Molecular Factors

p53 is a tumor-suppressor gene located on the short arm of chromosome 17. Alterations in this gene have been implicated in the pathogenesis of many tumors. However, it was not until 2002 that Lopes et al. evaluated, for the first time, the

Table 10.3 Variables and prognostic accuracy of different integrated systems to predict pathological lymph node involvement (NA - not available)

Solsona

EAU

Ornellas

Ficarra

Bhagat

Prognostic

Variables

risk-groups

risk-groups

risk-groups

nomogram

nomogram

index

pT

Y

Y

Y

Y

N

N

Grading

Y

Y

Y

Y

Y

Y

Vascular

N

N

N

N

Y

N

embolization

Perineural invasion

N

N

N

Y

N

Y

Tumor thickness

N

N

N

Y

N

N

Growth pattern

N

N

N

Y

N

N

Anatomical

N

N

N

N

N

Y

infiltration

Age

Y

Y

Y

Y

Y

Y

Clinical N stage

N

N

N

Y

Y

N

Concordance index

0.697

0.632

NA

0.876

0.740

NA

prognostic significance of p53 in patients with penile SCC. The group demonstrated positive inguinal lymph nodes in 39.6% of p53-negative and 67.6% of p53-positive patients (p = 0.01). In multivariate analysis p53 was an independent predictor of inguinal lymph node metastases.20 In a more recent article,, Zhu et al. observed metastatic node disease in 29% of patients with low p53 expression and in 67% of those with high p53 expression. Additionally, in this study, p53 was an independent predictor of node metastases, together with the presence of lymphatic and venous emboli.47 The same investigators noted 3-year cancer-specific survival rates of 87% in men with low p53 levels and 41% in those with high p53 (p < 0.001) and p53 was subsequently reported to be an independent predictor of cancer-specific survival (p = 0.01).

E-cadherins are a type of intercellular cell adhesion molecule. Decrease in expression of E-cadherins promotes invasion and the development of metastatic disease.49 Low E-cadherin expression has been correlated with the risk of metastases in several malignancies. In 2007 Zhu et al. reported 28% of patients with node metastases among those with high E-cadherin expression and 58% of patients among those with low E-cadherin levels (p=0.0009), but this variable was not associated with lymph node involvement.48 Additionally, Campos et al. showed that low E-cadherin levels were not independent predictors of survival at multivariable analysis.22

MMP-2 and MMP-9 are part of a group of enzymes that degrade type IV collagen in the basement membrane and are involved in the invasion mechanism.50 In relation to disease-free survival, Campos et al. identified high MMP-9 expression as an independent predictor of disease recurrence (HR 3.2-95% CI 1.2-8.3), as well as distant metastases (HR 57.9- 95%CI 7.4-453.9), and urethral infiltration (HR 3.5-95%CI 1.3-9.2).22 Conversely, Zhu et al. observed a significant 3-year cancer-specific survival difference between patients with low and high MMP-9 expression (p = 0.006), but this result was not confirmed in multivariate analysis.48

Ki-67 is a nonhistone nuclear matrix protein expressed in all cell-cycle phases except G0 and thus Ki-67 protein expression (assessed, for example, by immunohistochemistry)

is a reliable tool to evaluate tumor cell proliferation. Most authors have not demonstrated any significant correlation between Ki67 expression and pathological lymph node involvement or patient survival..8,51 In contrast, Guimaraes et al. observed a positive correlation between MIB-1/Ki-67 overexpression (>10%) and the presence of inguinal metastases.25 Similar conclusions were drawn by Protzel et al., who reported lymph node metastases in 0% of patients with Ki-67 <15%, whereas lymph nodes were positive in 53% of those with Ki-67 between 15% and 60%, and in 100% of those with Ki-67 over 60% (p = 0.005).39

Proliferating cell nuclear antigen (PCNA) has been rarely evaluated in penile cancer. Guimaraes et al. showed that node metastases were present in 31.7% of PCNA-negative and 50% of PCNA positive patients. In multivariate analysis, PCNA was an independent predictive factor for node involvement together with lymphatic and/or vascular embolization, lymph node clinical stage, and MIB-1/Ki-67 absence. However, PCNA was not an independent predictor of overall or disease-free survival.25

The cell membrane protein KAI11 ("Kang ai" = Chinese for "anti-cancer") was originally demonstrated as a metastasis suppressor gene in prostate cancer.52 Downregulation of KAI11/CD82 is associated with the development of metastases and poor prognosis in several carcinomas.53-55 Protzel et al. found that all patients with reduced or absent KAI11/CD82 expression had inguinal lymph node metastases (p = 0.0002). Moreover, they reported a significant overall survival advantage in patients expressing more than 50% of these suppressor proteins.56

In conclusion, the tumor suppressor gene p53, E-cadherin and matrix metallo-proteinases (MMP) 2 and 9, Ki-67, proliferating cell nuclear antigen (PCNA) and cell membrane protein KAI11 are the most extensively studied and promising molecular prognostic factors used in predicting the risk of lymph node involvement in patients with penile cancer. As a result of the conflicting results available in the literature and, above all, the limited number of cases included in the studies, the panel of the international consultation on penile cancer have recommended their use as only investigational tools for the moment.

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