors a t(12;15) (p13;q25) translocation resulting in ETV6-NTRK3 fusion product. Histologically, conventional MASC displays bland histomorphology and a lobulated growth pattern and is often composed of microcystic, tubular, and solid structures with abundant eosinophilic homogenous or bubbly secretions. Colloid-like secretory material stains positively for periodic acid-Schiff with and without diastase as well as for Alcian Blue. We present for the first time, 3 patients with MASC of the parotid gland in which high-grade (HG) transformation developed in each case characterized by an accelerated clinical course and poor outcome. The HG component revealed strong membrane staining for EGFR and β-catenin, cytoplasmic/nuclear staining for S-100 protein, and nuclear staining for cyclin-D1, whereas HER-2/neu was absent. Analysis for the presence of the ETV6-NTRK3 fusion transcript revealed positivity in both HG and low-grade component of MASC in 2 of the 3 studied cases. The tumor in case 2 was negative in both its elements for the t(12;15) translocation, but ETV6 gene rearrangement was detected in both components in all 3 cases. Analysis of TP53 and CTNNB1 gene mutations in the HG component of MASCs as well as detection of copy number aberration of EGFR and CCND1 gene did not harbor any abnormalities. All 3 patients with HG-transformed MASC died of disseminated disease within 2 to 6 years after diagnosis. Recognizing HG-transformed MASC and testing for ETV6 rearrangement may be of potential value in patient treatment, because the presence of the ETV6-NTRK3 translocation may represent a therapeutic target in MASC.

Nuclear protein in testis midline carcinomas (NMC) are highly aggressive carcinomas typically arising in midline structures in young individuals. These carcinomas are characterized by the presence of a chromosomal rearrangement of nuclear protein in testis the (NUT) gene on chromosome 15 (15q14), resulting from a chromosomal translocation most commonly involving the BRD4 gene on chromosome 19p13. Rarely, in about 1/3 of cases, other translocation partners are involved (termed NUT-variants). Most cases have involved midline structures and with few exceptions were located in the upper aerodigestive tract and the mediastinum. Except for a single case, all reported NMC have been fatal, proving resistant to multimodality treatment. We report an exceptional case of a NMC presenting outside of midline structures in the parotid gland and showing mesenchymal chondroid differentiation in a 15-year-old male. The presence of the t(15;19) chromosomal translocation in the chondroid component was confirmed by fluorescence in situ hybridization analysis and immunohistochemical staining, indicating mesenchymal transdifferentation of the tumor. The findings demonstrate the first case of NMC arising within salivary gland, and the first example of mesenchymal differentiation in this group of tumors.

High-grade transformation of acinic cell carcinoma (AciCC) (previously referred to as dedifferentiation) is a rare phenomenon characterized by histologic progression of low-grade AciCC to high-grade adenocarcinoma or undifferentiated carcinoma. We report 9 new cases with immunohistochemical analysis and examination of HER-2/neu and p53 genes to further define the profile of this tumor. Histologically, the high-grade component was composed of polymorphic cells with a high mitotic rate arranged in glandular and solid growth patterns with comedonecrosis. The MIB-1 labeling indices were elevated in the high-grade component, as compared with the low grade conventional AciCC. The high-grade component of AciCC was characterized by strong membrane staining for CK18 and beta-catenin, and nuclear staining for cyclin-D1. HER-2/neu, androgen receptor, C-kit, and epidermal growth factor receptor were absent from both low-grade and high-grade components. In contrast, S-100 protein, alpha-1-antitrypsin, and lysozyme were lost only in high-grade foci of transformed AciCC. The median age was 61 years (with range from 43 to 76 y). Lymph node (LN) metastases were found in 5 of 9 cases (56%). Distant metastases to the lungs (n=4), pleura (n=2), brain (n=3), and peritoneum (n=1), and paraaortic, paratracheal, and mediastinal LNs (n=2) were observed. Six of 9 patients (66%) died from tumor dissemination, all with a median overall survival of 4.3 years (range: 1 to 9 y). The high propensity for LN metastases indicates the need for neck dissection at the time of diagnosis.

The majority of AIDS-related non-Hodgkin's lymphomas are clinically aggressive monoclonal B-cell Burkitt's lymphomas, large cell lymphomas, or immunoblastic lymphomas. In contrast, the lymphoid proliferations arising in solid organ transplant recipients, collectively referred to as posttransplantation lymphoproliferative disorders (PT-LPDs), represent a clinically and histopathologically heterogeneous group of Epstein-Barr virus (EBV)-driven B-cell proliferations of variable clonal composition. During a retrospective histopathologic review of lymphoid proliferations associated with human immunodeficiency virus (HIV) infection we identified 10 cases that morphologically resemble the polymorphic PT-LPDs. They arose in lymph nodes (five), lungs (two), and the parotid gland, perineum, and skin (one each). They exhibit a diffuse growth pattern and are composed of a polymorphic lymphoid cell population exhibiting a variable degree of plasmacytic differentiation, cytologic atypia, and numbers of atypical immunoblasts. A clonal B-cell population was detected by immunoglobulin heavy and light chain gene rearrangement and/or EBV terminal repeat analysis in 8 of the 10 (80%) cases by Southern blotting. The nongermline hybridizing bands were usually faint, however, suggesting that the clonal B-cell population represented only a subpopulation within the polymorphic lesion. Strong clonal rearrangement bands were present in one case in which there was clear morphologic evidence of transformation to diffuse large cell lymphoma. This case exhibited C-MYC, BCL-6, and p53 gene mutations. One other case exhibited a p53 gene mutation. The remaining eight cases lacked C-MYC, BCL-6, RAS, and p53 gene alterations. Clonal EBV infection was detected in 4 of the 10 (40%) lesions. Like EBV-containing PT-LPDs, all four EBV-positive HIV-associated polymorphic lesions were associated with type A EBV. The Kaposi's sarcoma-associated herpesvirus was detectable in two cases by polymerase chain reaction analysis, but not by Southern blotting. In situ hybridization demonstrated Kaposi's sarcoma-associated herpesvirus in some of the cytologically malignant-appearing cells. In conclusion, polymorphic B-cell lymphoproliferative disorders comparable morphologically and molecularly to those arising after solid organ transplantation also occur in association with HIV infection. As in the case of their polymorphic PT-LPD counterparts, their malignant status, biologic significance, and relationship to monomorphic B-cell lymphomas remain to be elucidated.

Low-grade mucosa-associated lymphoid tissue (MALT) type B-cell lymphomas of the salivary gland arise in a background of myoepithelial sialadenitis (MESA), usually in association with Sjögren's syndrome. The distinction between benign MESA and early lymphoma has proved difficult using histological criteria alone and the significance of B-cell monoclonality in this respect is controversial. We have used immunohistochemistry and polymerase chain reaction (PCR) amplification of immunoglobulin heavy-chain VDJ regions to assess clonality in biopsies from 45 patients with lymphoid infiltration of the parotid. Sequential biopsies spanning 3-18 years were available from seven patients, three of whom had developed disseminated nodal B-cell lymphoma. In light of previous studies, each biopsy was additionally analyzed for the presence of t(14;18) and Epstein Barr Virus (EBV) DNA using PCR. Monoclonality was detected in 34/45 cases. Comparison of histology with clonality confirmed earlier suggestions that the emergence of an identifiable population of centrocyte-like B cells around ducts or epithelial islands correlated with monoclonality. In six of seven patients with sequential biopsies PCR fragments of identical size were amplified from each biopsy, suggesting that demonstrable monoclonality in "lymphoepithelial" lymphoproliferative lesions of the salivary gland is indicative of lymphoma. No t(14;18) chromosome translocations were identified; EBV sequences were detected in three of 45 cases.