Human Papillomavirus–Related Malignancies in the Setting of Posttransplantation Immunosuppression

In immunocompetent patients, HPV-infected epithelium may progress from dysplasia to carcinoma in a subset of individuals. More than 100 genotypes of HPV have been identified, which may be designated as either low or high risk based on their potential for oncogenesis.^2,3  Human papillomavirus has been causally linked to several forms of cancer, most notably via mechanisms involving dysregulation of the cell cycle.³  The process of cell division is normally orchestrated under the strict regulation of several genes and checkpoints, ensuring that only properly replicated products are able to continue through the cycle to divide and sustain life as a new cell.⁴  However, HPV disrupts this balance by way of a number of genetic pathways that result in evasion of the normal cell cycle regulatory processes. Such pathways include inhibition of the tumor suppressor genes p53 and Rb^3,5  by the HPV proteins E6 and E7.^6,7 

The conclusion of this interference ultimately results in uncontrolled cellular proliferation, and specifically in the propagation of defective cells with the potential for malignancy. As HPV incorporates into the host genome, the uncontrolled proliferation typically results clinically in warty lesions. These may progress into dysplastic squamous proliferations and eventually carcinoma, at both noncutaneous (ie, cervical, vaginal, vulvar, anal, penile, and oropharyngeal) and cutaneous sites.

In transplant recipients, the increased incidence of HPV-related malignancies suggests the greater oncogenic potential of the virus in the setting of impaired immune surveillance.¹  In solid organ transplants, the use of immunosuppressive agents to prevent allograft rejection targets the patient's immune system and interferes with immune surveillance. The lifelong nature of these therapies creates a unique opportunity for virally infected cells to escape the immune system and proliferate, rather than undergo cell-mediated destruction.^6,7  Conventional immunosuppressive drugs, such as calcineurin inhibitors, work by directly inhibiting T-cell stimulation. In this circumstance, normal T-cell surveillance is diminished, preventing the recognition and destruction of foreign agents, and thereby facilitating the development of malignancy.⁸  Moreover, these immunosuppressive drugs are also believed to stimulate growth factors, such as vascular endothelial growth factor and transforming growth factor-β, which augment tumor growth, metastatic potential, and angiogenesis.⁹  A newer class of immunosuppressive drugs, the mammalian target of rapamycin (mTOR) inhibitors, do not appear to have the same potential for the development of malignancy.^8,10  Further investigation into this class of drugs and their potential protective effect against oncogenesis, in comparison with the calcineurin inhibitors, may improve our understanding of posttransplantation-related malignancies as well as outcomes for these patients.

Compared with immunocompetent patients, the incidence of HPV-related cancers and precancerous lesions is significantly increased in the posttransplantation setting, an anticipated observation given the increased susceptibility of posttransplantation patients to HPV. The frequency of cutaneous and mucosal warts appears to be influenced by the type of organ transplant. In a study conducted by Kruger-Corcoran et al,¹¹  the incidence of warty lesions during an 11-year period after transplantation showed gradual upward trends in all groups of recipients, including heart, liver, lung, kidney, and kidney-pancreas recipients.¹¹  However, at the end of the first year, kidney transplant recipients showed the highest incidence of HPV-associated warts (11.9% incidence), with lung, kidney-pancreas, heart, and liver following in order of decreasing frequency. At 11 years after transplantation, lung recipients had the highest incidence of warts (above 30%), followed by heart, kidney, kidney-pancreas, and finally liver recipients. Interestingly, the trends in incidence observed among different types of transplants were commensurate with the cumulative amount of immunosuppression administered, correlating with the highest incidence of warts observed in lung and heart transplant recipients at the conclusion of the 11-year study. Higher doses of immunosuppressive therapy, resulting in more profound immunosuppression in these transplant populations, again suggest an environment of impaired immune surveillance that promotes the development of HPV-related lesions.¹¹ 

The anatomic distribution of HPV-related malignancies is unique in the immunosuppressed posttransplantation setting.¹  In the immunocompetent setting, genital lesions, head and neck tumors, and cervical carcinoma account for the vast majority of HPV-related lesions. In transplant recipients, there is a 100-fold increase in the incidence of cutaneous squamous cell carcinoma, that appears to be associated with HPV, compared with the general population that appears to be associated with HPV.¹²  Among cutaneous sites, sun-exposed areas are the most frequently affected, manifesting as nonmelanoma skin carcinomas and overall comprising most HPV-related tumors in transplant recipients.¹  Among noncutaneous sites, vulvar cancer is the most frequently occurring HPV-associated posttransplantation malignancy, followed by oropharyngeal and anal sites.¹³  According to the Transplant Cancer Match Study, invasive carcinoma at noncutaneous sites is increased 2- to 7-fold for most types of HPV-associated cancers, with the exception of those of cervical origin.¹³  For in situ carcinoma, a 20-fold increase in penile and vulvar lesions and a 3-fold increase in lesions of the uterine cervix have been observed in transplant recipients (Figure).

In immunocompetent patients, basal cell carcinoma is the most common form of nonmelanoma skin cancer, occurring 3 to 6 times more frequently than squamous cell carcinoma.⁷  In contrast, when studied within the posttransplantation population, a 50- to 100-fold increase in the incidence of squamous cell carcinoma compared with basal cell carcinoma is observed, attesting to the influence of HPV-associated squamous tumors in these patients.¹⁴  Although the histogenesis of virtually all HPV-related lesions is squamous in nature, the strains of HPV identified within nonmelanoma skin cancers also appears to vary with immune status. Human papillomavirus associated with cutaneous lesions in immunocompetent patients most often includes strains that are classically associated with epidermodysplasia verruciformis, including types 5, 14, 19, 20, 22, 23, 24, 25, 36, 37, 38, 49, 75, RTRX1, RTRX2, RTRX5, RTRX32, vs20-4, vs42-1, vs73-1, vs92-1, and Z95963, whereas “cutaneous-type” strains (10, 27, 2, 1, 3, 77, and 28) tend to be uncommonly encountered. Human papillomavirus types related to cutaneous tumors in the posttransplantation setting similarly contain strains of the epidermodysplasia verruciformis type, found in 87.9% of positive lesions. However, many of these lesions differ in that they frequently demonstrate infection by multiple types of HPV. Immunosuppressed patients are noted to have a higher prevalence of strains associated with cutaneous types, found in 63.6% of HPV-positive lesions, as well as mucosal types (types 11, 16, and 66) of HPV, identified within 15.2% of HPV-positive lesions. As these statistics suggest, there is also a difference in the number of strains of HPV that are detected in malignancies found within a single patient. Mixed infection with multiple HPV types is found within only 13% of immunocompetent patients, in comparison with 54% of transplant recipients.¹⁴  These findings may be accounted for by differences in exposure, increased susceptibility to infection, and an inability to clear the virus in the immunosuppressed state.

In both transplant recipients and the general population, fair skin and exposure to ultraviolet light are risk factors for the development of skin malignancies; however, the effect of light appears to be accentuated in posttransplantation patients. Although the determinants of oncogenesis in this setting are multifactorial, the presence of HPV infection significantly contributes to the accelerated rate at which these tumors arise. In particular, the DNA damage incurred by ultraviolet radiation may become irreparable in the presence of HPV infection, because both DNA damage repair and apoptotic pathways within the cell are deleteriously affected by the virus.^15,16  For similar reasons, fair skin is a risk factor for developing skin carcinoma because of the low levels of melanin, which protects against ultraviolet light.¹⁷ 

In addition, the length of time a patient receives immunosuppressive therapy greatly influences the likelihood of developing HPV-related malignancies. The incidence of skin cancer directly correlates with the duration of therapy, showing similar trends for all transplant types.¹⁸  Geographic variations have been reported, however, possibly related to differences in environmental factors.¹⁸  In the United States and Europe, the incidence of squamous cell carcinoma 10 years after transplantation is between 10% and 27%. At 20 years after transplantation, this incidence increases to 40% to 60%. The highest rates are seen in Australia, where at 20 years after transplantation, the incidence of squamous cell carcinoma is approximately 80%.¹⁸ 

Accompanying the length of immunosuppression, the type of immunosuppressive therapy also influences the probability of developing an HPV-related malignancy. Both calcineurin inhibitors and azathioprine cause an increase in the prevalence of HPV-related skin carcinomas compared with patients on other immunosuppressive drugs. Calcineurin inhibitors act to inhibit the tumor suppressive activity of p53 and E-cadherin, thus promoting oncogenesis.¹  Azathioprine, when associated with ultraviolet-A radiation, acts to generate reactive oxygen species, causing direct DNA damage.¹⁹  Oncogenesis in this setting results from the influence of HPV causing the inability to appropriately repair damaged DNA.

Finally, patient age at the time of transplantation appears to be a risk factor in the process of oncogenesis. For patients older than 50 years, the relative risk of developing carcinoma in the posttransplantation setting rises rapidly within the first 6 years. In patients younger than 50 years, this steep rise in relative risk occurs later in the course of treatment, typically 10 to 12 years after transplantation.²⁰  In addition to relative risk, advancing age is also positively correlated with viral load of HPV. This phenomenon suggests a correlation between older posttransplantation immunosuppressed patients and higher levels of HPV, potentially leading to higher rates of carcinoma, although a definitive causal link implicating HPV viral load independently has not been discovered.²¹ 

Treatment of HPV-related carcinomas in posttransplantation patients is often challenging because of the variety of strains encountered in a single patient in combination with the lack of immune response. Malignancies in these patients are often resistant to conventional treatment and/or frequently recur at significantly higher rates compared with immunocompetent patients.²²  As a result, treatment of HPV-related malignancies is often insufficient or temporary in the posttransplantation setting, requiring essentially lifelong surveillance.

The posttransplantation setting creates a unique environment in which the immunocompromised state of the recipient, in combination with the use of immunosuppressive therapies, results in a greatly increased risk of developing HPV-related malignancies and precursor lesions. Although immunocompetent patients typically develop lesions at genital, cervical, and head/neck sites, transplant recipients are more prone to skin carcinoma, especially in sun-exposed areas. These patients frequently acquire multistrain infections that differ in HPV subtype from those of immunocompetent patients. Moreover, certain immunosuppressive medications, such as calcineurin inhibitors, further potentiate oncogenesis by blocking genes involved in tumor-suppressive activity. Predictably, the incidence of carcinoma in this patient population increases with higher doses of immunosuppressive therapy, such as in heart and lung transplants, and as a time-dependent phenomenon. These factors, in conjunction with the inability to appropriately clear the virus, result in an environment that is highly advantageous toward tumor development and frequent recurrences. Further investigation into preventive strategies that may protect against carcinogenesis, as identified in the mTOR inhibitor class of immunosuppressive agents, may reduce HPV-related lesions and significantly improve outcomes in this patient population.