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Originally published as JCO Early Release 10.1200/JCO.2005.02.7052 on February 6 2006 © 2006 American Society of Clinical Oncology. Nonmelanoma Skin and Mucosal Cancers After Hematopoietic Cell TransplantationFrom the Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA Address reprint requests to Wendy Leisenring, ScD, Clinical Statistics, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D5-360, PO Box 19024, Seattle, WA 98109; e-mail: wleisenr{at}fhcrc.org
PURPOSE: To evaluate the incidence of and risk factors for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in survivors of hematopoietic cell transplantation (HCT). PATIENTS AND METHODS: The impact of patient-, disease-, treatment-, and toxicity-related factors on risk of BCC and SCC was determined in a retrospective cohort study of 4,810 patients who received allogeneic HCT and who survived for at least 100 days. RESULTS: Among allogeneic HCT recipients, 237 developed at least one skin or mucosal cancer (BCC, n = 158; SCC, n = 95). Twenty-year cumulative incidences of BCC and SCC were 6.5% and 3.4%, respectively. Total-body irradiation was a significant risk factor for BCC (P = .003), most strongly among patients younger than 18 years old at HCT (P = .02, interaction). Light-skinned patients had an increased risk of BCC (P = .01). Acute graft-versus-host disease (GVHD) increased the risk of SCC (P = .02), whereas chronic GVHD increased the risk of both BCC (P = .01) and SCC (P < .001). CONCLUSION: This analysis suggests that immutable factors, such as age and complexion, have a significant impact on BCC and SCC. However, specific treatment (radiotherapy) and transplantation complications (GVHD) may modify that risk. These additional risk factors suggest the contribution of immunologic mechanism DNA and tissue repair in the development of BCC and SCC. We confirm previous reports that exposure to ionizing radiation increases the risk of BCC but not SCC. Survivors of HCT should be monitored for the development of BCC and SCC and use preventive strategies.
Over the last three decades, the successful treatment of malignant and nonmalignant diseases with hematopoietic cell transplantation (HCT) has resulted in an increasingly large cohort of long-term survivors. With this increasing survival, understanding adverse long-term outcomes associated with HCT in general and the susceptibility of specific subpopulations in particular has become critical. With the knowledge gained, we may be able to appropriately modify treatment and develop more targeted long-term monitoring to reduce risks for the patient. One serious late complication of HCT is the occurrence of secondary malignant neoplasms (SMNs). The risk factors for SMNs after HCT have been described and have consistently included the use of total-body irradiation (TBI), underlying diagnosis, pre-HCT therapy, use of immunosuppressive agents, the occurrence of graft-versus-host disease (GVHD), age at HCT, and, for squamous cell carcinoma (SCC) of the buccal cavity and skin, male sex.1-4 These known risk factors support our hypothesis that inadequate repair mechanisms for dealing with the significant assault on cells as a result of radiotherapy and chemotherapy used in the conditioning regimens during HCT may play a key role in the increased risk for SMN. To further evaluate this hypothesis, we carried out an analysis that focused on skin and mucosal cancers, specifically basal cell carcinoma (BCC) and SCC. BCC and SCC of the skin represent the most common cancers in the United States, with more than a million patients diagnosed annually. Although the majority of these patients survive, they are at risk for multiple occurrences, which can lead to disfigurement and increased health care utilization.
Patients Data were available for 4,810 consecutive patients who underwent a transplantation with an allogeneic HCT at the Fred Hutchinson Cancer Research Center (FHCRC; Seattle, WA) or affiliated hospitals in Seattle between November 1969 and April 2003 and who survived at least 100 days after transplantation. Data available as of April 2004 were analyzed.
Conditioning Regimen and Post-Transplantation Treatment
Patient Follow-Up and Data Collection Clinical surveillance of HCT recipients treated at FHCRC was approved by the institutional review board, and patients signed informed consent for collection of long-term outcome data. Patient characteristics, HCT treatment regimens, and clinical outcome data were collected prospectively on patients and stored in the FHCRC clinical database. Patients underwent a comprehensive medical evaluation before discharge from the transplantation service. One year after the transplantation, patients were invited to return to Seattle for a comprehensive medical evaluation and again thereafter, if clinically indicated. Annually, both the physician and patient were sent health questionnaires to obtain current status data. Among surviving patients, 97% had last contact in the previous 5 years, and 95% had last contact in the last 4 years. The questionnaires inquired specifically about tumors or cancers that might have developed and how they were treated. All SMN cases were verified by physicians' reports, and whenever possible, pathology (and surgical) reports were obtained for confirmation. BCC and SCC were defined by standard histologic criteria.
Statistical Analyses
Of the 4,810 allogeneic transplantation patients, 2,445 are surviving at a median time of 9.7 years (range, 0.4 to 33.5 years) after transplantation, and 2,365 died at a median of 0.9 years (range, 0.3 to 31.9 years) after transplantation. The median age at transplantation for this cohort was 31.3 years (range, 0.3 to 72.6 years). Patient characteristics are listed in Table 1. There were 158 patients who developed at least one BCC at a median of 7.9 years (range, 0.5 to 30.2 years) after HCT and at a median age of 47.9 years (range, 12.6 to 72.3 years). Ninety-five patients developed SCC at a median of 6.3 years (range, 0.3 to 24.8 years) after HCT and at a median age of 48.9 years (range, 17.4 to 72.1 years). A total of 58 patients had more than one occurrence of nonmelanoma skin or mucosal cancer (39 patients had two cancers, and 19 had three cancers). Table 2 shows the cross tabulation of occurrence of multiple BCC and SCC events per patient. All 158 reported incidents of first BCC were of the skin. Among the 95 SCCs, 24 occurred on internal mucosal surfaces, such as the tongue, tonsil, vocal cord, esophagus, and genitourinary tract (cervix, vagina, and vulva), and the remainder occurred in the skin (n = 53) or at undefined sites (n = 18), possibly with skin involvement. Cumulative incidence estimates for BCC and SCC at 20 years after HCT were 6.5% (95% CI, 5.3% to 7.7%) and 3.4% (95% CI, 2.6% to 4.3%), respectively (Table 3; Fig 1).
In univariable Cox proportional hazards regression analyses adjusted for current age, we examined the impact of potential risk factors on development of BCC and SCC separately (Table 4). Younger age at HCT (< 10 years) significantly increased the risk of both BCC and SCC, with significantly decreased HRs for patients 10 to 17 (BCC only), 18 to 39, and  40 years of age. Use of a TBI-containing conditioning regimen was a significant risk factor for BCC but not for SCC. In an evaluation of dose response for TBI, a single-dose TBI regimen marginally significantly increased the hazard of BCC by 1.8-fold (95% CI, 1.2- to 2.6-fold) relative to a non–TBI-containing conditioning regimen, as did fractionated cumulative doses of 14 Gy (HR = 2.3; 95% CI, 1.5 to 3.6). Fractionation doses of less than 13.9 Gy did not significantly affect the hazard of BCC. Similarly, race/ethnicity was a significant risk factor for BCC but not for SCC. White patients had a 4.5-fold increased hazard of BCC relative to nonwhite patients (95% CI, 1.4- to 14.1-fold). Development of acute GVHD of grades 2 to 4 increased the risk of SCC (HR = 1.6; 95% CI, 1.1 to 2.5), and chronic GVHD increased the risks for both BCC and SCC (BCC: HR = 1.5; 95% CI, 1.1 to 2.1; SCC: HR = 2.8; 95% CI, 1.8 to 4.5). A primary diagnosis of leukemia or lymphoma also seemed to be associated with a significantly increased hazard of BCC or SCC relative to patients with nonmalignant diseases, although the effect of underlying disease was difficult to separate from that of TBI. After adjusting for current age, the risk of BCC was increased when more than 15 years had passed since HCT, whereas the risk of SCC was increased in patients with a follow-up time of more than 20 years (Table 4).
In the cohort of 1,183 patients who were less than 18 years of age at HCT, all 22 BCC incidents occurred among the 920 patients who received a TBI-containing conditioning regimen. Among the 3,574 adult patients (18 years or older), only 98 (74%) of the 133 BCC incidents occurred in the 2,558 patients who received a TBI-containing regimen (Fig 2). This disparity in effect of TBI suggests an interaction between age at HCT and TBI, and although a Cox model could not be fit to the data to test for this, an exact test for an interaction between the two factors was significant (P = .02, exact logistic regression). There was no evidence of such an interaction for SCC (Fig 3).
In multivariable analyses, age at HCT, TBI-containing conditioning regimen, race/ethnicity, and chronic GVHD remained significant risk factors for BCC. For the SCC outcome, age at HCT and acute and chronic GVHD remained significant risk factors in multivariable models (Table 5). Because there was evidence of an interaction between TBI and age at transplantation for BCC, we also fit a model limiting the analysis to patients over the age of 18 years and, for all factors, found results consistent with those seen in the model with data for all patients, although the impact of single-dose TBI was no longer significant, whereas increased fractionated dose was significant (data not shown). It was not possible to fit this model to data for the patients under the age of 18 years because of the complete agreement between TBI and BCC outcome.
Over the last few decades, the late consequences of cancer and its associated therapy have been subjects of great interest, particularly for survivors of HCT. This has been a natural result of the dramatic improvement in the long-term survival of patients who have received a transplantation, leading to more patients at risk for these events. However, the size and composition of the study populations, as well as the duration and completeness of follow-up, have often limited this research. This can restrict the ability to draw valid conclusions and may introduce selection or other bias within the studied populations. The FHCRC cohort presents an ideal cohort to study risk factors for these late-occurring second malignancies because of the excellent follow-up, with mechanisms in place for survivors or health care providers to report SMNs, including BCC and SCC. This research will permit a better understanding of the pathogenesis and will also permit development of strategies for both prevention and targeted surveillance for patients at highest risk. Radiation has long been known to be carcinogenic, and radiation-associated skin malignancies have been reported in atomic bomb survivors, uranium miners, radiologists, and individuals treated with radiation for benign or malignant skin disorders.12-22 In fact, the first evidence for ionizing radiation being a carcinogen in humans came from a 1902 case report of nonmelanoma skin cancers on the hands of early radiation workers.12 Nearly all reports point to a role of radiation in inducing almost exclusively BCC, with little evidence to suggest susceptibility to SCC as a result of radiation exposure. The results of our analyses showing single fraction and increasing fractional doses of TBI to increase the risk of BCC, but not SCC, are consistent with this data. These observations suggest that the basal skin layer of the epidermis is sensitive to radiation, and with increasing total doses, even interfraction intervals do not allow for complete repair. In contrast, a gamma irradiation effect was not seen for SCCs, which seem to be more common after ultraviolet (sunlight) exposure23 or exposure to various chemical agents.24 However, a common theme is the need for tissue and DNA repair. The focus of this analysis on skin and mucosal cancers was designed to explore the possible susceptibility of specific patients to damage caused by myeloablative therapy and its consequences. In the cohort of HCT survivors, a single etiologic agent is unlikely. Patients are exposed to ionizing radiation, cytotoxic chemotherapy, and immunosuppressive agents, all of which may share the etiologic limelight. In this cohort, acute GVHD increased risk of SCC, and chronic GVHD increased the risk of both BCC and SCC. This, in part, supports the data reported from a recent case-control study carried out by the FHCRC and the International Bone Marrow Transplant Registry, which identified the duration of chronic GVHD and its therapy as a major risk factor for SCC (BCC was not considered in that analysis).25 This association between BCC and SCC and GVHD or immunosuppressive therapy is not well understood. The role of host defense and inflammatory gene polymorphisms is currently being investigated with respect to the risk for GVHD but not to its sequelae.26,27 One may hypothesize that differences in immune response may play a role in GHVD and secondary carcinogenesis, although these may be mediated by an inability to repair DNA damage occurring as a consequence of the immune damage. This may be particularly important in BCC and SCC where there may also be abnormal inflammatory responses and cell turnover rates with a lack of appropriate DNA repair. Such a scenario would also be consistent with data suggesting an association between chronic inflammation and the development of cancer.28,29 Age at exposure was a significant effect modifier of response in the present study, similar to reports by others.30 In previous reports, individuals exposed to radiation at age less than 10 years showed 2 to 4 times greater risks than older individuals18,19,22; in general, the risk declined by 10% for each year of age.22 The differential effect of TBI on the younger patients in our study supports these findings, as well as those from reports on SMNs among childhood cancer survivors (mostly nontransplantation patients), where younger age at time of radiation exposure increased risk of SMN.31,32 These combined data suggest that children may have greater inherent radiation sensitivity. Latencies of cancer development in the current study were long, reaching significant incidences only between 10 and 20 years after exposure. In view of recent reports by Yasui et al,11 which show strong effects of attained age on the development of SMNs, this may be a result of young age at exposure. Furthermore, the rates of BCC development do not decline with time from HCT. Our analysis appropriately addresses this issue, as we accounted not only for age at diagnosis and years of follow-up, but also for the change in risk for BCC and SCC with attained age. In evaluating risk factors for second cancer, the question of which time scale to use in the analysis is an important one to consider. In additional analyses using time since HCT as the time scale, all of our results were consistent with those shown here, with the exception that increasing age at HCT seemed to incur an increasing risk of both BCC and SCC (data not shown). Because this was likely an artifact of the increasing risks of BCC and SCC with increased attained age, we elected to present results that appropriately adjust for current age, using age as the time scale for analysis. Indeed, when we examined only patients who had been observed for 15 to 20 years after HCT and compared risks of BCC within groups defined by age at HCT, the risk of BCC appeared higher for patients who were older at HCT and who had, therefore, reached a higher attained age (data not shown). This observation further substantiated our choice of time scale for the models. Metachronous tumor formation may be, in part, a result of the risk factors that are chronic (such as GVHD) or of the increasing incidence in the general population with older age. Because there is no defined population-based cancer registry to which BCC and SCC are reported, our ability to compare with age-matched peers is limited. One published article on BCC and SCC in New Hampshire reports incidence rates of BCC per 100,000 person-years of 8.7, 113.4, 276.4, and 532.9 among residents less than 35, 35 to 44, 45 to 54, and 55 to 64 years of age, respectively, during 1993 to 1994. Similar calculations from our cohort reveal rates of 189.2, 655.0, 1,103.8, and 1,886.2 per 100,000 person-years for patients less than 35, 35 to 44, 45 to 54, and 55 to 64 years of age, respectively, which is a three- to 22-fold increase over the New Hampshire data. The reported New Hampshire SCC incidence rates per 100,000 person-years were 0.3, 5.6, 30.1, and 98.2 for persons aged less than 35, 35 to 44, 45 to 54, and 55 to 64 years, respectively, whereas the incidence rates for SCC in the current cohort per 100,000 person-years were 87.5, 331.2, 551.5, and 1,304.3, respectively.33 Reports of secondary malignancies after HCT, including nonskin cancers, indicate a similar range of significant risk factors.2,34-38 BCC and SCC account for 90% of the skin cancer reported after solid organ transplantation.39 Etiologic risk factors include ultraviolet exposure, skin color, and level of immunosuppression. Somatic mutations in the tumor suppressor gene TP53 are frequently reported in these tumors, and for SCC, the human papillomaviruses seem to be cocarcinogens.39 The role of TP53 and human papillomavirus has been evaluated in a small number of SCC samples after stem-cell transplantation, and similar findings have been noted.40 A recent report from the Childhood Cancer Survivor Study showed a similar high rate of nonmelanoma skin cancer in the 5+ year survivors of childhood cancer, most of whom were treated with conventional chemoradiotherapy.41 Patients treated with radiotherapy had a 6.3-fold increase in risk of nonmelanoma skin cancer versus patients who had not received radiotherapy. One limitation of our study was that skin or mucosal cancers, particularly BCC, were likely underreported in the study population. Because patients with ongoing medical conditions, such as GVHD, are more likely to have contact with their physician and the FHCRC long-term follow-up department, patients without post-transplantation complications may be less likely to report skin or superficial mucosal cancers. If this were true, the resulting bias would inflate our estimates of association between these cancers and GVHD. Host risk factors, such as complexion, hair and eye color, family history of skin cancer, smoking, and ultraviolet light exposure, are important factors to evaluate in a study of this type. In a retrospective study such as this one, these data were not systematically collected for all patients. It is possible that, if adjustment for such factors were made, the associations shown here would be modified. However, this patient population is one of the largest and longest followed in the world and, therefore, provides a unique opportunity to evaluate long-term sequelae to HCT such as BCC and SCC. With identification of such a large cohort of secondary BCC and SCC, future analyses will focus on host, tumor, and environmental factors. In conclusion, HCT survivors should be closely monitored for skin and mucosal surface cancers. This is particularly true for patients who are white, were young at the time of transplantation, were treated with TBI, and were treated for GVHD. Such surveillance is relatively noninvasive and, thus, cost effective compared with surveillance for other second cancers for which they are also at risk. Regular skin and mucosal examinations by health professionals, as well as self-examinations, should be emphasized together with promotion of healthy behaviors such as avoidance of excess sun exposure, not smoking, and not consuming alcohol in excess. Further research on other risk factors, such as family history of cancer, tobacco and sun exposure, location of tumor with respect to sun exposure, the role of human papillomavirus and TP53, inherent radiosensitivity, and deficits in DNA repair, is required to better understand the etiology of these cancers and to develop more targeted preventive and surveillance strategies.
The authors indicated no potential conflicts of interest.
We thank our patients; Judy Campbell, Carina Moravec, Heather Hooper, Colleen Mckinnon, and the Long-Term Follow-Up staff of the Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance; and Gary Schoch and Linda Glockling for data collection and management.
Supported by Grants No. HL36444, CA18029, CA102542, and CA15704 from the National Institutes of Health, Bethesda, MD and Grant No. DE-FG03-003462908 from the Low Dose Radiation Research Program, Biological and Environmental Research, US Department of Energy. Presented in part at the 45th Annual Meeting of the American Society of Hematology, San Diego, CA, December 6-9, 2003. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
