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INTRODUCTION: The tumor microenvironment of sarcomas has not been studied in detail; in particular, little is known about cancer-associated fibroblasts (CAFs). Sarcoma cells are difficult to distinguish from CAFs, either histomorphologically or immunohistochemically. METHODS: We scored expression of individual CAF markers (fibroblast activating protein (FAP), CD10, and podoplanin) in the intratumoral and marginal areas of 133 sarcomas. We also examined the association between these markers, as well as the number of CD163-positive macrophages (i.e., tumor-associated macrophages), and clinical outcome. RESULTS: In all cases, the log-rank test revealed that those with high marker scores and macrophage counts (except for marginal CD10+ CAFs) showed significantly worse disease-free survival (DFS). Grade 2/3 cases with high CAF scores (excluding the marginal FAP and CD10 scores) showed significantly worse DFS, whereas those with high intratumoral FAP/CD10 and marginal podoplanin scores showed significantly worse metastasis-free survival (MFS), and those with a high intratumoral CD10 score showed significantly worse local recurrence-free survival (LFS). Multivariate analysis identified intratumoral CD10/podoplanin scores and marginal FAP/podoplanin scores as independent prognostic factors for DFS, intratumoral FAP/CD10 and marginal FAP/podoplanin/CD163-positive macrophage scores as independent prognostic factors for MFS, and the intratumoral podoplanin score as an independent prognostic factor for LFS. There was a weak-to-moderate correlation between each score and CD163-positive macrophage counts. CONCLUSION: Patients with high CAF marker expression in the intratumoral and marginal areas have a poorer outcome.
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BACKGROUND: PEComa is a mesenchymal tumor that can occur in various organs including the uterus and soft tissues. PEComas are composed of perivascular epithelioid cells, and angiomyolipoma (AML), clear cell sugar tumor (CCST), and lymphangiomyomatosis (LAM) are considered lesions of the same lineage as tumors of the PEComa family. Histologically, a common PEComa shows solid or sheet-like proliferation of epithelioid cells. This is accompanied by an increase in the number of dilated blood vessels. Here, we report a case of pancreatic PEComa with marked inflammatory cell infiltration. CASE PRESENTATION: A 74-year-old male patient underwent an appendectomy for acute appendicitis. Postoperative computed tomography and magnetic resonance imaging revealed a 30 × 25 mm non-contrast-enhanced circular lesion in the tail of the pancreas. The imaging findings were consistent with a malignant tumor, and distal pancreatectomy was performed. Histologically, most area of the lesion was infiltrated with inflammatory cells. A few epithelioid cells with large, round nuclei, distinct nucleoli, and eosinophilic granular cytoplasm were observed. Spindle-shaped tumor cells were observed. Delicate and dilated blood vessels were observed around the tumor cells. Immunohistochemically, the atypical cells were positive for αSMA, Melan A, HMB-45, and TFE3. The cytological characteristics of the tumor cells and the results of immunohistochemical staining led to a diagnosis of pancreatic PEComa. CONCLUSIONS: A histological variant known as the inflammatory subtype has been defined for hepatic AML. A small number of tumor cells present with marked inflammatory cell infiltration, accounting for more than half of the lesions, and an inflammatory myofibroblastic tumor-like appearance. To our knowledge, this is the first report of pancreatic PEComa with severe inflammation. PEComa is also a generic term for tumors derived from perivascular epithelioid cells, such as AML, CCST, and LAM. Thus, this case is considered an inflammatory subtype of PEComa. It has a distinctive morphology that is not typical of PEComa. This histological phenotype should be widely recognized.
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Neoplasias Renais , Leucemia Mieloide Aguda , Neoplasias de Células Epitelioides Perivasculares , Masculino , Feminino , Humanos , Idoso , Biomarcadores Tumorais , Imuno-Histoquímica , Neoplasias de Células Epitelioides Perivasculares/cirurgia , Neoplasias de Células Epitelioides Perivasculares/patologia , Pâncreas/patologiaRESUMO
Even when treated comprehensively by surgery, chemotherapy, and radiotherapy, soft-tissue sarcoma has an unfavorable outcome. Because soft-tissue sarcoma is rare, it is the subject of fewer clinicopathological studies, which are important for clarifying pathophysiology. Here, we examined tumor-associated macrophages in the intratumoral and marginal areas of sarcomas to increase our knowledge about the pathophysiology. Seventy-five sarcoma specimens (not limited to a single histological type), resected at our institution, were collected, and the number of CD68-, CD163-, and CD204-positive macrophages in the intratumoral and marginal areas was counted. We then performed statistical analysis to examine links between macrophage numbers, clinical factors, and outcomes. A high number of macrophages positive for all markers in both areas was associated with worse disease-free survival (DFS). Next, we divided cases according to the FNCLCC classification (Grade 1 and Grades 2/3). In the Grade 1 group, there was no significant association between macrophage number and DFS. However, in the Grade 2/3 group, high numbers of CD163- and CD204-positive macrophages in the marginal area were associated with poor DFS. By contrast, there was no significant difference between the groups with respect to high or low numbers of CD68-, CD163-, or CD204-positive macrophages in the intratumoral area. Multivariate analysis identified the number of CD163- and CD204-positive macrophages in the marginal area as an independent prognostic factor. Macrophage numbers in the marginal area of soft-tissue sarcoma may better reflect clinical behavior.
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Sarcoma , Neoplasias de Tecidos Moles , Humanos , Prognóstico , Macrófagos/patologia , Neoplasias de Tecidos Moles/patologia , Antígenos de Diferenciação Mielomonocítica , Sarcoma/patologiaRESUMO
Dilated cardiomyopathy (DCM) is a primary myocardial disease, the pathology of which is left ventricular or biventricular dilation and impaired myocardial contractility. The clinical and pathological diagnosis of DCM is difficult, and other cardiac diseases must be ruled out. Several studies have reported pathological findings that are characteristic of DCM, including cardiomyocyte atrophy, nuclear pleomorphism, and interstitial fibrosis, but none of these findings are DCM-specific. In this study, we examined the morphological differences in the intercalated discs (ICDs) between three groups of patients, a DCM group, a chronic heart failure group, and a control group. A total of 22 autopsy cases, including five DCM cases, nine CHF cases and eight control cases, were retrieved from the archives of the Department of Pathology at Akita University, Japan. The morphological differences were examined using multiple methods: macroscopic examination, light microscopy, immunohistochemistry, electron microscopy, and gene expression analyses. We observed disorganized ICDs, clearly illustrated by N-cadherin immunostaining in the DCM group. "Reduction of N-cadherin immunostaining intensity" and "ICD scattering" was DCM-specific. The results suggest that disorganized ICDs contribute to the development of DCM, and that N-cadherin immunostaining is useful for determining the presence of disorganized ICDs and for the pathological diagnosis of DCM.
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Cardiomiopatia Dilatada/fisiopatologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Atrofia , Autopsia , Caderinas/metabolismo , Estudos de Casos e Controles , Feminino , Fibrose , Seguimentos , Insuficiência Cardíaca/metabolismo , Humanos , Japão , Masculino , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Miocárdio/metabolismo , Função Ventricular EsquerdaRESUMO
BACKGROUND: Epstein-Barr virus (EBV)-positive gastric carcinoma (GC) is defined by the proliferation of GC cells with EBV infection. The co-existence of EBV-positive and -negative components in a single GC is rare. We report a case of GC with the co-existence of EBV-positive and EBV-negative components, in which we performed-for the first time-various molecular analyses to elucidate their histogenesis. CASE PRESENTATION: An 81-year-old man was diagnosed with GC based on the results of endoscopy and a pathological examination of the biopsy specimen. Systemic chemotherapy was performed, since lymph node and lung metastases were diagnosed based on computed tomography. Total gastrectomy and lymph node dissection were performed after chemotherapy, after confirming that the size of the metastatic lymph nodes had decreased and that the lung metastasis had disappeared. Grossly, a type 3 tumor was located in the middle posterior part of the stomach body. At the cut section, the tumor consisted of a white and solid part on the anal side of the tumor and a flat and elevated part on the oral side. Histologically, the former part consisted of GC with lymphoid stroma and the latter part was composed of poorly differentiated adenocarcinoma without prominent lymphocytic infiltration. The two histopathological components were clearly separated from each other. On EBV-encoded small RNA (EBER)-in situ hybridization (ISH), the part with the lymphoid stroma component was positive, while the other part was negative. Immunohistochemistry revealed that both components showed the overexpression of p53. Sequencing of TP53 using DNA extracted from the two components was conducted, and revealed different patterns. Targeted next generation sequencing revealed MYC amplification in the EBV-positive component of the tumor and HER2 amplification in the EBV-negative part. Immunohistochemistry revealed that the EBV-positive part was C-MYC( +)/HER2(-) and the EBV-negative part was C-MYC(-)/HER2( +). Correspondingly, chromogenic ISH and dual-color ISH showed amplification of C-MYC and no amplification of HER2 in the EBV-positive part, and no amplification of C-MYC and amplification of HER2 in the EBV-negative part. CONCLUSION: We presented a case of collision of two different GCs composed of EBER-ISH ( +)/C-MYC ( +) and EBER-ISH (-)/HER2 ( +) cells.
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Infecções por Vírus Epstein-Barr , Neoplasias Gástricas , Idoso de 80 Anos ou mais , Infecções por Vírus Epstein-Barr/complicações , Gastrectomia , Herpesvirus Humano 4/genética , Humanos , Hibridização In Situ , Masculino , RNA Viral , Neoplasias Gástricas/cirurgiaRESUMO
Adenomyoma of the uterus is a biphasic nodular lesion composed of a mesenchymal component with smooth muscle differentiation and a glandular epithelium. The neoplastic nature of uterine adenomyomas has been controversial because some are considered to be nodular adenomyosis. MED12 mutations are involved in the pathogenesis of uterine smooth muscle tumors (leiomyomas and leiomyosarcomas) and biphasic tumors of the breast (fibroadenomas and phyllodes tumor). To investigate the histogenesis of uterine adenomyomas, we performed pathological and genetic analyses, including Sanger sequencing of MED12. In total, 15 cases of uterine adenomyomas were retrieved and assessed for clinicopathological factors. Immunohistochemistry for smooth muscle actin, desmin, and CD10 was performed. Exon 2 of MED12 was Sanger sequenced using DNA obtained by macrodissection of the adenomyomas. For cases that were positive for somatic MED12 mutations, we next performed microdissection of the mesenchymal and epithelial components. The DNA extracted from each component was further analyzed for MED12 mutations. MED12 mutations were detected in two adenomyomas (2/15, 13%), all in a known hot spot (codon 44). In both lesions, MED12 mutations were detected in multiple spots of the mesenchymal component. The epithelial component did not harbor MED12 mutations. The relatively low frequency of MED12 mutations suggests that not all adenomyomas are leiomyomas with entrapped glands. However, the results of our study suggest that a subset of uterine adenomyomas are true mesenchymal neoplasms.
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Adenomioma/genética , Complexo Mediador/genética , Mutação/genética , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Adenomioma/patologia , Adenomiose/genética , Adulto , Biomarcadores Tumorais/análise , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Análise Mutacional de DNA/métodos , Feminino , Humanos , Leiomioma/genética , Leiomioma/patologia , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/patologiaRESUMO
Endometrial stromal nodule (ESN) and low-grade endometrial stromal sarcoma (LG-ESS) are rare uterine tumors known as endometrial stromal tumors (ESTs). In addition to their similarity in morphological features, recent studies have shown that these two tumors share common genetic alterations. In particular, JAZF1-SUZ12 fusion is found with high frequency in both ESN and LG-ESS. In LG-ESS, some minor fusions have also been described, which include rearrangements involving PHF1 and its partner genes, such as JAZF1, EPC1, MEAF6, BRD8, EPC2, and MBTD1. Because of the rarity of ESN, genetic alterations other than JAZF1 fusion have not been investigated in detail. In this study, we performed a next-generation sequencing-based analysis in a case of ESN with peripheral metaplastic bone formation and detected MEAF6-PHF1 fusion, which has been reported in a small subset of uterine LG-ESSs and soft tissue ossifying fibromyxoid tumors. The finding that MEAF6-PHF1 fusion is a background genetic abnormality detected both in ESN and LG-ESS, along with JAZF1-SUZ12, provides further support for the similarity and continuum between these two types of ESTs. Furthermore, the association between metaplastic bone formation and MEAF6-PHF1 fusion may not be limited to soft tissue tumors.
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AIMS: Recent advances in next-generation sequencing have made it clear that clonal expansion of cells harbouring driver gene mutations occurs in physiologically normal epithelium. Molecular analysis of tubal epithelium has been almost exclusively confined to the TP53 pathway, which is involved in serous carcinogenesis. Other oncogenic events have not been explored in detail. Here, we report the linear expansion of fallopian tubal epithelial cells exhibiting an altered ß-catenin profile (ß-catenin signature). Through molecular analyses, we determined the incidence and clinicopathological significance of ß-catenin signatures. METHODS AND RESULTS: We evaluated 64 specimens of surgically removed bilateral fallopian tubes. Thirty-three ß-catenin signatures were identified in 13 cases (20.3%); these patients were significantly younger than those without ß-catenin signatures (median ages of 44 and 57 years, respectively, P = 0.0317). No correlation between ß-catenin signature and any clinical factor was observed. CTNNB1 mutations were detected in three of eight ß-catenin signatures when tissues were microdissected and subjected to Sanger sequencing in two representative cases. CONCLUSIONS: This is the first report of the CTNNB1 mutation in clusters of morphologically bland tubal epithelial cells. The results of this study indicate that ß-catenin signatures are common, and they may be a part of diverse molecular alterations occurring in normal tubal epithelium.
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Células Epiteliais/metabolismo , Tubas Uterinas/citologia , beta Catenina , Adulto , Células Epiteliais/patologia , Neoplasias das Tubas Uterinas/etiologia , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Mutação , Análise de Sequência de DNA , beta Catenina/genética , beta Catenina/metabolismoRESUMO
Russell body gastritis is an extremely rare gastritis characterized by abundant infiltration of plasma cells with Russell body and eccentric nuclei, known as Mott cells. An 81-year-old Japanese woman with Helicobacter pylori and hepatitis C virus infection complaining of abdominal discomfort underwent upper gastrointestinal endoscopy, which detected an elevated lesion 2 cm in diameter at the anterior wall of the gastric body. A histological examination of the lesion revealed the infiltration of numerous Mott cells with an abundant eosinophilic crystal structure and eccentric nuclei in the lamina propria, resulting in a pathological diagnosis of Russell body gastritis. Endoscopic submucosal dissection (ESD) was performed subsequently. The histological findings of the resected specimen were compatible with those of Russell body gastritis. Upper gastrointestinal endoscopy performed 2 months after endoscopic submucosal dissection revealed the presence of new multiple flat elevated lesions in the antrum up to 1 cm in diameter, distant from the site of endoscopic submucosal dissection. A histological examination revealed a few Mott cells in the biopsy specimens taken from the new lesions. In turn, H. pylori eradication therapy was performed 1 month after the detection of the new lesions. One year after the eradication therapy, follow-up upper gastrointestinal endoscopy revealed that multiple lesions had almost disappeared, and the histological examination of the gastric biopsy specimens confirmed the disappearance of Mott cells. We herein report a case of Russell body gastritis in which multifocal lesions were observed after endoscopic submucosal dissection, and which was subsequently treated by H. pylori eradication therapy.
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Eosinophilic granulomatosis with polyangiitis (EGPA), formerly called Churg-Strauss syndrome, is an uncommon disease with pathological features consisting of systemic necrotizing vasculitis, eosinophilic infiltration, and granulomatous or nongranulomatous extravascular eosinophilic inflammation. EGPA preferentially affects certain organ systems, including the airways, peripheral nerves, heart, kidney, and gastrointestinal tract. Although gastrointestinal involvement, such as ulcerations, is common in EGPA, gastrointestinal perforation is relatively uncommon and is associated with a poor prognosis. Ulceration, perforation, and stenosis of the gastrointestinal tract are assumed to be the result of ischemia caused by vasculitis. The histological finding in the biopsy specimens of EGPA is generally only eosinophil infiltration, and vasculitis is not often seen. Therefore, in biopsy specimens, it is difficult to distinguish eosinophilic gastroenteritis from the gastrointestinal involvement of EGPA. In addition, in general, steroid therapy is the first-choice treatment for EGPA, but some reports have described the frequent occurrence of acute ulcer or perforation of the gastrointestinal tract in association with steroid treatment. We herein report an EGPA patient who was treated with steroid therapy and subsequently developed perforation of the small intestine.
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Síndrome de Churg-Strauss/tratamento farmacológico , Glucocorticoides/efeitos adversos , Perfuração Intestinal/induzido quimicamente , Intestino Delgado/efeitos dos fármacos , Úlcera/induzido quimicamente , Idoso , Síndrome de Churg-Strauss/patologia , Progressão da Doença , Evolução Fatal , Humanos , Perfuração Intestinal/diagnóstico por imagem , Perfuração Intestinal/patologia , Perfuração Intestinal/cirurgia , Intestino Delgado/diagnóstico por imagem , Intestino Delgado/patologia , Intestino Delgado/cirurgia , Masculino , Metilprednisolona , Recidiva , Fatores de Risco , Resultado do Tratamento , Úlcera/diagnóstico por imagem , Úlcera/patologia , Úlcera/cirurgiaRESUMO
Recent genomic studies on cancer tissues obtained during rapid autopsy have provided insights into the clonal evolution and heterogeneity of cancer. However, post-mortem blood has not been subjected to genetic analyses in relation to cancer. We first confirmed that substantial quantities of cell-free DNA were present in the post-mortem plasma of 12 autopsy cases. Then, we focused on a pilot case of prostate cancer with multiple metastases for genetic analyses. Whole-exome sequencing of post-mortem plasma-derived cell-free DNA and eight frozen metastatic cancer tissues collected during rapid autopsy was performed, and compared their mutational statuses. The post-mortem plasma cell-free DNA was successfully sequenced and 344 mutations were identified. Of these, 160 were detected in at least one of the metastases. Further, 99% of the mutations shared by all metastases were present in the plasma. Sanger sequencing of 30 additional formalin-fixed metastases enabled us to map the clones harboring mutations initially detected only in the plasma. In conclusion, post-mortem blood, which is usually disposed of during conventional autopsies, can provide valuable data if sequenced in detail, especially regarding cancer heterogeneity. Furthermore, post-mortem plasma cell-free DNA sequencing (liquid autopsy) can be a novel platform for cancer research and a tool for genomic pathology.
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Autopsia/métodos , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/genética , Neoplasias/genética , Neoplasias/patologia , Plasma/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Testes Genéticos/métodos , Genômica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Projetos Piloto , Estudo de Prova de Conceito , Sequenciamento do Exoma/métodosRESUMO
AIMS: Uterine adenomatoid tumour (AT) is a benign proliferation of cells showing mesothelial differentiation within the myometrium that usually presents as a single nodule. Rare diffuse uterine ATs have been reported, often in patients undergoing immunosuppressive therapy. Herein, we aimed to elucidate the general association between the incidence of uterine AT and iatrogenic immunosuppression by cohort analysis. METHODS AND RESULTS: We analysed 611 consecutive hysterectomy specimens to determine the incidence of AT and its correlation with the immunosuppressive status. Mesothelial lineage, p16 expression, mismatch repair (MMR) protein alterations, and the possible integration of tumorigenic viruses were examined by in situ hybridizasion and immunohistochemistry. ATs were detected in 14 of 611 hysterectomy cases (2.3%). The incidence of AT was significantly higher in the immunosuppressed (IS) group (5/20, 25.0%) than in the non-IS group (9/591, 1.52%), with a relative risk of 16.4. Of the five ATs in the IS group, three were multifocal or diffuse. Latent uterine AT was detected, by in toto sectioning, in one of four immunosuppressed autopsy cases. The tumor cells of ATs commonly expressed calretinin and podoplanin. Characteristic block-type (≥90%) positivity for p16 was observed in most ATs. None of the ATs were positive for human herpes virus type 8, Merkel cell polyomavirus, SV40 large T antigen, Epstein-Barr virus, and human papilloma virus, and the MMR proteins were retained. A TRAF7 mutation was identified from macrodissected tissue in one of 12 ATs by Sanger sequencing. CONCLUSION: Uterine AT is an immunosuppression-associated mesothelial lesion characterised by p16 overexpression.
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Tumor Adenomatoide/etiologia , Terapia de Imunossupressão/efeitos adversos , Imunossupressores/efeitos adversos , Neoplasias Uterinas/etiologia , Tumor Adenomatoide/patologia , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Uterinas/patologiaRESUMO
In the female genital tract, extrauterine leiomyomas such as those that arise in the ovary and paraovarian/paratubal regions are rare. Currently, little is known about the background genetic changes in such adnexal leiomyomas. Recent studies have found that the MED12 mutation is common in uterine leiomyomas, which suggests that such mutations may play an oncogenic role in smooth muscle neoplasms in females. Herein, we examined a series of ovarian and other adnexal leiomyomas in terms of MED12 mutational status to investigate possible MED12 involvement in the pathogenesis of extrauterine smooth muscle tumors. We evaluated 10 cases of adnexal leiomyomas (5 ovarian, 3 paraovarian, and 2 paratubal) and 49 cases of ovarian sex cord-stromal tumors as controls. We performed polymerase chain reaction followed by direct sequencing of exon 2 of MED12, and immunohistochemical staining for smooth muscle actin and desmin. We identified somatic MED12 mutations in 90% (9/10) of the adnexal leiomyomas. None of the sex cord-stromal tumors in the control group harbored MED12 mutations. Diffuse immunoreactivity for both smooth muscle actin and desmin was characteristic of adnexal leiomyomas only. Thus, we conclude that ovarian leiomyomas are distinct from sex cord-stromal tumors. MED12 mutations are key molecular features of ovarian and other adnexal leiomyomas. We speculate that the pathogenesis of adnexal leiomyoma is similar to that of its uterine counterpart.
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Biomarcadores Tumorais/genética , Neoplasias das Tubas Uterinas/genética , Leiomioma/genética , Complexo Mediador/genética , Mutação , Neoplasias Ovarianas/genética , Actinas/análise , Adulto , Idoso , Biomarcadores Tumorais/análise , Diferenciação Celular , Análise Mutacional de DNA , Desmina/análise , Neoplasias das Tubas Uterinas/química , Neoplasias das Tubas Uterinas/patologia , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Leiomioma/química , Leiomioma/patologia , Pessoa de Meia-Idade , Taxa de Mutação , Neoplasias Ovarianas/química , Neoplasias Ovarianas/patologia , Fenótipo , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Fatores de Risco , TóquioRESUMO
Adenocarcinomas showing fetal gut-like (enteroblastic) differentiation can arise in a variety of organs and are frequently accompanied by an elevated serum α-fetoprotein (AFP) level. However, no study has investigated fetal gut-like differentiation in gallbladder cancer in detail. Herein, we performed morphological and immunohistochemical analyses of fetal gut-like differentiation in 49 consecutive gallbladder cancer cases. The expression of Sal-like protein 4 (SALL4), an embryonic stem cell marker reported to represent fetal gut-like differentiation, as well as other oncofetal proteins, including glypican-3 (GPC3) and AFP, was assessed. We found 1 case of fetal gut-like adenocarcinoma that coexisted with conventional-type adenocarcinoma. The fetal gut-like adenocarcinoma component revealed diffuse immunoreactivity for SALL4 and partial positivity for AFP, whereas the conventional-type adenocarcinoma component was negative. We also found 2 poorly differentiated adenocarcinomas with hepatoid morphology and 1 clear cell carcinoma, none of which showed SALL4 positivity. In other conventional-type adenocarcinomas, focal immunoreactivity for SALL4 and GPC3 was occasionally observed. The overall positivity rates for SALL4 and GPC3 were 12.2% (6/49) and 16.3% (8/49), respectively. SALL4 and GPC3 expression was not associated with clinicopathological factors, including T category, lymphovascular invasion, and lymph node metastases. In conclusion, fetal gut-like adenocarcinoma was found in 2% of our gallbladder cancer series. We conclude that fetal gut-like adenocarcinoma is a distinct histological subtype of gallbladder cancer, characterized by SALL4 expression.
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Adenocarcinoma/patologia , Diferenciação Celular , Enterócitos/patologia , Neoplasias da Vesícula Biliar/patologia , Células-Tronco Neoplásicas/patologia , Adenocarcinoma/química , Adenocarcinoma/genética , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Enterócitos/química , Feminino , Neoplasias da Vesícula Biliar/química , Neoplasias da Vesícula Biliar/genética , Glipicanas/análise , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/química , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Fatores de Transcrição/análise , alfa-Fetoproteínas/análiseRESUMO
AIMS: Hidradenoma papilliferum (HP) is a benign vulvar neoplasm that arises from anogenital mammary-like glands, and its morphology is similar to mammary intraductal papilloma. The aim of this study was to investigate oncogenic mutations involved in the tumourigenesis of HP. We focused specifically on PIK3CA and AKT1 mutations, which are both reported to be detected in 33% of mammary intraductal papillomas. METHODS: In total, seven HP cases were analysed. Clinicopathological analyses and immunohistochemistry for oestrogen receptor, p63, smooth muscle actin (SMA), p53 and ß-catenin were performed. Furthermore, PIK3CA, AKT1, BRAF and KRAS hot spot mutations were examined by Sanger sequencing. RESULTS: Morphologically, all HPs had a papillary and tubular architecture with a biphasic pattern of epithelial and myoepithelial cells. Immunohistochemistry revealed that oestrogen receptor expression was restricted to epithelial cells, whereas p63 and SMA were exclusively expressed in myoepithelial cells. The patterns of p53 and ß-catenin immunostaining suggested wild-type genotypes. Direct sequencing revealed the presence of somatic PIK3CA mutations (Ex9. c.1633G>A, p.E545K and Ex20. c.3140A>G, p.H1047R) in two of the HPs and an AKT1 (c.49G>A, p.E17K) mutation in one. BRAF and KRAS mutations were not found in any of the HP cases. CONCLUSIONS: PIK3CA and AKT1 are frequently mutated in HP tumours (29% and 14%, respectively). PIK3CA/AKT1 pathway alterations in HP further support the hypothesis that HP is the vulvar (anogenital mammary-like gland) analogue of breast intraductal papilloma.
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Acrospiroma/genética , Biomarcadores Tumorais/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Neoplasias Cutâneas/genética , Neoplasias das Glândulas Sudoríparas/genética , Neoplasias Vulvares/genética , Acrospiroma/diagnóstico , Acrospiroma/patologia , Adulto , Biomarcadores Tumorais/metabolismo , Transformação Celular Neoplásica , Classe I de Fosfatidilinositol 3-Quinases , Feminino , Genótipo , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Mutação , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Análise de Sequência de DNA , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Neoplasias das Glândulas Sudoríparas/diagnóstico , Neoplasias das Glândulas Sudoríparas/patologia , Neoplasias Vulvares/diagnóstico , Neoplasias Vulvares/patologiaRESUMO
[This corrects the article DOI: 10.1371/journal.pone.0156069.].
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There is a growing body of evidence regarding cell competition between normal and mutant mammalian cells, which suggest that it may play a defensive role in the early phase of carcinogenesis. In vitro study in the past has shown that overexpression of vimentin in normal epithelial cells at the contact surface with transformed cells is essential for the cell competition involved in epithelial defense against cancer. In this study, we attempted to examine cell competition in human tissue in vivo by investigating surgically resected human fallopian tubes that contain p53 signatures and serous tubal intraepithelial lesions (STILs), a linear expansion of p53-immunopositive/TP53 mutant tubal epithelial cells that are considered as precursors of pelvic high grade serous carcinoma. Immunofluorescence double staining for p53 and the cell competition marker vimentin was performed in 21 sections of human fallopian tube tissue containing 17 p53 signatures and 4 STILs. The intensities of vimentin expression at the interface between p53-positive cells at the end of the p53 signature/STIL and adjacent p53-negative normal tubal epithelial cells were compared with the background tubal epithelium. As a result, the average vimentin intensity at the interfaces relative to the background intensity was 1.076 (95% CI, 0.9412 -â 1.211 for p53 signature and 0.9790 (95% CI, 0.7206 -â 1.237) for STIL. Thus, it can be concluded that overexpression of the cell competition marker vimentin are not observed in human tissue with TP53 alterations.