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Pathology and Genetics

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Book cover Management of Penile Cancer

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Abstract

Squamous cell carcinoma of the penis (SCCP) has behaved similarly to squamous cell carcinoma in other parts of the skin. Stage is important in the treatment of primary lesion. Pathological factors with a known prognostic value, other than lymph node metastasis, are tumor thickness, grade, histological type, lymphovascular embolization, and stage. The histological grade of penile carcinoma, including SCCP usual type, should attend the protocol based on the American Joint Committee on Cancer.

Apart from the carcinogens, oncoviruses such as human papillomavirus (HPV) and Epstein-Barr virus (EBV) can help to cause penile cancers. The mechanism by which HPV promotes cancer is not affecting the genes. HPV encodes for E6 and E7 proteins that are able to bind to two important tumor suppressor proteins, p53 and pRB, respectively, inactivating them.

By conventional cytogenetics, only four karyotypes were described for penile carcinoma. The rarity of karyotype description is due to technical difficulties related to the low mitotic index, contamination of primary cultures, and the occurrence of large areas of necrosis in the tumor. The frequency of DNA aneuploidy showed correlation with histological type of invasive squamous cell carcinoma of the penis. Epidermoid tumors of various organs can be originated from similar genetic alterations. MYC numerical aberrations and c-MYC protein expression were determined and correlated with the clinicopathological parameters and the HPV infection status of the patients. A significant association between MYC gains and tumor progression and poor outcome was demonstrated. These findings were independent of HPV infection. Protein c-MYC expression was increased in samples with HPV infection, probably reflecting direct activation of MYC. A gain in the region 5p15 appears very interesting, because the gene hTERT was mapped on this region. This gene codes for the major protein of the catalytic site of telomerase, the enzyme that stabilizes the telomeres of chromosomes.

Disruption of p53 function is very a common genetic event in many cancers, and there are many ways to cause it. The prognostic significance of p53, Ki-67, PCNA, E-cadherin, and Matrix metalloproteases-9 (MMP-9) was evaluated in SSCP tumors. Tumor embolization and the expression of p53 are independent predictors of metastasis. The comparison of the prognostic value of PCNA and Ki-67 revealed that there was a correlation between the expression of both and the presence of lymph node metastasis.

Telomerase activity was measured in samples of SSCP by the Telomeric Repeat Amplification Protocol (TRAP), a PCR-based assay with fluorescence label. In some patients, it was also possible to measure the activity of telomerase in the region adjacent to the tumor, either skin or corpus cavernous, which were free of tumor cells according to histopathological analysis. These results indicated that telomerase is reactivated either in normal tissues or adjacent tissues of SCCP.

Expression of two members of Bcl-2 family (the antiapoptotic Bcl-2 and the proapoptotic Bax) was analyzed in 16 SCCP using Western blot. Bcl-2 and Bax were completely imbalanced when the tumor, adjacent to either skin or corpus cavernous, was compared in the same way. This means that the adjacent tissues are at least under the influence of the tumor.

The mutations in RAS and PIK3CA were mutually exclusive, suggesting that deregulation of either the phosphatidylinositol 3-kinase or ras pathway would be sufficient for the development and progression of penile carcinoma.

In general, the studies that have searched for DNA methylation of tumor suppressor genes in SSCP also addressed other questions related to gene expression control (in special HPV infection), reflecting the complexity of this issue. Publications analyzed DNA methylation status of several gene promoters.

Proteins from plasma of 36 healthy subjects (controls) were compared to 25 plasmas from patients with SCCP. Two peptides were identified by an MALDI-TOF-TOF as fragments of C3 and C4a/b complement proteins. The conclusion was that fragments C3 and C4 a/b are less expressed in comparison with healthy subjects as the disease progresses. TA-4 antigen, also known as SSC antigen, was originally isolated from patients showing squamous cell carcinoma of the uterine cervix. Later it was shown that TA-4 values were elevated in serum of metastatic SSCP patients.

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Authors and Affiliations

  1. Department of Urology, Instituto Nacional de Câncer, Praça da Cruz Vermelha 23, Rio de Janeiro, 20230-130, Brazil

    Antonio Augusto Ornellas MD, PhD

  2. Laboratório de Genética Aplicada, Serviço de Hematologia, Instituto Nacional de Câncer, Rio de Janeiro, Brazil

    Gilda Alves PhD

  3. Department of Pathology, Instituto Nacional de Câncer, Rio de Janeiro, Brazil

    Aline Barros dos Santos Schwindt MD, MSc

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  1. Antonio Augusto Ornellas MD, PhD
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  1. Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

    Daniel J. Culkin

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Ornellas, A.A., Alves, G., Schwindt, A.B.d.S. (2014). Pathology and Genetics. In: Culkin, D. (eds) Management of Penile Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-0461-7_4

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