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Although gastric juvenile polyposis (GJP) often coexists with gastric cancer, a preoperative accurate diagnosis is still difficult to obtain. A 70-year-old woman was referred for epigastralgia and anemia. Esophagogastroduodenoscopy with a conventional endoscope showed numerous gastric polyps with no cancerous findings. Magnifying endoscopy with narrow-band imaging (M-NBI) showed cancerous findings, and a target biopsy revealed adenocarcinoma. Histopathological findings after endoscopic resection confirmed a diagnosis of juvenile polyposis with intramucosal adenocarcinoma. Genetic analyses revealed a germline pathogenic variant of SMAD4. A target biopsy using M-NBI and endoscopic resection proved useful for confirming the preoperative diagnosis of coexisting cancerous lesions in GJP.
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Adenocarcinoma , Neoplasias Gástricas , Feminino , Humanos , Idoso , Neoplasias Gástricas/complicações , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/cirurgia , Gastroscopia/métodos , Adenocarcinoma/complicações , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/cirurgia , Endoscopia GastrointestinalRESUMO
Adenocarcinomas with enteroblastic differentiation are rare clear cell tumors that are positive for enteroblastic markers. Enteroblastic differentiation is particularly uncommon in colorectal adenocarcinomas. Herein, we report a case of clear cell adenocarcinoma with enteroblastic differentiation in the sigmoid colon of a 38-year-old Japanese woman that metastasized to the lower left ureter. After neoadjuvant chemotherapy, the patient underwent low anterior resection. The tumor consisted of tubular, cribriform, and focal micropapillary proliferation of clear cells immunopositive for spalt-like transcription factor 4 (SALL4), glypican 3, and alpha-fetoprotein. Six months after the colonic resection, a tumor was found in the left lower ureter, which was resected. The ureteral tumor revealed clear cell adenocarcinoma, which was identical to the colonic tumor proliferating in the ureteral mucosa. Metastatic ureteral tumors are rare. We performed a literature search and found only 50 reported cases of ureteral metastases from colorectal cancer. Of these, only 10 metastatic tumors were identified in the ureteral mucosa. No case of ureteral metastasis of clear cell colorectal adenocarcinoma or colorectal adenocarcinoma with enteroblastic differentiation has been reported. Hence, it can be challenging to distinguish them from clear cell adenocarcinoma of the urinary tract and/or clear cell urothelial carcinoma. This paper discussed the differential diagnosis of these tumors and reviewed the clinicopathological features of colorectal carcinomas metastasizing to the ureter.
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Adenocarcinoma de Células Claras , Carcinoma de Células de Transição , Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Gástricas , Neoplasias da Bexiga Urinária , Sistema Urinário , Feminino , Humanos , Adulto , Adenocarcinoma de Células Claras/diagnóstico , Biomarcadores Tumorais , Neoplasias Gástricas/patologia , Neoplasias do Colo/diagnóstico , Sistema Urinário/patologia , Diferenciação CelularRESUMO
Esophageal basaloid squamous cell carcinoma (EBSCC) is a poorly differentiated variant of esophageal squamous cell carcinoma (ESCC). We aimed to investigate the clinicopathological and molecular biological characteristics of EBSCC and enrolled 58 patients with EBSCCs. Clinicopathological factors including age, sex, tumor size and location, gross tumor type (superficial, protrusive, ulcerative, and unclassifiable), lymphovascular invasion, infiltrative growth, intramural invasion, TNM stage, and dominant histological type were examined. EBSCCs were classified into four types (solid, cribri, microcystic, and tubular) according to the dominant histology. Next-generation sequencing (NGS) of a cancer hotspot panel was performed in 19 cases. NGS identified TP53 as the most frequently mutated gene, and copy number variation analysis revealed the most frequent loss of heterozygosity (LOH) at the ataxia telangiectasia mutated (ATM) and retinoblastoma 1 (RB1) loci. Target sequencing for TP53 was performed for the remaining 39 cases. We also performed LOH analysis for TP53, ATM, and RB1 and immunohistochemical staining for p53, ATM, and Rb in all cases. The rates of TP53 mutations and LOH and p53 aberrant expression were high (79.3%, 63.2%, and 72.4%, respectively); however, the frequencies were similar to those reported for ESCC. LOH rates of the RB1 and ATM loci were also high (55.3% and 67.2%, respectively). Overall survival rate was 66.5%, and recurrence-free survival rate was 55.0%. Only conventional clinicopathological factors had a prognostic impact in EBSCC; the microcystic type had the poorest prognosis. Our findings could be useful in developing novel treatment strategies for EBSCC.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Variações do Número de Cópias de DNA , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Humanos , Mutação , Proteína Supressora de Tumor p53/genéticaRESUMO
The histological diagnosis of type 1 autoimmune pancreatitis (AIP) based on the findings obtained by an endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) is feasible, but the diagnostic consistency of this method has not been confirmed. We determined the interobserver agreement among 20 pathologists regarding the diagnosis of type 1 AIP, including the distinction from pancreatic ductal adenocarcinoma (PDAC) using large tissue samples obtained by EUS-FNB. After guidance for diagnosing AIP with biopsy tissues was provided, a round 2 was performed. The median sensitivity and specificity for diagnosing PDAC vs. non-neoplastic diseases were 95.2% and 100%, respectively. In groups of specialists (n = 7) and the generalists (n = 13), Fleiss' к-values increased from 0.886 to 0.958 and from 0.750 to 0.816 in round 2. The concordance was fair or moderate for obliterative phlebitis and storiform fibrosis but slight for ductal lesion of type 1 AIP. Discordant results were due to ambiguous findings and biopsy tissue limitations. Among the specialists, the ratio of cases with perfect agreement regarding the presence of storiform fibrosis increased in round 2, but agreement regarding obliterative phlebitis or ductal lesions was not improved. Although the histological definite diagnosis of type 1 AIP was achieved by most observers in > 60% of the cases, the confidence levels varied. Because some ambiguities exist, the histological diagnostic levels based on the diagnostic criteria of type 1 AIP should not be taken for granted. Guidance is effective for improving accurate PDAC diagnoses (notably by recognizing acinar-ductal metaplasia) and for evaluating storiform fibrosis.
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Doenças Autoimunes , Pancreatite Autoimune , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Flebite , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/patologia , Pancreatite Autoimune/diagnóstico , Biópsia por Agulha Fina/métodos , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/patologia , Fibrose , Humanos , Variações Dependentes do Observador , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patologia , Flebite/patologia , Ultrassonografia de Intervenção , Neoplasias PancreáticasRESUMO
Celiac disease has a morbidity of 0.2 to 1% in Europe and the United States (US), but appears to be extremely rare in Japan with only a few case reports. This report details a Japanese woman with celiac disease diagnosed by histopathological findings and the improvement of her clinical symptoms on a gluten-free diet. The woman was in her 60s and presented with diarrhea, abdominal pain, and vomiting which were repeatedly exacerbated over several weeks. Therefore, she was referred to our hospital for a detailed examination and treatment. Upper gastrointestinal endoscopy revealed a crude granular mucosa with an erythematous color in the duodenum. No special findings were noted on colonoscopy or capsular endoscopy. Histopathological ï¬ndings of the duodenum noted villous atrophy, crypt hyperplasia, and lymphocytic inï¬ltration within the surface epithelium, which were suspicious for celiac disease. A gluten-free diet was started which resulted in improved clinical symptoms. Repeat endoscopic imaging and histopathological ï¬ndings after initiation of the gluten-free diet demonstrated improved small bowel villous atrophy. In this case, appropriate testing had ruled out inflammatory bowel disease, amyloidosis, infectious enteritis, parasitic disease, and allergies. Although anti-gliadin antibody (AGA) and anti-tissue transglutaminase antibody (ATTGA) were serologically negative, and HLA typing was HLA-DQ6, the patient was ultimately diagnosed as having celiac disease based on the characteristic pathological findings and clinical course. In many cases of celiac disease reported in Japan, serum antibodies such as AGA and ATTGA have not been detected, and HLA testing has been negative for DQ2 or DQ8. Therefore, it is possible that celiac disease in Japan might have different genetic and immunological characteristics than the disease in the US and Europe. In the future, additional cases with histology and molecular biological analysis are necessary to test this hypothesis.
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Doença Celíaca , Dieta Livre de Glúten , Europa (Continente) , Feminino , Gliadina , Humanos , Mucosa Intestinal , JapãoRESUMO
BACKGROUND: Gastric adenocarcinoma of fundic-gland type (GA-FG) is a rare variant of gastric neoplasia. However, the etiology, classification, and clinicopathological features of gastric epithelial neoplasm of fundic-gland mucosa lineage (GEN-FGML; generic term of GA-FG related neoplasm) are not fully elucidated. We performed a large, multicenter, retrospective study to establish a new classification and clarify the clinicopathological features of GEN-FGML. METHODS: One hundred GEN-FGML lesions in 94 patients were collected from 35 institutions between 2008 and 2019. We designed a new histopathological classification of GEN-FGML using immunohistochemical analysis and analyzed via clinicopathological, immunohistochemical, and genetic evaluation. RESULTS: GEN-FGML was classified into 3 major types; oxyntic gland adenoma (OGA), GA-FG, and gastric adenocarcinoma of fundic-gland mucosa type (GA-FGM). In addition, GA-FGM was classified into 3 subtypes; Type 1 (organized with exposure type), Type 2 (disorganized with exposure type), and Type 3 (disorganized with non-exposure type). OGA and GA-FG demonstrated low-grade epithelial neoplasm, and GA-FGM should be categorized as an aggressive variant of GEN-FGML that demonstrated high-grade epithelial neoplasm (Type 2 > 1, 3). The frequent presence of GNAS mutation was a characteristic genetic feature of GEN-FGML (7/34, 20.6%; OGA 1/3, 33.3%; GA-FG 3/24, 12.5%; GA-FGM 3/7, 42.9%) in mutation analysis using next-generation sequencing. CONCLUSIONS: We have established a new histopathological classification of GEN-FGML and propose a new lineage of gastric epithelial neoplasm that harbors recurrent GNAS mutation. This classification will be useful to estimate the malignant potential of GEN-FGML and establish an appropriate standard therapeutic approach.
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Linhagem da Célula , Pólipos/classificação , Neoplasias Gástricas/classificação , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor/métodos , Medição da Dor/estatística & dados numéricos , Pólipos/patologia , Estudos Retrospectivos , Neoplasias Gástricas/patologiaRESUMO
Background and study aims We aimed to evaluate the diagnostic performance of magnifying endoscopy with narrow-band imaging (M-NBI) in superficial non-ampullary duodenal epithelial tumors (SNADETs) regarding the absence or presence of biopsy before M-NBI diagnosis. Patients and methods Clinicopathological data were retrospectively reviewed for 99 SNADETs from 99 patients who underwent endoscopic resection. The 99 tumors were divided into the non-biopsy group (32 lesions not undergoing biopsy before M-NBI examination) and the biopsy group (67 lesions undergoing biopsy before M-NBI examination). We investigated the correlation between the M-NBI diagnosis and the histopathological diagnosis of the SNADETs in both groups. Results According to the modified revised Vienna classification, 31 tumors were classified as category 3 (C3) (low-grade adenoma) and 68 as category 4/5 (C4/5) (high-grade adenoma/cancer). The accuracy, sensitivity, and specificity of preoperative M-NBI diagnoses in the non-biopsy group vs the biopsy group were 88â% (95â% confidence interval: 71.0â-â96.5) vs 66â% (51.5â-â75.5), P â=â0.02; 95â% (77.2â-â99.9) vs 89â% (76.4â-â96.4), P â=â0.39; and 70â% (34.8â-â93.3) vs 14â% (3.0â-â36.3), P â<â0.01, respectively. Notably, in the biopsy group, the specificity of M-NBI in SNADETs was low at only 14â% because we over-diagnosed most C3 lesions as C4/5. M-NBI findings might have been compromised by the previous biopsy procedure itself. Conclusions In the non-biopsy group, the accuracy of M-NBI in SNADETs was excellent in distinguishing C4/5 lesions from C3. The M-NBI findings in SNADETs should be evaluated while carefully considering the influence of a previous biopsy.
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AIMS: We aimed to clarify the endoscopic/clinicopathological features of superficial non-ampullary duodenal epithelial tumors (SNADETs) based on their mucin phenotypes. METHODS: We analyzed 62 SNADET lesions and classified them based on mucin phenotypic expression. Endoscopic and clinicopathological findings were compared according to mucin phenotypes. RESULTS: Eleven lesions had the gastric phenotype (GP) and 43 lesions had the intestinal phenotype (IP). All GP lesions were located in the first portion of the duodenum, while most IP lesions (72.1%) were located in the second portion (p < 0.01). Tumor size was significantly larger in the GP than in the IP group (14.4 mm vs. 10.2 mm, p < 0.05). Reddish color (72.7% in GP vs. 37.2% in IP, p < 0.05), type 0-I (72.7% vs. 11.6%, p < 0.01), lobular/granular pattern (81.8% vs. 4.7%, p < 0.01), and category 4/5 in Vienna classification (81.8% vs. 30.2%, p < 0.01) were observed significantly more often in the GP than in the IP group. Regarding findings of magnifying endoscopy with narrow-band imaging (M-NBI), white opaque substance (22.2% in GP vs. 89.7% in IP, p < 0.01) and light blue crest (0% vs. 43.6%, p < 0.05) were significantly less frequently observed in the GP group. Oval-shaped marginal epithelium (66.7% vs. 17.9%, p < 0.01), dense pattern (55.6% vs. 2.6%, p < 0.01), and dilatation of the intervening part (100% vs. 12.8%, p < 0.01) were more frequently observed in the GP group. CONCLUSIONS: SNADETs showed distinct endoscopic/clinicopathological features according to the mucin phenotype. Tumor location, coloration, macroscopic type, and endoscopic findings including M-NBI are useful to distinguish the mucin phenotypes of SNADETs.
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Neoplasias Duodenais , Neoplasias Duodenais/diagnóstico por imagem , Duodeno/diagnóstico por imagem , Endoscopia , Humanos , Mucinas , FenótipoRESUMO
AIMS: This study was performed to elucidate the clinicopathological characteristics, genetic alterations and therapeutic targets of primary malignant melanoma of the oesophagus (PMME). METHODS AND RESULTS: The clinicopathology and molecular pathology of 13 PMME cases and 10 skin malignant melanoma (SKMM) cases were analysed with next-generation sequencing (NGS) and immunohistochemistry. The 3-year overall survival rate and the median survival time for PMME patients were 23.1% and 11.9 months, respectively. Three (23.1%) and eight (61.5%) PMME cases showed a papillary structure and lymph node metastasis, respectively. DNA and RNA hybridization capture-based NGS analysis revealed that NF1 was the most frequently mutated gene (30%) in 10 of the PMME cases. Other mutations detected in PMME included SF3B1 (20%), KRAS (10%), BRCA2 (10%), KIT (10%) and TP53 (10%) mutations. Commonly detected BRAF mutations in SKMM were not detected in PMME. Immunohistochemistry and mutation status were concordant between p53/c-Kit and TP53/KIT, respectively. Focal expression of programmed death-ligand 1 was observed in one PMME sample. The tumour mutation burden in PMME was significantly lower than that in SKMM (P = 0.030). No PMME case showed high microsatellite instability. RNA sequencing revealed a distinctive pattern with respect to RNA expression. T-cell co-stimulation differed between PMME and SKMM. CONCLUSIONS: The RAS-mitogen-activated protein kinase pathway is one of the main pathways involved in PMME. The genetic profile of PMME was similar to that of mucosal/acral melanoma, but differed from the SKMM profile. A subset of PMMEs may contain actionable mutations. Immunotherapy seemed to be less effective for most PMMEs in this series.
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Neoplasias Esofágicas , Melanoma , Oncogenes/genética , Neoplasias Cutâneas , Idoso , Biomarcadores Tumorais , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Esôfago/patologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Mutação , Neurofibromina 1/genética , Prognóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Melanoma Maligno CutâneoRESUMO
Appendiceal mucinous tumors (AMTs) include low-grade mucinous appendiceal neoplasms (LAMNs), high-grade mucinous appendiceal neoplasms (HAMNs), and mucinous adenocarcinomas (MACs). We collected 51 AMT samples (LAMN: 34, HAMN: 8, MAC: 9). Three of the eight HAMN cases contained LAMN components, and four out of nine MAC cases contained LAMN and/or HAMN components within the tumor. A next-generation sequencing (NGS) cancer hotspot panel was used to analyze 11 pure LAMN, 4 HAMN, and 3 MAC cases. The results revealed KRAS and GNAS as the most frequently mutated genes. Sanger sequencing was then performed to detect KRAS, GNAS, and TP53 mutations in the remaining 31 cases and RNF43 mutations in all cases. KRAS/GNAS and TP53 mutations occurred exclusively in pure LAMNs; however, five LAMN cases had mutations in both KRAS and GNAS. RNF43 mutations almost exclusively occurred with KRAS/GNAS mutations in pure LAMNs. In MAC and HAMN, KRAS/GNAS mutation status was nearly preserved between lower-grade areas. Most of the detected RNF43 mutations was missense type. RNF43 mutations were detected in both components of MAC with lower-grade area; however, RNF43 mutations detected in these two lesions were entirely different. RNF43 mutations were detected in only one of the eight HAMN patients, which was the sole case without pseudomyxoma peritonei (PMP). None of the four MAC patients with RNF43 mutation showed PMP. These findings suggest that RNF43 mutations occur at a later stage of MAC development and do not associate with PMP. Furthermore, a gradual transition from LAMN to MAC via HAMN could be considered.
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Adenocarcinoma Mucinoso/genética , Neoplasias do Apêndice/genética , Biomarcadores Tumorais/genética , Mutação , Adenocarcinoma Mucinoso/química , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Apêndice/química , Neoplasias do Apêndice/patologia , Neoplasias do Apêndice/cirurgia , Biomarcadores Tumorais/análise , Cromograninas/genética , Análise Mutacional de DNA , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas p21(ras)/genética , Tóquio , Proteína Supressora de Tumor p53/genética , Ubiquitina-Proteína Ligases/genética , Adulto JovemRESUMO
BACKGROUND: Gastric adenocarcinoma of foveolar type (GA-FV) is a raspberry-shaped gastric cancer (RSGC) and garners much attention as H. pylori (Hp)-uninfected gastric cancer. However, the classification and clinicopathological and endoscopic features of RSGCs in Hp-uninfected patients are poorly defined. We designed a new histopathological classification of RSGC and compared them via endoscopic and clinicopathological characteristics. SUMMARY: From 996 patients with early gastric cancers resected by endoscopy in our hospital, we studied 24 RSGC lesions from 21 (2.4%) Hp-uninfected patients. RSGCs were classified into 3 histological types as follows: GA-FV (n = 19), gastric adenocarcinoma of fundic gland type (GA-FG, n = 2), and gastric adenocarcinoma of fundic gland mucosa type (GA-FGM, n = 3). Most of the lesions were found at the greater curvature of the upper or middle third of the stomach. GA-FV lesions were homogeneously reddish and frequently accompanied with a whitish area around the tumor and an irregular microvascular (MV) pattern; these features were confirmed histopathologically by the presence of homogeneous neoplastic foveolar epithelium with foveolar hyperplasia around the tumors. GA-FG lesions might be heterogeneously reddish with a submucosal tumor shape and regular MV pattern; these were confirmed by the presence of covered or mixed nonneoplastic epithelium on deeper regions of tumors. GA-FGM lesions might be homogeneously reddish and occasionally had a submucosal tumor shape and irregular MV pattern; these were confirmed by the presence of homogeneous neoplastic foveolar epithelium on deeper regions of the tumors. Key Messages: RSGCs in Hp-uninfected patients are classified into 3 histopathological types. For accurate diagnosis of RSGCs, it may be necessary to fully understand endoscopic features of these lesions based on these histological characteristics and to take a precise biopsy.
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The molecular and clinical characteristics of non-ampullary duodenal adenomas and intramucosal adenocarcinomas are not fully understood because they are rare. To clarify these characteristics, we performed genetic and epigenetic analysis of cancer-related genes in these lesions. One hundred and seven non-ampullary duodenal adenomas and intramucosal adenocarcinomas, including 100 small intestinal-type tumors (90 adenomas and 10 intramucosal adenocarcinomas) and 7 gastric-type tumors (2 pyloric gland adenomas and 5 intramucosal adenocarcinomas), were investigated. Using bisulfite pyrosequencing, we assessed the methylation status of CpG island methylator phenotype (CIMP) markers and MLH1. Then using next-generation sequencing, we performed targeted exome sequence analysis within 75 cancer-related genes in 102 lesions. There were significant differences in the clinicopathological and molecular variables between small intestinal- and gastric-type tumors, which suggests the presence of at least two separate carcinogenic pathways in non-ampullary duodenal adenocarcinomas. The prevalence of CIMP-positive lesions was higher in intramucosal adenocarcinomas than in adenomas. Thus, concurrent hypermethylation of multiple CpG islands is likely associated with development of non-ampullary duodenal intramucosal adenocarcinomas. Mutation analysis showed that APC was the most frequently mutated gene in these lesions (56/102; 55%), followed by KRAS (13/102; 13%), LRP1B (10/102; 10%), GNAS (8/102; 8%), ERBB3 (7/102; 7%), and RNF43 (6/102; 6%). Additionally, the high prevalence of diffuse or focal nuclear ß-catenin accumulation (87/102; 85%) as well as mutations of WNT pathway components (60/102; 59%) indicates the importance of WNT signaling to the initiation of duodenal adenomas. The higher than previously reported frequency of APC gene mutations in small bowel adenocarcinomas as well as the difference in the APC mutation distributions between small intestinal-type adenomas and intramucosal adenocarcinomas may indicate that the adenoma-carcinoma sequence has only limited involvement in duodenal carcinogenesis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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Adenocarcinoma/genética , Adenoma/genética , Biomarcadores Tumorais/genética , Neoplasias Duodenais/genética , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Mutação , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Adenoma/diagnóstico , Adenoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinogênese/genética , Carcinogênese/patologia , Variações do Número de Cópias de DNA , Metilação de DNA , Neoplasias Duodenais/diagnóstico , Neoplasias Duodenais/patologia , Duodeno/patologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
Cancer metastasis, particularly multiple metastatic cancer, is a significant event that affects patient prognosis. However, single metastasis can be treated by partial resection, although the clinicopathological and molecular profile of single lung metastasis has not been thoroughly elucidated. The present study examined tumor heterogeneity by comparing the mutation status between primary colorectal cancer (CRC) and corresponding metastatic lesions to identify prognostic factors associated with single lung metastasis and multiple metastases. The present study enrolled 31 cases of CRC; 20 cases with multiple metastases and 11 cases with single lung metastasis. Clinicopathologically, all cases with multiple metastases were tubular adenocarcinoma, and 3/11 cases with single metastasis were mucinous adenocarcinoma originating from the left side, the remaining 8 cases were tubular adenocarcinoma from the left side. CRC cases with multiple metastases exhibited more frequent vascular invasion, but not lymphatic invasion, than those with single lung metastasis. Furthermore, CRC with multiple metastases was associated with strong tumor budding (P=0.04). Patients with CRC with multiple metastases had lower recurrence-free survival rates compared with those with single lung metastasis (P=0.02). However, there was no significant difference between these two groups in terms of overall survival rates. A next-generation sequencing cancer hotspot panel was used to analyze a heterochronous multiple metastases case, including brain metastasis. Sanger sequencing, immunohistochemistry and microsatellite instability were examined for all 31 cases to reveal the molecular features. KRAS and TP53 mutation signatures were largely preserved throughout the metastatic events. TP53/APC mutations and overexpression of p53 appeared to be associated with the presence of lymphovascular invasion and strong tumor budding, respectively, although these differences were not statistically significant. Early relapses in patients with CRC could be a sign for eventual multiple metastases, although these may not affect the overall survival of patients with CRC. Considerable mutational changes were seemingly rare during metastatic events in patients with CRC.
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BACKGROUND: Colorectal adenocarcinoma with enteroblastic differentiation (CAED) is a rare subtype of colorectal malignancy with expression of enteroblastic markers (glypican 3, SALL4, AFP); however, the clinicopathological and epidemiological features are not fully elucidated. AIMS: The aims of this study were to elucidate and establish the molecular and clinicopathological characteristics of CAED. MATERIALS AND METHODS: In addition to three cases recently diagnosed as CAED, colorectal carcinoma (CRC) with expression of enteroblastic markers were selected by using immunohistochemistry (IHC) on tissue microarrays of 988 advanced CRC. We employed next-generation sequencing (NGS) and Sanger sequencing for the detection of genetic alterations. IHC for p53 and HER2, HER2-FISH and MSI status was also investigated. Survival analyses for clinicopathological parameters were performed using Kaplan-Meier methods. RESULTS: Thirty-nine cases (4.0%) were positive for at least one enteroblastic marker. Histological evaluation of the total of 42 cases revealed that 10 contained tumour cells with clear cytoplasm. Enteroblastic marker-positive cases had aggressive behaviour and poor prognosis. NGS revealed TP53 as the most frequently mutated gene. The rate of HER2-positive cases and MSI-H cases was 9.5% (four of 42) and 12.2% (five of 41), respectively. Among these 42 cases, there were no molecular and clinicopathological differences according to the presence of tumour cells with clear cytoplasm. CONCLUSIONS: Enteroblastic marker-positive CRC could be grouped together as CAED regardless of clear cell cytoplasm. Using this definition, the frequency of CAED is 4.0% and has a poorer prognosis than that for conventional CRCs. HER2 targeted therapy would be a meaningful treatment for CAED, and CAEDs contain both MSI-H and MSI-stable CRCs, although the MSS phenotype is dominant.
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Adenocarcinoma/patologia , Neoplasias Colorretais/patologia , Adenocarcinoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Diferenciação Celular , Neoplasias Colorretais/genética , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The molecular pathogenesis of esophageal carcinosarcoma (ECS) has not been fully investigated. This study includes 16 consequent cases of surgically resected ECS. Genetic alterations were independently examined for carcinoma in situ, carcinomatous, and sarcomatous areas. Six cases were analyzed by next-generation sequencing, and the remaining cases were analyzed by Sanger sequencing for TP53, PTEN, and INI1. Sarcomatous components in 3 cases showed histologically heterogenous feature of osteosarcoma. Lymph node metastasis was found in 12 out of 16 cases. Survival analysis revealed 5-year overall survival rate of 59.9%, and the median survival time was 5.37 years. TP53 was the most frequently mutated gene, being identified in 11 of 16 patients (68.8%), 7 of whom (63.6%) had the same mutations in both carcinomatous and sarcomatous areas. Almost complete concordance was found between p53 immunohistochemistry and TP53 missense mutations. Five-year overall survival tended to be worse for patients with p53 overexpression, although the data was not significant (p = 0.186). Nine of 16 patients (56.3%) showed loss of heterozygosity (LOH) at the INI1 locus, and this LOH status was consistent with both components. However, interestingly, INI1 expression was preserved in all cases. In addition, copy number variation analysis revealed gene amplification in several tyrosine kinase receptors. Accumulation of mutations in tumor suppressor genes such as TP53 and INI1 seemed to occur during ECS development.
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Carcinossarcoma/genética , Carcinossarcoma/patologia , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinossarcoma/mortalidade , Neoplasias Esofágicas/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína SMARCB1/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
Gastric adenocarcinoma with enteroblastic differentiation (GAED) is a rare variant of gastric adenocarcinoma. Clinicopathologically, GAED is known to be aggressive and is characterized by frequent vascular invasion, lymphatic invasion, and liver metastasis even in early stages. SMAD4 was identified as a frequently deleted gene in GAED by copy number variation analysis in our previous next-generation sequencing study; therefore, we examined the clinicopathological impacts of SMAD4 in 51 cases of GAEDs (early: 17, advanced: 34). We performed Sanger sequencing for SMAD4 mutations and loss of heterozygosity (LOH) analysis of the SMAD4 locus, in addition to immunohistochemistry for SMAD4, to determine its clinicopathological correlations and impacts on survival. The frequency of LOH at the SMAD4 locus was 45.1%, and it was significantly higher in GAED compared to in conventional gastric adenocarcinoma. SMAD4 mutations were not found in any case. Reduced SMAD4 expression was found in 60.8% of cases; it was significantly correlated with advanced stages and lymph node metastasis and showed trends of larger tumor size and lymphatic invasion. Reduced SMAD4 expression in metastatic lymph nodes was found in 21 of 36 cases. Survival analysis revealed that reduced SMAD4 expression significantly affected the patient's overall survival (OS) and recurrence-free survival (RFS), although multivariate analysis showed that only liver metastasis and lymphatic infiltration (Ly+) were independent prognostic factors for OS and RFS. The SMAD4 locus is one of the susceptibility genes in this tumor, although SMAD4 mutation was not detected. Furthermore, the inactivation of SMAD4 appeared to contribute to the aggressiveness of GAED.
Assuntos
Adenocarcinoma/genética , Adenocarcinoma/patologia , Perda de Heterozigosidade , Proteína Smad4/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Adenocarcinoma/química , Diferenciação Celular , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Metástase Linfática/patologia , Mutação , Estadiamento de Neoplasias , Prognóstico , Proteína Smad4/análise , Neoplasias Gástricas/química , Taxa de SobrevidaRESUMO
Gastric adenocarcinoma with enteroblastic differentiation (GAED) is a rare variant of aggressive adenocarcinoma. We demonstrated previously that GAED is genetically characterized by frequent TP53 mutation. In this study, we aimed to further clarify the mechanism of inactivation of TP53 in GAED in the light of promoter methylation of TP53, and expression of methylation-associated proteins such as Ten-eleven translocation (TET) 1 and 5-hydroxymethylcytosine (5-hmc) in addition to ATM mutations. We analyzed 51 cases of GAED. The ATM mutation was detected in only one case. Promoter methylation of TP53 was detected in 18% and frequency of loss of heterozygosity (LOH) at TP53 locus was 37.2%. Reduced TET1 expression was found in 29 cases (56.9%) and was significantly associated with advanced stage (p = 0.01), lymph node metastasis (p = 0.04), and macroscopic type (p = 0.01). Reduced 5-hmc expression was found in 28 cases (54.9%) and was significantly associated with advanced stage (p = 0.01), gender (p = 0.01), tumor location (p = 0.03), tumor size (p = 0.01), and lymph node metastasis (p = 0.01). Among 9 cases with TP53 promoter methylation, reduced expression of TET1 was observed in 6 cases, and reduced expression of 5-hmc was observed in 5 cases. Reduced expression of both TET1 and 5-hmc was significantly associated with adverse clinical outcomes. In summary, promoter methylation of TP53 is partly involved in loss of p53 expression. Aberrant methylation by reduced TET1 and 5-hmc may be involved in the development of aggressive GAED.
Assuntos
Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Biomarcadores Tumorais , Diferenciação Celular , Metilação de DNA , Inativação Gênica , Oxigenases de Função Mista/análise , Proteínas Proto-Oncogênicas/análise , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/genética , Proteína Supressora de Tumor p53/genética , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/análise , Adenocarcinoma/secundário , Adenocarcinoma/cirurgia , Idoso , Idoso de 80 Anos ou mais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Feminino , Humanos , Perda de Heterozigosidade , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Regiões Promotoras Genéticas , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Resultado do Tratamento , Proteína Supressora de Tumor p53/análiseRESUMO
Histologically tubulopapillary structures with glycogen-rich clear cytoplasm in gastric adenocarcinoma with enteroblastic differentiation (GAED) are well known, but a solid growth pattern can also be observed as a minor component. In contrast, hepatoid adenocarcinoma (HAC) of the stomach shows many overlapping features, including solid pattern and α-fetoprotein expression. In this study, we employed next-generation sequencing (NGS) to establish a molecular/clinicopathological concept of GAED and clarify whether these two tumors should be grouped together in one category. Among 2273 primary gastric cancers treated in our hospital between 2008 and 2017, we defined 51 cases as GAEDs showing tubulopapillary or solid patterns that express at least one of the following markers: α-fetoprotein, glypican-3, or spalt-like transcription factor 4. All cases previously diagnosed as HAC in our hospital had clear cytoplasm and were included as GAEDs by histological re-evaluation and immunohistochemical findings. We performed NGS for 24 histologically typical GAEDs and Sanger sequencing for the remaining cases. The most frequently mutated gene was TP53, and almost all cases with missense mutation showed p53 overexpression. An analysis of copy number variation revealed that ERBB2 amplification was the most frequent in GAED. Additionally, HER2 immunohistochemistry and fluorescence in situ hybridization confirmed that 22% of informative cases were HER2 positive. There was no correlation between molecular/clinicopathological parameters and α-fetoprotein expression or growth patterns in GAED. Our analysis showed that GAED frequently harbors TP53 mutations and ERBB2 amplification. As with conventional gastric adenocarcinoma, trastuzumab may be effective for GAED. Furthermore, HAC may be subcategorized as a solid-type GAED.
Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Variações do Número de Cópias de DNA/genética , Neoplasias Gástricas/genética , Adenocarcinoma/tratamento farmacológico , Idoso , Diferenciação Celular/genética , Feminino , Glipicanas/genética , Glipicanas/metabolismo , Humanos , Imuno-Histoquímica/métodos , Masculino , Pessoa de Meia-Idade , Neoplasias Gástricas/tratamento farmacológico , Trastuzumab/uso terapêuticoRESUMO
Glomangiopericytoma (GPC) is a rare sinonasal perivascular tumor that accounts for < 0.5-1% of all sinonasal tumors. GPC is categorized as a low-grade neoplasm with borderline malignancy and a tendency of local recurrence. GPC is a rare mesenchymal neoplasm characterized by the perivascular proliferation of tumor cells, and it requires being distinguished from solitary fibrous tumors. Here, we report a case of GPC in a 68-year-old male patient who presented at the emergency room of our hospital with a complaint of sudden epistaxis. A small, reddish, protruding tumor was observed on the right nasal septum. A biopsy revealed a possible perivascular tumor such as a GPC or solitary fibrous tumor. Thus, we performed complete resection with endoscopic surgery. The size of the resected tumor was 12 × 5 mm, and it showed a uniform proliferation of oval-to-short spindle-shaped cells with slightly branching vascular structures. The tumor cells showed minimal cytologic atypia and there were an average of 3 mitoses in 10 high power fields. Necrosis was not observed. The tumor cells showed strong and diffuse nuclear immunostaining with beta catenin and were negative with STAT6, CD34 and bcl-2. The MIB-1 labeling index was approximately 5%. Genetic testing revealed CTNNB1 mutation (p.S33C). Thus, a diagnosis of low grade GPC was made on the biopsy and the patient could be successfully treated with endoscopic resection.
Assuntos
Tumor Glômico/patologia , Septo Nasal/patologia , Neoplasias Nasais/patologia , Tumor Glômico/cirurgia , Humanos , Masculino , Septo Nasal/cirurgia , Neoplasias Nasais/cirurgiaRESUMO
BACKGROUND AND AIM: White globe appearance (WGA) is a small white lesion with a globular shape that can be identified by magnifying endoscopy with narrow-band imaging (M-NBI). WGA was recently reported as a novel endoscopic marker that can differentiate between gastric cancer (GC) and low-grade adenoma. However, the usefulness of WGA for differentiating GC from non-cancerous lesions (NC), including those of gastritis, is unknown. METHODS: To compare the prevalence of WGA in GC and NC, we carried out a prospective study of 994 patients undergoing gastroscopy. All patients were examined for target lesions that were suspected to be GC. When a target lesion was detected, the presence or absence of WGA in the lesion was evaluated using M-NBI, and all target lesions were biopsied or resected for histopathological diagnosis. Primary endpoint was a comparison of WGA prevalence in GC and NC. Secondary endpoints included WGA diagnostic performance for diagnosing GC. RESULTS: A total of 188 target lesions from 156 patients were analyzed for WGA, and histopathological diagnoses included 70 cases of GC and 118 cases of NC. WGA prevalence in GC and NC was 21.4% (15/70) and 2.5% (3/118), respectively (P < 0.001). WGA diagnostic accuracy, sensitivity, and specificity for detecting GC were 69.1%, 21.4%, and 97.5%, respectively. CONCLUSIONS: WGA prevalence in GC is significantly higher than that in NC. Because WGA is highly specific for GC, the presence of WGA is useful to diagnose GC.