Genomic landscapes of ovarian clear cell carcinoma from latin countries reveal aberrations linked to survival and progression.

BACKGROUND: Ovarian clear cell carcinomas (OCCCs) are rare, aggressive and chemoresistant tumors. Geographical and ethnic differences in the incidence of OCCC have been reported with a higher incidence in Asiatic countries. There is a paucity of information regarding OCCC in Latin America (LA) and other countries. METHODS: Here, we characterized two cohorts of 33 patients with OCCC from LA (24 from Brazil and 9 from Costa Rica) and a cohort of 27 patients from Spain. Genomic analysis was performed for 26 OCCC using the OncoScan platform. Tumors were classified according to their genomic landscapes into subgroups. Clinical parameters were related to the frequency of genomic aberrations. RESULTS: The median overall survival (OS) was not significantly different between the cohorts. Genomic landscapes were characterized by different homologous recombination deficiency (HRD) levels. No difference in the distribution of genomic landscapes profiles was detected between patients from the different cohorts. OCCCs with MYC-amplified tumors harboring a concomitant loss of a region in chromosome 13q12-q13 that includes the BRCA2 gene had the longest OS. In contrast, patients carrying a high number (> 30) of total copy number (CN) aberrations with no concomitant alterations in MYC and BRCA2 genes presented the shortest OS. Furthermore, amplification of the ASH1L gene was also associated with a shorter OS. Initial-stage OCCCs with early progression were characterized by gains in the JNK1 and MKL1 genes. CONCLUSIONS: Our results provide new data from understudied OCCC populations and reveal new potential markers for OCCCs.

The Frequency and Prognostic Significance of the Histologic Type in Early-stage Ovarian Carcinoma: A Reclassification Study by the Spanish Group for Ovarian Cancer Research (GEICO).

The frequency and prognostic significance of the histologic type in early-stage ovarian cancer (OC) is not as well established as in advanced stages. In addition, histologic typing based only on morphologic features may be difficult, especially in high-grade tumors. In this study, we have analyzed a prospective cohort of 502 early-stage OCs to investigate their frequency, immunohistochemical characteristics, and survival of the 5 main histologic types. Histotype was assigned according to not only the morphologic features but also according to the expression pattern of WT1, p53, Napsin A, and progesterone receptors. In addition, an extended panel including p16, ß-catenin, HER2, Arid1A, HINF1B, CK7, CDX2, and CK20 was used to refine the diagnosis in difficult cases. In this series, the frequency of the 5 major histologic types was as follows: endometrioid carcinoma, 32.7%; clear cell carcinoma, 25.1%; high-grade serous carcinoma (HGSC), 24.7%; mucinous carcinoma, 10.2%; low-grade serous carcinoma, 4.6%; and others, 2.8%. The combination of morphology and immunohistochemistry allowed the reclassification of 23% of OCs. The lowest concordance was found between samples initially diagnosed as endometrioid, but finally classified as high-grade serous tumors (22% error rate). Endometrioid carcinoma was the most favorable histologic type, whereas HGSC and low-grade serous carcinoma had the worst prognosis. Clear cell carcinoma with abnormal p53 immunostaining pattern also had poor prognosis. Although histologic grade was not a prognostic factor among early-stage endometrioid OCs, distinction between grade 3 endometrioid OC and HGSC is recommended, taking into account differences in prognosis and molecular alterations that can guide different treatments.

Prognostic classification of endometrial cancer using a molecular approach based on a twelve-gene NGS panel.

Endometrial Cancer (EC) is one of the most common malignancies in women in developed countries. Molecular characterization of different biotypes may improve clinical management of EC. The Cancer Genome Atlas (TCGA) project has revealed four prognostic EC subgroups: POLE, MSI; Copy Number Low (CNL) and Copy Number High (CNH). The goal of this study was to develop a method to classify tumors in any of the four EC prognostic groups using affordable molecular techniques. Ninety-six Formalin-Fixed Paraffin-embedded (FFPE) samples were sequenced following a NGS TruSeq Custom Amplicon low input (Illumina) protocol interrogating a multi-gene panel. MSI analysis was performed by fragment analysis using eight specific microsatellite markers. A Random Forest classification algorithm (RFA), considering NGS results, was developed to stratify EC patients into different prognostic groups. Our approach correctly classifies the EC patients into the four TCGA prognostic biotypes. The RFA assigned the samples to the CNH and CNL groups with an accuracy of 0.9753 (p < 0.001). The prognostic value of these groups was prospectively reproduced on our series both for Disease-Free Survival (p = 0.004) and Overall Survival (p = 0.030).Hence, with the molecular approach herein described, a precise and suitable tool that mimics the prognostic EC subtypes has been solved and validated. Procedure that might be introduced into routine diagnostic practices.

Relevance of minor discrepancies at second pathology review in gynaecological cancer.

AIM: To determine the incidence of discrepancy rate between the initial pathology diagnosis and referral diagnosis in women with gynaecological cancer. METHODS: A retrospective observational study was performed including all consecutive patients with gynaecological cancer referred and who underwent pathologic review between January 2013 and May 2017. Discrepancies were minor when future treatment was not altered or major when the treatment was modified. RESULTS: A total of 259 patients were included. The original diagnosis was ovarian cancer (n = 126, 48.6%), endometrial cancer (n = 84, 32.4%), cervical cancer (n = 43, 16.6%) and vulvar cancer (n = 6, 2.3%). Eighteen women (6.9%) had major discrepancies and 69 patients (26.6%) had minor discrepancies. The main reason for the minor discrepancy was tumour grade or histology subtype. Regarding ovarian cancer, 13 out of 16 patients had minor discrepancies at histology subtype among serous, endometrioid, mucinous or undifferentiated tumours. The main issue for the minor discrepancy in patients with cervical cancer was among different subtype of cervical adenocarcinoma. Minor discrepancies due to tumour grade were also observed in 14, 19, 8 and 3 patients with endometrial, ovarian, cervical and vulvar cancer, respectively. CONCLUSIONS: A second pathology review also adds valid information in those cases with minor discrepancies leading to a difference in patients´ counselling regarding follow-up and prognosis.

Mutational profile of primary breast diffuse large B-cell lymphoma.

Primary breast lymphoma is a rare form of extra-nodal lymphoid neoplasm. The most common histological type is the diffuse large B-cell lymphoma, which represents 60-80% of all the cases. Our study analyzes the mutational profile of the primary lymphoma of the breast through targeted massive sequencing with a panel of 38 genes in a group of 17 patients with primary breast diffuse large B-cell lymphoma. Seventy-point-five percent of the patients presented with stage IE and 29.5% with stage IIE. 44% of the cases correspond to lymphomas with germinal center phenotype and 33.3% to activated B-cell. The genes with a higher mutational frequency include PIM1 (in 50% of the analyzed samples), MYD88 (39%), CD79B, PRDM1 and CARD11 (17%), KMT2D, TNFIAP3 and CREBBP (11%). The profile of mutant genes involves mostly the NFκB signaling pathway. The high frequency of mutations in PIM1 compared with other lymphomas may have implications in the clinical presentation and evolution of this type of lymphoma.

Small cell neuroendocrine tumour of the endometrium and the importance of pathologic diagnosis.

Small cell carcinoma of the endometrium is a very rare entity. They are very aggressive tumours, with a poor prognosis. They represent a clinical challenge because of a lack of a standardised treatment. We see here a case of a 67-year-old woman with a history of a lobular breast carcinoma, diagnosed in 2002. After presenting with postmenopausal vaginal bleeding in October 2014, she underwent a hysteroscopy-guided biopsy which revealed a metastasis of breast carcinoma. A hysterectomy and bilateral oophorectomy was performed because of uncontrolled uterine bleeding. The pathologic diagnosis was small cell carcinoma (SCC) of the endometrium. A surgical complete cytoreduction was achieved after the case being presented in a multidisciplinary tumour board. Pathologic results revealed metastasis from peritoneal implants of SCC on the endometrium, and metastasis in pelvic and para-aortic lymph nodes from serous carcinoma of the endometrium. A total of four cycles of adjuvant chemotherapy based on cisplatin (80mg/m² day one) and etoposide (100mg/m² day one, two, three) every 21 days was given. The patient experienced persistent disease and died 17 months after the diagnosis. SCC of the endometrium is a very rare and aggressive disease that requires an individualised multidisciplinary management.

Diagnostic and therapeutic update of mantle cell lymphoma (MCL): analysis of seven cases treated in a centre in one year.

Mantle cell lymphoma (MCL) is an infrequent subtype of non-Hodgkin's lymphoma (NHL) and represents between 4-8% of adult lymphomas. Recently an increase in its incidence to 1-2 cases/100,000 inhabitants/year has been observed. The first line of treatment is based on chemoimmunotherapy and depends on age and the initial stage at diagnosis. There are no second line or successive treatments. There are currently several drugs available that provide acceptable results.

Linfoma de Hodgkin con presencia de t(14; 18) en paciente con antecedentes de linfoma folicular / Hodgkin's lymphoma with t(14; 18) translocation in a patient with a previous diagnosis of follicular lymphoma

Se describe un caso inusual con diagnóstico de linfoma folicular (LF) que subsecuentemente desarrolló un linfoma de Hodgkin (LH). Las células neoplásicas en el LF mostraron positividad para CD20, bcl2 y bcl6, y fueron negativas para CD10, MUM-1, CD5, CD43, CD30, CD15 y EBV. Las células de Hodgkin y de Reed-Sternberg en el LH fueron positivas para CD30, CD15, MUM1, bcl2 y focalmente para CD20, pero negativas para CD45, CD3, CD4, CD5 y EBV. El estudio por biología molecular detectó la t(14;18) en ambos linfomas (LF y LH) y el producto de la PCR mostró características similares en ambas muestras. El presente estudio sugiere, como se ha reportado previamente, la probabilidad de un origen clonal común de ambos linfomas cuando ocurren en un mismo paciente. Adicionalmente, estos resultados confirman que los pacientes con linfoma no Hodgkin pueden desarrollar subsecuentemente un LH enfatizando en la necesidad de rebiopsiar los pacientes con linfoma no Hodgkin que muestren una aparente recaída clínica(AU)

An unusual case of follicular lymphoma (FL) with subsequent development of Hodgkin’s lymphoma (HL) is described. The lymphoma cells of the FL were positive for CD20, bcl-2 and bcl-6, and negative for CD10, MUM-1, CD5, CD43, CD30, CD15 and EBV. The Hodgkin and Reed-Sternberg cells of HL were positive for CD30, CD15, MUM1, bcl-2 and focally positive for CD20 but negative for CD45, CD3, CD4, CD5 and EBV. The t(14;18) translocation was detected in both lymphoma samples and the PCR products of similar characteristics were found in both FL and HL samples. The results of present study suggest a probable common clonal origin of FL and HL occurring in the same patient, as has been previously reported. Furthermore, these results confirm that patients with non-Hodgkin lymphoma can subsequently develop HL and emphasizes the need to perform a new biopsy in non-Hodgkin lymphoma patients with an apparent clinical relapse(AU)

Monoclonalidad T en paciente con linfoma de Hodgkin. ¿Linfoma compuesto o linfoma de Hodgkin con población T monoclonal reactiva? / T-cell monoclonality in Hodgkin's lymphoma. Composite lymphoma or Hodgkin's lymphoma with reactive T-cell monoclonal population

Introducción. El diagnóstico de los linfomas precisa la integración de hallazgos clínicos, morfológicos, inmunohistoquímicos (IHQ) y moleculares. En algunos casos en los que existe solapamiento en la morfología y/o la IHQ, los estudios de clonalidad B y/o T ofrecen pistas importantes que ayudan al diagnóstico definitivo. Material y métodos. Se describe el caso de un paciente masculino de 72 años de edad con micosis fungoide, pancitopenia y hepatoesplenomegalia sin adenopatías. Se realiza biopsia hepática y de médula ósea con estudio morfológico, IHQ y molecular. Se discute el diagnóstico diferencial entre procesos reactivos y neoplásicos. Resultados. La biopsia de médula ósea y hepática mostró una infiltración por dos poblaciones tumorales diferentes. Una de ellas estaba compuesta de células grandes tipo Reed-Sternberg y sus variantes con expresión IHQ de CD30, CD15, MUM1 y EBV. El otro componente, más extenso, estaba constituido por un infiltrado polimorfo de linfocitos de mediano/pequeño tamaño con núcleos irregulares y fenotipo CD3+, CD4+, CD7+ y CD2+. El estudio por biología molecular en la muestra procedente de médula ósea mostró reordenamiento clonal del receptor de células T así como reordenamiento clonal de IGH. Conclusión. La interpretación de los resultados moleculares en el diagnóstico de los linfomas debe correlacionarse estrictamente con la evolución clínica y los hallazgos morfológicos e IHQ(AU)

Introduction. The diagnosis and management of malignant lymphoma should be based on clinical, morphological, immunohistochemical and molecular information. Particularly in cases with morphological and/or immunohistochemistry overlapping, molecular biology provides important diagnostic clues. Material and methods. A 72 year-old male with mycosis fungoides, pancitopenia and hepatosplenomagly without lymph node enlargement, underwent both hepatic and bone marrow biopsies and histopathological, immunohistochemical and molecular studies were performed. Results. The bone marrow and hepatic biopsies showed two different populations, one composed of large cells including typical Reed-Sternberg cells and their variant, with expression of CD30, CD15, MUM1 and EBV. The other was more extensive and revealed polymorphic medium to small cells with convoluted nuclei positive for CD3, CD4, CD2, CD7. Clonal T cell receptor gamma and monoclonal immunoglobulin H gene were detected in the bone marrow infiltration. Conclusion. The interpretation of the molecular results in the diagnosis of lymphoma should be strictly correlated with the clinical evolution and the morphological and immunohistochemical findings(AU)

Pleomorphic hyalinizing angiectatic tumor: a report of 3 new cases, 1 with sarcomatous myxofibrosarcoma component and another with unreported soft tissue palpebral location.

Pleomorphic hyalinizing angiectatic tumor (PHAT) is an uncommon soft tissue tumor usually located in extremities or trunk. We report 3 new cases with histopathologic diagnosis of PHAT, one with recurrence and sarcomatous myxofibrosarcoma component and another with unreported soft tissue palpebral location. Clinical data, histopathology, immunohistochemistry, fluorescence in situ hybridization, and follow-up data are described. The histopathology showed a tumor with angiectatic blood vessel proliferation and perivascular hyaline material associated with focal pleomorphic cells. The recurrent tumor revealed a histopathologic pattern corresponding to a myxofibrosarcoma. Vimentin and CD99 were positive in tumor cells and CD34 was strongly positive in the tumor cells from the recurrence. Ki-67 was poor positive but with increased positivity in the recurrence. The positivity of p53 and chromosome 22 polysomy were detected in the recurrence. At present, the 3 patients are free of disease and no metastases have been detected. Indeed, the possibility that PHAT may represent a histopathologic pattern and not a true neoplastic entity with specific genetic alterations cannot be excluded at present, and further studies are required.

Uncommon vascular tumor of the ovary. Primary ovarian epithelioid hemangioendothelioma or vascular sarcomatous transformation in ovarian germ cell tumor?

Epithelioid hemangioendothelioma (EHE) is an unusual vascular tumor, which usually occurs in the soft tissue, liver, breast, lung and bone. We submit a case of EHE, a tumor never before reported in the ovary. A 20-year-old woman was admitted with a medical history of unilateral ovarian tumor. The right ovary was totally removed and histologically, the tumor was composed of epithelioid cells with eosinophilic cytoplasm and prominent intracytoplasmic vacuoles associated with myxohyaline matrix. No morphologic evidence of germ cell tumor was observed. Immunohistochemically, the tumor cells were positive for CD31 and CD34. However, all germ cell tumor markers were negative. The final diagnosis was EHE of the ovarian gland and sarcomatous transformation in ovarian germ cell tumor was excluded after extensive histopathological and immunohistochemical study. EHE is an uncommon vascular tumor, which is rarely seen in female genital tract and this is the first report of EHE in ovarian gland. Final diagnosis depends on histopathological and immunohistochemical features.