**9. Biomarkers in genital SCC**

Vaginal squamous cell carcinoma (VaSCC) is a tumor with a relatively low occurrence rate of 1–2% of all gynecological malignancies [112], but it can occur in approximately 30% of cervical cancer cases [113, 114]. Despite the low number of studies concerning this type of cancer, epidemiological, virological and clinical-pathological data available show two distinct entities of this genital SCC. They develop through two etiopathogenic pathways: one is linked to HPV infection, while the second is HPV-independent. Available studies do not provide enough information on their significance to the final outcome and they require further investigation. However, it is known that most VaSCCs are closely related to HPV, emphasizing the idea that it shares a common pathway with cervical cancer [114].

As far as the biomarkers linked to genital SCC [23, 115–117] are concerned, their discovery is relevant due to their significant impact on early diagnosis and timely treatment. Numerous studies link p16 expression with a less aggressive form of vulvar SCC and a reduced death rate. On the other hand, patients exhibiting p53 mutation have a worse prognosis, frequent relapses, and greater associated mortality [118]. Other molecular markers with a negative impact on SCC patients are cofilin-1, galectin-7, and wee1 [119]. Moreover, it has been found that lymphatic invasion and poor tumor differentiation correlate with downregulation of galactin-7 and wee1 [120, 121]. A very important role is played by cofilin which has major implications in carcinogenesis and vulvar SCC invasion [122]. This has turned it into a therapeutic option as it significantly reduces tumor progression. Also, other reports worthy to be considered indicate that downregulation of galectin-7 and high wee1 expressions have been correlated with an increased metastasis risk [120, 121].

Regarding treatment options, surgical resection is associated with a high mortality rate; therefore, attempts are being made to avoid and replace it with radiotherapy associated with chemotherapy [123, 124]. Due to limited options available, there is a real need for new targeted therapies being developed grounded on specific biomarkers.

SCC with penile localization (PSCC) has a relatively low incidence and is associated with poor hygiene, lack of circumcision, HPV infection, and tobacco use [122, 125–127]. Much the same as vulvar SCC, HPV infections play an important role. Starting with the HPV DNA incorporation step into the human genome, E6 and E7 genes deactivate tumor-suppressing genes. Due to the low occurrence rate of PSCC, there are not many studies looking at this type of cancer. These studies have found an increased concentration of Hsp70 [128]. Although not specific to PSCC and present in other types of cancer such as breast, colon, liver, and prostate cancer [129], it is believed to play a protective role for the tumor cells and is thus involved in carcinogenesis. A study looking at families of plaque molecules involved in the binding of filaments, desmosomes, and hemidesmosomes [130] has linked poor expression of plectin (a cytolinker of this family) with rapid cancer progression [131]. Since the diagnosis of inguinal metastases is currently the most important prognostic factor, the discovery of other biomarkers involved in a possible therapeutic management is imperative [128].
