Human papillomavirus independent status on pathologic response and outcomes in locally advanced cervical cancer managed with chemoradiotherapy followed by surgery

Abstract

ObjectiveWhile human papillomavirus (HPV) has been shown to play a significant role in cervical cancer carcinogenesis (HPV associated cases), a considerable percentage of cervical cancers occur independently of HPV status (HPV independent).MethodsIn this retrospective study of 254 locally advanced cervical cancer patients treated with chemoradiotherapy and radical surgery, HPV genotypes were determined using the Anyplex II HPV28 kit that uses multiplex, real time polymerase chain reaction technology. The primary endpoints of this study were to evaluate the complete response to chemoradiotherapy (pathologic complete response), the presence of microscopic (<3 mm, pathologic micro partial response, group 1) and macroscopic (>3 mm, pathologic macro partial response, group 2) residual carcinoma in the cervix, and the persistence of metastatic lymph nodes (group 3) in HPV independent cervical cancers. Secondary endpoints were evaluation of disease-free survival and overall survival.ResultsOf 254 patients studied, 21 cases (8.3%) of cervical cancer were determined to be HPV independent. The percentage of pathologic complete response was found to be higher in the HPV associated group compared with the HPV independent group (p<0.001). In the HPV associated cervical cancer group, 5 year disease free survival was found to be 80.8% versus 59.9% in the HPV independent group (p=0.014). Overall survival was also higher in the HPV associated group (87.9%) compared with the HPV independent patients (69.4%) (p=0.023). In the multivariate analysis, the International Federation of Gynecology and Obstetrics (FIGO) stage and HPV genotypes maintained their relevant impact on pathologic complete response to chemoradiotherapy: FIGO stages IIIC1 and IIIC2 were associated with a 13-fold increased risk for the presence of metastatic lymph nodes compared with group 1 (p<0.001). HPV independent cervical cancers showed the highest risk for the development of macroscopic/stable disease (p=0.007), and persistence of metastatic lymph nodes (p=0.004) versus group 1, respectively.ConclusionsThis study showed that HPV status at diagnosis could be a relevant factor for clinical outcomes in locally advanced cervical cancer patients.

Invasive Squamous Cell Carcinoma of the Cervix: A Review of Morphological Appearances Encountered in Human Papillomavirus-associated and Papillomavirus-independent Tumors and Precursor Lesions

“…To date, treatment of both HPVA and HPVI SCCs is similar across international guidelines, including the 2023 National Comprehensive Cancer Network (NCCN) and the European Society of Radiotherapy and Oncology/European Society of Gynaecological Oncology (ESTRO/ESGO) guidelines. However, evidence indicates HPVI tumors do not respond to conventional oncologic therapy (complete response to chemo- and radiotherapy is much lower in HPVI tumors compared with HPVA tumors), and thus additional studies will be beneficial to develop alternative management options 17 . Turco et al[17] suggested that HPV status should be assessed at initial diagnosis, but this would require extensive and mostly unnecessary testing.…”

“…However, evidence indicates HPVI tumors do not respond to conventional oncologic therapy (complete response to chemo-and radiotherapy is much lower in HPVI tumors compared with HPVA tumors), and thus additional studies will be beneficial to develop alternative management options. 17 Turco et al [17] suggested that HPV status should be assessed at initial diagnosis, but this would require extensive and mostly unnecessary testing.…”

“…Similarities between HPVI SCCs and HPVI ECAs were noted in a few recent studies. In contrast to HPVA SCCs, HPVI SCCs occur in older age, are diagnosed at an advanced stage, are associated with lymph node metastases, have a worse prognosis, have a propensity to develop distant metastasis, and are typically resistant to conventional oncologic treatment 10,15–17 …”

“…In contrast to HPVA SCCs, HPVI SCCs occur in older age, are diagnosed at an advanced stage, are associated with lymph node metastases, have a worse prognosis, have a propensity to develop distant metastasis, and are typically resistant to conventional oncologic treatment. 10,[15][16][17] HPVA and HPVI ECAs can be distinguished microscopically on hematoxylin and eosin-stained slides by the presence of abundant apical mitotic figures and apoptotic bodies, as initially described in the International Endocervical Adenocarcinoma Criteria and Classification (IECC). 11 In contrast, the 2020 WHO classification states that HPVI and HPVA SCCs cannot be distinguished by morphology alone, suggesting that additional staining and HPV testing may be required 1 ; however, when this classification was published, little was known about HPVI SCC morphology, and there was no evidence of HPVI precursor lesions.…”

Incidence and Clinicopathologic Characteristics of Human Papillomavirus–independent Invasive Squamous Cell Carcinomas of the Cervix

“…In the 2020 WHO classification, cervical SCCs are distinguished by HPVA versus HPVI status 12 . In cervical SCCs, however, HPVI tumors are rare and consequently difficult to study 20–22 . Estimates of the frequency of HPVI tumors vary widely, ranging from 0.23% to 9.09% of total cases depending on the cohort studied and HPV detection methods used 3,7,21–33 .…”