Lack of association between deficient mismatch repair expression and outcome in endometrial carcinomas of the endometrioid type.

OBJECTIVE: Endometrial carcinomas of the endometrioid type (EEC) are associated with a good prognosis. However, about 20% of them recur and new prognostic markers are needed. Microsatellite instability (MSI), associated with mismatch repair (MMR) deficiency, is a frequent alteration in EECs that has been associated with prognosis. However, its prognostic impact on EECs remains unclear. The aim of the present study was to clarify the relationship between MMR deficiency and outcome in a large cohort of well classified EECs. METHODS: A total of 212 EEC samples were analyzed by immunohistochemistry for the MMR genes MLH-1, MSH-2, MSH-6 and PMS-2. Kaplan-Meier survival analysis and log-rank tests were performed to study the prognostic significance of dMMR taking into account clinical and pathological parameters. RESULTS: We observed no association between MMR deficiency and OS or PFS in our 212 EEC patients (p-value=0.6565 and 0.4380, respectively). When we performed the analysis in different FIGO-stage groups, we did not find association between MMR and OS or PFS in stages I, I/II or III/IV. When we analyzed the specific group of patients with lymphatic invasion separately, MMR expression was not associated with OS or PFS either. CONCLUSIONS: MMR deficiency does not seem to be a good prognostic marker in endometrioid type endometrial carcinomas.

Biphasic papillary (biphasic squamoid alveolar) renal cell carcinoma: a clinicopathologic and molecular study of 17 renal cell carcinomas including 10 papillary adenomas.

Biphasic papillary renal cell carcinoma (synonymous with biphasic squamoid alveolar renal cell carcinoma) is considered within the spectrum of papillary renal cell carcinoma (PRCC). With < 70 reported cases of biphasic PRCC, there is limited data on the pathologic spectrum and clinical course. Seventeen biphasic PRCC cases and 10 papillary adenomas with similar biphasic morphology were assessed. The mean age of the biphasic PRCC patients was 62 years (male to female ratio of 1.8:1), from 10 partial nephrectomies, 6 radical nephrectomies, and 1 biopsy. The mean tumor size was 3.6 cm (range 1.6-8 cm), with 24% showing multifocality. Fifteen out of 17 cases were limited to the kidney (one of which was staged as pT2a but had lung metastases at diagnosis) and 2/17 cases were staged as T3a. All tumors showed typical biphasic morphology with an extent of squamoid foci widely variable from 10 to 95%. Emperipolesis was identified in 88% of cases. All biphasic PRCC tested exhibited positivity for PAX8 (16/16), keratin 7 (17/17), EMA (15/15), AMACR (17/17), and vimentin (12/12) in both large and small cells; cyclin D1 was only expressed in the large cells (16/16). The 10 papillary adenomas showed a similar immunoprofile to biphasic PRCC. NGS testing performed on 13 biphasic PRCC revealed 4 (31%) harboring MET SNVs. In 1/5 (20%) papillary adenomas, a pathogenic MET SNV was identified. Biphasic PRCC is rare with a generally similar immunoprofile to "type 1" PRCC but with notable strong positivity for cyclin D1 in the large cell component. Although most of the biphasic PRCC cases were of small size, low stage, and with an indolent behavior, one patient had metastatic disease and one patient died of the disease.

Papillary Renal Neoplasm With Reverse Polarity: A Clinical, Pathologic, and Molecular Study of 8 Renal Tumors From a Single Institution.

CONTEXT.­: In 2019, papillary renal neoplasm with reverse polarity (PRNRP) was defined as a new neoplasm because it has a predominately tubulopapillary pattern lined by a single layer of cuboidal and eosinophilic cells with apically located round nuclei. Immunohistochemically, this neoplasm showed expression of GATA-3 and L1CAM and had recurrent KRAS mutations. OBJECTIVE.­: To estimate the incidence of PRNRP and provide 8 additional cases with some variations in the morphology. DESIGN.­: We reviewed 1627 renal tumors from our hospital during a 21-year period (2000-2020). We reexamined 196 papillary renal cell carcinomas and selected those that met the diagnostic criteria for PRNRP. RESULTS.­: We found 8 cases consistent with PRNRP. The median age of the patients was 64.75 years; 7 patients were male, and 1 was female. Two patients had end-stage renal disease. No recurrence, metastasis, or tumor-related death occurred in a mean follow-up period of 67.62 months. Tumor size ranged from 1.6 to 3.7 cm. All cases were pT1. Seven cases (7 of 8; 87.5%) had predominantly cystic changes, and 1 had solid architecture. No foamy cells, clear cell change, or psammoma bodies were seen in any cases. All cases were positive for CK7, EMA, GATA3, and L1CAM. KRAS gene mutation was detected in 5 cases (5 of 8; 62.5%). CONCLUSIONS.­: PRNRP represents 4.08% (8 of 196 cases) of papillary renal cell carcinomas and 0.49% (8 of 1627 cases) of all renal tumors in the 21-year period in our series. In our study, all cases exhibited an indolent clinical course. This supports that PRNRP has characteristic morphologic and molecular features.

microRNA sequencing for biomarker detection in the diagnosis, classification and prognosis of Diffuse Large B Cell Lymphoma.

Despite being considered a single disease, Diffuse Large B Cell Lymphoma (DLBCL) presents with variable backgrounds, which results in heterogeneous outcomes among patients, with 40% of them still having primary refractory disease or relapse. Thus, novel biomarkers are needed. In addition, multiple factors regarding its pathogenesis remain unclear. In this context, recent investigations point to the relevance of microRNAs (miRNAs) in cancer. However, regarding DLBCL, there is inconsistency in the data reported. Therefore, in this work, the main goals were to determine a miRNA set with utility as biomarkers for DLBCL diagnosis, classification, prognosis and treatment response, as well as to decipher the mechanism of action of deregulated miRNAs in the origin of the disease. We analyzed miRNA expression in a cohort of 78 DLBCL patients and 17 controls using small RNA sequencing and performed a miRNA-mRNA interaction network analysis. This way, we were able to define new miRNA expression signatures for diagnosis, classification, treatment response and prognosis, and we identified plausible mechanisms of action by which deregulated miRNAs could be involved in DLBCL pathogenesis. In summary, our study remarks that miRNAs could play an important role in DLBCL.

Bcl-2 and BLIMP-1 expression predict worse prognosis in gastric diffuse large B cell lymphoma (DLCBL) while other markers for nodal DLBCL are not useful.

AIMS: Previous studies have identified clinicopathological and immunohistochemical differences among diffuse large B cell lymphomas (DLBCL) as a function of disease location. Nevertheless, there is a continuing tendency to generalize the prognostic value of various identified markers without taking into account tumour site. Accordingly, we analysed the prognostic value of several of the immunohistochemical markers that have been proposed for nodal DLBCL in a group of patients with gastric DLBCL. METHODS AND RESULTS: Using histochemical methods, CD10, Bcl-6, Gcet1, MUM-1, Bcl-2 and BLIMP-1 expression was investigated in 43 cases of gastric DBLCL. As in nodal DLBCLs, expression of BLIMP-1, and of Bcl-2 in non-germinal centre B cell-like (non-GCB) patients, was associated with a worse prognosis. However, unlike nodal DBLCL, there was no significant association of prognosis with expression of CD10, Bcl-6, Gcet1 or MUM-1, or with categorization according to Hans or Muris algorithms. CONCLUSIONS: Although most markers of prognosis in nodal DLBCL are not useful indicators for gastric DLBCL, Bcl-2 or BLIMP-1 expression does correlate with worse prognosis. These data support the notion that clinicopathological features in DLBCL vary according to the disease location.

Chromosome instability in lymphocytes of children with coeliac disease.

Undiagnosed individuals with celiac disease (CD) or those who do not comply with gluten-free diet (GFD) are at a higher risk of developing malignancies. A possible origin of chromosomal alteration in autoimmune reaction could be mistakes in the rearrangement of V(D)J of the IgH gene. Our aim was to verify whether higher genomic instability was found in coeliac individuals and whether GFD reduced it. As marker of genomic instability we analysed the frequency of 2 translocations, t(14;18) and t(11;14), in peripheral blood by nested PCR, in 37 patients with CD at diagnosis, 27 patients with CD after 2 years on GFD, and 36 control individuals. No significant differences were found.

Methylation of CpG sites in BCL2 major breakpoint region and the increase of BCL2/JH translocation with aging.

The BCL2 breakage mechanism has been shown to be highly dependent on DNA methylation at the major breakpoint region (MBR) CpG sites. We recently described an increased frequency of BCL2/ JH translocation with aging. It is known that methylation levels change with aging. The present study aimed to determine whether methylation alterations at CpG sites of BCL2 MBR were the cause of increased breakages with aging. We analyzed the methylation levels of three CpG sites on the region by pyrosequencing and studied if methylation levels and/or polymorphisms affecting CpG sites were associated with an increase of translocations. We observed that although the methylation levels of MBR CpG sites were higher in individuals with BCL2/JH translocation, in contrast to our expectations, these levels decreased with the age. Moreover, we show that polymorphisms at those CpG sites leading to absence of methylation seem to be a protective factor for the apparition of translocations.

The Presence of Mutations in the K-RAS Gene Does Not Affect Survival after Resection of Pulmonary Metastases from Colorectal Cancer.

Introduction. Our objective was to identify mutations in the K-RAS gene in cases of pulmonary metastases from colorectal cancer (CRC) and determine whether their presence was a prognostic factor for survival. Methods. We included all patients with pulmonary metastases from CRC operated on between 1998 and 2010. K-RAS mutations were investigated by direct sequencing of DNA. Differences in survival were explored with the Kaplan-Meier method log-rank tests and multivariate Cox regression analysis. Results. 110 surgical interventions were performed on 90 patients. Factors significantly associated with survival were disease-free interval (P = 0.002), age (P = 0.007), number of metastases (P = 0.001), lymph node involvement (P = 0.007), size of the metastases (P = 0.013), and previous liver metastasis (P = 0.003). Searching in 79 patients, K-RAS mutations were found in 30 cases. We did not find statistically significant differences in survival (P = 0.913) comparing native and mutated K-RAS. We found a higher rate of lung recurrence (P = 0.040) and shorter time to recurrence (P = 0.015) in patients with K-RAS mutations. Gly12Asp mutation was associated with higher recurrence (P = 0.022) and lower survival (P = 0.389). Conclusions. The presence of K-RAS mutations in pulmonary metastases does not affect overall survival but is associated with higher rates of pulmonary recurrence.

Determination of a low risk group for having metastatic nodules not detected by computed tomography scan in lung metastases surgery.

INTRODUCTION: In recent years, there has been debate regarding the diagnostic accuracy of computed tomography (CT) in the identification of lung metastases and the need for lung palpation to determine the number of metastatic nodules. The aim of this study was to determine in which patients the CT scan was more effective in detecting all metastases. METHODS: We studied all patients who underwent curative thoracotomy for pulmonary metastasis between 1998 and 2012. All cases were reviewed by two expert pulmonary radiologists before surgery. Statistical analyses were performed using Systat version 13. RESULTS: The study included 183 patients (63.6% male) with a mean age of 61.7 years who underwent 217 interventions. The CT scan was correct in 185 cases (85.3%). Discrepancies observed: 26 patients (11.9%) with more metastases resected than observed and 6 cases (2.8%) with fewer metastases. In patients with one or two metastases of colorectal origin or a single metastasis of any other origin, the probability of finding extra nodules was 9.5%. In the remaining patients, the probability was 27.8%, with statistically significant differences (P=.001). The mean age of the patients in whom no unobserved nodules were detected was 62.9 years compared to 56.5 years on average in patients who were free from any metastases (P=.001). CONCLUSIONS: Patients older than 60 years, with one or two metastases of colorectal origin or a single metastasis from any other origin were considered to be the group with low probability of having more metastases resected than observed.