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      Gastric Invasive Micropapillary Carcinoma with Intestinal Phenotypes Harboring a TP53 R175H Mutation

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          Abstract

          We report a case of gastric invasive micropapillary carcinoma (IMPC) in an 86-year-old female patient. She was admitted to our hospital with a chief complaint of bloody emesis. Upper gastrointestinal endoscopy found a gastric adenocarcinoma at the antrum. The biopsy specimens showed moderately differentiated adenocarcinoma with invasive small tumor nests. Distal gastrectomy with systematic lymph node dissection demonstrated that the tumor had IMPC through a pathological examination. Despite the depth of tumor invasion (the submucosa), extensive lymph node metastases were observed. Anti-D2-40 immunostaining revealed numerous infiltrating tumor cell nests in the lymphatic vessels, which could explain subsequent multiple lymph node metastases. The adenocarcinoma showed intestinal phenotypes by several immunohistochemical studies. One of these antibodies (CD10) clearly demonstrated the inverted apical-basal (inside-out) pattern of IMPC, whereas it showed an ordinary pattern in intestinal metaplasia adjacent to the tumor. Furthermore, genetic analysis by direct sequencing revealed a point mutation in the exon 5 of TP53 in the tumor. The mutation presumably harbors a missense mutation from Arg to His at the codon 175 (R175H). R175H has been previously described as a ‘gain-of-function' mutation with a high invasive or metastatic potential in several types of cancers. In summary, this is one of the first reported cases of gastric IMPC with intestinal phenotypes harboring a TP53 R175H mutation in the literature.

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          Most cited references16

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          Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database.

          The tumor suppressor gene TP53 is frequently mutated in human cancers. More than 75% of all mutations are missense substitutions that have been extensively analyzed in various yeast and human cell assays. The International Agency for Research on Cancer (IARC) TP53 database (www-p53.iarc.fr) compiles all genetic variations that have been reported in TP53. Here, we present recent database developments that include new annotations on the functional properties of mutant proteins, and we perform a systematic analysis of the database to determine the functional properties that contribute to the occurrence of mutational "hotspots" in different cancer types and to the phenotype of tumors. This analysis showed that loss of transactivation capacity is a key factor for the selection of missense mutations, and that difference in mutation frequencies is closely related to nucleotide substitution rates along TP53 coding sequence. An interesting new finding is that in patients with an inherited missense mutation, the age at onset of tumors was related to the functional severity of the mutation, mutations with total loss of transactivation activity being associated with earlier cancer onset compared to mutations that retain partial transactivation capacity. Furthermore, 80% of the most common mutants show a capacity to exert dominant-negative effect (DNE) over wild-type p53, compared to only 45% of the less frequent mutants studied, suggesting that DNE may play a role in shaping mutation patterns. These results provide new insights into the factors that shape mutation patterns and influence mutation phenotype, which may have clinical interest.
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            Invasive micropapillary carcinoma of the breast.

            Nine examples of a rare variant of invasive breast carcinoma characterized by the formation of micropapillae within clear spaces separated by a fibrocollagenous or delicate fibrovascular stroma are presented. Designated as invasive micropapillary carcinoma, the unusual morphology of this tumor requires its distinction from metastatic ovarian serous papillary carcinoma and extensive vascular/lymphatic invasion by either a primary or metastatic breast carcinoma. The micropapillary pattern is retained in metastatic foci and areas of recurrence. This pattern also occurs admixed with regular infiltrating duct carcinoma either in the primary mammary tumor or when it recurs.
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              Clinicopathological and molecular characterization of colorectal micropapillary carcinoma.

              Invasive micropapillary carcinoma is associated with frequent lymph node metastasis and adverse clinical outcome. Initially described as a variant of breast and ovarian carcinoma, it has subsequently been found in other organs, most recently the colon. Reports of colorectal micropapillary carcinoma to date are limited in number, and their molecular profile has not been established. The aims of the present study were to analyze their clinicopathological features and molecular profile, and compare them with those of conventional adenocarcinoma. Clinicopathological features of a cohort of 379 patients with primary colorectal cancer were retrospectively reviewed for the presence of the pattern characteristic of micropapillary carcinoma. We also assessed the expression of KRT7, KRT20, CEACAM5, MUC1 (EMA, clone E29), MUC1 (clone MA695), MLH1, MSH2, MSH6 and TP53 by immunohistochemistry. Genetic assessments of microsatellite instability, chromosomes 17p and 18q, and mutations in TP53, BRAF and KRAS were performed using DNA extracted from formalin-fixed, paraffin-embedded sections. In all, 60 of the reviewed cases (16%) had a micropapillary component that ranged from 5 to 95% of the tumor, characterized by a higher frequency of an infiltrative pattern, lymphovascular and perineural invasion, a higher depth of invasion and more positive lymph nodes than conventional adenocarcinoma. Immunohistochemistry for MUC1 (clone MA695) and MUC1 (EMA, clone E29) enhanced the characteristic inside-out staining pattern of the micropapillary carcinoma component, whereas the rest of the tumor showed luminal staining patterns. KRT7 expression was slightly increased in micropapillary carcinoma, but did not reach significance (17-3%, P=0.1967). The molecular parameters showed a higher frequency of TP53 alterations and a low incidence of microsatellite instability and RER phenotype (loss of mismatch repair protein) in micropapillary carcinoma. With regard to the histological parameters, micropapillary carcinoma appears to be more aggressive than conventional colorectal adenocarcinoma. The molecular profile supports the hypothesis that micropapillary carcinoma carcinogenesis develops through the classical chromosomal instability pathway.
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                Author and article information

                Journal
                CRO
                CRO
                10.1159/issn.1662-6575
                Case Reports in Oncology
                S. Karger AG
                1662-6575
                2014
                September – December 2014
                03 September 2014
                : 7
                : 3
                : 611-620
                Affiliations
                Divisions of aSurgical Pathology, bInternal Medicine and cSurgery, Rumoi City Hospital, Rumoi, dDepartment of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, and eDivision of Surgery, Sapporo Memorial Hospital of Surgery, Sapporo, Japan
                Author notes
                *Hideyuki Ikeda, Division of Surgical Pathology, Rumoi City Hospital, 2 Chome Shinonome-cho, Rumoi, Hokkaido 077-0011 (Japan), E-Mail hideyukiikeda9@yahoo.co.jp
                Article
                367583 PMC4209268 Case Rep Oncol 2014;7:611-620
                10.1159/000367583
                PMC4209268
                25408652
                326d47cc-2d0f-4b44-8005-22ec9d9c09a0
                © 2014 S. Karger AG, Basel

                Open Access License: This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) ( http://www.karger.com/OA-license), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                Page count
                Figures: 3, Tables: 3, Pages: 10
                Categories
                Published: September 2014

                Oncology & Radiotherapy,Pathology,Surgery,Obstetrics & Gynecology,Pharmacology & Pharmaceutical medicine,Hematology
                R175H,CD10,Intestinal phenotypes,Invasive micropapillary carcinoma, TP53 ,Gastric cancer

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