Unclear role of human papillomavirus infection in response to adjuvant radiotherapy: conflicting results on the prognostic significance of irradiation in vulvar cancer patients with lymph node metastasis

I have read the article entitled “The prognostic role of lymph node metastasis and F.I.G.O. stage in patients with vulvar cancer: a systemic review and meta-analysis”, by Zhou and Shan, published in Current Medical Research and Opinion¹ with great interest.

The authors performed a systemic review of the literature and meta-analysis to examine the 5 year survival rates of patients with vulvar cancer who undergo vulvar surgery with inguino-femoral lymph node dissection based on the number of metastatic lymph nodes and F.I.G.O. stage.

They indicated that the 5 year overall survival (O.S.) rate was inversely correlated with the number of lymph node metastases and with increasing F.I.G.O. stage. Similarly, 5 year disease free survival (D.F.S.) and progression free survival (P.F.S.) decreased with an increasing number of lymph node metastases and, what seems to be the most important, patients with at least one lymph node metastasis had a 5 year O.S. and P.F.S. of <26% and 50% respectively.

It is widely known that a patient’s prognosis is mainly determined by the patient’s lymph node status. Adjuvant radiotherapy after surgical excision of the primary tumor and inguino-femoral lymphadenectomy improved the prognosis in patients with nodal involvement².

The prognostic impact of the number of affected lymph nodes and the subsequent benefit of irradiation, however, are controversial³.

A potential benefit of adjuvant radiotherapy to groins and pelvises was demonstrated for patients with two or more affected nodes by Homesley et al., but this benefit was not observed for women with only one metastasis². More recent analyses provided evidence that one intracapsular macrometastasis can lead to an impaired prognosis compared with node-negative disease⁴, and patients might benefit from adjuvant radiotherapy³.

It can be assumed that most of the patients included in the meta-analysis performed by Jinhong et al.¹ were postoperatively radiated only in cases of positive inguinal lymph nodes, unless there was only one intranodal lymph node metastasis combined with well differentiated vulvar cancer and/or positive margins.

These non-radiated, single-node metastatic cases have shown a substantial decrease in 5 year O.S. and P.F.S. This fact indirectly suggests the need for adjuvant treatment for these patients.

In my opinion, most of the conflicting results on the prognostic impact of the irradiation of patients with single lymph node metastasis originate from the unclear role of human papillomavirus (H.P.V.) infection in response to adjuvant radiotherapy in vulvar cancer patients.

Data on other squamous cell carcinomas (S.C.C.s), including those of the head and neck region and the esophagus, has consistently shown that H.P.V.-positive tumors have a significantly better prognosis than H.P.V.-negative tumors. This favorable prognosis for H.P.V.-positive cancers was associated with better response to radiochemotherapy⁵.

In H.P.V.-transformed cells, the downstream p16^ink4a-CDK4-pRB pathway is blocked by the inactivation of pRB through the H.P.V. E7 protein; this blockage results in the nuclear and cellular accumulation⁶ of the cyclin-dependent kinase inhibitor p16^ink4a.

H.P.V.-related cancers presenting p16^ink4a overexpression are very sensitive to radiotherapy and have a better prognosis than those unrelated to H.P.V. In this context, p16^ink4a overexpression has been suggested to have a major impact on treatment response and survival in patients with head and neck cancer treated with conventional radiotherapy⁶.

Several reports investigating the relationship between H.P.V. infection and vulvar S.C.C. prognosis have produced conflicting results. Nevertheless, the evidence provided by these studies is mainly indirect, as most of it provided data on either H.P.V. detection or p16^ink4a overexpression⁷.

Although it has been suggested that 16^ink4a overexpression in vulvar cancer correlates with the presence of H.P.V.⁸, a recent study revealed a substantial overlap between p16^ink4a overexpression and H.P.V. status. Thus, the use of p16^ink4a in combination with H.P.V. D.N.A. detection is recommended as an ancillary test for research and clinical studies when H.P.V. is not necessarily a cause⁹.

For the same reason (overlapping), a separate assessment of prognostic significance of p16^ink4a overexpression and H.P.V. D.N.A. status should be performed in vulvar cancer patients.

If one of these biomarkers proves to be a prognostic and/or predictive value (in relation to radiotherapy) this could imply an appropriate selection of cases for adjuvant treatment in future prospective studies.

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Declaration of funding

This editorial was not funded.

Declaration of financial/other relationships

J.J.S. has disclosed that he has no significant relationships with or financial interests in any commercial companies related to this study or article.

The C.M.R.O. peer reviewer on this manuscript has no relevant financial or other relationships to disclose.