Renal transplantations (RTs) account for the major part of solid organ transplantations that are performed worldwide. In 2010, more than 850 RTs were performed in the Netherlands (16 million inhabitants) according to the Netherlands Organ Transplantation Registration (1).
In general, solid organ transplantation requires the use of lifelong immunosuppressive medication. Because of the improvement of immunosuppressive regimens, the current 1-year patient and graft survival is more than 90% and the incidence of acute rejection has decreased to 10–15% (2, 3). As a result of the enhanced long-term transplant survival and the increasing age of renal transplant recipients (RTRs), the development of cancer is becoming a major cause of morbidity and mortality after RT. A clear association between the duration and dose of immunosuppressive medication and posttransplant malignancies is known (4–7).
RTRs have at least a threefold to fivefold increased risk to develop any type of cancer compared with the general population (7–10). The relative risk for specific cancers, such as skin cancer, Kaposi’s sarcoma, and posttransplant lymphoproliferative disorders may even be higher (7–9, 11–13). Moreover, many authors have established a significantly increased risk for human papillomavirus (HPV)-associated dysplasia and cancers of the anogenital tract (cervix, vagina, vulva, and anus) in female RTRs (7–9, 14–24). Recently, we found a remarkably increased risk for cervical intraepithelial neoplasia (CIN) (twofold to sixfold), cervical carcinoma (threefold), and vulvar carcinoma (50-fold) in a population of 224 female RTRs who underwent a RT between 1991 and 1995 in our center (18). As a consequence of this increased risk, several publications and international guidelines (17, 18, 25–28) have implemented the advice to intensify cervical screening in those patients by means of smaller intervals than common in many national screening programs (target population in the Netherlands since 1996: 30–60 years of age; interval 5 years).
It was previously documented that RTRs are more often affected with (multifocal; i.e., having two or more localizations of the anogenital tract, synchronously or metachronously within a single patient) HPV infections compared with the general population (14, 15, 17, 27, 29, 30). Persistent infections with high-risk HPV (hrHPV) types (the majority HPV 16 and 18) are important risk factors for cervical cancer development (31). Additionally, HPV is etiologically related to a number of cancers of the anus and vulva (31–37). Of all anal carcinomas, 71% to 88% are positive for HPV, with a preponderance of hrHPV types (38–40). Vulvar squamous cell carcinoma (SCC) and its precursor lesions may originate from an HPV-independent or an HPV-dependent pathway. Carcinogenesis of the HPV-dependent (generally HPV type 16 and 18) pathway largely resembles that of cervical SCCs. This type of vulvar cancer primarily affects younger women and encompasses the minority of vulvar SCCs in the general population (only ∼20%). Conversely, HPV-dependent vulvar SCCs seem to comprise the majority of vulvar carcinomas in immunocompromised women (33, 41).
A long-standing hrHPV infection may cause multifocal (pre)malignancies of the anogenital tract (31). It was recently shown that in the general population frequently identical HPV types are found in both vulvar and cervical (pre)malignancies within the same patient, even after an interval of more than 10 years (42). Hence, a patient with a hrHPV-related anogenital (pre)malignancy is at higher risk to develop other hrHPV-related anogenital (pre)malignancies.
The elevated risk for RTRs to develop HPV-related anogenital (pre)malignancies may result in severe morbidity and mortality, mainly as these lesions may give rise to major dilemmas regarding therapy as radiation therapy or extensive surgery may harm the renal transplant. Therefore, understanding the elevated risk, the role of HPV, prevention and early treatment of premalignant lesions in this vulnerable patient population is important.
In this report, we aim to give a clinical overview (including treatment) of all incident cases of anogenital malignancies after RT in our center who has 40 years of experience with RT. Additionally, the HPV genotype distribution in all these malignancies and possible (multifocal) premalignancies within the same patient will be determined. Finally, we offer practical advice to improve the future health and quality of life of female RTRs.
During the study period, 1253 RTs were performed on female patients at the Radboud University Nijmegen Medical Centre. One hundred twenty-seven patients were transplanted more than once, with a maximum of four RTs per patient. For this analysis, patients were considered only once, whether they received multiple RTs or not. A total duration of renal transplant function less than 90 days was seen in 81 patients, who were excluded from further analysis. Consequently, the final cohort included a total of 1023 consecutive female patients whose data were suitable for analysis. Baseline characteristics are reflected in Table 1. Transplantations were predominantly carried out between the age of 40 and 60 years. The median age at first RT was 44.5 years (range, 3.5–74.6 years).
Malignancies of the Female Lower Anogenital Tract
Sixteen patients in our cohort (1.6%) developed an anogenital malignancy (see Table 2 for a detailed overview of all patients). All but one of these patients were transplanted once; patient 6 went through two RTs. The majority of the patients started with double immunosuppressive therapy (prednisolone and azathioprine or cyclosporine). Seven patients who experienced acute rejections were all successfully treated with prednisolone or antithymocyte globulin.
Six vulvar, five cervical, and five anal de novo carcinomas were diagnosed. The majority of the malignancies were SCCs. One adenocarcinoma of the anus was observed (patient 12). One patient (patient 12) developed a high-grade liposarcoma with unknown localization 18 years before transplantation. This tumor was excised without any recurrence or metastases. Five patients (patient 1, 2, 4, 10, and 15) developed multiple posttransplant (pre)malignant skin lesions on nongenital skin before and after the diagnosis of their anogenital malignancy. Patient 1 and 14 developed a Merkel cell carcinoma of the skin and an adenocarcinoma of the colon, respectively, 3 months and 5 years before the diagnosis of their vulvar carcinomas. The colon carcinoma showed local recurrence without metastases 2 years after initial treatment and was treated with local resection. Patient 15 had been successfully treated for breast cancer 13 years before the diagnosis of her anal carcinoma.
The median age at diagnosis of the anogenital malignancies in our cohort was 45 years (range, 37.2–72.5 years). The median interval between RT and diagnosis of malignancy was 136 months (range, 16–288 months). At the end of our study, seven patients were free of disease, five patients died of the disease, and four patients died of another cause. The median age at death was 53.2 years (range, 40.4–79.9 years). Table 3 presents data separated for the various types of the anogenital malignancies in our cohort.
Four of five patients with cervical cancer (patient 7, 11, 13, and 16) had modified surgical procedures, with only unilaterally removed pelvic lymph nodes and parametric tissue because of the presence of the renal transplant on the other side of the pelvis. Radiotherapy was indicated but abandoned to preserve renal function in patient 16. Patient 13 lost renal transplant function as a result of radiotherapy and is currently on dialysis.
Evaluation of last cervical smear before and first cervical smear after RT in the 16 patients is presented in Table 4. It shows that 12 of 16 patients never had a cervical smear before their transplantation. Among the four patients who underwent at least one cervical smear before transplantation (interval between last smear and RT ranging between 1 and 7 years), there was one patient with a cytological normal cervix 3 years before RT that was diagnosed with a cervical carcinoma approximately 2 years after RT. Patient 11 was diagnosed with a CIN 3 lesion before RT. After RT, a cytological high-grade squamous intraepithelial lesion of the cervix was diagnosed again. However, an intentional wait-and-see policy was carried out, and she was diagnosed with a cervical carcinoma 118 months after her RT.
Nine patients only had cervical smears after RT; in three of them, the first cervical smear was even more than 10 years after transplantation. Five patients were diagnosed with a high-grade cervical lesion (CIN 3) at the moment of first cytological cervical screening after RT (interval between RT and first smear ranging between 3 and 17 years).
HPV Prevalence and Genotype
An overview of the distribution of HPV genotypes in (multifocal) anogenital (pre)malignancies of female RTRs related to time periods before and after RT is given in Table 5. Of the 16 patients with anogenital malignancies, seven patients developed a premalignant lesion in the anogenital region as well. Of these seven patients, six developed CIN before their malignancy and one (patient 2) developed CIN afterward. Patient 10 was diagnosed with an additional CIN 1 lesion at the time of diagnosis of her vulvar carcinoma as well.
Of the 24 investigated (pre)malignant lesions, HPV was detected in 22 (91.7%). HPV type 16 predominated, with 12 of 22 lesions being positive for this type of HPV (54.5%). Nine lesions contained other hrHPV types. One vulvar carcinoma (patient 14) showed HPV positive for an unknown HPV genotype. Four of the seven patients with multifocal anogenital lesions had different HPV genotypes in the different lesions (57.1%). Two of the seven patients had the same HPV types in both lesions and in one patient (patient 3), one of the lesions showed repeatedly β-globin negative after DNA extraction. Therefore, the HPV status could not be determined.
This long-term follow-up study on a large cohort of female RTRs gives an overview of the development of anogenital malignancies after transplantation. We found five cervical, six vulvar, and five anal carcinomas. Especially vulvar carcinomas developed more often and at a younger age compared with the general population. Analysis showed presence of HPV in nearly all lesions, all concerning high-risk genotypes. Multifocal lesions within one patient frequently contained different hrHPV genotypes in both lesions.
The cases in our study had a significantly longer duration of transplant function compared with the other RTRs, and probably longer immunosuppressive use as a consequence. Also, the high number of other (second or third) carcinomas in our cohort is remarkable, which is probably also a consequence of long-term immunosuppression use. The incidence of 1.6% that was found in our cohort seems higher than the overall occurrence of anogenital malignancies in the general population. A rough calculation, not adjusted for age or follow-up years, with the numbers recorded by the Netherlands Cancer Registry shows an estimated raised risk of fivefold for cervical, 41-fold for vulvar, and 122-fold for anal carcinoma in our cohort. If age-adjusted calculations had been performed, the risks would probably even be higher, because of the relatively young age at diagnosis of anogenital malignancies in our cohort. Moreover, as the Pathological Anatomical National Automated Archive has only complete national coverage since 1991, it is possible that the total number of anogenital (pre)malignancies in our cohort is even underreported.
The median age at diagnosis of vulvar SCC in the Dutch general population is 70.4 years (43). In this study, five of six RTRs developed a vulvar carcinoma at approximately 40 years of age, which is remarkably young. However, this young age is in agreement with the finding that all these vulvar carcinomas originated from the HPV-dependent pathway. Comparably, an earlier publication reported a 100% HPV infection rate among RTRs with vulvar carcinomas, compared with a 20% to 57% HPV infection rate in vulvar neoplasms of immunocompetent patients (27, 44). Generally, HPV types 16 and 33 are considered to be the most common genotypes in vulvar lesions (present in ∼60% and 20% of vulvar carcinomas in the general population, respectively), although other hrHPV subtypes such as 18, 52, and 58 also have been reported (33, 42, 44). This corresponds to the types that predominantly have been detected in our cohort (HPV type 16 [50%], 33 [17%], and 58 [17%]).
Surprisingly, there is a difference in the interval times between transplantation and malignancy between the different anogenital cancer types in our cohort. It seems that, in the general population, the rate of malignant transformation of HPV-related vulvar and anal premalignancies is much lower compared with cervical premalignancies (41, 45, 46). However, as there are no screening programs and frequently no histopathological examination is performed for vulvar and anal intraepithelial lesions, the mean interval times between HPV infection and the development of these malignancies remain largely unknown. The median interval between RT and the diagnosis of cervical carcinoma in our cohort appeared to be very short. As anogenital malignancies do not develop over such a short period in general, it is attractive to speculate that those RTRs already had asymptomatic dysplastic cervical lesions at the time of their RT, followed by rapid progression toward invasive carcinoma after the beginning of immunosuppressive therapy. Evaluation of cytological cervical screening in the cases with anogenital malignancies showed that only occasionally cervical smears were performed before RT. Screening of all women before RT would enable to diagnose possible anogenital (pre)malignancies at an early stage and provide adequate treatment for these lesions. However, it may also be possible that HPV-related cervical cancer develops faster in immunosuppressed patients compared with the general population. Because the majority of the cases were diagnosed with invasive lesions, it is difficult to draw a conclusion with respect to transformation rate in these cases.
Various publications and international guidelines advise at least yearly cervical screening with pelvic examination and cervical smear after RT (17, 18, 25–28). Wong et al. (47) have shown that this policy is effective in reducing cancer-specific mortality in RTRs. However, yearly follow-up smears were by no means regular in our cohort. This is in concordance with the low cervical screening rate in a previously studied larger cohort of female RTRs (18). In that study, no differences in screening rate before the detection of any low- or high-grade cervical lesion were seen between RTRs with cervical pathology and those without (18). The disappointing screening intensity may possibly be explained by the fact that these relatively recent guidelines were not well implemented in the former cohort. However, even though our overview of cervical screening is limited to a subgroup of RTRs with proven anogenital disease, we believe that the high number of high-grade cervical lesions at the time of the first cervical smear after RT point at the importance of regular cervical screening in RTRs. Especially because the treatment of these malignancies in RTRs frequently requires concessions such as modified surgery or omission of radiotherapy, which may result in a negative outcome.
The observation of HPV infection in women at older ages may be explained by true new infections or by reactivation of a latent infection (48). It is known that reduced immune surveillance secondary to HIV progression may trigger viral reactivation and may ultimately lead to progression of dysplasia (49). Presumably, the beginning of immunosuppressive medication in RTRs probably has the same effect, resulting in a rise of the viral load and progression to (pre)malignancies.
Almost 92% of our investigated samples showed a hrHPV infection. hrHPV type 16 was detected in particular (12 of 22; 54.5%), which corresponds with the preponderance of HPV subtype 16 in cervical, vulvar, and anal cancer in the immunocompetent population (50%–70%) (33, 42, 44, 50). However, less common hrHPV types (e.g., 52, 56, and 58) were present as well. Brown et al. (27) found an obviously higher HPV prevalence in specimens of RTRs (65%) compared with specimens of immunocompetent patients (38%). The high number of hrHPV-positive cases in our study emphasizes this finding. Because only specimens of histopathologically proven (pre)malignant lesions were analyzed in our study, a large number of female RTRs probably have undetected HPV infections or even (pre)malignant anogenital lesions; in particular, when considering that vulvar- and anal intraepithelial neoplasia (AIN) were frequently not histopathologically examined in earlier daily practice. This emphasizes the importance of regular cervical surveillance combined with close inspection of the anogenital area for female RTRs, as we recently advised (18, 51); especially as 11 of the 16 diagnosed malignancies in our cohort developed in the external anogenital area that should be suitable for close observation.
Anal SCC is biologically rather similar to cervical cancer. Its precursor lesion (high-grade AIN) is analog to high-grade CIN. Besides, both anal cancer and AIN are strongly associated with HPV infection. Several studies reported a detection rate of HPV in invasive anal cancers between 71% and 88% (38–40). Oncogenic HPV subtype 16 predominates, detected in approximately 70% of the HPV-positive anal tumors (38–40). RTRs are obviously at higher risk of developing anal HPV infection and neoplasia compared with the general population (52). It is interesting to note that, in this study, hrHPV subtypes (16 [66.7%] and 58 [33.3%]) were present in all three anal SCCs. The only HPV-negative anal carcinoma found was of the adenocarcinoma type. This corresponds with other studies that suggest that a large part of anal adenocarcinomas are not HPV related (38–40).
Seven RTRs developed a second anogenital lesion at least 6 months before or after the diagnosis of their anogenital malignancies. Of these patients, only two showed identical hrHPV types in both lesions. In contrast, four patients (57.1%) had different hrHPV genotypes in both lesions. Compared with earlier research in our center on nearly only immunocompetent patients with HPV-related vulvar cancer and additional cervical abnormalities (89% of patients with identical, and no patients with different HPV types in both lesions) (42), our immunocompromised cohort showed a remarkably high number of patients with different hrHPV genotypes in both lesions. As time intervals and severity of the lesions did not differ significantly between both cohorts, it is highly possible that the difference in immune status causes the dissimilarities found.
Hampl et al. (53) recently published a hypothesis regarding different pathogenetic mechanisms leading to the development of multifocal anogenital lesions. They stated that immunocompromised patients are characterized by multiple genital lesions caused by different HPV types, including types that are untypical for high-grade lesions. So, an immunocompromised host would be target for repeated independent infections with various HPV types that induce independent lesions (53). Our findings support this hypothesis.
As we stated earlier, the major role of HPV in the oncogenesis of anogenital (pre)malignancies and the increased risk for these lesions in RTRs strengthen the importance of studying the role of hrHPV vaccination for women before transplantation (51). The available vaccines (containing hrHPV types 16 and 18) seem to have great potential in the prevention of hrHPV-related anogenital (pre)malignancies in transplant recipients. The present study shows that the relative contribution (=the percentage of positive samples for a specific HPV type in relationship to all the HPV-positive samples) of hrHPV genotypes 16 and 18 in anogenital lesions of female RTRs (13 of 22; 60%) approaches the relative contribution of these genotypes in invasive cervical cancer in the general population (71%) (54). Nevertheless, it is conceivable that patients with end-stage renal disease and transplant recipients may be less responsive to the vaccine than immunocompetent individuals, as they may not produce the required protective immune response (47, 55). At present, no data about effectiveness or safety of the HPV vaccination in RTRs are available and prospective studies to elucidate possible clinical benefits of this vaccination in RTRs are needed.
A high number of RTRs was included in our study. Although the follow-up period was extensive for most patients, we must acknowledge that recently transplanted patients had a relatively short period of follow-up. It is known that anogenital malignancies do not develop over such a short period in general. Therefore, the numbers of anogenital malignancies in our cohort can be underestimated and may rise in the future. Nonetheless, we believe that our large and representative population of female RTRs, despite the lack of a control group, gives important insights in the problem of posttransplantation anogenital malignancies.
To conclude, anogenital malignancies are relatively frequently seen in female RTRs, with a crucial role for infections with various (uncommon) hrHPV subtypes. Frequent complete gynecological examination, including inspection of the anogenital area, may contribute to early detection of these (pre)malignancies of the anogenital tract of women. These relatively simple tools should therefore be implemented both before and periodically after RT to improve general health and quality of life of female RTRs. Besides, our findings give rise to further research into the course of HPV infections in a larger cohort of RTRs, preferentially in a prospective setting.
MATERIALS AND METHODS
Data of all consecutive female RTRs who underwent a RT in the Radboud University Nijmegen Medical Centre, the Netherlands, between January 1968 and December 2008 were collected. We assembled sociodemographic patient characteristics, medical data on RT, and on incident cases of malignancies of the female lower anogenital tract (i.e., cervix, vagina, vulva, and anal canal), up to the end of July 2010. Total duration of transplant function of all patients of our cohort was analyzed, taking into account repeated RTs in one patient. Patients with a total duration of transplant function less than 90 days were excluded from further analyses.
Histo- and cytological data were obtained from Pathological Anatomical National Automated Archive, which is a nationwide histo- and cytopathology network and archive that covers the entire country since 1991 (56). Medical charts and electronic patient files were used to complete medical data.
Patients With Malignancy of the Lower Anogenital Tract: Clinical Characteristics
Data of female RTRs with a malignancy of the lower anogenital tract were registered: localization and histopathological type of malignancy, date of diagnosis, history of (pre)malignancies, and cervical smears, treatment, recurrence, or metastases of the tumor after treatment. In case of development of anogenital premalignancies pre- or postmalignancy, the histopathological type, localization, and date of diagnosis were registered. If applicable, we also collected the date and cause of death. Patients were followed up until the date denominated as “lost to follow-up,” date of decease, or the end of July 2010.
HPV Presence and Genotyping
Specimens of all primary anogenital tumors were available for detection of genotype-specific HPV infections. Whenever there was an interval of at least 6 months between diagnosis of the tumor and of previous or subsequent (multifocal) premalignant lesions, we also determined the distribution of HPV genotypes in these lesions. We choose an interval of 6 months to make probable that both lesions were separate entities.
DNA was isolated from formalin-fixed, paraffin-embedded tissue sections (6 μm) with the EZ1 robot (with the DNA tissue kit of Qiagen) according to standard procedures (57) and used for polymerase chain reaction (PCR) analysis. A negative water control was included with each batch of 10 samples. Broad-spectrum HPV DNA amplification was performed using a short PCR fragment (SPF-PCR) assay. The SPF-PCR system amplifies a 65-bp fragment of the L1 open reading frame, allowing the detection of at least 43 HPV types. In case of a positive PCR result, subsequent HPV genotyping was performed using a reverse hybridization line probe assay, allowing simultaneous typing of 25 HPV genotypes. The combined SPF-PCR- line probe assay system for detection and genotyping of HPV has been described in detail elsewhere (57). As a quality control for the presence of DNA and absence of PCR inhibitors in the isolated material, a β-globin PCR was performed as described earlier (58).
Descriptive statistics were used to reproduce study results as percentages, means, medians, standard deviations, and ranges. Calculations were performed using Statistical Package for Social Sciences version 16.0 (SPSS, Chicago, IL).
The authors thank H.P. van de Nieuwenhof and L.C.G. van den Einden for their excellent assistance in processing the samples for HPV analysis and I.M.P. Hendriks for her enthusiastic help in data collection.
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