Simona Maria Fragomeni1, Frediano Inzani2, Anna Fagotti3,4, Luigi Della Corte5, Stefano Gentileschi6,7, Luca Tagliaferri8, Gian Franco Zannoni2,9, Giovanni Scambia3,4, Giorgia Garganese3,10. 1. Unità di Ginecologia Oncologica, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy. simona.fragomeni@gmail.com. 2. Unità di Gineco-Patologia e Patologia Mammaria, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. 3. Unità di Ginecologia Oncologica, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy. 4. Istituto di Clinica Ostetrica e Ginecologica, Università Cattolica del Sacro Cuore, Rome, Italy. 5. Dipartimento di Neuroscienze e Scienze Riproduttive ed Odontostomatologiche, Scuola di Medicina e Chirurgia, Università degli studi di Napoli Federico II, Naples, Italy. 6. Unità di Chirurgia Plastica, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. 7. Istituto di Clinica Chirurgica, Università Cattolica del Sacro Cuore, Rome, Italy. 8. Unità Operativa Complessa di Radioterapia, Dipartimento di Scienze Radiologiche, Radioterapiche ed Ematologiche, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy. 9. Istituto di Anatomia Patologica, Università Cattolica del Sacro Cuore, Rome, Italy. 10. Gynecology and Breast Care Center, Mater Olbia Hospital, Olbia, Italy.
Abstract
BACKGROUND: Additional prognostic factors and personalized therapeutic alternatives for vulvar squamous cell carcinoma (VSCC), especially for advanced stages with poor prognosis, are urgently needed. OBJECTIVES: To review and assess literature regarding underlying molecular mechanisms of VSCC target therapeutic and prognostic approaches. METHODS: We performed a narrative literature review from the inception of the database up to January 2020 limited to English language, organizing knowledge in five main fields: extracellular and intracellular cell cycle deregulation, tumor immune microenvironment, tumor angiogenesis and hormones. RESULTS: EGFR immunohistochemical overexpression/gene amplification, representing early events in VSCC carcinogenesis, have been correlated with a worse prognosis and led to inclusion of erlotinib in cancer guidelines. p16 expression and HPV positivity are linked to a better prognosis, while p53 overexpression is linked to a worse prognosis; thus, biomarkers could help tailoring conventional treatment and follow-up. The implications of PD-L1 positivity in reference to HPV status and prognosis are still not clear, even though pembrolizumab is part of available systemic therapies. The role of tumor angiogenesis emerges through data on microvessel density, immunohistochemical VEGF staining and evaluation of serum VEGF concentrations. Few data exist on hormonal receptor expression, even though hormonal therapy showed great manageability. CONCLUSIONS: We suggest adding p16, p53 and HPV status to routine hystopathological examination of vulvar biopsies or surgical specimens. Predictive biomarkers for anti-EGFR and anti-PD-1/PD-L1 drugs are needed. Enough preclinical data supporting anti-angiogenic target therapies in clinical trials are existing. Hormonal receptor expression deserves further investigation.
BACKGROUND: Additional prognostic factors and personalized therapeutic alternatives for vulvar squamous cell carcinoma (VSCC), especially for advanced stages with poor prognosis, are urgently needed. OBJECTIVES: To review and assess literature regarding underlying molecular mechanisms of VSCC target therapeutic and prognostic approaches. METHODS: We performed a narrative literature review from the inception of the database up to January 2020 limited to English language, organizing knowledge in five main fields: extracellular and intracellular cell cycle deregulation, tumor immune microenvironment, tumor angiogenesis and hormones. RESULTS:EGFR immunohistochemical overexpression/gene amplification, representing early events in VSCC carcinogenesis, have been correlated with a worse prognosis and led to inclusion of erlotinib in cancer guidelines. p16 expression and HPV positivity are linked to a better prognosis, while p53 overexpression is linked to a worse prognosis; thus, biomarkers could help tailoring conventional treatment and follow-up. The implications of PD-L1 positivity in reference to HPV status and prognosis are still not clear, even though pembrolizumab is part of available systemic therapies. The role of tumor angiogenesis emerges through data on microvessel density, immunohistochemical VEGF staining and evaluation of serum VEGF concentrations. Few data exist on hormonal receptor expression, even though hormonal therapy showed great manageability. CONCLUSIONS: We suggest adding p16, p53 and HPV status to routine hystopathological examination of vulvar biopsies or surgical specimens. Predictive biomarkers for anti-EGFR and anti-PD-1/PD-L1 drugs are needed. Enough preclinical data supporting anti-angiogenic target therapies in clinical trials are existing. Hormonal receptor expression deserves further investigation.
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