Human Papillomavirus (HPV)-Attributable Subsequent Neoplasms (SNs) After Hematopoietic Cell Transplantation (HCT) – a Potentially Preventable Outcome

Centers for Disease Control estimate that 26,000 cancers diagnosed each year in the general population are attributable to HPV; oropharyngeal and female genital cancers account for 75% of these. We hypothesized that HCT recipients are at an especially increased risk of HPV-attributable SNs, because of exposure to high-intensity therapy, coupled with immune dysregulation. However, the magnitude of this risk and sub-populations at highest risk are not known. Clinically this information is important because of the ability to institute primary prevention (HPV vaccine) for the young (<26y-olds); and the need to develop targeted surveillance and intervention strategies across all age groups.

We determined the risk of post-HCT oral/pharyngeal and female genital neoplasms in 5701 (2424 female, 3277 male) consecutive patients transplanted for hematologic malignancies (leukemia [49%], lymphoma [35%], myeloma [12%]) between 1976 and 2007 at a single institution. Near-complete ascertainment of SNs was accomplished by combining institutional follow-up with linkage of the cohort with California Cancer Registry, and National Death Index Plus programs.

Median age at HCT was 41y (0–78); 48% had received autologous HCT; 37% related and 15% unrelated donor HCT. Chronic graft vs. host disease (GvHD) developed in 44% of related and 66% of unrelated donor HCT recipients. Oral/pharyngeal cancer: After 34,621 p-y of observation, 25 patients developed oral cancer; 76% after allogeneic HCT. Squamous cell carcinoma (SCC) of tongue, lip, and mouth/alveolar ridge accounted for 84% of the oral SNs; 16% were salivary gland tumors. Pathology reports did not capture HPV status. Oral/cutaneous (adjacent to lip) chronic GvHD was present in 62% of SCC, and 6% of non-SCC oral cancers. Median latency from HCT to oral cancer was 7.7y (0.9–32); median age at diagnosis was 45y (24–69). While autologous HCT recipients were not at statistically significant increased risk (standardized incidence ratio [SIR] = 1.9 (p=0.12), related donor recipients were at a 9-fold (4.5–14.8, p<0.001) and unrelated donor HCT recipients at a 23-fold (10.7–43.4, p<0.001) increased risk of developing oral cancer compared with the age- and sex-matched general population. Multivariate Cox-regression analysis (adjusted for age at HCT, gender, race/ethnicity, conditioning, and year of HCT) revealed that unrelated donor HCT recipients with chronic GvHD were at a 10.8-fold increased risk of developing oral cancer (p=<0.001), compared with autologous HCT recipients. Female genital tract neoplasms: Evaluation of the 2424 female HCT recipients with 14,587 p-y of follow-up revealed 51 patients with genital tract neoplasms (premalignant and malignant lesions of the cervix, vagina, vulva and clitoris); 71% of the cases among allogeneic HCT recipients had chronic GvHD. Forty-nine of the 51 neoplasms were of squamous cell origin. Importantly, 39 of 41 (95%) evaluable cases had findings consistent with HPV infection. Median latency from HCT to genital tract SNs was 3.3y (0.2–16.5); median age at diagnosis was 42y (20–66). In an analysis restricted to SEER-reportable neoplasms, the cohort was at 5.8-fold (3.2–9.5, p<0.001) increased risk of developing genital tract neoplasms when compared with an age-matched general population. Autologous, allogeneic related and unrelated HCT female recipients were at 4.1- (1.5–8.7, p=0.002), 7.2- (2.9–14.6, p<0.001) and 10.8-fold (1.8–33.8, p<0.001) increased risk respectively, of developing genital tract neoplasms compared with the general population. Multivariate Cox-regression analysis (adjusted for age at HCT, race/ethnicity, conditioning, and year of HCT) revealed that unrelated donor HCT recipients with chronic GvHD were at a 2.5-fold increased risk of developing female genital tract neoplasms (p=0.04) when compared with autologous HCT recipients.

Chronic GvHD significantly increases risk of oral and female genital tract neoplasms; populations at risk should be followed closely, with appropriate and aggressive management of suspicious lesions. Over 90% of post-HCT female genital tract neoplasms are attributable to HPV. The contribution of specific HPV strains to the development of post-HCT oral and female genital tract neoplasms is currently underway, as are studies examining immunogenicity/safety of HPV vaccine for the <26y-old HCT survivors.

No relevant conflicts of interest to declare.