CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study.

BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

Carcinoma neuroendocrino de mama con diferenciación pulmonar. Reporte de un caso / Neuroendocrine breast carcinoma with pulmonary differentiation. A case report

Resumen ANTECEDENTES: Los carcinomas neuroendocrinos de mama son neoplasias malignas poco frecuentes, con incidencia de 2%. El diagnóstico es difícil de establecer debido a sus características clínicas y morfológicas inespecíficas. La inmunohistoquímica es un estudio útil para identificar marcadores neuroendocrinos. Es importante descartar los casos de metástasis relacionados con algún origen primario distinto, para de esta forma prescribir el tratamiento adecuado. CASO CLÍNICO: Paciente de 37 años, procedente de otra institución con diagnóstico sugerente de carcinoma de alto grado de células medianas, con diferenciación neuroendocrina, afectación de los tres niveles de Berg y adenopatías supraclaviculares patológicas. Después de los estudios de imagen y determinación de marcadores tumorales específicos de la enfermedad se estableció el diagnóstico de carcinoma neuroendocrino de mama. Se indicó tratamiento neoadyuvante con cisplastino y etoposido, con el que se observó reacción parcial de 50%. Posteriormente se efectuó la mastectomía radical, con vaciamiento de los tres niveles de Berg y extirpación de los ganglios supraclaviculares, sin complicaciones aparentes. En la actualidad, la paciente permanece estable, en tratamiento con quimioterapia coadyuvante. CONCLUSIÓN: Lo importante en estos casos es determinar los marcadores tumorales asociados con los carcinomas neuroendocrinos de mama y así poder establecer el diagnóstico certero e implementar el tratamiento adecuado, que puede variar en función de su origen. Hasta la fecha no existe un consenso de tratamiento, por lo que cada caso debe individualizarse. Se requieren estudios adicionales para ampliar el conocimiento de esta variante tumoral.

Abstract BACKDROUND: Neuroendocrine carcinomas are infrequent breast neoplasms representing less than 2% of breast neoplasms. The diagnosis is difficult, since their clinical and morphological characteristics do not help to differentiate them from other types of breast neoplasms. The immunohistochemistry that will determine the characterization of the tumor by the presence of neuroendocrine markers. It is important to rule out a cases of metastasis related to a different primary origin, in order to prescribe the appropriate treatment for the patient. CLINICAL CASE: A 37-year-old patient from another institution with a diagnosis suggestive of high-grade carcinoma of medium cells, with neuroendocrine differentiation, involvement of the 3 levels of Berg and pathological supraclavicular adenopathies. After performing the imaging studies and determining the specific tumor markers of the disease, the diagnosis of breast neuroendocrine carcinoma. Neoadjuvant treatment with cisplastin and etoposide is indicated, with the same partial reaction of 50%. Subsequently, the radical mastectomy was performed, with the emptying of the 3 levels of Berg and the removal of the supraclavicular nodes without apparent complications. Currently remains stable in the treatment with adjuvant chemotherapy. CONCLUSIONS: It is important to determine the tumor markers associated with breast neuroendocrine carcinomas, with the aim of establishing accurate diagnosis and implementing the appropriate treatment, which may vary depending on its origin. To date there is no consensus of treatment, so each case must be individualized. Additional studies are required to expand the knowledge of this tumor variant.

The NER-related gene GTF2H5 predicts survival in high-grade serous ovarian cancer patients.

OBJECTIVE: We aimed to evaluate the prognostic and predictive value of the nucleotide excision repair-related gene GTF2H5, which is localized at the 6q24.2-26 deletion previously reported by our group to predict longer survival of high-grade serous ovarian cancer patients. METHODS: In order to test if protein levels of GTF2H5 are associated with patients' outcome, we performed GTF2H5 immunohistochemical staining in 139 high-grade serous ovarian carcinomas included in tissue microarrays. Upon stratification of cases into high- and low-GTF2H5 staining categories (> and ≤ median staining, respectively) Kaplan-Meier and log-rank test were used to estimate patients' survival and assess statistical differences. We also evaluated the association of GTF2H5 with survival at the transcriptional level by using the on-line Kaplan-Meier plotter tool, which includes gene expression and survival data of 855 high-grade serous ovarian cancer patients from 13 different datasets. Finally, we determined whether stable short hairpin RNA-mediated GTF2H5 downregulation modulates cisplatin sensitivity in the SKOV3 and COV504 cell lines by using cytotoxicity assays. RESULTS: Low expression of GTF2H5 was associated with longer 5-year survival of patients at the protein (hazard ratio [HR], 0.52; 95% CI, 0.29 to 0.93; p=0.024) and transcriptional level (HR, 0.80; 95% CI, 0.65 to 0.97; p=0.023) in high-grade serous ovarian cancer patients. We confirmed the association with 5-year overall survival (HR, 0.55; 95% CI, 0.38 to 0.78; p=0.0007) and also found an association with progression-free survival (HR, 0.72; 95% CI, 0.54 to 0.96; p=0.026) in a homogenous group of 388 high-stage (stages III-IV using the International Federation of Gynecology and Obstetrics staging system), optimally debulked high-grade serous ovarian cancer patients. GTF2H5-silencing induced a decrease of the half maximal inhibitory concentration upon cisplatin treatment in GTF2H5-silenced ovarian cancer cells. CONCLUSION: Low levels of GTF2H5 are associated with enhanced prognosis in high-grade serous ovarian cancer patients and may contribute to cisplatin sensitization.

Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): clinico-pathological study of three cases.

INTRODUCTION: We report three cases of sinus histiocytosis, a rare disease of unknown aetiology with massive lymphadenopathy (SHML), also known as Rosai-Dorfman (RD) disease, in a paediatric population. This proliferative histiocytic disorder is defined by histological and immunohistochemical (IHC) characteristics and can manifest as nodal involvement with variable enlargement of the lymph nodes (two cases) and extranodal manifestations involving skin and larynx involvement (one case). One patient had hypergammaglobulinemia. The morphological investigation revealed that all lymph nodes showed hyperplasia of sinuses with abundant histiocytic cell with intracytoplasmic lymphocytes. Skin and larynx biopsies showed a histiocyte and lymphocyte infiltrate with similar characteristics. An ultrastructural study was carried out on material from one patient. In the IHC study, SHML cells expressed phagocytic markers such as CD68 and S100, but markers for Langerhan's (CD1a) or dendritic cells (DRC, CD23 and CNA42) were absent. Two patients had a complete remission after surgical excision and no other treatment, but the third patient was treated with radiotherapy after a relapse with obstruction of the upper airway. CONCLUSION: This disorder must be considered in the differential diagnosis of young patients who exhibit massive or multiple lymphadenopathies, especially when involvement of the cervical area occurs. Due to the good outcome of the disease, a conservative approach is justified.