Can routine post-transplant HPV vaccination prevent commonly occurring epithelial cancers after allogeneic stem cell transplantation?

Abstract

The association between squamous cell carcinoma (SCC) of the oral cavity, female genital tract and skin with human papilloma virus (HPV) subtypes is well established in the general population and in solid organ transplant recipients but no consistent link has been reported between HPV infection and SCC after allogeneic stem cell transplantation (allo-SCT). Studies are needed to determine if SCC, the most common secondary malignancies after allo-SCT, which is linked to chronic graft versus host disease and immunosuppressive therapy, are HPV-related. Consideration should be given to assessing pre-transplant HPV antibodies to identify patients at risk for HPV reactivation. If a strong relationship between HPV and second malignancies after SCT exists, studies to evaluate the immunogenicity and efficacy of quadrivalent HPV vaccine (subtypes 6, 11, 16, 18) should be considered in both male and female long term survivors after allo-SCT.

Introduction

Relative mortality decreases with time from allogeneic stem cell transplantation (allo-SCT), but remain significantly elevated.^1;2 One of the most devastating long-term complications is the development of a second cancer which has a significantly higher incidence than in the general population.^3–8 In a large multicenter European study, the actuarial risk of second malignances at 15 years was 11.5 ±2.3%.³ In the largest study of over 28,000 patients after allo-SCT, the risk for squamous cell carcinomas (SCC) was 5 times higher than the general population in patients with history of chronic graft versus host disease (cGVHD).⁴ A recent study showed late mortality attributed to treatment-related causes in 25%, including 7% due to secondary cancer in long term survivors after allo-SCT.² Individuals in this large study were 3.6 times more likely to have died of a new malignancy. In this review we discuss the common secondary solid cancers associated with immunosuppression, their link with human papilloma virus (HPV) and the implications for HPV vaccination in long term allo-SCT survivors.

Common secondary SCC after allo- SCT

Solid cancers have a long latency period, but are increasingly encountered because long-term survival after SCT has improved.^3–6 In a recently published multi-institutional cohort of 28,874 allo-SCT recipients, the risk of secondary solid cancers risk rose 3-fold among patients followed for longer than 15 years after transplant.⁴ Radiation was a significant risk factor for the development of mainly non-SCC (breast, thyroid, brain and CNS, bone and connective tissue, and melanoma); whereas chronic graft-versus-host disease (cGVHD) and immunosuppressive therapy (IST) was shown to contribute to an excess risk of SCC.^4;9;10 Occurrence of cGVHD was associated with a 5-fold increased risk of SCC,⁴ confirming earlier reports.^7;9 Importantly, in this large series, there was no association between SCC risk and radiation exposure. Both the duration of IST and the use of particular immunosuppressive agents have been shown to contribute to second cancers, especially SCC.^3–5;7;9;10 Head and neck, female genital tract and skin are frequently reported SCC after allo SCT.^3–6 Median time from allo-SCT to diagnosis of solid malignancy was 3.3 to 6.8 years⁶ but a plateau has not yet been reached in long-term follow-up, and the cumulative incidence continues to rise.

Head and neck SCC (HNSCC)

There is an increased risk of tumors of the oral cavity after allo- SCT.^3–5 Bhatia et al⁵ reported 17 times higher risk of cancer of the oral cavity in long term survivors. In this study all patients with SCC of the oral cavity (excluding salivary gland tumors) also had cGVHD, as did the patient who developed SCC of the esophagus. The Center for International Blood and Marrow transplant Research (CIBMTR) and investigators from the Fred Hutchinson Cancer Research Center reported a 6-fold higher risk both for oral and skin SCC after allo-SCT.⁷

Female genital cancer

Cervical SCC is a frequent second solid tumor in long term SCT survivors.^3–5;7 A 13-fold increased risk compared to the general population has been reported.⁵ Older age at transplantation was associated with an increased risk of cervical cancer (> 34 years; 18.5 × higher risk). We reported a higher prevalence of cervical dysplasia in long term survivors after allo-SCT (occurring in more than one third). Prolonged IST for cGVHD was an independent factor associated with cervical dysplasia.¹¹ Lower genital tract dysplasia is also common among solid organ transplant recipients.¹²

Skin SCC

Skin cancers, especially SCC, are the most common IST related tumors.^13;14 Depending on the intensity of IST, their prevalence varies from 40 and 70%.^13–15 Many publications excluded skin cancer during their analysis for second malignancies, but in those studies which included it, an association was demonstrated between SCC of skin and cGVHD/IST.^3–5

HPV infection in the immunocompromised host

Reported prevalence of genital HPV in the general population ranges from 20% to 46%^16–19 and in clinic-based populations, prevalence as high as 64% has been reported²⁰ (an order of magnitude higher than the prevalence of N gonorrhea, C trachomatis, T vaginalis, or M genitalium). Although HPV infection is common; studies suggest approximately 90% of infections clear within 2 years.²¹

Interestingly, a study investigating asymptomatic HPV infection in oral cavity (brushings collected for HPV analysis by consensus PCR) showed HPV DNA in 18% of renal transplant versus 1% control samples (P<0.001).²² In addition, in the renal transplant group, the risk of an HPV-positive sample was higher in older patients (P=0.05). The high rate of HPV carriage is noteworthy; this study extends previous observation of asymptomatic infection, and identifies IST and older age as risk factors for oral HPV infection.

Reactivation of latent DNA viruses has been well documented in immunocompromised hosts. Herpes viruses such as herpes simplex, varicella zoster, human herpes virus 6, Epstein-Barr, and cytomegalovirus reactivations are well-recognized, and hepatitis B virus has also been found to reactivate following allo-SCT.²³ Similarly, HPV may reactivate and lead to SCC in long-term SCT survivors. The appearance of anti-HPV antibodies and the clearance of HPV from the serum occurs in over 90% of individuals and indicates resolution of infection. However, many patients in whom HPV has been eliminated from the serum still have detectible HPV DNA in tissues such as skin, oral cavity and the female genital tract as discussed above.^{13;14;16;22;24} After allo-SCT, renal transplantation or intensive chemotherapy dormant HPV may reactivate in these sites. Late onset HPV reactivation can be predicted by monitoring the progressive disappearance of anti-HPV antibodies. While it is possible that a new HPV infection in immunocompromised host could occur, we found increased prevalence of cervical dysplasia in non sexually active long-term survivors, suggesting that HPV reactivated from dormant virus.¹¹

Links between HPV and commonly occurring SCC after allo-SCT

Head and Neck SCC (HNSCC)

HPV has been etiologically linked with HNSCC.^24;25 Among HNSCC biopsies, the true prevalence of HPV DNA remains uncertain, yet studies have estimated that up to 70% of HNSCCs may be HPV positive.^24;25 In a recently published meta-analysis of 5,046 HNSCC cancer specimens from 60 studies, the overall HPV prevalence was 25.9%; however, HPV prevalence was significantly higher in oropharyngeal SCC (35.6%). HPV16 accounted for the majority of HPV-positive oropharyngeal SCCs (86.7%)²⁴. Although other oncogenic HPVs were detected in HNSCC, in a recent case-controlled study HPV-16 DNA predominated occurring in 72% of 100 paraffin-embedded tumor specimens of oropharyngeal cancer.²⁵

Female genital cancer

HPV is the obligate cause of cancer of the cervix and HPV16, the most prevalent HPV type seen in cervical SCC.²⁶ High-risk HPV types are detected in 99% of cervical cancers, and worldwide approximately 70% of cervical cancers are due to HPV types 16 and 18. We also found HPV-related cervical dysplasia in 31% of long term survivors, most with high risk HPV16 and 18 subtypes.¹¹ It would be important to study prospectively the prevalence of HPV-related cervical dysplasia in long term SCT survivors by examining PAP smears for HPV-DNA. Guidelines for the screening and prevention of second malignancies would be helpful in reducing the risk of cancer development.

Skin SCC

HPV also play a role in SCC of the skin.^13;14 Among organ transplant recipients HPV DNA was detected in more than 70% of SCC skin.^13–15 The risk of skin SCC increases with the degree of immunosuppression^27;28 Both UV radiation and immunosuppression may increase the activity of HPV, which may also contribute to cancer development.

Implications for HPV vaccinations after allo-SCT

The fact that HPV16 and HPV18 predominate in SCC of cervix, HNSCC and some skin cancer, suggests that the newly developed prophylactic HPV vaccines for cervical cancer might be useful to prevent SCC occurring after allo-SCT. The success of this strategy would depend upon the proportion of cancers that are HPV-positive and therefore preventable by HPV vaccination. The results reviewed here provide a strong rationale for HPV vaccination in both male and female- since SCC occur equally in both sexes after allo-SCT. Vaccination might result in a substantial reduction in the incidence of SCC after allo- SCT expected but validation of the approach would require long follow-up in a large patient group.

Several questions remain to be resolved by serial studies of HPV antibodies before definitive application of HPV vaccines post SCT: How long would the vaccine confer protection in immunosuppressed patients? How effective is the current vaccine schedule in immunosuppressed patients? To address these questions we now plan to follow HPV antibodies in seropositive patients to determine the frequency of negative seroconversion and to vaccinate both pre-transplant seropositive and seronegative patients older than 12 years undergoing allogeneic SCT with the quadrivalent (types 6, 11, 16, 18) HPV recombinant vaccine. Three doses of vaccine (at 0,2 and 6 months) will be given, starting one year after SCT, or as soon as the patient is no longer receiving systemic immunosuppressive agents. Additional doses of vaccine at 6 month intervals would be given for patients who do not seroconvert. HPV titers, will be monitored pre-vaccine and at 2, 6, 7, 12 months, and annually post vaccine or every six months for non-seroconverters.

Statement of Translational Relevance.

Human papilloma virus has been linked to cervical, skin and oral cavity cancer. These are also common second malignancies in long term survivors after allogeneic stem cell transplantation (allo-SCT). Here we present data linking squamous cell cancer (SCC) occurring after SCT with immunosuppression predisposing to reactivation human papilloma virus (HPV). This association is of clinical importance because it is now possible to vaccinate SCT recipients against HPV16 and HPV18 which account for the majority of HPV types detected in SCC occurring in the general populations and after solid organ transplantation. Our data provide a strong rationale for HPV vaccination in males and females since SCC occur equally in both sexes after allo-SCT. To reduce late morbidity and mortality from secondary SCC in long-term survivor after allo-SCT, it would therefore be timely to establish a multicenter randomized study of the safely and effectiveness of HPV vaccination.