Pathologic and imunohistochemical characterization of tumoral inflammatory cell infiltrate in invasive penile squamous cell carcinomas: Fox-P3 expression is an independent predictor of recurrence.

Penile carcinomas (PeCa) are relatively rare, but devastating neoplasms, more frequent among people of underprivileged socioeconomic status. There is mounting evidence that immune cells may trigger various mechanisms that enhance tumor growth and metastasis, but no data on the peritumoral inflammation is available for PeCa. The objectives of the present study are to evaluate the immunohistomorphology of tumoral inflammation in PeCa, and to correlate it with clinicopathological parameters, which could contribute to the prognostic evaluation. One hundred and twenty-two patients with the diagnosis of usual-type squamous cell penile carcinoma were included. Paraffin-embedded tissue was submitted to immunohistochemical evaluation of p16 protein, CD3, CD4, CD8, CD20, CD68, CD138, granzyme B, and Fox-P3. The Fisher's exact test was employed for comparison between histological variables and parameters, and the Kaplan-Meier method for the analysis of survival. Improved 5-year overall survival was significantly associated to age ≤60 years, stage I + II, tumor size T1 + T2, lymph node status N0, and absent perineural invasion. In a multivariate analysis age ≥60 years, presence of lymph node metastasis, urethral invasion, and high histologic grade retained a significantly more unfavorable outcome. Improved 5-year failure free survival was associated to stage of the disease I + II, lymph node status N0, absence of perineural, vascular, and urethral invasion, and Fox-P3 expression. In a multivariate analysis, presence of lymph node metastasis, perineural and vascular invasion, and of Fox-P3-positive lymphocytes together with low inflammatory infiltrate retained a significantly more unfavorable outcome. These results support the prognostic value of determining the levels of Fox-P3-positive lymphocytes by immunohistochemistry in PeCa, as this parameter adds value to the traditional clinicopathological features.

Avaliação da expressão imunohistoquímica de PD-L1 em carcinomas de pênis / Evaluation of the immunohistochemical expression of PD-L1 in penis carcinomas

INTRODUÇÃO: O carcinoma de pênis (CaPe) é uma doença devastadora do ponto de vista físico e psicológico. Sua etiopatogenia é pouco conhecida e o tratamento limitado. Existem evidências do papel de células do sistema imune, como macrófagos e linfócitos no prognóstico desses tumores. Com o avanço do conhecimento da imunoterapia, esta possibilidade se abre para os casos avançados de CaPe. Um dos biomarcadores preditivos para o seu uso é a expressão da proteína ligante (PD-L1) ao receptor programado de morte celular (PD-1). No momento, pouco se sabe sobre o padrão de imunoexpressão deste biomarcador no CaPe e sua relação com as características clinico-patológicos destes pacientes. OBJETIVO: Avaliar a presença, por imunohistoquímica de PD-L1 em CaPe, a relação de linfócitos nos microambiente tumoral e a relação com variáveis clínico-patológicas em pacientes com CaPe. METODOLOGIA: Por imunohistoquímica foi avaliada a presença de PD-L1 em células tumorais e células inflamatórias: macrófagos, CD4, CD8 e CD20 em biopsias de 49 pacientes com diagnostico prévio de CaPe. Os dados foram analisados utilizando o programa R versão 3.5. O teste exato de Fisher foi empregado para comparação estatística entre a expressão de PD-L1 em células tumorais e macrófagos, CD4, CD8 e CD20 e nas variáveis clínico-patológicas. RESULTADOS: Em relação às características clínico-patológicas, 55,1% dos pacientes eram casados, 61,2% foram submetidos a penectomia parcial, 71.4% não necessitou de esvaziamento linfonodal, sendo 49% localizado na glande. A histologia usual para esse tumor estava presente em 64,6% dos pacientes. Em relação ao processo de invasão da neoplasia a outros tecidos, 81,6% apresentaram invasão ao corpo esponjoso, 75,5% não apresentou invasão à uretra, 89,8% não apresentou invasão vascular. As células tumorais do CaPe expressaram PD-L1 em 19% dos casos. Esta se associou positivamente com o predomínio de células CD4 e CD20 no microambiente tumoral. CONCLUSÃO: Por imunohistoquímica PD-L1 foi expresso em cerca de um quinto dos casos e se associou a uma resposta imune anérgica. Embora expresso na minoria dos casos, a capacidade da célula neoplásica ter o inibidor de check-point com o mecanismo de evasão da resposta imune levanta a possibilidade de se testar a imunoterapia como estratégia terapêutica em casos selecionados (AU)

INTRODUCTION: Penile carcinoma (PeCa) is a physically and psychologically devastating disease. Knowledge of its etiopathogenesis and its treatment is limited. There is evidence of the role of immune system cells such as macrophages and lymphocytes in the prognosis of these tumors. With the advance of immunotherapy knowledge, this possibility opens up for advanced cases of PeCa. One of the predictive biomarkers for its use is the expression of the binding protein (PD-L1) to the programmed cell death receptor (PD-1). At the moment, little is known about the immunoexpression pattern of this biomarker on PeCa and its relationship with the clinical and pathological characteristics of these patients. OBJECTIVE: To evaluate the presence, by immunohistochemistry of PD-L1 in PeCa, the relationship of macrophages and lymphocytes in the tumor microenvironment and the relationship with clinical-pathological variables in patients with PeCa. METHODOLOGY: The presence of PD-L1 in tumor cells and inflammatory cells: macrophages, CD4, CD8 and CD20 cells in biopsies of 49 patients with the previous diagnosis of PeCa were evaluated. The data were analyzed using the R version 3.5 program. Fisher's exact test was used for statistical comparison between the expression of PD-L1 in tumor cells and macrophages, CD4, CD8, and CD20 cells and in the clinical-pathological variables. RESULTS: Regarding the clinical and pathological characteristics, 55.1% of the patients were married, 61.2% underwent partial penectomy; 71.4% did not require lymph node dissection and 49% of which were located in the glans. The usual histology for this tumor was present in 64.6% of the patients. Regarding the process of invasion of the neoplasm to other tissues, 81.6% presented invasion to the spongy body of penis; 75.5% did not present invasion to the urethra and 89.8% did not show vascular invasion. Tumor cells from CaPe expressed PD-L1 in 19% of cases. This was positively associated with the predominance of CD4 and CD20 cells in the tumor microenvironment. CONCLUSION: By immunohistochemistry PD-L1 was expressed in about one-fifth of the cases and was associated with an anergic immune response. Although expressed in a minority of cases, the ability of the neoplastic cell to have the checkpoint inhibitor with the immune response evasion mechanisms raises the possibility of testing immunotherapy as a therapeutic strategy in selected cases.