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  • 1
    Online Resource
    Online Resource
    Mismatch Repair Deficiency in Ovarian Carcinoma : Frequency, Causes, and Consequences
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  American Journal of Surgical Pathology Vol. 44, No. 5 ( 2020-05), p. 649-656
    Details
    In: American Journal of Surgical Pathology, Ovid Technologies (Wolters Kluwer Health), Vol. 44, No. 5 ( 2020-05), p. 649-656
    Abstract: Mismatch repair deficiency (MMRD) is involved in the initiation of both hereditary and sporadic tumors. MMRD has been extensively studied in colorectal cancer and endometrial cancer, but not so in other tumors, such as ovarian carcinoma. We have determined the expression of mismatch repair proteins in a large cohort of 502 early-stage epithelial ovarian carcinoma entailing all the 5 main subtypes: high-grade serous carcinoma, endometrioid ovarian carcinoma (EOC), clear cell carcinoma (CCC), mucinous carcinoma, and low-grade serous carcinoma. We studied the association of MMRD with clinicopathologic and immunohistochemical features, including tumor-infiltrating lymphocytes in EOC, the histologic type in which MMRD is most frequent. In addition, MLH1 promoter methylation status and massive parallel sequencing were used to evaluate the proportion of sporadic and Lynch syndrome–associated tumors, and the most frequently mutated genes in MMRD EOCs. MMRD occurred only in endometriosis-associated histologic types, and it was much more frequent in EOC (18%) than in CCC (2%). The most frequent immunohistochemical pattern was loss of MLH1/PMS2, and in this group, 80% of the cases were sporadic and secondary to MLH1 promoter hypermethylation. The presence of somatic mutations in mismatch repair genes was the other mechanism of MMRD in sporadic tumors. In this series, the minimum estimated frequency of Lynch syndrome was 35% and it was due to germline mutations in MLH1 , MSH2 , and MSH6. ARID1A , PTEN , KTM2B , and PIK3CA were the most common mutated genes in this series. Interestingly, possible actionable mutations in ERRB2 were found in 5 tumors, but no TP53 mutations were detected. MMRD was associated with younger age and increased tumor-infiltrating lymphocytes. Universal screening in EOC and mixed EOC/CCC is recommended for the high frequency of MMRD detected; however, for CCC, additional clinical and pathologic criteria should be evaluated to help select cases for analysis.
    Type of Medium: Online Resource
    ISSN: 0147-5185
    URL: Article
    DOI: 10.1097/PAS.0000000000001432
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 2029143-7
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  • 2
    Online Resource
    Online Resource
    Molecular Heterogeneity of Endometrioid Ovarian Carcinoma : An Analysis of 166 Cases Using the Endometrial Cancer Subrogate Molecular Classification
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  American Journal of Surgical Pathology Vol. 44, No. 7 ( 2020-07), p. 982-990
    Details
    In: American Journal of Surgical Pathology, Ovid Technologies (Wolters Kluwer Health), Vol. 44, No. 7 ( 2020-07), p. 982-990
    Abstract: Endometrioid ovarian carcinoma (EOC) has clinical and biological differences compared with other histologic types of ovarian carcinomas, but it shares morphologic and molecular features with endometrioid endometrial carcinoma. To analyze the molecular heterogeneity of EOC according to the new molecular classification of endometrial cancer and to evaluate the prognostic significance of this molecular classification, we have analyzed 166 early-stage EOC by immunohistochemistry for mismatch repair proteins and p53 expression, and by Sanger sequencing for the exonuclease domain of polymerase epsilon ( POLE EDM ). In addition, we have carried out next-generation sequencing analysis of tumors with POLE EDM mutations to confirm the ultramutated profile. Eight tumors carried POLE EDM mutations and were classified as ultramutated (5%), 29 showed mismatch repair deficiency and were classified as hypermutated (18%), 16 tumors had a mutated pattern of p53 expression and were classified as p53 abnormal (11%), and 114 tumors did not have any of the previous alterations and were classified as no specific type (66%). Five tumors showed 〉 1 classification criteria. The frequencies of ultramutated and hypermutated tumors were lower in EOC compared with the frequency reported in endometrial cancer. Subrogate molecular groups differed in both morphologic features (histologic grade, squamous and morular metaplasia, and necrosis) and immunohistochemical expression of several biomarkers (ARID1A, nuclear β-catenin, estrogen receptors, Napsin A, and HINF1B). In addition, the number of CD8 + tumor-infiltrating lymphocytes was higher in ultramutated and hypermutated tumors. The most commonly mutated genes in the ultramutated group were ARID1A (100%), PIK3R1 , PTEN , BCOR , and TP53 (67% each), whereas no mutations were detected in KRAS. Although the prognosis did not differ among subgroups in the multivariate analysis, a trend toward a better prognosis in POLE -mutated and a worse prognosis in p53 abnormal tumors was observed. In addition, this classification could have important therapeutic implications for the use of immunotherapy in tumors classified as ultramutated and hypermutated.
    Type of Medium: Online Resource
    ISSN: 0147-5185
    URL: Article
    DOI: 10.1097/PAS.0000000000001478
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 2029143-7
    Location Call Number Limitation Availability
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  • 3
    Online Resource
    Online Resource
    Next generation sequencing to decipher concurrent loss of PMS2 and MSH6 in colorectal cancer
    Springer Science and Business Media LLC ; 2020
    In:  Diagnostic Pathology Vol. 15, No. 1 ( 2020-12)
    Details
    In: Diagnostic Pathology, Springer Science and Business Media LLC, Vol. 15, No. 1 ( 2020-12)
    Abstract: Immunohistochemistry (IHQ) is commonly used for the detection of mismatch repair proteins deficiency (MMRD). One very infrequent abnormal pattern of MMR protein expression is the loss of PMS2 and MSH6, with intact expression of MLH1 and MSH2. Case presentation We review the frequency of this MMRD IHC pattern among 108 colorectal (CRCs) and 35 endometrial cancers in our files with loss of expression of at least one protein, and present two CRCs showing loss of PMS2 and MSH6 protein expression (1.9% of CRCs). NGS analysis of these tumours identified PMS2 mutations (R134* germline mutation in one tumour and M1R and c.1239delA somatic mutation in the other) as the primary event and somatic MSH6 mutation (c.3261dupC) as the secondary event in both tumours. Conclusions This study suggests that Next Generation Sequencing (NGS) tumour analysis should be considered in the algorithm of Lynch syndrome screening to detect MMR gen somatic mutation in inconclusive cases.
    Type of Medium: Online Resource
    ISSN: 1746-1596
    URL: Article
    DOI: 10.1186/s13000-020-01001-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2210518-9
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  • 4
    Online Resource
    Online Resource
    The Clonal Relationship Between the Ductal and Lobular Components of Mixed Ductal-Lobular Carcinomas Suggested a Ductal Origin in Most Tumors
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  American Journal of Surgical Pathology Vol. 46, No. 11 ( 2022-11), p. 1545-1553
    Details
    In: American Journal of Surgical Pathology, Ovid Technologies (Wolters Kluwer Health), Vol. 46, No. 11 ( 2022-11), p. 1545-1553
    Abstract: The relationship between the ductal and lobular components of invasive ductolobular carcinomas (IDLC) has not been fully elucidated. In this study, the molecular alterations of both components were analyzed in a series of 20 IDLC that were selected, not only by morphologic criteria, but also by the loss of E-cadherin expression in the lobular component. We found that 80% of tumors shared alterations of driver genes in both components, being PIK3CA the most common alteration. In addition, 45% of IDLC carried CDH1 mutations in their lobular component that were absent in the ductal component. Fluorescent in situ hybridization analysis of the CDH1 gene excluded homozygous CDH1 loss as a frequent cause of E-cadherin loss in tumors without CDH1 mutations. In addition, no pathogenic mutations of catenin genes were detected in this series of tumors. In 25% of tumors, actionable mutations in PIK3CA , AKT1 , and ERBB2 were found in only 1 component. Altogether, our results confirm that most IDLC derive from invasive carcinoma of no special type, in which a population of cells lose E-cadherin and acquire a lobular phenotype. The frequency of CDH1 mutations in IDLC appears to be lower than in conventional invasive lobular carcinomas, suggesting the implication of alternative mechanisms of E-cadherin loss. Moreover, molecular heterogeneity between ductal and lobular areas suggests the need for molecular characterization of both components to guide targeted therapies.
    Type of Medium: Online Resource
    ISSN: 0147-5185
    URL: Article
    DOI: 10.1097/PAS.0000000000001936
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 2029143-7
    Location Call Number Limitation Availability
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