Immunologic impairment may predispose patients to the development of squamous cell carcinoma of the oral cavity and skin, particularly in the context of cGVHD. These tumors have been observed particularly in patients with aplastic anemia conditioned with limited field irradiation or treated with Azathioprine for cGVHD [65]. In immune suppressed patients, oncogenic viruses, such as human papillomaviruses, may contribute to squamous cell cancers of the skin and buccal mucosa. The observed excess risk of squamous cell cancers of the buccal cavity and skin in males is unexplained but may be indicative of an interaction between ionizing radiation, immunodeficiency, and, conceivably factors such as smoking habits or alcohol consumption.
Patients with a family history of early‐onset (< age 40 years) cancers are at an increased risk for developing secondary cancers, and genetic predisposition is likely to have a substantial impact on the risk of secondary cancers. Studies exploring genetic predisposition and gene‐environment interactions have focused thus far on patients exposed to nontransplant conventional therapy for cancer. Future studies are needed in the transplant population to understand how genetic predisposition interacts with myeloablative chemotherapy, TBI and the attendant posttransplant immunosuppression, thereby leading to secondary solid tumors.
Skin and mucosal carcinoma and cGVHD
As already implied above, transplant recipients with cGVHD have an especially high risk of developing squamous cell carcinoma (SCC) of the oral cavity and skin, with rather aggressive behavior being noted for some of these tumors. Among solid organ transplant recipients, the frequency of rejection episodes (requiring intensified immunosuppression) and the duration of immunosuppressive therapy strongly correlate with the occurrence of skin cancer. Patients undergoing HSCT, in contrast to solid organ recipients, generally receive immunosuppressive therapy only for limited periods of time, unless they develop cGVHD. Thus, prolonged immunosuppression and (persistent) cGVHD are usually linked. A case‐control analysis in HSCT recipients was designed to quantify the association of GVHD and its therapy with the development of secondary SCC (including those of the oral mucosa) [65]. This case‐control study included 183 patients with posttransplant solid cancers (58 SCC, 125 non‐SCC) and 501 matched control patients within a cohort of 24#011 patients who received HCT at 215 centers worldwide. Results showed that cGVHD and its therapy were strongly related to the risk of SCC, whereas no such increase in risk was found for non‐SCC cancers. Long duration of cGVHD therapy (p=0.0001), the use of Azathioprine, particularly when combined with CSP and steroids (p= 0.0002), and the severity of cGVHD (p=0.004) were identified as major risk factors for the development of SCC. Since Azathioprine was mostly used in patients who received prolonged immunosuppressive therapy and had severe cGVHD, the independent effects of these factors could not be evaluated. Consistent with a previous cohort study, there was no evidence that cGVHD or duration of therapy were related to the development of non‐SCC solid cancers.
In a separate study, the Seattle group evaluated the incidence of and risk factors for basal cell carcinoma (BCC) and SCC in survivors of HSCT [66]. Patient‐, disease‐, treatment‐, and toxicity‐related factors were analyzed in regards to the risk of BCC and SCC in a retrospective cohort study of 4810 patients who received allogeneic HSCT and who survived for at least 100 days. Among allogeneic HSCT recipients, 237 developed at least one skin or mucosal cancer (BCC, n#=#158; SCC, n#=#95). Among the 95 SCC, 24 occurred on internal mucosal surfaces, such as the tongue, tonsil, vocal cord, esophagus, and genitourinary tract (cervix, vagina, and vulva). Twenty‐year cumulative incidence rates of BCC and SCC were 6.5% and 3.4%, respectively. TBI was a significant risk factor for BCC (but not for SCC), most strongly among patients who were younger than 18 years at HSCT. Light‐skinned patients had an increased risk of BCC. Acute GVHD was associated with increased risk of SCC, and cGVHD with both BCC and SCC. Thus, this analysis suggested that immutable factors, such as age and complexion, have a significant impact on the development of BCC and SCC. However, specific treatment modalities (radiotherapy) and transplant‐related complications (GVHD) may modify the risk. These additional risk factors suggest a contribution of immunologic mechanism and DNA and tissue repair in the development of BCC and SCC. Overall, these data confirmed previous reports which showed that exposure to ionizing radiation increased the risk of BCC but not SCC.
The major predisposing factor for cGVHD is preceding acute GVHD, i.e. a syndrome characterized by alloreactivity and immunodeficiency. The immunodeficiency is further aggravated by the treatment of cGVHD, which may continue over several years. However, cGVHD, which most frequently affects the skin, liver, mouth and eyes, also shows features of autoimmunity and inflammation. Both aspects are relevant since patients with autoimmune disorders develop malignant tumors more frequently than individuals with apparently normal immunity. Chronic inflammation and scar formation have also been associated with an increased risk of cancer. The interactions between inflammation and immunosuppression are not fully understood, but one might speculate that immunosuppression administered in a milieu of inflammation as occurs with cGVHD, would interfere with tissue repair, and thereby enhance the risk of tumor evolution. The risk would be further heightened when immunosuppressive therapies were given for prolonged periods, as observed in previous investigations in solid organ transplant recipients. If immunosuppression consisted of compounds which are known carcinogens then one would also expect new malignancies in recipients of HSCT, which has been reported, in fact, in patients with severe aplastic anemia. In addition, it suggests that other components; in particular interactions with agents, such as CSP, and the duration of treatment and severity of cGVHD are contributing factors. Reports from the early 1980s suggested that cyclosporine, in many instances given at doses much higher than in use today, contributed to the development of malignancies, in particular posttransplant lymphoproliferative disorders. More recent work suggests that cyclosporine may induce phenotypic changes and enhance invasiveness of non‐transformed cells via a TGF β‐dependent mechanism. Finally, it should be noted that Mycophenolate Mofetil (which has largely replaced Azathioprine in the treatment of cGVHD) has a mechanism of action similar to Azathioprine and could, thus, represent a potent risk factor in the future!
Thyroid carcinoma and cGVHD
While thyroid carcinoma is generally considered a prototype of radiation‐induced carcinoma, data from the European group strongly suggest that cGVHD may play a role in the genesis of this cancer. We performed a retrospective analysis comparing data obtained by means of a two‐step questionnaire from the 166 centers who replied, and data reported to the European Group for Blood and Marrow Transplantation (EBMT) registry on their transplantation activity [67]. During the follow‐up period (1985 to 2003), 32 instances of thyroid carcinoma were found within the EBMT cohort of 68#936 patients who received HSCT. The standardized incidence ratio of thyroid carcinoma in the transplant population was 3.26, in comparison with the general European population. Multivariate analysis revealed that young age at HSCT was the strongest risk factor (relative risk [RR], 24.61 for ages 0 to 10 years; RR, 4.80 for ages 11 to 20 years). Other risk factors were irradiation (RR, 3.44), female sex (RR, 2.79), and cGVHD (RR, 2.94). Nine patients showed no clinical signs of thyroid disease at diagnosis. Total thyroidectomy and iodine ablation were the standard treatment for the majority of patients, and only one patient died due to cancer progression.
References
1 1. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project