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The article presents a case study that determines the characteristics of the acrodermatitis continua of Hallopeau (ACH), a rare acropustular subtype of psoriasis. It cites the case of an 80-year-old Japanese man who was presented with chronic persistent pustules and erosions on fingers, toes and the right upper arm. It also mentions the treatment intervention given to the patient to help improve his condition.

Background: A substantial portion of gastric cancer (GC) is linked to Epstein-Barr virus (EBV) infection. The characteristics of this viral genome, such as specific viral strains and large structural variations, influence the progression of diseases like nasopharyngeal carcinoma and hematological malignancy. However, the EBV genomes from GC have not been thoroughly characterized., Methods: Our study involved 849 consecutive GC patients diagnosed at Nagoya City University Hospital, Japan (NCU cohort). We detected EBV from formalin-fixed, paraffin-embedded sections using a novel direct PCR-based rapid detection method. Additionally, we analyzed 142 EBV whole genomes (125 newly sequenced) from GC, comparing them with 205 genomes from other EBV-associated diseases., Results: We identified 32 (3.8%) patients associated with EBVaGC in the NCU cohort. Moreover, the direct PCR identified several GC specimens containing EBV-infected lymphocytes or their follicles. The dominant viral strain in GC was type 1 EBV, prevalent in most parts of the world, and no GC-specific strain was identified. We found no significant associations between single-nucleotide variants in the viral genome and GC. Structural variations of the EBV genome were infrequent in GC (4 cases, 2.1%), contrasting with EBV-associated hematological malignancy, which frequently carries large deletions., Conclusions: This study is the first to uncover the genomic variations of EBV in GC. While EBV is definitively linked to GC, the characteristics of its genomes do not strongly correlate with disease development or progression. Our findings on viral genomes supplement the current understanding of human genomes in EBVaGC., Competing Interests: Declarations. Conflict of interest: Akira Satou received a research grant from Eisai Company. Other authors declare that they have no conflict of interest., (© 2024. Japanese Society of Gastroenterology.)

Competing Interests: Conflicts of interest The authors declare no conflicts of interest.

Squamous cell carcinoma (SCC) is one of the most common malignancies involving the parotid gland, but it has been recognized that the vast majority of parotid SCC represents metastases, especially from the ipsilateral facial skin. Bona fide primary SCC of the parotid is so rare that it is unclear whether it truly exists at all. We sought to molecularly characterize cases diagnosed as primary parotid gland SCC to see if they possess a unique genetic makeup.We identified cases in our archives which had been diagnosed as primary SCC of the parotid gland. In all cases, metastatic disease was excluded by a thorough history and physical examination. Cases with histologic evidence of a precursor neoplasm (e.g., carcinoma ex-pleomorphic adenoma) were also excluded. Targeted next-generation sequencing (NGS) was attempted on all cases.Six cases diagnosed as primary parotid SCC were identified, arising in 4 males and 2 females ranging from 8 to 73 years (mean, 51.8 years). All cases exhibited keratinization and unequivocal invasion. Four of 6 appeared to be arising from cystically dilated ducts. Five of 6 exhibited well-developed cellular atypia; the remaining case, while cytologically bland, demonstrated perineural invasion. Targeted NGS was successful in 5 of 6 cases. Two SCC harbored several mutations in a mutational profile reminiscent of SCCs seen in other organs. One case harbored YAP1::MAML2, a fusion previously reported in porocarcinoma and other neoplasms. One case harbored IRF2BP2::RUNX2, and presumably represents keratocystoma or SCC ex-keratocystoma. Finally, one case an increase of C > T mutations consistent with ultraviolet damage, suggesting that this case represented a cryptic metastasis from cutaneous SCC.Our analysis did not confirm a unifying genetic signature for purported primary parotid SCC. Indeed, our findings suggest that true primary parotid gland SCC is even rarer than already believed. In our 5 cases with results, NGS findings demonstrated that one was likely a keratocystoma, one a cryptic metastasis from a cutaneous SCC, and one a porocarcinoma, either metastatic or primary. The two remaining cases had complex genotypes reminiscent of SCCs from other sites. This may be the signature of genuine parotid primary SCC, but metastasis from an SCC from another organ cannot be excluded. Accordingly, a diagnosis of primary parotid gland SCC should be viewed with skepticism., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Many researchers have focused on the role of the autonomic nervous system in the tumor microenvironment. Autonomic nerves include the sympathetic and parasympathetic nerves, which are known to induce cancer growth and metastasis. However, in salivary duct carcinoma (SDC), a rare and highly malignant tumor, the issue should be investigated from both biological and therapeutic perspectives. We explored the clinicopathological and prognostic implications of the autonomic nerves in 129 SDCs. Immunohistochemistry was performed to determine the nature of each nerve using antibodies against S100, tyrosine hydroxylase (TH) as a sympathetic marker, and vesicular acetylcholine transporter (VAChT) as a parasympathetic marker. The area of each marker-positive nerve was digitized and evaluated quantitatively. Double immunofluorescence for TH and VAChT was performed in selected cases. The expression of the secreted neurotrophins was also examined. S100-positive nerves were present in the cancer tissue in 94 of 129 cases (72.9%). Among them, TH-positive sympathetic nerves and/or VAChT-positive parasympathetic nerves were identified in 92 cases (97.9%), and 59 cases (62.8%) had TH/VAChT-co-expressing nerves. Double immunofluorescence revealed a mosaic pattern of sympathetic and parasympathetic fibers in co-expressing nerve bundles. The presence of autonomic nerves, regardless of their area, was significantly associated with aggressive histological features, advanced T/N classification, and a poor prognosis, with shorter disease-free and overall survival. There was an association between some tumor immune microenvironment-related markers and the autonomic nerve status, but not the latter and the secreted neurotrophin expression. This study suggests that autonomic nerves might play a role in the progression of SDC., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The differential diagnosis of salivary gland lesions with epithelial components and lymphoid stroma is often challenging. Salivary gland carcinoma with tumor-associated lymphoid proliferation, tumors composed of both epithelial and lymphoid components, lymphoid neoplasms in the salivary gland, and inflammatory lesions are all included in this category. It encompasses inflammatory lesions and neoplastic lesions. With the exception of Warthin tumors, these lesions are rare, making them more difficult to diagnose. Carcinoma showing thymus-like elements has recently been reported in the salivary gland. Similar to thymic carcinoma, tumor cells are positive for CD5 and are accompanied by T lymphocytes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of competing interest The author declares no conflicts of interest in association with the present study. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The author is an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for [Journal name] and was not involved in the editorial review or the decision to publish this article. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Masato Nakaguro.

High-grade carcinomas of the salivary glands are a group of several tumor entities with highly malignant histologic appearances, and have an aggressive biological behavior accompanied by poor a prognosis. In general, they require more intensive treatment than low- or intermediate-grade carcinomas. High-grade salivary carcinomas are rare and the microscopic features often overlap between different tumor types, making an appropriate diagnosis challenging in daily practice settings. However, with recent rapid advances in molecular pathology and molecular-targeted therapy in this field, there is a growing need to properly classify tumors, rather than just diagnosing the cases as "high-grade carcinomas". This leads to specific treatment strategies. In this article, we review representative high-grade salivary gland carcinomas, including salivary duct carcinoma and its histologic subtypes, high-grade mucoepidermoid carcinoma, solid-type adenoid cystic carcinoma, and high-grade transformation of low- or intermediate-grade carcinomas, and discuss their differential diagnoses and clinical implications. Other rare entities, such as neuroendocrine carcinoma, NUT carcinoma, and metastatic carcinoma, should also be considered before diagnosing high-grade carcinoma, NOS. Of these tumors, salivary duct carcinoma has received the most attention because of its strong association with androgen deprivation and anti-HER2 therapies. Other tumor-type-specific treatments include anti-TRK therapy for high-grade transformation of secretory carcinoma, but further therapeutic options are expected to be developed in the future. It should be emphasized that detailed histological evaluation with adequate sampling, in addition to the effective use of molecular ancillary tests, is of the utmost importance for a suitable diagnosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Salivary gland tumors (SGT) display morphological diversity and pose diagnostic challenges. Preoperative fine needle aspiration cytology (FNAC) is a minimally invasive and efficient diagnostic test. However, due to the limited sample size, the final diagnosis may not be established based on FNAC alone. Although cytomorphology and architecture are usually preserved on FNAC, morphologic changes specific to FNAC can complicate the diagnosis. The Milan System for Reporting Salivary Gland Cytopathology categorizes complex FNAC interpretations. Because the cytological diagnosis is closely linked to the histological diagnosis, a multidimensional approach considering the possibility of several differential diagnoses is necessary. From the standpoint of treatment, distinguishing high-grade malignancy from low-grade malignancy is more important than distinguishing malignancy from benign tumors., Competing Interests: Declaration of competing interest The author declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The author is a Guest Editor for Seminars in Diagnostic Pathology and was not involved in the editorial review or the decision to publish this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Keratocystoma is a rare salivary gland lesion that has been reported primarily in children and young adults. Because of a scarcity of reported cases, very little is known about it, including its molecular underpinnings, biological potential, and histologic spectrum. Purported to be a benign neoplasm, keratocystoma bears a striking histologic resemblance to benign lesions like metaplastic Warthin tumor on one end of the spectrum and squamous cell carcinoma on the other end. This overlap can cause diagnostic confusion, and it raises questions about the boundaries and definition of keratocystoma as an entity. This study seeks to utilize molecular tools to evaluate the pathogenesis of keratocystoma as well as its relationship with its histologic mimics. On the basis of targeted RNA sequencing (RNA-seq) results on a sentinel case, RUNX2 break-apart fluorescence in situ hybridization (FISH) was successfully performed on 4 cases diagnosed as keratocystoma, as well as 13 cases originally diagnosed as tumors that morphologically resemble keratocystoma: 6 primary squamous cell carcinomas, 3 metaplastic/dysplastic Warthin tumors, 2 atypical squamous cysts, 1 proliferating trichilemmal tumor, and 1 cystadenoma. RNA-seq and/or reverse transcriptase-PCR were attempted on all FISH-positive cases. Seven cases were positive for RUNX2 rearrangement, including 3 of 4 tumors originally called keratocystoma, 2 of 2 called atypical squamous cyst, 1 of 1 called proliferating trichilemmal tumor, and 1 of 6 called squamous cell carcinoma. RNA-seq and/or reverse transcriptase-PCR identified IRF2BP2::RUNX2 in 6 of 7 cases; for the remaining case, the partner remains unknown. The cases positive for RUNX2 rearrangement arose in the parotid glands of 4 females and 3 males, ranging from 8 to 63 years old (mean, 25.4 years; median, 15 years). The RUNX2 -rearranged cases had a consistent histologic appearance: variably sized cysts lined by keratinizing squamous epithelium, plus scattered irregular squamous nests, with essentially no cellular atypia or mitotic activity. The background was fibrotic, often with patchy chronic inflammation and/or giant cell reaction. One case originally called squamous cell carcinoma was virtually identical to the other cases, except for a single focus of small nerve invasion. The FISH-negative case that was originally called keratocystoma had focal cuboidal and mucinous epithelium, which was not found in any FISH-positive cases. The tumors with RUNX2 rearrangement were all treated with surgery only, and for the 5 patients with follow-up, there were no recurrences or metastases (1 to 120 months), even for the case with perineural invasion. Our findings solidify that keratocystoma is a cystic neoplastic entity, one which appears to consistently harbor RUNX2 rearrangements, particularly IRF2BP2::RUNX2 . Having a diagnostic genetic marker now allows for a complete understanding of this rare tumor. They arise in the parotid gland and affect a wide age range. Keratocystoma has a consistent morphologic appearance, which includes large squamous-lined cysts that mimic benign processes like metaplastic Warthin tumor and also small, irregular nests that mimic squamous cell carcinoma. Indeed, RUNX2 analysis has considerable promise for resolving these differential diagnoses. Given that one RUNX2 -rearranged tumor had focal perineural invasion, it is unclear whether that finding is within the spectrum of keratocystoma or whether it could represent malignant transformation. Most important, all RUNX2 -rearranged cases behaved in a benign manner., Competing Interests: Conflicts of Interest and Source of Funding: Supported by Jane B. and Edwin P. Jenevein M.D Endowment for Pathology at UT Southwestern Medical Center. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Superficial non-ampullary duodenal epithelial tumors (SNADETs) include low-grade adenoma (LGA) and high-grade adenoma or carcinoma (HGA/Ca) and are classified into two different epithelial subtypes, gastric-type (G-type) and intestinal-type (I-type). We attempted to distinguish them by endoscopic characteristics including magnifying endoscopy with narrow-band imaging (M-NBI)., Methods: Various endoscopic and M-NBI findings of 286 SNADETs were retrospectively reviewed and compared between G- and I-types and histological grades. M-NBI findings were divided into four patterns based on the following vascular patterns; absent, network, intrastructural vascular (ISV), and unclassified. Lesions displaying a single pattern were classified as mono-pattern and those displaying multiple patterns as mixed-pattern. Lesions showing CDX2 positivity were categorized as I-types and those showing MUC5AC or MUC6 positivity were categorized as G-types based on immunohistochemistry., Results: Among 286 lesions, 23 (8%) were G-type and 243 (85%) were I-type. More G-type lesions were located oral to papilla (91.3 vs. 45.6%, p < 0.001), and had protruding morphology compared to those of I-types (65.2 vs. 14.4%, p < 0.001). The major M-NBI pattern was ISV in G-type (78.2 vs. 26.3%, p < 0.001), and absent for I-type (0 vs. 34.5%, p = 0.003). Three endoscopic characteristics; location oral to papilla, protruding morphology, and major M-NBI pattern (ISV) were independent predictors for G-type. Mixed-pattern was more common in HGA/Ca than LGA for I-type (77.0 vs. 58.8%, p = 0.01); however, there was no difference for those in G-type., Conclusion: Endoscopic findings including M-NBI are useful to differentiate epithelial subtypes., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Recently, the detection of superficial non-ampullary duodenal epithelial tumors (SNADETs) including adenomas and superficial duodenal carcinomas has increased. Various endoscopic treatment methods have also been reported for SNADETs, but there are few reports on the natural history. The aim of this study was to analyze factors related to tumor growth and determine the characteristics of SNADETs which need early therapeutic intervention., Methods: A single-center, retrospective study was performed on the medical records of 309 patients with SNADETs who underwent endoscopic or surgical resection between January 2010 and May 2021. Of these, 41 patients who were followed up for more than 1 year by endoscopy were analyzed. The primary outcome was an analysis of the tumor growth speed. Secondary outcomes were the relationship between the tumor growth speed and mucin phenotype, tumor size and findings of magnifying endoscopy with narrow-band imaging (M-NBI)., Results: The observation period was 24 months (13-182). Tumor growth speed was 1.1 mm/year (0-21.6). Tumor diameter ≥10 mm at first detection (p = 0.004; odds ratio 19.5 [2.03-186.96]) and mixed type by M-NBI (p = 0.036; odds ratio 9.69 [1.05-89.88]) were identified as risk factors of tumors growing at a rate of ≥3 mm/year. There was no statistically significant difference in the speed of tumor growth between the different mucin immunohistochemical phenotypes., Conclusion: Initial tumor size and findings of M-NBI are useful to predict tumor growth and consider early intervention., (© 2024 S. Karger AG, Basel.)

Adenocarcinoma, not otherwise specified (NOS) is a heterogenous group of salivary gland tumors that likely contains distinct tumors that have not yet been characterized. Indeed, in recent years, cases previously diagnosed as adenocarcinoma, NOS have been recategorized into novel tumor designations such as secretory carcinoma, microsecretory adenocarcinoma, and sclerosing microcystic adenocarcinoma. We sought to describe a distinctive, hitherto-undescribed salivary gland tumor encountered in the authors' practices. Cases were pulled from the surgical pathology archives of the authors' institutions. Histologic, immunohistochemical, and clinical findings were tabulated, and targeted next-generation sequencing was performed on all cases. Nine cases were identified, arising in 8 women and 1 man ranging from 45 to 74 years (mean, 56.7 y). Seven tumors (78%) arose in the sublingual gland, while 2 (22%) arose in the submandibular gland. The cases shared a distinctive morphologic appearance. They were biphasic, with ducts scattered among a predominant polygonal cell with round nuclei, prominent nucleoli, and pale eosinophilic cytoplasm. These cells were arranged as trabeculae and palisaded as pseudorosettes around hyalinized stroma and vessels, resembling a neuroendocrine tumor. Four of the cases were well-circumscribed, while the remaining 5 showed infiltrative growth including perineural invasion in 2 (22%) and lymphovascular invasion in 1 (11%). Mitotic rates were low (mean, 2.2/10 HPFs); necrosis was absent. By immunohistochemistry, the predominant cell type was strongly positive for CD56 (9 of 9) and variably positive for pan-cytokeratin (AE1/AE3) (7 of 9) with patchy S100 (4 of 9), but negative for synaptophysin (0 of 9) and chromogranin (0 of 9), while the ducts were strongly positive for pan-cytokeratin (AE1/AE3) (9 of 9) and CK5/6 (7 of 7). Next-generation sequencing did not reveal any fusions or obvious driver mutations. All cases were resected surgically, with external beam radiation also done in 1 case. Follow-up was available in 8 cases; there were no metastases or recurrences after 4 to 160 months (mean, 53.1 mo). A dual population of scattered ducts with a predominance of CD56-positive neuroendocrine-like cells characterizes a unique salivary gland tumor which is often encountered in the sublingual glands of women, for which we propose the term "palisading adenocarcinoma." Although the tumor was biphasic and had a neuroendocrine-like appearance, it lacked convincing immunohistochemical evidence of myoepithelial or neuroendocrine differentiation. Although a subset showed unequivocally invasive growth, this tumor appears to behave in an indolent manner. Moving forward, recognition of palisading adenocarcinoma and its separation from other salivary adenocarcinomas, NOS will facilitate a better understanding of the characteristics of this previously unrecognized tumor., Competing Interests: Conflicts of Interest and Source of Funding: Supported by Jane B. and Edwin P. Jenevein M.D Endowment for Pathology at UT Southwestern Medical Center. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Approximately 60% of adenoid cystic carcinoma (AdCC) cases are positive for MYB::NFIB or MYBL1::NFIB, whereas MYB/MYBL1 oncoprotein, a key driver of AdCC, is overexpressed in most cases. Juxtaposition of superenhancer regions in NFIB and other genes into the MYB/MYBL1 locus is an attractive oncogenic hypothesis for AdCC cases, either negative or positive for MYB/MYBL1::NFIB. However, evidence supporting this hypothesis is insufficient. We examined 160 salivary AdCC cases for rearrangements in MYB/MYBL1 loci and peri-MYB/MYBL1 areas (centromeric and telomeric areas of 10 Mb each) using formalin-fixed, paraffin-embedded tumor sections. For the detection of the rearrangements, we employed conventional fluorescence in situ hybridization split and fusion assays and a 5 Mb fluorescence in situ hybridization split assay. The latter is a novel assay that enabled us to detect any possible splits within a 5 Mb distance of a chromosome. We found MYB/MYBL1- and peri-MYB/MYBL1-associated rearrangements in 149/160 patients (93%). AdCC cases positive for rearrangements in MYB, MYBL1, the peri-MYB area, and the peri-MYBL1 area numbered 105 (66%), 20 (13%), 19 (12%), and 5 (3%), respectively. In 24 peri-MYB/MYBL1 rearrangement-positive cases, 14 (58%) were found to have a juxtaposition of the NFIB or RAD51B locus into the MYB/MYBL1 loci. On comparing with a tumor group positive for MYB::NFIB, a hallmark of AdCC, other genetically classified tumor groups had similar features of overexpression of the MYB transcript and MYB oncoprotein as detected by semiquantitative RT-qPCR and immunohistochemistry, respectively. In addition, clinicopathological and prognostic features were similar among these groups. Our study suggests that peri-MYB/MYBL1 rearrangements may be a frequent event in AdCC and may result in biological and clinicopathological consequences comparable to MYB/MYBL1 rearrangements. The landscape of MYB/MYBL1 and peri-MYB/MYBL1 rearrangements shown here strongly suggests that juxtaposition of superenhancers into MYB/MYBL1 or peri-MYB/MYBL1 loci is an alteration that acts as a key driver for AdCC oncogenesis and may unify MYB/MYBL1 rearrangement-positive and negative cases., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Based on computed tomography (CT) findings of lung cancer, solid nodules have a much worse prognosis than subsolid nodules, even if the nodules are subcentimeter in size. There is, however, no systematic method for determining the prognosis of solid tumors on CT. This study aimed to discover the prognostic factor of early-stage solid lung adenocarcinoma using three-dimensional CT volumetry., Methods: Patients with pathological stage I solid lung adenocarcinoma who underwent complete resection between 2007 and 2012 were selected in this retrospective study. Clinicopathological data and preoperative multidetector CT findings, such as tumor size on the two-dimensional axial image, three-dimensional tumor volume between -600 and 199 HU, and three-dimensional solid volume between 0 and 199 HU, which corresponded to highly solid components, were compared between recurrence and non-recurrence. Furthermore, these radiological values were compared to pathological invasive volume (PIV)., Results: During this time, 709 patients had their lung cancer completely removed. From this cohort, 90 patients with pathological stage I solid lung adenocarcinoma were selected. In addition, recurrence was found in 26 patients (28.9%). Although two-dimensional axial image, serum carcinoembryonic antigen (CEA) level, and SUVmax on 18F fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) did not differ statistically between recurrent and non-recurrent patients, three-dimensional tumor and solid tumor volume did. Multivariate analysis indicated that three-dimensional solid tumor volume [hazard ratio: 2.440; 95% confidence interval (CI): 1.110-5.361, P=0.026] and epidermal growth factor receptor (EGFR) mutation (hazard ratio: 4.307; 95% CI: 1.328-13.977, P=0.015) were significantly associated with disease-free survival (DFS). When three-dimensional tumor and solid tumor volume were compared to PIV, three-dimensional solid tumor volume (3,091 mm 3 on average) showed a highly similar value with PIV (2,930 mm 3 on average), whereas three-dimensional tumor volume (6,175 mm 3 on average) was significantly larger than PIV (P<0.001)., Conclusions: In patients with early-stage solid lung adenocarcinoma, the measurement of three-dimensional solid tumor volume, which is correlated with PIV, accurately predicted the postoperative outcome., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-23-36/coif). The authors have no conflicts of interest to declare., (2023 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Salivary duct carcinoma (SDC) is an aggressive type of salivary gland carcinoma. Recently, immunotherapies targeting immune checkpoints, including PD1, PD-L1, CTLA4, and LAG3, have had a considerable prognostic impact on various malignant tumors. The implementation of such immune checkpoint inhibitor (ICI) therapies has also been attempted in cases of salivary gland carcinoma. The tumor immune microenvironment (TIME) is implicated in tumorigenesis and tumor progression and is closely associated with the response to ICI therapies. However, the TIME in SDC has not been fully explored. We examined the immunohistochemical expression of CD8, FOXP3, PD1, PD-L1, CTLA4, LAG3, and mismatch repair (MMR) proteins, tumor-infiltrating lymphocytes (TILs), and microsatellite instability (MSI) status in 175 cases of SDC. The associations between these TIME-related markers and the clinicopathological factors and prognosis were evaluated. An elevated expression of CD8, FOXP3, PD1, CTLA4, and LAG3 was associated with more aggressive histological features and an advanced N and/or M classification, elevated Ki-67 index, and poor prognosis. Furthermore, cases with a high PD-L1 expression exhibited more aggressive histological features and adverse clinical outcomes than those with a low expression. Alternatively, there was no significant correlation between TILs and clinicopathological factors. No SDC cases with an MSI-high status or MMR deficiency were found. The coexistence of both an immunostimulatory and immunosuppressive TIME in aggressive SDC might play a role in the presence of T-cell exhaustion. The contribution of multiple immune escape pathways, including regulatory T cells and immune checkpoints, may provide a rationale for ICI therapy, including combined PD1/CTLA4 blockade therapy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Salivary gland intraductal papillary mucinous neoplasm (SG IPMN) is a recently proposed entity characterized by a papillary-cystic proliferation of mucin-producing cells. Because of overlapping histologic features and a clonal AKT1 p.E17K variant, SG IPMN has been presumed to be a precursor or a low-grade subtype of mucinous adenocarcinoma. NKX3.1 is a tumor suppressor gene located on chromosome 8p and is a known immunohistochemical marker of prostate epithelium and mucinous acinar cells of the intraoral salivary glands., Methods: We retrieved 12 SG IPMN cases, and performed histologic and genetic analysis. Given the association of SG IPMN with mucinous acinar cells, we also investigated the performance of NKX3.1 as a marker of this tumor entity., Results: Diffuse and strong NKX3.1 expression was observed in all SG IPMN cases (12/12, 100%) as well as in normal mucinous acinar cells. In contrast, mucoepidermoid carcinoma and pancreatic IPMN cases as well as normal serous acinar cells were negative for NKX3.1. Genetically, 11 of 12 cases (92%) harbored an AKT1 p.E17K variant. A novel PTEN frameshift deletion (p.G36Dfs*18) was detected in the other single case. At least one of the histologic features implying malignant tumors, such as severe cellular atypia, brisk mitotic activity, high Ki-67 proliferating index, lymphovascular invasion, and lymph node metastasis, was detected in 6 SG IPMN cases (50%)., Conclusion: The findings suggest that SG IPMN is a low-grade subtype of mucinous adenocarcinoma which may be derived from mucinous acinar cells of the minor salivary gland., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Molecular targets and predictive biomarkers for prognosis in salivary duct carcinoma (SDC) have not been fully identified. We conducted comprehensive molecular profiling to discover novel biomarkers for SDC. A total of 67 SDC samples were examined with DNA sequencing of 464 genes and transcriptome analysis in combination with the clinicopathological characteristics of the individuals. Prognostic biomarkers associated with response to combined androgen blockade (CAB) treatment were explored using mRNA expression data from 27 cases. Oncogenic mutations in receptor tyrosine kinase (RTK) genes or genes in the MAPK pathway were identified in 55 cases (82.1%). Alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway were identified in 38 cases (56.7%). Interestingly, patient prognosis could be predicted using mRNA expression profiles, but not genetic mutation profiles. The risk score generated from the expression data of a four-gene set that includes the ADAMTS1, DSC1, RNF39, and IGLL5 genes was a significant prognostic marker for overall survival in the cohort (HR = 5.99, 95% confidence interval (CI) = 2.73-13.1, p = 7.8 × 10 -6 ). Another risk score constructed from the expression of CD3E and LDB3 was a strong prognostic marker for progression-free survival for CAB treatment (p = 0.03). Mutations in RTK genes, MAPK pathway genes, and PI3K/AKT pathway genes likely represent key mutations in SDC tumorigenesis. The gene expression profiles identified in this study may be useful for stratifying patients who are good candidates for CAB treatment and may benefit from additional systemic therapies., (© 2022. The Author(s).)

Background and Aims: Parkinson's disease (PD) is the second most neurodegenerative disease after Alzheimer's disease. Accumulating knowledge points to the notion that abnormal aggregation of alpha-synuclein (αSyn) starts in the gut and ascends to the substantia nigra via the vagus nerve in about a half of PD patients. Epidemiological studies revealed that ulcerative colitis (UC) increases a risk for PD 1.3 to 1.8-folds. However, it remains unknown whether αSyn is abnormally aggregated in the enteric neurons in UC patients., Methods: We first inspected and optimized the immunostaining protocols with an anti-phosphorylated αSyn antibody, pSyn#64, using the brain and the gut of eight autopsied cases (five with PD and three without PD). Then, we examined abnormal αSyn aggregation in the enteric neurons in 23 and 18 colectomized patients with and without UC, respectively. Five or more sections were stained for αSyn in each of 87 and 25 paraffin- embedded blocks in patients with and without UC, respectively., Results: Ten different protocols of epitope exposure appropriately stained aggregated αSyn in the brain, but only complete lack of epitope exposure stained aggregated αSyn in the colon with low background. Abnormal αSyn aggregates, which was confirmed by co-localization of p62, in the enteric neurons were detected in a single patient with UC but not in any patients without UC., Conclusions: Omission of epitope exposure enabled us to immunostain aggregated αSyn in the colon by pSyn#64 with low nonspecific staining, but the number of 23 UC patients was not high enough to discern whether abnormal αSyn aggregation in the colonic neural plexus was increased in UC or not.

Background: The efficacy and safety of human epidermal growth factor receptor 2 (HER2)-targeted therapy and androgen deprivation therapy (ADT) for locally advanced or recurrent or metastatic (LA/RM) salivary duct carcinoma (SDC) have been reported in prospective studies. However, the survival benefit of these therapies to conventional therapy remains controversial, and whether HER2-targeted therapy or ADT should be chosen in HER2- and androgen receptor (AR)-positive SDC patients remains unknown., Methods: Overall, 323 LA/RM SDC patients treated at seven institutions between August 1992 and June 2020 were retrospectively enrolled. The primary aim was to analyze the effect of HER2-targeted therapy and ADT on overall survival from the diagnosis of LA/RM disease to death from any cause (OS1). The secondary indicators included the overall response rate (ORR), clinical benefit rate (CBR), overall survival from therapy initiation for LA/RM disease (OS2), progression-free survival (PFS), time to second progression (PFS2), duration of response (DoR), and duration of clinical benefit (DoCB) of HER2-targeted therapy or ADT as first-line therapy for HER2-positive/AR-positive SDC., Results: Patients treated with HER2-targeted therapy or ADT had longer OS1 than those treated without these therapies (Median OS1: historical control, 21.6 months; HER2-targeted therapy, 50.6 months; ADT, 32.8 months; HER2-targeted therapy followed by ADT, 42.4 months; and ADT followed by HER2-targeted therapy, 45.2 months, p  < 0.001). Among HER2-positive/AR-positive SDC patients, although HER2-targeted therapy had better ORR, CBR, and PFS than those of ADT as first-line therapy, we found no significant differences between HER2-targeted therapy and ADT regarding OS2, PFS2, DoR, and DoCB., Conclusion: Patients treated with HER2-targeted therapy and ADT showed longer survival in LA/RM SDC. HER2-targeted therapy can be recommended prior to ADT for HER2-positive/AR-positive SDC. It is warranted to establish a biomarker that could predict the efficacy of clinical benefit or better response in ADT., Competing Interests: Competing interests: The authors declare that there is no conflict of interest., (© The Author(s), 2022.)

Background: Polymorphous adenocarcinoma is a common intraoral minor salivary gland carcinoma in Western countries but is extremely rare in Japan. The current study aimed to characterize the clinicopathological features and status of molecular alterations of polymorphous adenocarcinoma-associated genes, such as PRKD1/2/3, ARID1A, and DDX3X, in a large cohort of Japanese patients with polymorphous adenocarcinoma., Methods: We examined the cases of 36 Japanese patients with salivary gland polymorphous adenocarcinoma and 26 cases involving histopathological mimics. To detect gene splits, fluorescence in situ hybridization was carried out for polymorphous adenocarcinoma-associated genes. Additionally, we applied a SNaPshot multiplex assay to identify PRKD1 hotspot mutations., Results: This study revealed the indolent clinical course of polymorphous adenocarcinoma with a high 10-year overall survival rate (92.9%), accompanied by occasional local recurrences and cervical lymph node metastasis (23.3%). Twenty cases (55.6%) of polymorphous adenocarcinoma (but none of the mimics) exhibited alterations in at least one polymorphous adenocarcinoma-associated gene. Rearrangement of polymorphous adenocarcinoma-associated genes and PRKD1 E710D were identified in 17 (47.2%) and 4 (11.1%) cases, respectively; one case showed coexisting PRKD3 split and PRKD1 E710D. In the multivariate analysis, high clinical stage (p = 0.0005), the presence of prominent nucleoli (p = 0.0003), and ARID1A split positivity (p = 0.004) were independent risk factors for disease-free survival., Conclusion: Japanese patients with polymorphous adenocarcinoma showed clinicopathological features similar to those reported in Western countries. This study disclosed that polymorphous adenocarcinoma-associated genetic alterations were common and specific findings in polymorphous adenocarcinomas. The diagnostic role and possible prognostic significance of polymorphous adenocarcinoma-associated genetic alterations in polymorphous adenocarcinomas were suggested., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Microsatellite instability (MSI)-high status is associated with good responsiveness to immune checkpoint inhibitors. Although MSI-high status has been actively investigated in pediatric brain tumors, studies of other pediatric solid tumors are lacking. Among 334 consecutive pediatric patients with solid tumors, we retrospectively analyzed formalin-fixed paraffin-embedded tumor tissues of 36 of 74 patients (49%) who died of disease. We assessed the MSI status in these tissues using five multiplexed markers. The results revealed that none of the patients had an MSI-high status. These results indicate that MSI-high status is a rare event in pediatric patients with refractory/relapsed solid tumors.Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2021.1998266.

Purpose: For the image classification problem, the construction of appropriate training data is important for improving the generalization ability of the classifier in particular when the size of the training data is small. We propose a method that quantitatively evaluates the typicality of a hematoxylin-and-eosin (H&E)-stained tissue slide from a set of immunohistochemical (IHC) stains and applies the typicality to instance selection for the construction of classifiers that predict the subtype of malignant lymphoma to improve the generalization ability., Methods: We define the typicality of the H&E-stained tissue slides by the ratio of the probability density of the IHC staining patterns on low-dimensional embedded space. Employing a multiple-instance-learning-based convolutional neural network for the construction of the subtype classifier without the annotations indicating cancerous regions in whole slide images, we select the training data by referring to the evaluated typicality to improve the generalization ability. We demonstrate the effectiveness of the instance selection based on the proposed typicality in a three-class subtype classification of 262 malignant lymphoma cases., Results: In the experiment, we confirmed that the subtypes of typical instances could be predicted more accurately than those of atypical instances. Furthermore, it was confirmed that instance selection for the training data based on the proposed typicality improved the generalization ability of the classifier, wherein the classification accuracy was improved from 0.664 to 0.683 compared with the baseline method when the training data was constructed focusing on typical instances., Conclusion: The experimental results showed that the typicality of the H&E-stained tissue slides computed from IHC staining patterns is useful as a criterion for instance selection to enhance the generalization ability, and this typicality could be employed for instance selection under some practical limitations., (© 2022. The Author(s).)

Background: We investigated predictors of failure of mitral valve repair (MVr) using expanded polytetrafluoroethylene (ePTFE) and its durability in the long term in a single institution., Methods: Four hundred twenty-one consecutive patients with primary mitral valve disease underwent MVr using artificial chordae (group A, n = 304) and suture repair (group S, n = 117) at our institution from January 2002 to April 2020. A comparison study was performed to examine the long-term outcomes, reoperation rate, and risk factors for reoperation., Results: One hospital death and 5 late deaths occurred in group S, and 20 late deaths occurred in group A. The reoperation rates were similar: group A, n = 8 (2.6%); and group S, n = 6 (5%). The major cause of reoperation was ruptured ePTFE (CV-4, n = 1; CV-5, n = 6) in group A, and suture rupture in group S. Reoperation was performed after a median of 88 months for ruptured ePTFE, and 26 months for group S. The rate of ePTFE rupture was 1.8% with CV-5 and 0.2% with CV-4. Risk factors for reoperation included postoperative arrhythmia, urgent operation, no annular ring, ruptured ePTFE, and suture rupture. The rates of freedom from reoperation and actuarial mitral valve survival rates at 5, 10, and 15 years were 99%, 95%, and 93% and 96%, 91%, and 89%, respectively, in group A; and 96%, 91%, and 91% and 95%, 94%, and 94%, respectively, in group S., Conclusions: The long-term surgical outcomes of MVr using both techniques were feasible. Over the long term, the ePTFE rupture rate of CV-5 was higher than that of CV-4., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: Salivary duct carcinoma (SDC) is a highly aggressive and uncommon tumor arising not only de novo but also in pleomorphic adenoma. Androgen receptor (AR)- and HER2-targeted therapy have recently been introduced for SDC as promising treatment options; however, no predictive biomarkers have yet been established. EZH2 and H3K27me3 are closely linked to the development and progression of various cancers, and EZH2 is also expected to be a desirable therapeutic target. We therefore explored the clinicopathological and prognostic implications of EZH2 and H3K27me3 in a large cohort of SDC patients, focusing on their impact on the therapeutic efficacy of AR- or HER2-targeted therapy., Materials and Methods: The EZH2 and H3K27me3 immunohistochemical expression and EZH2 Y646 gain-of-function mutation status were examined in 226 SDCs, and the relationship with the clinicopathological factors as well as clinical outcomes were evaluated within the three groups depending on the treatment: AR-targeted (combined androgen blockade with leuprorelin acetate and bicalutamide; 89 cases), HER2-targeted (trastuzumab and docetaxel; 42 cases), and conventional therapy (112 cases)., Results: EZH2 and H3K27me3 were variably immunoreactive in most SDCs. A positive correlation was found between the expression of EZH2 and H3K27me3. The EZH2 expression in the SDC component was significantly higher than that in the pre-existing pleomorphic adenoma component. EZH2 Y646 was not identified in any cases. EZH2-high cases more frequently had an advanced clinical stage and aggressive histological features than EZH2-low cases. An EZH2-high status in patients treated with AR-targeted therapy was associated with a significantly shorter progression-free and overall survival as well as a lower objective response rate and clinical benefit rate. In addition, a H3K27me3-high status in patients treated with AR-targeted therapy was related to a shorter overall survival. Conversely, there was no association between the EZH2 and H3K27me3 expression and the clinical outcomes in the conventional or HER2-targeted therapy groups., Conclusions: A high expression of EZH2 and H3K27me3 in SDC might be a predictor of a poor efficacy of AR-targeted therapy. Our data provide new insights into the role of EZH2 and H3K27me3 in therapeutic strategies for SDC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Saigusa, Hirai, Tada, Kawakita, Nakaguro, Tsukahara, Kano, Ozawa, Kondo, Okami, Togashi, Sato, Urano, Kajiwara, Shimura, Fushimi, Shimizu, Okamoto, Okada, Suzuki, Imanishi, Watanabe, Sakai, Ebisumoto, Sato, Honma, Yamazaki, Ueki, Hanazawa, Saito, Takahashi, Ando, Kohsaka, Matsuki and Nagao.)

Objectives: Salivary gland acinic cell carcinoma (AciCC) has recognizable cytomorphologic features that can overlap with benign and malignant entities, creating a diagnostic challenge. AciCC harbors a t(4;9) translocation increasing nuclear receptor subfamily 4 group A member 3 (NR4A3) expression, detectable by immunohistochemistry (IHC) on surgical resection (SR). NR4A3 IHC cytology data are limited. Here, we examine NR4A3 IHC on smears, cell blocks (CBs), and SRs of AciCC and its mimickers., Methods: Our cohort comprised AciCC (including high-grade transformation), secretory carcinoma, mucoepidermoid carcinoma (MEC), Warthin tumor, pleomorphic adenoma (PA), cellular PA, carcinoma ex-PA, oncocytic carcinoma, oncocytoma, and nodular oncocytosis. NR4A3 IHC (Santa Cruz Biotechnology and Origene antibodies) was positive if more than 5% tumor cells showed nuclear staining., Results: Among CBs, 90% of AciCC cases and none of the mimickers expressed NR4A3. Among SRs, 100% of AciCC cases showed diffuse NR4A3, whereas one high-grade MEC expressed focal NR4A3. Concordance was 95% with two antibody clones. Sensitivity, specificity, positive predictive value, and negative predictive value were 90%, 100%, 100%, and 94.7% for CBs and 100%, 98.8%, 92.3%, and 100% for SRs, respectively. NR4A3 immunostaining was demonstrable on smears from an AciCC case., Conclusions: NR4A3 IHC can be a robust diagnostic tool to identify AciCC, especially for cytology specimens., (© American Society for Clinical Pathology, 2021. All rights reserved.For permissions, please e-mail: journals.permissions@oup.com.)

Background: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) is a risk-stratification reporting system that was introduced in 2018. The objective of this multi-institutional study was to evaluate the utility of the MSRSGC in Japan., Methods: In total, 1608 fine-needle aspiration samples with matching histologic diagnoses were retrieved from 12 large institutions in Japan. The diagnostic categories of the MSRSGC were assigned prospectively or retrospectively, and the results were compared with the histologic diagnoses., Results: The cases were classified as follows: nondiagnostic, 18.1%; non-neoplastic, 4.1%; atypia of undetermined significance, 11.5%; neoplasm-benign, 43.7%; salivary gland neoplasm of uncertain malignant potential, 9.6%; suspicious for malignancy, 3.6%; and malignant, 9.4%. The risk of neoplasm and the risk of malignancy in each MSRSGC category were as follows: nondiagnostic, 72.9% and 13.4%, respectively; non-neoplastic, 15.2% and 9.1%, respectively; atypia of undetermined significance, 77.9% and 24.9%, respectively; neoplasm-benign, 99% and 1.8%, respectively; salivary gland neoplasm of uncertain malignant potential, 94.8% and 37%, respectively; suspicious for malignancy, 100% and 89.7%, respectively; and malignant, 100% and 99.3%, respectively. The accuracy of the MSRSGC for diagnosing neoplasms was 97.8%, and its accuracy for diagnosing malignancy was 97.3%. Institutions that used Romanowsky-stained preparations had lower nondiagnostic rates and lower risks of neoplasm and malignancy in the non-neoplastic category., Conclusions: The MSRSGC is useful for risk stratification and quality control. Widespread use of the MSRSGC would improve the accuracy of salivary gland cytology and lead to better patient care in Japan., (© 2021 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Microsecretory adenocarcinoma (MSA) is a recently described salivary gland tumor with a characteristic histologic and immunophenotypic profile and recurrent MEF2C-SS18 fusions. Because only six cases of MSA have been published, its complete clinicopathologic spectrum is unclear, and its biologic behavior has not been documented. Here, we present an updated and expanded experience of 24 MSA cases. All cases of MSA were obtained from the authors' files. Immunohistochemistry for S100, SOX10, p63, p40, SMA, calponin, and mammaglobin was performed. Molecular analysis was performed by targeted RNA sequencing, SS18 break apart fluorescence in situ hybridization, and/or reverse transcriptase polymerase chain reaction for MEF2C-SS18 fusion. Clinical follow-up was obtained from medical records. A total of 24 MSA cases were collected, from 13 women and 11 men, ranging from 17 to 83 years (mean 49.5 years). The vast majority (23 of 24) arose in the oral cavity, with the palate (n = 14) and buccal mucosa (n = 6) as the most frequent subsites. Tumors showed consistent histologic features including: (1) microcystic tubules, (2) flattened intercalated duct-like cells, (3) monotonous oval hyperchromatic nuclei, (4) abundant basophilic luminal secretions, (5) fibromyxoid stroma, and (6) circumscribed borders with subtle infiltration. The tumors were very consistently positive for S100 (24 of 24), p63 (24 of 24), and SOX10 (14 of 14) and negative for p40 (0 of 21), calponin (0 of 12) and mammaglobin (0 of 16), while SMA (4 of 20) was variable. MEF2C-SS18 fusion was demonstrated in 21 of 24 cases; in the remaining 3 cases with insufficient RNA, SS18 break apart FISH was positive. Treatment information was available in 17 cases, all of which were managed with surgery only. In 14 cases with follow-up (1-216 months, mean 30), no cases recurred or metastasized. MSA is a distinct salivary gland neoplasm with remarkably consistent clinical, histologic, immunophenotypic, and genetic features that generally behaves in an indolent manner following surgery alone. These observations solidify MSA as a unique, low-grade salivary gland carcinoma that warrants inclusion in the next version of the WHO classification of head and neck tumors., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Primary adrenal diffuse large B-cell lymphoma (PA-DLBCL) is rare. We investigate 23 Japanese patients with PA-DLBCL to understand the clinicopathologic features and biological behavior of this disease. The 17 males and 6 females had a median age of 74 years (range: 40 to 86 y). Tumor cells harbored Epstein-Barr virus-encoded small RNA (EBER) in 9 (39%) samples, including samples from the 2 patients with methotrexate-associated B-cell lymphoproliferative disorder. Programmed cell death ligand 1 (PD-L1) expression was detected in tumor cells of 6 (26%) samples, including 1 EBER+ and 5 EBER- samples. Four (17%) patients exhibited an intravascular proliferating pattern, and all 4 patient samples showed positive staining for PD-L1 in tumor cells. Among those patients, 3 showed intravascular proliferating pattern accompanied by a diffuse extravascular proliferation of tumor cells, and 1 patient was diagnosed with intravascular large B-cell lymphoma. We divided the 23 patients into 3 groups: EBER+ (n=9, 39%), EBER-PD-L1+ (n=5, 22%), and EBER-PD-L1- (n=9, 39%). A comparison of the outcomes among the 3 groups showed significant differences in overall survival (P=0.034). The EBER+ group had the worst prognosis, and the EBER-PD-L1- group had the best prognosis. We also compared the outcomes among the 3 groups that received rituximab-containing chemotherapies. Both the overall survival and progression-free survival were significantly different among these groups (P<0.001 and P=0.002, respectively). In conclusion, we evaluated 3 types of PA-DLBCL and found that each had unique clinical, pathologic, and prognostic features. Our results suggested that immune senescence, iatrogenic immunodeficiency, and immune evasion contribute to the development of PA-DLBCL., Competing Interests: Conflicts of Interest and Source of Funding: Supported, in part, by grants from the Grants-in-Aid for Scientific Research (grant number: 20K16204). 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.)

Aims: Salivary gland intraductal carcinoma (IDC) is a complex ductal neoplasm surrounded by a layer of myoepithelial cells. Recent insights have shown that there are three different types: intercalated duct-like, with frequent NCOA4-RET fusions; apocrine, with salivary duct carcinoma-like mutations; and mixed intercalated duct-like/apocrine, with RET fusions, including TRIM27-RET. In addition, an oncocytic IDC has been described, but it remains unclear whether it represents a fourth variant or simply oncocytic metaplasia of another IDC type. Our aim was to more completely characterize oncocytic IDC., Methods and Results: Six IDCs with oncocytic changes were retrieved from the authors' archives, from three men and three women ranging in age from 45 to 75 years (mean, 63 years). Five arose in the parotid gland, with one in an accessory parotid gland. Four patients with follow-up were free of disease after 1-23 months. Several immunostains (S100, mammaglobin, androgen receptor, and p63/p40) and molecular tools (RNA sequencing, RET fluorescence in-situ hybridisation, BRAF V600E VE1 immunohistochemistry, and Sanger sequencing) were applied. Histologically, the tumours were variably cystic with solid intracystic nodules often difficult to recognise as intraductal. In all, tumour ducts were positive for S100 and mammaglobin, negative for androgen receptor, and completely surrounded by myoepithelial cells positive for p63/p40. Molecular analysis revealed TRIM33-RET in two of six cases, NCOA4-RET in one of six cases, and BRAF V600E in two of six cases. One case had no identifiable alterations., Conclusions: Oncocytic IDC shares similarities with intercalated duct-like IDC. Although additional verification is needed, the oncocytic variant appears to be sufficiently unique to be now regarded as the fourth distinct subtype of IDC. Because of its indolent nature, oncocytic IDC should be distinguished from histological mimics., (© 2021 John Wiley & Sons Ltd.)

After the publication of the 2017 World Health Organization Classification of Head and Neck Tumours, there has been increasing interest in the classification of newly categorized intraductal carcinomas. Intraductal carcinoma (IC) is an indolent tumor, typically arising in the parotid gland, with an intact myoepithelial layer and a cystic, papillary, often cribriform architecture. Early studies of IC identified a heterogeneous group of molecular alterations driving neoplasia, and recent studies have defined three primary morphological/immunohistochemical variants, subsequently linking these morphologic variants with defined molecular signatures. Although studies to date have pointed toward distinct molecular alterations after histological classification, this study used a novel approach, focusing primarily on six cases of IC with NCOA4-RET gene rearrangement as determined by next-generation sequencing and describing the spectrum of clinicopathologic findings within that molecularly-defined group, among them a unique association between the NCOA4-RET fusion and hybrid variant IC and the first case of IC arising in association with a pleomorphic adenoma. RET-rearranged IC show histological and immunohistochemical overlap with the more widely recognized secretory carcinoma, including low-grade morphology, a lumen-forming or microcystic growth pattern, and co-expression of S100, SOX10, and mammaglobin, findings undoubtedly leading to misdiagnosis. Typically regarded to have ETV6-NTRK3 fusions, secretory carcinomas may alternatively arise with RET fusions as well. Adding our cohort of six NCOA4-RET fusion-positive IC compared with four cases of secretory carcinoma with ETV6-RET fusions and a single case of fusion-negative IC with salivary duct carcinoma-like genetics, we propose a diagnostic algorithm that integrates histological elements, including atypia and invasiveness, and the likelihood of specific molecular alterations to increase diagnostic accuracy in what can be a very subtle diagnosis with important clinical implications., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Micronodular thymoma with lymphoid stroma (MNT) is a rare thymic epithelial neoplasm subtype characterized by a micronodular tumor cell growth pattern and abundant lymphoid stroma. Micronodular thymic carcinoma with lymphoid stroma (MNCA) is considered as a malignant counterpart of MNT and exhibits a growth pattern similar to that of MNT but has histologic features reminiscent of thymic squamous cell carcinoma, such as cytologic atypia and CD5 and CD117 immunoexpression. Although both MNT and MNCA are characterized by abundant lymphoid stroma, it remains unknown whether there are differences in infiltrating lymphocytes between MNT and MNCA. We analyzed the immune microenvironment profile in eight MNT and three MNCA cases. The cell density of CD8-positive T cells was significantly higher in MNT than in MNCA, whereas that of FOXP3-positive T cells was significantly higher in MNCA than in MNT. There was no significant difference in the cell density of programmed death protein 1-positive T cells and programmed death ligand 1 expression between the MNT and MNCA cases. Our findings indicated that the immune microenvironment of MNCA differed from that of MNT and, compared with the T-cell profile of MNT, that of MNCA was more suppressive to patients' antitumor immune response., (© 2021 The Authors. Pathology International published by Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Epithelial-myoepithelial carcinoma (EMC) is a rare salivary gland cancer characterized by biphasic tubular structures composed of inner ductal and outer clear myoepithelial cells. Because of its histologic variety and overlap of histologic features with other salivary gland tumors, there are broad differential diagnoses. The HRAS Q61R mutation has been reported to be frequent in and specific to EMC. We evaluated the usefulness of RAS Q61R mutant-specific immunohistochemical (IHC) staining for detecting this genetic alteration in EMC. We investigated 83 EMC cases and 66 cases of salivary gland tumors with an EMC-like component, including pleomorphic adenoma, adenoid cystic carcinoma, basal cell adenoma/adenocarcinoma, and myoepithelial carcinoma. Sanger sequencing was performed for HRAS, KRAS, and NRAS. The diffuse and membranous/cytoplasmic RAS Q61R IHC expression was observed in 65% of EMC cases, in which all cases harbored the HRAS Q61R mutation. IHC-positive cases were present only in de novo EMCs (54/76 cases, 71%) but not in EMCs ex pleomorphic adenoma. The immunoreactivity was almost always restricted to the myoepithelial cells. Conversely, all EMC cases lacking the HRAS Q61R mutation were negative on IHC. In addition, only 3% of EMC-like tumors showed the abovementioned immunopositivity. None of the cases examined carried KRAS or NRAS mutations. IHC for RAS Q61R is highly sensitive and specific for detecting the HRAS Q61R mutation in EMC. Since significant immunopositivity was almost exclusively identified in nearly two thirds of EMCs but seldom in the histologic mimics, the IHC of RAS Q61R is a useful tool for diagnosing EMC in general pathology laboratories., Competing Interests: Conflicts of Interest and Source of Funding: Supported by NIH/NHS 1P01CA240239-01 (W.C.F., P.M.S.). 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.)

Pediatric solid tumors are a heterogeneous group of neoplasms with over 100 subtypes. Clinical and histopathological diagnosis remains challenging due to the overlapping morphological and immunohistochemical findings and the presence of atypical cases. To evaluate the potential utility of including RNA-sequencing (RNA-seq) in the diagnostic process, we performed RNA-seq in 47 patients with suspected pediatric sarcomas. Histopathologists specialized in pediatric cancer re-evaluated pathological specimens to reach a consensus diagnosis; 42 patients were diagnosed with known subtypes of solid tumors whereas 5 patients were diagnosed with undifferentiated sarcoma. RNA-seq analysis confirmed and refined consensus diagnoses and further identified diagnostic genetic variants in four of the five patients with undifferentiated sarcoma. Genetic lesions were detected in 23 patients, including the novel SMARCA4-THOP1 fusion gene and 22 conventional or recently reported genetic events. Unsupervised clustering analysis of the RNA-seq data identified a distinct cluster defined by the overexpression of rhabdomyosarcoma-associated genes including MYOG and CHRNG. These findings suggest that RNA-seq-based genetic analysis may aid in the diagnosis of suspected pediatric sarcomas, which would be useful for the development of stratified treatment strategies.

Sialadenoma papilliferum (SP) is a rare benign tumor of the salivary glands, and only 3 unequivocal cases of SP arising in the bronchus have been reported. We herein describe the histomorphologic and molecular features of 4 bronchial SP cases and discuss the differential diagnosis of this entity and the relationship with its clinicopathologic mimics, in particular, glandular papilloma and mixed squamous cell and glandular papilloma (GP/MP). We encountered 2 male and 2 female patients with bronchial SP (mean: 66.8 y old). All 4 tumors arose in the central bronchus and were characterized by a combination of surface exophytic endobronchial papillary proliferation and a submucosal multicystic component with complex architecture. The neoplastic epithelium consisted predominantly of nonciliated stratified columnar cells with ciliated, squamous, and mucinous cells present focally. While 2 tumors (50%) harbored a BRAF V600E mutation by molecular and immunohistochemical analysis, similar to GP/MP, no KRAS, HRAS, AKT1, or PIK3CA mutations were detected in any of the cases. Two patients were treated with limited resection, while 2 patients underwent lobectomy based on the diagnosis of adenocarcinoma or possible squamous cell carcinoma in situ in the preoperative biopsy. All survived without recurrence or metastasis for 23 to 122 months after treatment. SP can develop in the central bronchus as the bronchial counterpart of the salivary gland tumor and should be considered in the differential diagnosis of endobronchial tumors. In addition, some histologic resemblance and frequent BRAF V600E mutation raise the possibility of SP and GP/MP being on the same disease spectrum., Competing Interests: Conflicts of Interest and Source of Funding: 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.)

Background: High-grade transformation (HGT) is a rare process whereby conventional low- to intermediate-grade salivary gland carcinomas (SGC) transform into high-grade, poorly or undifferentiated malignancies with focal or complete loss of their conventional histomorphologic features. Because tumors with HGT are associated with a worse prognosis than their conventional counterparts, preoperative recognition of HGT may be of benefit for optimal patient management. Using a multi-institutional approach, we describe the largest fine needle aspiration (FNA) cohort of salivary gland carcinomas with HGT., Methods: The archives of 9 large academic medical centers were searched, and 22 cases of SGC with HGT were identified by surgical excision accompanied by preoperative FNA. Clinical and cytomorphologic features were retrospectively reviewed., Results: The male-to-female ratio was 14:8, and the mean patient age was 60.2 years. The average tumor size was 3.6 cm, and 19 cases were from the parotid gland. Acinic cell carcinoma with HGT was the most common tumor subtype, comprising 12 cases with HGT, followed by adenoid cystic carcinoma, secretory carcinoma, and other subtypes. Eighteen cases were classified as malignant; however, a specific diagnosis of HGT was not made. Sixteen cases contained a high-grade cytologic component, and 7 cases had a mixture of both conventional and high-grade components retrospectively., Conclusions: SGC with HGT should be considered in the differential diagnosis of a salivary gland aspirate exhibiting high-grade cytomorphologic features. The presence of distinct tumor populations, conventional and high-grade, should prompt consideration of HGT, especially when the conventional component is acinic cell carcinoma or adenoid cystic carcinoma., (© 2020 American Cancer Society.)

Three pathological grading systems advocated by Perzin/Szanto, Spiro, and van Weert are currently used for adenoid cystic carcinoma (AdCC). In these systems, the amount or presence of the solid tumor component in AdCC specimens is an important index. However, the "solid tumor component" has not been well defined. Salivary AdCC cases (N = 195) were collected after a central pathology review. We introduced a novel criterion for solid tumor component, minAmax (minor axis maximum). The largest solid tumor nest in each AdCC case was histologically screened, the maximum oval fitting the solid nest was estimated, and the length of the minor axis of the oval (minAmax) was measured. The prognostic cutoff for the minAmax was determined using training and validation cohorts. All cases were evaluated for the four grading systems, and their prognostic impact and interobserver variability were examined. The cutoff value for the minAmax was set at 0.20 mm. Multivariate prognostic analyses showed the minAmax and van Weert systems to be independent prognostic tools for overall, disease-free, and distant metastasis-free survival while the Perzin/Szanto and Spiro systems were selected for overall survival but not for disease-free or distant metastasis-free survival. The highest hazard ratio for overall survival (11.9) was obtained with the minAmax system. The reproducibility of the minAmax system (kappa coefficient of 0.81) was scored as very good while those of the other three systems were scored as moderate. In conclusion, the minAmax is a simple, objective, and highly reproducible grading system useful for prognostic stratification for salivary AdCC., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Epithelial-myoepithelial carcinoma is an uncommon low-grade salivary gland carcinoma. It is classically characterized by biphasic tubular structures composed of inner eosinophilic ductal cells and outer clear myoepithelial cells. In addition, epithelial-myoepithelial carcinoma sometimes shows various histologic features, including a cribriform pattern, basaloid appearance, and sebaceous differentiation. Because clear myoepithelial cells are also noted in other benign and malignant salivary gland tumors, the histologic variety and similarity with other tumor entities make the diagnosis of epithelial-myoepithelial carcinoma challenging. A recent analysis revealed that HRAS hotspot point mutations are specifically identified in epithelial-myoepithelial carcinoma and the assessment of given genes facilitate the correct diagnosis., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The gastrointestinal tract is a rare site for metastatic lung cancer. Programmed cell death-ligand 1 (PD-L1) expression in lung cancer is a biomarker for the response to anti-PD-1/PD-L1 therapy. We investigated clinicopathological features and PD-L1 expression in 25 gastrointestinal metastatic tumors from the lung and primary adenocarcinoma of the small bowel. The small bowel was the most common site (16/25; 64%) of gastrointestinal tract lung cancer metastasis. A total of 19 (76%) of the gastrointestinal metastasis showed PD-L1 expression in ≥5% of tumor cells, with 14 (56%) showing high expression levels (≥50%). In contrast, 21 (84%) expressed PD-L1 in ≥5% immune cells, including 4 (16%) showing a high expression levels (≥50%). The PD-L1 expression on tumor cells and immune cells in primary lung cancer and corresponding gastrointestinal metastasis was concordant in 13 (68%) and 11 (58%) of the 19 paired cases, respectively. Small-bowel metastasis of lung cancer was characterized by a higher incidence of perforation (31% vs. 0%), ulcerated mass (83% vs. 60%), and neoplastic PD-L1 expression (75% vs. 0%) compared to primary small-bowel adenocarcinoma. Gastrointestinal metastasis from lung cancer might be a potential target for immune checkpoint inhibitor therapy, given its high expression of PD-L1., (© 2020 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Background.: Immunoglobulin (Ig) G4-related diseases (RDs) are systemic diseases in which serum IgG4 levels are frequently elevated. They can cause diffuse or focal tumor formation, organ swelling, and tissue thickening in organs infiltrated by IgG4 + plasma cells. The diagnostic criteria for IgG4-RDs include an IgG4/IgG ratio >40%, but counting IgG + cells can be difficult because of the weakness of IgG staining density. We hypothesized that an antibody cocktail of mixed IgG1, IgG2, IgG3, and IgG4 (AC-IgG) might give immunohistochemistry results comparable with those of IgG in IgG4-RD., Methods.: We compared AC-IgG reactivity with IgG expression in type 1 autoimmune pancreatitis (AIP), a representative IgG4-RD. We compared immunohistochemistry results using AC-IgG and IgG-only in 10 cases of AIP. The coefficient of variation (Cv) was used to analyze differences between AC-IgG and IgG findings in AIP by 13 board-certified pathologists., Results.: Although mean values for IgG + cells did not significantly differ between AC-IgG (34.3; range = 27.4-37.1) and IgG (30.0; range = 23.0-45.6; P = .6254), Cv was lower for AC-IgG (33.4%) than for IgG (51.4%; regression equation; y [IgG] = 0.988 x + 0.982; correlation coefficient = 0.907). The data showed that the results of both methods were largely consistent., Conclusion.: AC-IgG could replace IgG to count IgG + cells because of its lower Cv.

Solitary fibrous tumor/hemangiopericytoma (SFT/HPC) is a rare tumor derived from mesenchymal tissue. Although standard chemotherapy for SHT/HPC has not been established, temozolomide plus bevacizumab (TMZ+Bev) therapy for SFT/HPC has been reported. The effectiveness and safety of TMZ+Bev (temozolomide 150 mg/m 2 orally on days 1-7 and days 15-21 and bevacizumab 5 mg/kg intravenously on day 8 and day 22 on a 28-day cycle), which was administered from December 2013 until April 2019 to four patients with SFT/HPC, were retrospectively analyzed. Four patients with SFT/HPC received TMZ+Bev. The age of the patients ranged from 41 to 75 years. Two were male, and the primary tumor sites were the meninges in three patients and the pleura in one. One achieved partial response; the others, stable disease (SD). The progression-free survival time ranged from 9.4 to 29.6 months according to RECIST v1.1. One patient died 59 months after using TMZ+Bev, and the others survived for 17 to 64 months. All patients experienced Grade 3 or higher lymphopenia, and three had Grade 3 or higher leukopenia and neutropenia. One patient subsequently received doxorubicin; another, pazopanib. TMZ+Bev therapy for SFT/HPC is safe and effective for maintaining long-term SD., Competing Interests: Yuichi Ando received research funding from Chugai Pharmaceutical Co., Ltd., outside the submitted work. The other authors have no conflicts of interest to disclose.

Background: Owing to the low incidence of adenoid cystic carcinoma (AdCC), reliable survival estimates and prognostic factors remained unclarified., Methods: In this multi-institutional retrospective analysis, we collected 192 AdCC cases, and investigated the impact of clinicopathological factors on clinical outcomes of the patients. All AdCC cases were of salivary gland origin and were surgically treated with curative intent. Diagnoses of AdCC were validated by a central pathology review by expert pathologists., Results: The 5-year overall survival (OS) and disease-free survival (DFS) rates were 92.5 and 50.0%, respectively. Treatment failure occurred in 89 patients (46%) with the distant failures in 65 (34%). Multivariate analysis indicated that pN2 and a pathologically positive surgical margin were independent prognostic factors for both OS and DFS. Histological grade III was an independent prognostic factor for OS. A primary site in the submandibular gland, pT3/4, pN1, and histological grade II were independent prognostic factors for DFS. Postoperative radiation therapy (PORT) improved the locoregional control (LRC) rate. Prophylactic neck dissection was not associated with a better OS or better LRC among patients with cN0. Facial nerve dissection did not improve clinical outcomes in parotid AdCC cases without facial nerve palsy., Conclusions: A higher TN classification, a pathologically positive surgical margin, and a higher histological grade were associated with a lower OS. PORT improved LRC rates but neck dissection failed to improve clinical outcomes in patients with cN0. As the distant metastasis was frequent, effective systemic therapy is imperative to improve the survival of AdCC patients.

Salivary duct carcinoma (SDC) is an aggressive subtype of primary salivary gland carcinoma, often with an advanced stage at presentation and high rates of metastasis and recurrence. It most commonly arises in the parotid gland of older men and microscopically resembles high-grade breast ductal carcinoma. While 50 years have lapsed since the first report of this entity, recent intensive studies have shed light on its biologic, genetic, and clinical characteristics. The diagnosis of SDC is aided by the immunohistochemical expression of androgen receptor (AR) coupled with its characteristic histomorphology. Fine-needle aspiration typically reveals cytologic features of high-grade carcinoma, and ancillary studies using cell block material can facilitate the specific diagnosis of SDC. In surgical specimens, certain histologic features are important prognostic factors, including nuclear pleomorphism, mitotic counts, vascular invasion, and the morphology at the invasion front. Several clinical studies have shown promising results using targeted therapy for AR and human epidermal growth factor receptor 2 (HER2), and the latest version of the National Comprehensive Cancer Network guidelines recommends the evaluation of AR and HER2 status before treatment. Recent molecular analyses have revealed multiple heterogeneous alterations in well-known oncogenes and tumor suppressor genes, including TP53, HRAS, PIK3CA, PTEN, and BRAF. Clinical trials of drugs targeting these genes may broaden the treatment options for SDC in the near future., (© 2020 American Cancer Society.)