João Lobo

The epigenetics of testicular germ cell tumors: looking for novel disease biomarkers.

Testicular germ cell tumors (TGCT) are a group of heterogeneous, biologically diverse and clinically challenging neoplasms. Despite the relatively low incidence and mortality rates, a subgroup of patients with disseminated disease relapse after conventional therapy and have a dismal prognosis. Moreover, TGCT afflict mostly young men and have therapeutic peculiarities, with some patients showing resistance to cisplatin-based treatments and others being troubled by irreversible side effects, such as infertility. Most TGCT share a common tumorigenic pathway and are cytogenetically similar, making room for Epigenetics to explain its heterogeneity at pathological and clinical level. In this review, we summarize the foremost epigenetic alterations among TGCT focusing on their clinical potential as diagnostic, prognostic and predictive biomarkers.

High immunoexpression of Ki67, EZH2, and SMYD3 in diagnostic prostate biopsies independently predicts outcome in patients with prostate cancer

INTRODUCTION Overtreatment is a major concern in patients with prostate cancer (PCa). Prognostic biomarkers discriminating indolent from aggressive disease in prostate biopsy are urgently needed. We aimed to evaluate the prognostic value of Ki67, EZH2, LSD1, and SMYD3 immunoexpression in diagnostic biopsies from a cohort of PCa patients with long term follow-up. MATERIALS AND METHODS A series of 189 consecutive prostate biopsies diagnosed with PCa (1997-2001) in a cancer center was included in the study, with follow-up last updated in November 2016. Biopsies were reviewed and graded according to 2016 WHO criteria. Immunohistochemistry was performed in the most representative block. Nuclear staining was assessed using digital image analysis. Study outcomes included disease-specific, disease-free, and progression-free survival. Statistical analysis was tabulated using SPSS version 22.0. Survival curves and hazard ratios (HRs) were estimated using Kaplan-Meyer and Cox-regression models, respectively. Statistical significance was set at P<0.05. RESULTS The proportion of patients who completed the study was 177/189 (94%). In univariable analysis, high Ki67, EZH2, and SMYD3 immunoexpression associated with significantly worse disease-specific survival (HR = 1.86, 95% CI: 1.05-3.29; HR = 1.87, 95% CI: 1.10-3.27; HR = 2.68, 95% CI: 1.02-7.92). In multivariable analysis, the 3 biomarkers displayed significantly worse DSS adjusted for CAPRA score (HR = 1.78, 95% CI: 1.01-3.16; HR = 1.93, 95% CI: 1.12-3.32; HR = 2.71, 95% CI: 1.04-7.10). Among patients with low/intermediate risk CAPRA score, high Ki67 immunoexpression identified those more prone to experience disease recurrence (HR = 9.20, 95% CI: 1.27-66.44) and progression (HR = 2.97, 95% CI: 1.05-8.43). CONCLUSIONS High Ki67, EZH2, and SMYD3 immunoexpression, adjusted for standard clinicopathological parameters, independently predicts outcome in patients with PCa, at diagnosis. This might assist in discriminating indolent from aggressive PCa, improving treatment selection.

Epididymal metastasis from prostate adenocarcinoma: An unusual and challenging diagnosis suspected in gallium-68 prostate-specific membrane antigen-positron emission tomography/computed tomography and histologically confirmed

A few cases of prostate adenocarcinoma (PCa) metastases to the epididymis have been documented in literature. We report a case of a 69-year-old man with a left epididymal metastasis, 6 years after radical prostatectomy and adjuvant radiation therapy for PCa. Although he developed biochemical recurrence, only gallium-68 prostate-specific membrane antigen-positron emission tomography/computed tomography revealed high uptake in the left testis and retrovesical space. An unrecognized painless firm nodule was palpable on the left epididymis. Radical orchiectomy was performed, and histopathological examination confirmed PCa metastasis located in the epididymis. To the best of our knowledge, this is the 27th reported case of epididymal metastasis from PCa.

ALK‐negative anaplastic large cell lymphoma with urinary bladder involvement diagnosed in urine cytology: A case report and literature review

Anaplastic large cell lymphoma is an aggressive T‐cell neoplasm. It rarely involves the urinary bladder, with just twelve cases reported thus far and only one being ALK‐negative. Immunophenotyping (particularly for ALK) is mandatory, both for prognostic and therapeutic reasons. Herein, we report the case of a patient with an ALK‐negative anaplastic large cell lymphoma involving the bladder which was diagnosed and fully characterized by immunocytochemistry in urine cytology. The patient underwent a cystoscopy and the urine sample disclosed tumor diathesis background and aggregates of atypical cells, with evidence of multinucleation and mitotic figures. Immunocytochemistry revealed strong membrane/Golgi positivity for CD30 and negativity for ALK. The patient was submitted to transurethral resection for therapeutic purposes, which confirmed the diagnosis. To the best of our knowledge, this represents only the third case of anaplastic large cell lymphoma with bladder involvement diagnosed in urine cytology and the very first with diagnostic findings allowing for immunophenotyping of the disease in a bladder wash. The present report reinforces the role of urine cytology as a suitable method for establishing an earlier diagnosis and characterization of the disease, avoiding submitting patients to invasive procedures like transurethral resections. Diagn. Cytopathol. 2017;45:354–358.

Differential expression of E-cadherin and P-cadherin in pT3 prostate cancer: correlation with clinical and pathological features

Cadherins seem to play and important role in prostate cancer (PCa) progression. E-cadherin loss of expression has been associated with poor prognosis; P-cadherin’s role is still elusive. Although pT3 PCa is often considered “high-risk cancer,” it does not exhibit an uniformly poor prognosis. Herein, we assessed the prognostic value and survival impact of E-cadherin and P-cadherin immunoexpression in pT3 PCa. Radical prostatectomy (RP) specimens from 102 pT3 PCa patients treated between 1991 and 2014 in a single institution were designated for E-cadherin and P-cadherin immunoexpression analysis. A representative block from each specimen was selected for tissue micro-array (TMA) construction, using 3 cores per case. E-cadherin immunoexpression was assessed via a digital image analysis system. For P-cadherin, scoring criteria for HER2 in gastric cancer were used. Clinical records of all patients were reviewed for baseline clinical/pathologic characteristics and follow-up data. E-cadherin-low PCa patients displayed worse disease-specific survival (DSS), although not reaching statistical significance (HR 2.65, 95%CI 0.81–7.88). However, considering the pT3b group only, those with low E-cadherin immunoexpression displayed significantly worse overall-survival (OS) and DSS (HR 3.69, 95%CI 1.18–11.50; HR 5.90, 95%CI 1.40–24.81). No significant differences in survival were found for P-cadherin differential immunoexpression. Furthermore, an association between E-cadherin and P-cadherin immunoexpression (p = 0.019) was found, as among E-cadherin-low PCa, 96.6% were P-cadherin negative. We demonstrated that low E-cadherin immunoexpression discriminates among pT3b PCa patients those with poorer survival and which might benefit from specific therapy. The role of P-cadherin in PCa seems context-dependent deserving further investigation.