Reiko Dehari

Hiratsuka City Hospital

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Mutations of BRAF and KRAS Precede the Development of Ovarian Serous Borderline Tumors

Cancer Research (2004)

Chung‐Liang Ho Robert J. Kurman Reiko Dehari Tian‐Li Wang Ie‐Ming Shih

Abstract Molecular genetic changes that are associated with the initiating stage of tumor development are important in tumorigenesis. Ovarian serous borderline tumors (SBTs), putative precursors of low-grade serous carcinomas, are among the few human neoplasms with a high frequency of activating mutations in BRAF and KRAS genes. However, it remains unclear as to how these mutations contribute to tumor progression. To address this issue, we compared the mutational status of BRAF and KRAS in both SBTs and the adjacent epithelium from cystadenomas, the presumed precursor of SBTs. We found that three of eight SBTs contained mutant BRAF, and four SBTs contained mutant KRAS. All specimens with mutant BRAF harbored wild-type KRAS and vice versa. Thus, seven (88%) of eight SBTs contained either BRAF or KRAS mutations. The same mutations detected in SBTs were also identified in the cystadenoma epithelium adjacent to the SBTs in six (86%) of seven informative cases. As compared to SBTs, the cystadenoma epithelium, like ovarian surface epithelium, lacks cytological atypia. Our findings provide cogent evidence that mutations of BRAF and KRAS occur in the epithelium of cystadenomas adjacent to SBTs and strongly suggest that they are very early events in tumorigenesis, preceding the development of SBT.

Serous Cystadenoma

Cystadenocarcinoma

10.1158/0008-5472.can-04-2067

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Citations (201)

Patterns of p53 Mutations Separate Ovarian Serous Borderline Tumors and Low- and High-grade Carcinomas and Provide Support for a New Model of Ovarian Carcinogenesis

The American Journal of Surgical Pathology (2005)

Gad Singer Robert Stöhr Leslie Cope Reiko Dehari Arndt Hartmann

The infrequent association of serous borderline tumors (SBTs) with invasive serous carcinoma has led to the view that SBTs are unrelated to invasive serous carcinoma. Nonetheless, mortality associated with SBTs is generally attributed to malignant transformation, and traditionally these tumors have been designated as "carcinomas of low malignant potential." Previous immunohistochemical studies evaluating p53 expression and molecular genetic studies evaluating mutational status have reported that p53 overexpression and mutations are infrequent in SBTs and occur in as many as 50% to 80% of invasive serous carcinomas. The different methodologies for determining p53 status and the failure to correlate the findings with tumor grade make these studies difficult to interpret. The current study was undertaken to overcome these deficiencies and to reconcile the relationship of SBTs to invasive serous carcinoma by performing a morphologic, immunohistochemical, and molecular genetic analysis comparing SBTs with low- and high-grade serous carcinoma. The molecular genetic analysis used a highly stringent, carefully designed nucleotide-sequencing method. A total of 96 sporadic serous tumors including 25 SBTs (11 atypical proliferative serous tumors and 14 intraepithelial low-grade serous carcinomas [noninvasive micropapillary serous carcinomas, MPSCs]), 12 low-grade serous carcinomas (invasive MPSCs), and 59 high-grade serous carcinomas were analyzed for their p53 mutational status of exons 5 to 9. Functional mutations, defined as mutations resulting in the alteration of the structure of the encoded protein, were detected in 30 of 59 (50.8%) high-grade serous carcinomas and 1 (8.3%) of 12 low-grade invasive serous carcinomas compared with 2 (8%) of 25 SBTs, both of these in intraepithelial low-grade serous carcinomas (noninvasive MPSCs). The similar frequency of p53 mutations in SBTs and low-grade invasive serous carcinomas in contrast to the significantly higher frequency of p53 mutations in high-grade serous carcinomas (P < 0.0005) suggests a common lineage for SBTs and low-grade invasive serous carcinomas and supports the view that SBTs are unrelated to the usual type of invasive serous carcinoma, which is a high-grade neoplasm. Mutational status was also correlated with p53 immunoreactivity. Although p53 immunoreactivity is generally higher in those specimens containing mutant p53, immunostaining is neither sufficiently specific nor sensitive enough to predict p53 mutations. The molecular genetic findings confirm our hypothesis of dual pathways of serous carcinogenesis based on previous analyses of KRAS and BRAF mutations on the same set of cases in which KRAS and BRAF mutations were found in 60% of SBTs and low-grade serous carcinoma but not in high-grade serous carcinomas. Based on these studies, we have proposed a model of serous carcinogenesis in which SBTs are the precursors of low-grade serous carcinomas whereas the usual type of invasive serous carcinoma is a high-grade neoplasm that develops "de novo" from in situ alterations in epithelial inclusion cysts.

Ovarian carcinomas

10.1097/01.pas.0000146025.91953.8d

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Citations (408)

Infrequent APC Mutations in Serrated Adenoma.

The Tohoku Journal of Experimental Medicine (2001)

Reiko Dehari

In 1990, Longacre and Fenoglio-Preiser introduced "serrated adenoma (SA)" combining architectural and cytological features of hyperplastic polyp and adenomatous epithelium. It has been reported that intramucosal carcinoma occurs in 10% of SAs. Although there have been many reports on SAs, its histogenesis and natural history still remain unknown. To clarify the genetic changes in SA, APC mutations in 28 SAs, 4 adenocarcinomas in/with SAs, 12 tubular adenomas (TAs) and 10 adenocarcinomas in/with TAs were evaluated in the present study. After polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) analyses, gene mutations were confirmed by direct sequencing. No APC mutation was detected in adenocarcinomas in/with SAs, and only one SA without adenocarcinoma (3.8%) was found to be positive for APC gene mutation, whereas the mutations were found in 66.7% of TAs and in 50% of adenocarcinomas in/with TAs. The frequency of APC gene mutation in SAs was significantly lower than that in control sporadic TAs. These findings suggest that SAs are genetically different from TAs.

Histogenesis

Hyperplastic Polyp

Adenomatous polyposis coli

10.1620/tjem.193.181

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Citations (27)

The Development of High-grade Serous Carcinoma From Atypical Proliferative (Borderline) Serous Tumors and Low-grade Micropapillary Serous Carcinoma

The American Journal of Surgical Pathology (2007)

Reiko Dehari Robert J. Kurman Sanjay Logani Ie‐Ming Shih

Recently, we have proposed a model for the development of ovarian surface epithelial tumors. In this model, all histologic types of surface epithelial tumors are divided into 2 categories designated type I and type II which correspond to 2 pathways of tumorigenesis. Type I tumors include low-grade serous carcinoma, mucinous carcinoma, endometrioid carcinoma, malignant Brenner tumor, and clear cell carcinoma which develop slowly in a stepwise fashion from well-recognized precursors, namely atypical proliferative (borderline) tumors. Type II tumors are high-grade, rapidly growing tumors that typically have spread beyond the ovaries at presentation. They include high-grade serous carcinoma ("moderately" and "poorly" differentiated), malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinoma. These tumors are rarely associated with morphologically recognizable precursor lesions and it has been proposed that they develop "de novo" from ovarian inclusion cysts. This model implies that the pathogenesis of type I and type II tumors are separate and independent but it is not clear whether some type II tumors develop from type I tumors. In this study, we attempted to address this issue by determining the clonality of 6 cases of high-grade serous carcinomas that were closely associated with atypical proliferative serous (borderline) tumors and invasive low-grade micropapillary serous carcinomas. We reviewed 210 ovarian serous tumors from the surgical pathology files of the Johns Hopkins Hospital and identified 3 high-grade serous carcinoma that were directly associated with atypical proliferative serous (borderline) tumors and 3 that were associated with invasive low-grade micropapillary serous carcinomas. A morphologic continuum between the high-grade carcinoma and the low-grade tumors was observed in 4 cases whereas in the remaining 2 cases the high-grade and low-grade components were separate. Mutational analyses for KRAS, BRAF, and p53 genes were performed on microdissected samples from the high-grade and low-grade tumor areas for each case. All 6 tumors demonstrated wild-type BRAF and p53 genes. Only 2 of the 6 cases were informative from a molecular genetic standpoint. In those 2 cases we found the same mutations of KRAS in both the atypical proliferative serous (borderline) tumor and the high-grade serous carcinoma component of the tumor, indicating a clonal relationship. The above results suggest that the majority of high-grade and low-grade carcinomas develop independently but in rare cases, a high-grade serous carcinoma may arise from an atypical proliferative serous (borderline) tumor.

Serous carcinoma

10.1097/pas.0b013e31802cbbe9

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Citations (142)

A Case of Cronkhite-Canada Syndrome Improved Markedly with Short-term Steroid Therapy

Progress of Digestive Endoscopy(1972) (1995)

Toshikazu Yamaguchi Reiko Dehari Kouichi Koizumi Shunkichi Kai Norio Kawamura

A 59-year-old male was admitted to the hospital complaining of lower abdominal pain, diarrhea of one month duration, and melena. In this case, numerous and uniform gastrointestinal polyposis, alopecia, onychotrophia, skin pigmentation, and mild hypoproteinemia were found. Histological examination of biopsy specimens from colonic polyps revealed cystic dilatation of the glans and edematous stroma. Cronkhite-Canada syndrome (CCS) was diagnosed. No especial changes of clinical manifestations were seen with conventional treatment (intra-venous hyperalimentation, t-AMCHA) , but diarrhea and polyposis improved remarkably with 10-days steroid therapy. Short-term steroid therapy may effective to CCS with uniform gastrointestinal polyposis, and one of its early phase.

Melena

Hypoproteinemia

10.11641/pdensks.46.0_196

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Citations (0)

Pancreaticoduodenectomy after neoadjuvant chemotherapy for gastric cancer invading the pancreatic head: A case report

World Journal of Gastroenterology (2021)

Masahiro Yura Kiminori Takano Kiyohiko Adachi Asuka Hara Keita Hayashi

Pancreaticoduodenectomy (PD) for advanced gastric cancer is rarely performed because of the high morbidity and mortality rates and low survival rate. However, neoadjuvant chemotherapy for advanced gastric cancer has improved, and chemotherapy combined with trastuzumab may have a preoperative tumor-reducing effect, especially for human epidermal growth factor receptor 2 (HER2)-positive cases.

Neoadjuvant Therapy

10.3748/wjg.v27.i6.534

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Citations (1)

Correlation of β-Catenin Localization with Cyclooxygenase-2 Expression and CpG Island Methylator Phenotype (CIMP) in Colorectal Cancer

Neoplasia (2007)

Takako Kawasaki Katsuhiko Nosho Mutsuko Ohnishi Yuko Suemoto Gregory J. Kirkner

The WNT/β-catenin (CTNNB1) pathway is commonly activated in the carcinogenic process. Cross-talks between the WNT and cyclooxygenase-2 (COX-2 or PTGS2)/prostaglandin pathways have been suggested. The relationship between (3-catenin activation and microsatellite instability (MSI) in colorectal cancer has been controversial. The CpG island methylator phenotype (CIMP or CIMP-high) with widespread promoter methylation is a distinct epigenetic phenotype in colorectal cancer, which is associated with MSI-high. However, no study has examined the relationship between (β-catenin activation and CIMP status. Using 832 population-based colorectal cancer specimens, we assessed (3-catenin localization by immunohistochemistry. We quantified DNA methylation in eight CIMP-specific promoters [CACNA1G, CDKN2A(p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1] by real-time polymerase chain reaction (MethyLight). MSI-high, CIMP-high, and BRAF mutation were associated inversely with cytoplasmic and nuclear (β-catenin expressions (i.e., β-catenin activation) and associated positively with membrane expression. The inverse relation between (β-catenin activation and CIMP was independent of MSI. COX-2 overexpression correlated with cytoplasmic (β-catenin expression (even after tumors were stratified by CIMP status), but did not correlate significantly with nuclear or membrane expression. In conclusion, β-catenin activation is inversely associated with CIMP-high independent of MSI status. Cytoplasmic β-catenin is associated with COX-2 overexpression, supporting the role of cytoplasmic β-catenin in stabilizing PTGS2(COX-2) mRNA.

MLH1

Microsatellite Instability

CpG site

10.1593/neo.07334

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Citations (82)

A Rare Solitary Fibrous Tumor Originating From the Distal Aortic Arch

The Annals of Thoracic Surgery (2018)

Sohsyu Kotani Yoshito Inoue Hirofumi Haida Reiko Dehari Ikuma Kato

Solitary Fibrous Tumor

10.1016/j.athoracsur.2018.07.063

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Citations (1)

Patient with a rapidly growing gastrointestinal stromal tumor of the esophagus presenting with dysphagia

Progress of Digestive Endoscopy (2014)

Tomoaki Moriyama Naoko Nagasu Reiko Dehari Takaaki Ikeda

A 67-year-old Japanese man was admitted to the hospital because of dysphagia. He had a past medical history of hypertension, atrial fibrillation, diabetes mellitus, and ureterolithiasis. Nine months earlier, endoscopy had revealed a protruding lesion in the lower esophagus. A barium study showed a giant elevated lesion with a deep ulcer associated with marked stenosis in the lower esophagus. Endoscopy revealed a multi-nodular protruding tumor covered with smooth and reddish mucosa. CT revealed a low-density mass. Biopsy specimens taken from the lesion showed proliferation of spindle cells, and immunohistochemical analysis of the tumor showed positive staining for c-kit and CD34. A diagnosis of gastrointestinal stromal tumor (GIST) was made and esophagectomy was performed. The resected specimen measured 9.3×8.1×5.1 cm in size and the risk of GIST was estimated to be high by histopathological examination. The diagnosis of submucosal tumor (SMT) should be carefully considered in cases where endoscopy reveals a smooth protruding lesion in the esophagus or compression of the esophagus. Rapidly growing esophageal GISTs should be borne in mind in such cases, and endoscopic follow-up of SMTs measuring more than 2 cm in diameter at least twice a year is thought to be necessary.

Stromal tumor

Esophagectomy

10.11641/pde.84.1_80

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Citations (1)

A case of primary biliary cirrhosis complicated with hepatocellular carcinoma showing negative results for HCV, HBV and HGV markers.

Kanzo (1997)

M. Ogura Naoaki Hashimoto Etsu Ohno Yasushi Takeda Reiko Dehari

69歳, 女性. 脳出血後の通院中, 偶然占拠性肝病変を指摘されて入院. 輸血歴あり. 黄疸, 掻痒感なし. ALP 560IU/l, γ-GTP 357IU/l, 抗ミトコンドリア抗体320倍, 非腫瘍部の肝生検で非化膿性破壊性胆管炎を認め, Scheuer II期の無症候性原発性胆汁性肝硬変 (PBC) と診断した. 占拠性病変は血管造影で濃染し, AFP 1, 350ng/ml, PIVKA II 0.4AU/mlより肝細胞癌 (HCC) と診断. ジノスタチンスチマラマー (SMANCS) の動注療法後, リピオドールの沈着を認めた. 血中のHBc抗体を含むHBVマーカー, HCV抗体, HCV-, HGV-RNAはいずれも陰性. 肝生検所見に加え, ICG 7.2%, 血小板数正常, 食道静脈瘤および血管造影上コルクスクリューサインを認めず, 肝硬変ではないと考えた. B型, C型肝炎ウイルスマーカー及びHGV-RNAが陰性で, 肝硬変のないPBCに合併したHCCは極めて稀と考え報告した.

Primary Biliary Cirrhosis

10.2957/kanzo.38.547

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Citations (2)