The female lower genital tract (cervix, vulva, vagina) is a common cancer site within the general population.1 Cervical cancer is the second most common cancer among women worldwide, while vulvar and vaginal cancers are much rarer, accounting for 7% of all gynecologic malignancies.2,3
More than 90% of cervical cancers and at least 60% to 70% of vulvar and vaginal cancers are caused by the human papillomavirus (HPV), the most common sexually transmitted infection.4–6 Because of the viral etiology of most lower genital tract cancers, women who are immunocompromised and thus unable to eliminate HPV or suppress its activity may be at a higher risk of developing these cancers.7,8 For example, solid organ transplant recipients who are on prolonged immunosuppressive therapy are more likely to develop lower genital tract precancers and cancers, and these diseases are more aggressive, advance more quickly, and occur earlier in life than in immune-competent women.9–11
Hematopoietic cell transplantation (HCT) entails immune dysregulation in both recipients of autologous HCT (auto-HCT)12,13 and allogeneic HCT (allo-HCT).14,15 Allo-HCT recipients in particular are susceptible to graft-versus-host disease (GvHD), a serious inflammatory condition resulting from the immunologic attack of recipient tissue by donor T cells.16 Both the acute and chronic manifestations of GvHD play a role in impeding immunologic recovery following HCT.14,15 Moreover, patients who develop chronic GvHD often require years of immunosuppressive therapy to treat the condition.17 The immune dysregulatory effects of GvHD and the prolonged immunosuppressive therapy used to treat it may provide a physiological milieu conducive to the reactivation, progression, or acquisition of HPV.7 Auto-HCT recipients do not experience the same degree of immune dysregulation because GvHD does not occur in these patients; however, the immune system may still be impaired for at least a year after auto-HCT.13 These biological underpinnings substantiate a model in which impaired immune surveillance of viral latency facilitates HPV replication en route to progressive lower genital tract disease.7
Ninety percent of immune-competent females infected with HPV will mount an effective immune response to clear the infection within 2 years.18 Those who are unable to do so may develop cervical, vulvar, or vaginal dysplasia. Screening with Papanicolaou (Pap) smears detects cytologic abnormalities such as low-grade and high-grade squamous intraepithelial lesions (LSIL and HSIL, respectively). Histology-confirmed koilocytic changes found on colposcopic biopsy are denoted, in increasing severity, as cervical intraepithelial neoplasia grades 1, 2, and 3 (CIN1, CIN2, and CIN3, respectively). Upon incident HPV infection, the transition from cervical dysplasia to invasive cancer is fairly low and slow: only 1%, 5%, and 12% of CIN1, CIN2, and CIN3, respectively, progress to cervical cancer,19 with a time frame of at least 5 to 10 years from the incident infection.20 Vulvar intraepithelial neoplasia progresses to cancer in 2.7% to 8.5% of women.21 Limited data are available on the rate of progression from vaginal intraepithelial neoplasia to cancer, due to the rarity of primary vaginal cancer. Importantly, because these low transition rates are reported in immune-competent women, rates of progression to cancer may be higher in female HCT recipients. Prompt detection of lower genital tract neoplasms is therefore paramount to providing clinicians with early intervention opportunities in this high-risk population.
The primary goal of this review is to summarize the current literature describing female lower genital tract neoplasms (dysplasias and cancers) after HCT. This information can provide key information on the potential for HCT-related risk and potentially assist in clinical decision-making on long-term follow-up strategies after HCT.
Methods
A comprehensive literature review was performed via PubMed encompassing the years 1994 to 2016 to search for articles covering 2 separate but related topics: first, all clinical and population-based studies on occurrence (presentation, incidence, or risk) of cervical, vulvar, and vaginal neoplasms after HCT, and second, all such studies broadened to include any kind of secondary neoplasm after HCT. A standard strategy using advanced search keywords was used with variations of terms (eg, “cervical dysplasia,” “cervical neoplasm,” “secondary cancers”) to incorporate wording differences in the literature. The initial search, along with additional articles identified from published reviews, yielded 355 articles, which were reviewed and screened to exclude 312 articles. Among the remaining 43 articles, 20 were excluded due to lack of cervical, vulvar, or vaginal cases, leaving 23 articles eligible for this review (Figure 1).
Results
Cervical Dysplasia After HCT
Our search yielded 4 studies assessing cervical dysplasia after HCT (Table 1). Sasadeusz et al22 were the first to show an increased occurrence of abnormal cervical cytology in women after undergoing allo-HCT. They conducted a retrospective analysis of all available pre-HCT and post-HCT Pap smears in 40 recipients of auto-HCT and 24 recipients of allo-HCT at a single center, finding that allo-HCT recipients had a 6.8-fold increased risk of LSIL or HSIL post-HCT compared with the age-matched general population. However, there was no increased risk of cervical dysplasia among auto-HCT recipients compared with the general population. The authors concluded that factors unique to the allogeneic setting—chronic GvHD and/or the requirement of long-term immunosuppressive therapy—likely exacerbated the risk of cervical dysplasia. However, the study was limited by the absence of both data on chronic GvHD severity and details regarding the intensity and duration of immunosuppressive therapy.
In another study of only allo-HCT recipients, Savani et al23 similarly found that patients had greater rates of cervical dysplasia post-HCT compared with pre-HCT. In this study, 35 women who had normal cervical cytology pre-HCT were followed for a median of 7 years after HCT. During the follow-up period, 43% developed cervical dysplasia, including 20% with HSIL and 14% with LSIL, all of which were biopsy-confirmed to be HPV-related (HPV DNA testing was not performed). The authors
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram for the systematic review of secondary cervical, vulvar, and vaginal neoplasms after hematopoietic cell transplantation.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 2; 10.6004/jnccn.2018.7005
A subsequent study by Wang et al24 followed a larger cohort of allo-HCT recipients (89 women) for a longer period (11 years) post-HCT, and also showed an increased rate of cervical dysplasia post-HCT compared with pre-HCT. All patients were screened on a standardized schedule after HCT and received an average of 6.5 Pap smears per patient during the follow-up period. Compared with pre-HCT smears, there was a 3-fold increase in the proportion of patients with abnormal smears at any time during the post-HCT follow-up. Among 69 patients who had normal cytology pre-HCT, 16 (23%) showed HSIL and 6 (9%) showed LSIL post-HCT. Most patients (57%) with persistent HSIL had biopsy-confirmed CIN3. HPV DNA testing in a small subset of patients revealed that 7 of 12 (58%) with HSIL were HPV-positive, but none of the 6 tested patients with LSIL were HPV-positive, implicating non-specific therapy-related changes. Significant risk factors for the development of HSIL (regardless of HPV status) included unrelated human leukocyte antigen–matched donor and vulvovaginal GvHD.
Most recently, Negri et al25 described how in 54 patients with normal cytology pre–allo-HCT, 13 (24%) showed abnormal cytology post-HCT, including LSIL that persisted on cytologic follow-up 3 to 6 months later in 11% of the entire cohort. However, they also found that among 3 patients whose initial cytology after HCT revealed atypical squamous cells cannot exclude HSIL (ASC-H), all had negative results on follow-up testing (2 had negative histologic follow-up; 1 had cytologic follow-up and a high-risk
Studies on Cervical Cytology After HCT (1994–2016)
Despite cohort and treatment differences, all of the aforementioned clinical studies provide evidence that the rate of abnormal cervical cytology increases after allo-HCT. But these studies are limited in important ways. First, small patient populations (38–89 patients) with no detected cervical cancers restricts the ability to draw conclusions about the risk of these cancers post-HCT. Second, the absence of HPV DNA cotesting alongside Pap smears (now standard in the general population) in most of the participants limits the ability to distinguish true cervical dysplasia from transient cytologic atypia. The high HPV negativity rate among patients who were tested implies that significantly larger patient numbers are needed to detect cervical cancer post-HCT.
Demonstrating whether cervical dysplasia tends to progress more readily in HCT recipients compared with the general population may provide further insight into the epidemiology of HPV in immunocompromised women. The evidence suggests that immunocompromised HCT recipients may indeed be more susceptible to cervical progression, because risk factors for cervical dysplasia after HCT include immunologic features such as vulvovaginal GvHD,24 unrelated donor,24 and long-term use of systemic immunosuppressive therapy.23 Future research should seek to compare dysplastic progression and regression rates in HCT recipients using standardized screening schedules with Pap smears and HPV DNA cotesting to minimize detection bias during the follow-up period. Studies should compare these rates with those in the general population, and elucidate the role of HCT-related risk factors in promoting the development of cervical dysplasia.
Cervical Cancer After HCT
Although few studies have examined cervical dysplasia after HCT, several large cohort studies assessing the risk of secondary cancers after HCT have determined the occurrence of cervical cancer post-HCT (Table 2). Studies by Bhatia et al26 and Shimada et al27 followed 919 and 324 women, respectively, who received either allo-HCT or auto-HCT and discovered a 13.3-fold and 8.6-fold elevated risk of cervical cancer compared with the general population. However, in much larger cohorts (range, 1,765–11,752 women) comprising only allo-HCT recipients, there was no increased risk of cervical cancer post-HCT compared with the general population.28–33
The explanation for Bhatia et al26 and Shimada et al's27 discovery of an increased cervical cancer risk in a mixed cohort of auto- and allo-HCT recipients presents a challenge in light of the average risk found in studies involving only allo-HCT recipients, who are hypothesized to have the highest risk relative to auto-HCT recipients or the general population. Their positive findings could be explained by their relatively small cohort sizes, in which a small number of detected cervical cancer cases may drive the risk toward significance. Only 426 and 227 women in these studies, respectively, developed cervical cancer after HCT. Additionally, neither of the 2 patients who developed cervical cancer in Shimada et al's27 study had chronic GvHD or were receiving immunosuppressive therapy—the most salient HCT-related risk factors for cervical cancer—when they were diagnosed. Although these findings do not disconfirm the influence of allogeneic factors on HPV progression in the cervix, they nevertheless indicate that allo-HCT may not—at least patently—increase the risk of cervical cancer. Notably, each study in Table 2 is limited by a lack of data on HPV types among HCT recipients, which may contribute in a crucial manner toward determining which individuals are most affected by allo-HCT (eg, those with high-risk HPV) versus those who are not (eg, those with low-risk or no detectable HPV).
One possible explanation for why studies have generally not found an increased risk of cervical cancer in allo-HCT recipients is that the duration of follow-up was not sufficiently long enough to detect cervical cancer. The incidence of secondary solid tumors has been shown to peak at approximately 6.8 years after allo-HCT,34 and this incidence continues to increase linearly with time for at least 2 decades post-HCT.31 The long latency period of secondary solid tumors, particularly cervical cancer, may mean that longer follow-up would allow more time for
Cervix-Related Findings on Secondary Cancers After HCT (1994–2016)
Collectively, these findings argue against an elevated risk of cervical cancer among female recipients of allo-HCT. However, this conclusion needs to be regarded cautiously, because young children (<10 years of age) comprised a substantial fraction of the HCT population in several studies that did not identify an elevated risk. In the largest cohort study by Rizzo et al,31 4,058 of 28,874 total HCT recipients (14%) were <10 years of age. Majhail et al30 reported 6% of total HCT recipients <10 years of age, and Kolb et al35 included 15% of female HCT recipients aged ≤10 years. Bhatia et al26 and Ringden et al28 also included very young children, but the proportion of those aged 0 to 10 years was not specified. Furthermore, all of these studies included HCT recipients as young as infants (≤1 year of age). Because children between the ages of 0 and 10 years are unlikely to contract HPV during the follow-up period, the number of cervical cancer cases may have been underestimated. These and future studies should therefore consider performing separate analyses for cervical cancer risk after excluding very young patients unlikely to have reached sexual debut.
Finally, the outcomes of small studies suggest no increased risk of cervical cancer after auto-HCT compared with the general population (Table 2).36–39 The only study that found an increased risk was based on only 1 case in a pediatric sample.36
Vulvar and Vaginal Neoplasms After HCT
Minimal information is available on vulvar and vaginal neoplasms after HCT; studies have been limited by small numbers detected post-HCT and by heterogeneity of follow-up (Table 3). Although an elevated risk of vulvar cancer post-HCT was found in 2 studies, these were based on the occurrence of only 1 case40 and 2 cases,28 respectively. Other studies have also identified single cases of vulvar dysplasia or cancer, without risk determination.33,34,41 There are no available risk assessments for vaginal cancer after HCT due to its rarity; among all the studies we reviewed, only 1 case of vaginal cancer was detected post-HCT.42 We are unaware of any studies reporting on the rate of vulvar or vaginal dysplasias after HCT or identifying HCT-related risk factors for their occurrence.
Implications for Screening and Vaccination After HCT
Existing studies of Pap-detected cervical abnormalities after HCT have not captured any cervical cancers during their respective follow-up periods.22–25 This may be due to small sample sizes or the long latency from HPV infection to cervical cancer. Nonetheless, one may question whether abnormal Pap smears post-HCT reliably predicts cancer in HCT recipients without HPV DNA cotesting, because abnormal cytology can occur transiently from non–HPV-related causes such as conditioning therapy.25 Important but unaddressed implications exist regarding screening schedules in HCT recipients and whether these should differ from those recommended for the general population. The HPV DNA test is now incorporated into general cervical screening recommendations (Table 4).43 We contend that this test should also be part of screening for HCT survivors, potentially replacing cytology-only screening.
Currently, there are no official guidelines for cervical screening in women post-HCT, although consensus-based recommendations suggest Pap smears every 1 to 3 years,44–46 which is in contrast to the official recommendations of 3 to 5 years for the general population.43 It is unknown whether screening every 1 to 3 years is optimal in HCT survivors, or whether certain subsets of women—for example, those who have extensive vulvovaginal GvHD or who are on protracted immunosuppressive therapy post-HCT—would benefit from more regular screening, and how HPV DNA testing should be incorporated into follow-up strategies for high-risk individuals. For instance, should women who develop vulvovaginal GvHD—which affects at least 25% to 49% of women within 2 years after allo-HCT—be screened more regularly, given that the condition may increase the risk of HPV-associated neoplasms?24,47,48 A modified evidence-based cervical screening schedule already exists for immunocompromised women who are HIV-positive (Table 4).49 In a similar fashion, we hope that further research will help guide an evidence-based process to establish guidelines in HCT survivors.
Vulva- and Vagina-Related Findings on Secondary Cancers After HCT (1994–2016)
Official Cervical Screening Guidelines for Women With Routine Normal Findingsa
Finally, we highlight that a clearer understanding of the role of HCT in HPV acquisition and progression will inform vaccination guidelines in HCT survivors, for whom there are presently no immunogenicity or safety data regarding the HPV vaccine. Significant declines in the occurrence of high-grade cervical, vulvar, and vaginal neoplasms in multiple populations around the world have been attributed to the HPV vaccine.50 However, the rate of HPV vaccination has remained low in childhood cancer survivors, a group that may experience significant long-term benefits from the vaccine.2 A study in Texas found that female pediatric cancer survivors aged 13 to 17 years do not begin the 3-dose HPV vaccine series as commonly as the general population (36% vs 57%).51,52 Another study in Tennessee found that female pediatric cancer survivors aged 9 to 17 years were less likely to initiate (32.6%) or complete (17.9%) the HPV vaccine series compared with healthy age-matched controls (34.3% initiated and 20.0% completed).53 Thus, the effort to elucidate the incidence, risk, and risk factors associated with female lower genital tract neoplasms may provide clinical evidence of HCT-related risks critical to improving the rate of vaccine uptake among young eligible women.
Conclusions
Small clinical studies suggest that cervical dysplasia increases in women after allo-HCT. This observation is supported by our current understanding of the HPV-related causes of cervical carcinogenesis, a process that may be facilitated by immune dysregulation in the peri–and post–allo-HCT setting. But despite this finding, large population-based studies generally do not show a greater risk of subsequent cervical cancer in allo-HCT recipients compared with the general population. Post-HCT cervical dysplasia may indeed be the transient result of transplant conditioning rather than HPV progression, and even true HPV-related dysplasias often revert to a normal presentation upon HPV clearance.18 The occurrence of vulvar and vaginal neoplasms, being much rarer than their cervical counterparts, has not been adequately studied post-HCT. Further elucidating the role of HCT in the progression of female lower genital tract neoplasms will be an important step towards clarifying optimal screening and vaccination measures in vulnerable patients.
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