[Clinicopathological features of thyroid-like low-grade nasopharyngeal papillary adenocarcinoma].

Objective: To investigate the clinicopathological features, immunophenotype and gene alterations of thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TL-LGNPPA). Methods: Fifteen case of TL-LGNPPA diagnosed at Zhejiang Cancer Hospital (5 cases) and the First Affiliated Hospital, Zhejiang University School of Medicine (10 cases) from November 2011 to August 2020 were collected. Clinical and pathological examinations, immunohistochemical staining and next-generation sequencing were performed. The clinicopathological and molecular characteristics were summarized, and relevant literature was reviewed. Results: Fifteen patients were identified and included. Their median age was 36 years (range, 20-60 years). The male-female ratio was 1.0∶1.1. The most common symptoms were epistaxis and nasal obstruction. The neoplasms were located on the roof of the nasopharynx or the posterior margin of the nasal septum. The pathological features included complex papillary and glandular structures mainly composed of single or pseudostratified cubic and columnar cells, with mild to moderate cytological atypia. In some cases, spindle cell features, nuclear grooves, ground glass nuclei, squamous metaplasia, or scattered psammoma bodies were identified. In addition, nuclear polar reversal cells, hobnail cells and micropapillary structures were found, but have not been reported in previous literature. Immunohistochemistry showed that the tumor cells were diffusely positive for TTF1, CK7, vimentin and CKpan; focally positive for p40, CK5/6 and p16; and negative for Tg, NapsinA, CK20, CDX2, S-100 and PAX8. The Ki-67 positive rates ranged from 1% to 20% and were≤10% in thirteen cases (13/15). EBER in situ hybridization was negative in all cases. DNA sequencing of 6 specimens was performed and all specimens were found harboring gene mutations (EWSR1, SMAD2, ROS1, JAK3, GRIN2A, ERRCC5, STAT3, and TET2), but no hot spot gene alterations were found. No MSI-H and MMR related gene changes were detected. All tumors showed low tumor mutation burden. All 15 patients underwent endoscopic surgery, and only 1 of them underwent radiotherapy postoperatively. All patients were recurrence free and alive at the end of follow-up periods (range: 23 to 129 months). Conclusions: TL-LGNPPA is a rare indolent tumor of the nasopharynx and exhibits a unique morphology and immunophenotype. Endoscopic resection is an effective treatment for TL-LGNPPA with excellent overall prognosis.

Clinicopathological and molecular characteristics of gastric papillary adenocarcinoma.

Papillary adenocarcinoma is defined as carcinoma with a well-defined papillary or villous structure. Despite sharing clinicopathological and morphological features with tubular adenocarcinomas, papillary adenocarcinomas frequently show microsatellite instability. The present study aimed to clarify the clinicopathological features, molecular classification, and programmed death-ligand 1 (PD-L1) expression characteristics of papillary adenocarcinoma, especially tumors with microsatellite instability. We examined the microsatellite status and expression of mucin core proteins and PD-L1 as well as the clinicopathological features in 40 gastric papillary adenocarcinomas. Surrogate immunohistochemical analysis of p53 and mismatch repair proteins along with Epstein-Barr virus-encoded RNA in situ hybridization were performed for molecular classification. Female predominance and frequent microsatellite instability were observed in papillary adenocarcinoma in comparison with tubular adenocarcinoma. The presence of microsatellite instability in papillary adenocarcinoma was significantly correlated with older age, tumor-infiltrating lymphocytes, and Crohn's-like lymphoid reactions. Surrogate examination demonstrated that the genomically stable type (17 cases, 42.5%) was the most common, followed by the microsatellite-unstable type (14 cases, 35%). Among the seven cases showing PD-L1-positive expression in tumor cells, four involved carcinomas with microsatellite instability. These results reveal the clinicopathological and molecular characteristics of gastric papillary adenocarcinoma.

Two distinct pathogenic pathways of digital papillary adenocarcinoma - BRAF mutation or low-risk HPV infection.

Digital papillary adenocarcinoma (DPA) is a rare neoplasm that can exhibit local recurrence and distant metastasis. We present a series of eight cases of DPA showing two distinct clinical presentations, morphologies, immunophenotypes, and molecular features. Four cases were characterized by painless, slow-growing nodules located on the digits. The lesions were small, well-defined, and confined in the dermis. Histopathologically, these tumors were composed of glandular structures lined by cuboidal epithelium with luminal papillary infoldings. Only rare mitotic figures and minimal squamoid differentiation were present, and cellular necrosis was absent. All four cases were positive for the BRAF V600E immunohistochemistry but negative for p16, low-risk and high-risk HPV in situ hybridization (ISH). In contrast, the remaining four cases were characterized by painful, rapidly growing masses on the digits. These four lesions were located in the deep dermis and consisted of a solid, tightly packed papillary architecture lined by atypical epithelioid cells with inconspicuous nucleoli. Cellular necrosis, numerous mitotic figures, and prominent squamoid differentiation were seen. All cases were negative for the BRAF V600E IHC. However, they showed strong, patchy to diffuse reactivity for p16 and were positive for low-risk HPV ISH and negative for high-risk HPV ISH. Our findings suggest that the current classification of DPA encompasses tumors that show two discrete pathogenic pathways - BRAF mutation or low-risk HPV infection. DPAs with low-risk HPV infection exhibit aggressive clinical features, high-grade morphology, marked squamoid differentiation, and wild-type BRAF. DPAs with BRAF V600E have less aggressive clinical features, low-grade morphologic findings, mild to absent squamoid differentiation, and negative HPV infection.

Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma: a clinicopathological and molecular study of four cases.

Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TLLGNPPA) is a rare nasopharyngeal carcinoma. To date, less than 60 cases of TLLGNPPA have been reported, and its clinical features and pathogenesis remain unclear. In this paper, four cases of TLLGNPPA were reported to clarify the clinicopathological and molecular features of this disease. Histopathological examination revealed that all tumors had papillary glandular arrangement, with a fibrovascular axis in the tumor stroma and focal nuclear groove. All tumors expressed pan-CK, CK7, and CK19, while TG and Pax-8 were negative, and the Ki-67 index was approximately 1-3%. The expression of TTF-1 was diffusely positive in two cases and focally positive in two cases. EBER was not expressed in four cases. Molecular testing was possible in three cases. No common driver event was noted, but unique, mutually exclusive molecular variants were found in each of the three tumors (FGFR4, PDK1, AXIN2, FOXL2, and PIK3C3), one also with copy number variants in MCL1 and STMN1. All four patients underwent surgical resection of the tumor and had no metastasis or recurrence from 7 to 60 months post-resection. Given the assertion that these tumors do not recur or metastasize in addition to their heterogeneous gene mutation spectrum, we propose that TLLGNPPA is a neoplasm with low malignant potential and should no longer to be referred to as an adenocarcinoma.

Genetic profile identification and clinicopathologic characteristics analysis of the thyroid-like low-grade nasopharyngeal papillary adenocarcinoma.

Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TL-LGNPPA) is an extremely rare malignancy bearing histomorphological similarities to papillary thyroid carcinoma with good prognosis. It's important to distinguish TL-LGNPPA from other papillary tumors including nasopharyngeal papillary adenocarcinoma (NPPA), metastatic and ectopic papillary thyroid cancer, and metastasized adenocarcinomas, etc. To date, only 48 cases of TL-LGNPPA have been reported in the English literatures. Here, we reported the genomic characteristics of additional 4 cases and reviewed other reports to clarify the clinicopathological features of this tumor. In this study, 41 mutations were detected by whole-exome sequencing, but no typical driver mutations were found. Two sample with Copy Number Variations (CNV) were found (7 q22. 17 q12), of which the segment spanned the regions of RASA4, POLR2J2, SPDYE2, CCL3, CCL4, etc. Additionally, no MSI and HLA LOH were found. To our knowledge, we are the first to reveal the genetic underpinnings of this rare tumor. The clinicopathological features of TL-LGNPPA were characterized, shedding more light on the essential difference between TL-LGNPPA with other papillary tumors.

Outcome of Ordinary Polymorphous Adenocarcinomas of the Salivary Glands in Comparison With Papillary and Cribriform Subtypes.

BACKGROUND/AIM: Polymorphous adenocarcinoma (PAC) is a low-grade salivary gland malignancy in contrast to variants with papillary (PAP) or cribriform (CASG) architecture and confers the second most common malignancy of minor salivary glands. Our study aimed to identify prognostic factors and to evaluate histomorphological and molecular diagnostic criteria of PACs. PATIENTS AND METHODS: A series of 155 PACs, including 10 PAPs and 12 CASGs from the population-based Cancer Registry of North Rhine-Westphalia (LKR-NRW) and the Hamburg Salivary Gland Reference Centre (HRC) were analyzed. RESULTS: One fifth of the tumors were located in the major salivary glands and PACS/CASGS invariably lacked p40 expression. Fifty-two percent of PACs showed a PRKD1 E710D mutation. Ordinary PACs had a disease-specific 10-year survival probability of 97% compared to 90% when combining PAPs and CASGs. T-stage at diagnosis was a prognostic factor with 98% for stages T1/T2 versus 75% for T3/T4. CONCLUSION: Diagnostic algorithms for the PAC/CASG spectrum of tumors need to be improved and should include molecular markers.

Repeat Fine Needle Aspiration Cytology Refines the Selection of Thyroid Nodules for Afirma Gene Expression Classifier Testing.

Background: Molecular testing (MT) refines risk stratification for thyroid nodules that are indeterminate for cancer by fine needle aspiration (FNA) cytology. Criteria for selecting nodules for MT vary and remain largely untested, raising questions about the best strategy for maximizing the usefulness of MT while minimizing the harms of overtesting. We used a unique data set to examine the effects of repeat FNA cytology-based criteria for MT on management decisions and nodule outcomes. Methods: This was a study of adults (age 25-90 years; 281 women and 72 men) with cytologically indeterminate (Bethesda III/IV) thyroid nodules who underwent repeat FNA biopsy and Afirma Gene Expression Classifier (GEC) testing (N = 363 nodules from 353 patients) between June 2013 and October 2017 at a single institution, with follow-up data collected until December 2019. Subgroup analysis was performed based on classification of repeat FNA cytology. Outcomes of GEC testing, clinical/sonographic surveillance of unresected nodules, and histopathologic diagnoses of thyroidectomies were compared between three testing approaches: (i) Reflex (MT sent on the basis of the initial Bethesda III/IV FNA), (ii) SemiRestrictive (MT sent if repeat FNA is Bethesda I-IV), and (iii) Restrictive (MT sent only if repeat FNA is Bethesda III/IV) testing approaches. Results: Restricting MT to nodules that remain Bethesda III/IV on repeat FNA would have missed 4 low-risk cancers and 3 noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) (collectively 2% of the test population) but would have avoided diagnostic surgery for 42 benign nodules (12% of the test population). The Restrictive testing strategy was more specific (delta 0.126 confidence interval [CI 0.093 to 0.159] and 0.129 [CI 0.097 to 0.161], respectively) but less sensitive (delta -0.339 [CI -0.424 to -0.253] and -0.340 [CI -0.425 to -0.255], respectively) than the Reflex and SemiRestrictive approaches for detecting NIFTP or cancer. Conclusions: Repeat FNA cytology can guide the selection of cytologically indeterminate thyroid nodules that warrant MT. The Restrictive model of performing Afirma GEC only on nodules with two separate biopsies showing Bethesda III/IV cytology would reduce the rate of diagnostic surgery for histologically benign nodules while missing only rare low-risk tumors. Given the low but nontrivial risks of thyroidectomy, the higher specificity of the Restrictive testing approach disproportionately outweighs the potential harms.

Papillary Neoplasms of the Salivary Duct System: A Review.

Papillary lesions of the salivary duct systems are uncommon. They encompass a heterogeneous group of benign, intermediate, and potentially aggressive neoplasms. With a few exceptions, historical descriptive terms such as papillary adenocarcinoma, papillary cystadenocarcinoma, and papillary adenoma are being replaced by defined entities, at same time acknowledging the papillary features as a histologic pattern. The evolving genetic landscape of these lesions increasingly permits their reproducible categorization. This article discusses those papillary proliferations encountered in the salivary glands with a focus on intraductal papillary mucinous neoplasms and cystadenomas. Intraductal carcinomas and sialadenoma papilliferum are addressed in separate articles in this issue.

Nasopharyngeal papillary adenocarcinoma harboring a fusion of ROS1 with GOPC: A case report.

RATIONALE: Nasopharyngeal papillary adenocarcinoma is a region-specific tumor originating from the nasopharyngeal surface epithelium. Owing to its rarity, more attention has been paid to its clinicopathologic features, while little effort has been made to study the gene abnormalities that drive this tumor. We describe the first case of nasopharyngeal papillary adenocarcinoma harboring a fusion of ROS1 with GOPC. PATIENT CONCERNS: A 22-year-old female patient was diagnosed with nasopharyngeal papillary adenocarcinoma in our hospital, and she had right nasal obstruction for more than 6 months. Nasal endoscopy revealed a mass on the posterior roof of the nasopharynx. DIAGNOSES: Immunohistochemical staining showed that the tumor cells were diffusely positive for transcription termination factor 1, vimentin, CK19, glypican-3, and CK7, and negative for melanocyte, CK5/6, CK20, P53, P63, S100, smooth muscle actin, p16, PAX8, and thyroglobulin. The Ki-67 index was approximately 5%; EBV-encoded small nuclear RNA was negative. INTERVENTIONS: The tumor was completely excised on endoscopy with a negative surgical margin. OUTCOMES: No sign of recurrence was observed during the 3-year follow-up period. LESSONS: Owing to its rarity, pathologists should be aware of this unusual neoplasm to avoid misdiagnosis. Further studies are needed to further characterize the relationship between ROS1-GOPC fusion and the pathogenesis of this carcinoma and its response to tyrosine kinase inhibitors in relapsed cases.

Cervical carcinomas with serous-like papillary and micropapillary components: illustrating the heterogeneity of primary cervical carcinomas.

Recent changes in the classification of cervical adenocarcinomas have re-categorized serous carcinoma as potentially nonexistent. However, clinical and pathological profiles of cervical adenocarcinomas with serous-like morphological features have not been systematically evaluated using the latest taxonomy and biomarkers. We studied 14 cases of primary cervical carcinomas with serous-like morphologies (papillary and micropapillary patterns). None of these cases exhibited evidence of serous carcinoma involving the upper tracts. Patient ages ranged between 34 and 86 years, most presented with abnormal uterine bleeding. Histologically, ten cases were classified as human papillomavirus (HPV)-associated carcinomas (eight usual-type endocervical adenocarcinomas and two adenosquamous carcinomas), of which six exhibited a papillary pattern and four had a micropapillary pattern. The four remaining cases were HPV-independent gastric-type adenocarcinomas, which displayed a papillary pattern in one case and a micropapillary pattern in three others. All ten HPV-associated carcinomas displayed block positive p16 and wild-type p53 by immunohistochemistry, with nine of them confirmed by HPV testing. Two of the four gastric-type adenocarcinomas had mutation-type p53, one of which also being p16 block positive. HER2 overexpression was demonstrated in 3/14 (21.4%) cases (2 HPV-associated and 1 HPV-independent). PD-L1 expression was identified in 4/10 (40%) cases, all HPV-associated. Targeted next-generation sequencing was performed in two cases with a micropapillary pattern, revealing a missense variant in ATM in an HPV-associated tumor and missense variants in TP53 and SMARCB1 in an HPV-independent tumor. The results demonstrated that primary endocervical adenocarcinomas can mimic the appearance of serous carcinoma, while not representing serous carcinoma. Serous-like papillary and micropapillary patterns may be present in both HPV-associated and HPV-independent cervical carcinomas, but none of the cases studied were unequivocally serous upon detailed analysis. Our findings support the exclusion of "cervical serous carcinoma" from existing classifications of cervical adenocarcinoma.

Frequent DYRK2 gene amplification in micropapillary element of lung adenocarcinoma - an implication in progression in EGFR-mutated lung adenocarcinoma.

The present study aimed to discern the molecular alterations involved in the progression of EGFR-mutated lung adenocarcinoma (LADC). We previously demonstrated that the micropapillary (mPAP) element is the most important histological factor for assessing malignant grades in LADCs. Therefore, mPAP and other elements were separately collected from three cases of EGFR-mutated LADC using laser capture microdissection and subjected to a comprehensive mRNA expression analysis. We focused on DYRK2 in this study because its level showed a substantial increase in EGFR-mutated LADCs with mPAP. We also immunohistochemically examined 130 tumors for the expression of DYRK2. The results confirmed a strong expression of DYRK2 in EGFR-mutated LADC with mPAP. Fluorescent in situ hybridization (FISH) analyses targeting the DYRK2 locus revealed frequent gene amplification in EGFR-mutated LADC, specifically occurring in the high-grade components, like mPAP. In summary, the results of this study suggest that DYRK2 overexpression through gene amplification is one of the molecular mechanisms responsible for promoting the progression of EGFR-mutated LADC.

A Case Report of Papillary Digital Adenocarcinoma With BRAFV600E Mutation and Quantified Mutational Burden.

ABSTRACT: Papillary digital adenocarcinoma (PDA) is a rare eccrine tumor that is most often found on the digits. Few case reports have described PDAs located on atypical sites. It is now accepted that PDAs cannot be distinguished from benign adenomas based on histological features, and it is recommended to excise all of these lesions. Even with excision, recurrence and metastasis rates are high. Only limited genomic analyses have been performed to date, and no driver mutations have been identified. We report a case of a 63-year-old woman with a PDA on the right forearm. Biopsy showed moderate cytologic atypia and mitotic figures. Next-generation DNA sequencing of the tumor showed a BRAFV600E mutation and high tumor mutational burden (5.51 mutations/Mb). This mutation is known for its response to small molecular inhibitors of BRAF and Mitogen-activated protein kinase kinase. Such therapy may be a consideration should our patient develop recurrent unresectable disease.

[Differential protein expressions in papillary thyroid carcinoma patients with or without Hashimoto's thyroiditis].

Objective: To explore the differential protein expressions in papillary thyroid carcinoma (PTC) with or without Hashimoto's thyroiditis (HT). Methods: Tissue microarray was prepared and the protein expression levels of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF), vascular endothelial growth factor (VEGF), cyclinD1, mesothelial cell (MC) , CD56 and Galectin3 in the PTC tissues with or without HT were detected by immunohistochemical staining. Results: The positive expression rates of BRAF protein in the PTC tissues with or without HT groups were 55.4% (36/65) and 63.6% (42/66), respectively, without significant difference (P=0.336). The positive expression rates of VEGF protein in the PTC tissues with or without HT groups were 25.7% (19/74) and 25.8%(17/66), respectively, without significant difference (P=0.991). The positive expression rates of cyclin D1 protein in the PTC tissues with or without HT groups were 93.4% (71/76) and 97.6% (80/82), without significant difference (P=0.206). The positive expression rates of MC protein in the PTC tissues with or without HT groups were 86.1% (62/72) and 83.5%(71/85), without significant difference (P=0.654). The positive expression rates of Galectin3 protein in the PTC tissues with or without HT groups were 98.7% (76/77) and 97.5% (78/80), without significant difference (P=0.583). The positive expression rates of CD56 in the PTC tissues and adjacent thyroid follicular epithelial cells were 27.4% (32/117) and 65.0% (76/117), respectively, and the difference was statistically significant (P=0.001). The positive expression rates of CD56 in PTC tissues with or without HT were 35.5% (24/68) and 16.5% (13/79), respectively, and the difference was statistically significant (P=0.009). Conclusions: There are no significant differences in the expressions of BRAF, VEGF, CyclinD1, MC and Galectin3 between the PTC tissues with or without HT. However, the significantly differential expression of CD56 between the two group suggests that CD56 may be related to the pathogenesis of PTC with HT. CD56 may be used as a potential molecular marker in PTC diagnosis.

Gallbladder Mixed Neuroendocrine-Non-neuroendocrine Neoplasm (MiNEN) Arising in Intracholecystic Papillary Neoplasm: Clinicopathologic and Molecular Analysis of a Case and Review of the Literature.

Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) of the gallbladder are generally composed of adenocarcinoma and neuroendocrine carcinoma (NEC). Rare cases associated with intracholecystic papillary neoplasm (ICPN) have been reported. Although recent molecular data suggest that the different components of digestive MiNENs originate from a common precursor stem cell, this aspect has been poorly investigated in gallbladder MiNENs. We describe the clinicopathologic and molecular features of a MiNEN composed of ICPN, adenocarcinoma, and NEC. A 66-year-old woman presented with severe abdominal pain. She underwent radical cholecystectomy and an intracholecystic mass was found. Histologically, it was composed of ICPN associated with adenocarcinoma and large cell neuroendocrine carcinoma (LCNEC). The three components were positive for DNA repair proteins and p53. EMA was positive in the ICPN and adenocarcinoma components, while it was negative in the LCNEC. Heterogeneous expression of Muc5AC, cytokeratin 20, and CDX2 was only observed in the ICPN component. Cytokeratin 7 was diffusely positive in both adenocarcinoma and LCNEC components, while it was heterogeneously expressed in the ICPN. The copy number variation analysis showed overlapping results between the adenocarcinoma and LCNEC components with some minor differences with the ICPN component. The three tumor components showed the same mutation profile including TP53 mutation c.700T > C (p. Tyr234His), without mutations in other 51 genes known to be frequently altered in cancer pathogenesis and growth. This finding may support the hypothesis of a monoclonal origin of the different tumor components. We have also performed a review of the literature on gallbladder MiNENs.

Thyroid-Like Low-Grade Nasopharyngeal Papillary Adenocarcinoma.

OBJECTIVES: Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TLLGNPPA) is a relatively rare nasopharyngeal tumor. We performed morphological characterization, immunohistochemical profiling, and investigated gene mutations. We also provide clinical follow-up data and brief review of the literature. METHODS: Immunohistochemistry was used to evaluate the expression of TTF-1, CK19, CK7, EMA, TG, Pax-8, CK5/6, S100, and Ki-67. Additionally, in situ hybridization was utilized to identify the presence of EBV. We investigated mutations in hot-spot exons of KRAS/NRAS/BRAF to rule out common mutations seen in thyroid tumors. RESULTS: Histopathologic examination of four cases identified tumors that were mainly occupied by papillary architectures. One case had a predominantly glandular structure. The tumors expressed TTF-1 and CK19, while TG and Pax-8 were negative. S100 was moderately expressed focally in three cases. CONCLUSIONS: While TLLGNPPA displays a morphological resemblance to papillary thyroid carcinoma (PTC), it is vital to differentiate nasopharyngeal metastasis from PTC for appropriate treatment.

Pancreatobiliary-type intraductal papillary mucinous neoplasm of the pancreas may have 2 subtypes with distinct clinicopathologic and genetic features.

We recently experienced cases of pancreatobiliary-type intraductal papillary mucinous neoplasms (PB-IPMNs) with imaging features resembling pancreatic ductal adenocarcinomas (PDACs), and histologic appearance of purely pancreatobiliary morphology and highly distorted papillary growth, which led to the present study aiming to systematically investigate PB-IPMNs in comparison with PDACs. Surgical cases of PB-IPMNs (n = 31) and PDACs (n = 24) were examined. PB-IPMNs were classified into monotypic tumors (n = 12; 39%) consisting of entirely high-grade pancreatobiliary-type neoplastic cells and polytypic cases (n = 19; 61%) associated with components of low-grade dysplasia and/or other histologic types (eg, gastric, intestinal, or oncocytic types). Clinically, monotypic PB-IPMNs less commonly had dilatation of the ampullary orifice (0% versus 74%) and mucin hypersecretion (17% versus 89%) than did polytypic cases. In most cases of monotypic PB-IPMNs, cystic dilatation of the lesional ducts was less obvious on imaging; therefore, 33% were radiologically diagnosed as PDACs. Histologically, intraductal tumors in monotypic cases showed a highly complex papillary architecture with tubular/cribriform glands and irregular branching, and all these cases were associated with invasive malignancy. GNAS mutations were detected in polytypic PB-IPMNs (6/19; 32%), but there were no GNAS mutations in monotypic cases. The recurrence-free survival of patients with monotypic PB-IPMN or PDAC was similar and significantly worse than that of patients with polytypic PB-IPMN. In conclusion, some cases of monotypic PB-IPMNs lacked the classic characteristics of IPMNs and shared features with PDACs, raising the possibility that these cases may be better classified as a papillary variant of PDACs rather than IPMNs.

In-silico analysis of Thr767Ile pathogenic variant in the MSH6 gene in family with endometrial cancer.

OBJECTIVE: To examine the mechanism of pathogenity of Thr767Ile variant on MSH6 protein. STUDY DESIGN: We describe a family diagnosed with endometrial cancer in two generations associated with variant in the MSH6 gene (p. Thr767Ile / c. 2300C>T) (rs587781462). MSH6 c. 2300C>T was associated with autosomal-dominant pattern of inheritance. MSH6 c. 2300C>T has pathogenic status in ClinVar and LOVD3 databases but it has never been described in context of hereditary endometrial cancer. We utilized a number of in-silico bioinformatic approaches using MSH6 protein sequence and structural information to assess influence of Thr767Ile on MSH6 properties. RESULTS: MSH6 Thr767 is highly conservative amino acid among various kingdoms of organisms. Thr767Ile was predicted deleterious and likely decreases affinity of MSH2-MSH6 complex to DNA but not affect interaction between MSH2 and MSH6. CONCLUSIONS: To the best of our knowledge, this is the first description of MSH6 T767I pathogenic variant that could be associated with a hereditary endometrial cancer. Bioinformatic analyses showed that T767I substitution most likely affects the MSH6 most important role, which is a DNA binding.