The etiology of cancer in childhood is multifactorial. An important factor that contributes to an increased incidence of cancer in children is the presence of underlying immunodeficiency, either inherited or acquired.1
Improved treatments and supportive care as well as allogeneic HCT for the PIDD have resulted in significant improvements in survival for these children. The Immunodeficiency-Cancer Registry was set up in 1973 to track the incidence of cancers in patients with PIDD. As of August 1986, 514 cases of malignancy had been registered in patients with PIDD. Of these, almost half were non-Hodgkin lymphoma, with leukemia or Hodgkin disease accounting for another 20% of cases. Nine percent of the cases were adenocarcinomas and other tumors accounted for the remainder. Although over half of these tumors occurred in patients with Ataxia-Telangiectasia (AT) (30%) and common variable immunodeficiency (24%), about 25% were seen in patients with the WAS and SCID.7-9
A recent analysis of data reported to the Australasian Society of Clinical Immunology and Allergy PID Registry showed that while there was a 1.6-fold excess relative risk of cancer observed for PID patients, the standardized incidence ratio (SIR) was 5.36-8.82 for non-Hodgkin lymphoma, leukemia and stomach cancer. The SIRs for all cancers were significantly increased in patients with CVID and AT.10
Patients with leukemia or aplastic anemia who have undergone bone marrow transplantation are at a significantly higher risk of developing a secondary cancer compared to age-matched healthy controls.11
In a recent analysis of over 18,000 BMT recipients by Curtis et al., the cumulative incidence of a PTLD was 1.0 ± 0.3% at 10 years after HCT with the highest incidence in the first 5 months post-HCT.12
Patients with non-Hodgkin lymphoma, Fanconi anemia and PIDD were excluded from this analysis.
Although our analysis can only serve to assess the risk factors that contribute to the development of a malignancy post-HCT for PIDD, the overall incidence of malignancies in transplanted PIDD patients (52/2266 or 2.3%) is lower than what has been reported in previous reports of patients with PIDD. LPD constitute the most frequent malignancy in patients with PIDD, especially those with WAS, common variable immune deficiency, AT and SCID. It has been estimated that the risk of malignancy in WAS, CVID and AT may be 100 times that of the general population. Since patients with SCID invariably die in infancy or early childhood without successful HCT, there is little data on long-term incidence of malignancies in non-transplanted patients. However, the median survival of patients with WAS who do not undergo HCT has been estimated to be in the late teens. Two large analyses of WAS patients by Perry et al. and Sullivan et al.13,14
reported development of a malignancy in 12 and 13% amongst 301 and 154 WAS patients respectively.
Of the 52 malignancies reported here, 45 (87%) were lymphoproliferative disorders. In the report by Curtis et al. discussed above, the risk of early PTLD was strongly associated with TCD of donor marrow (RR = 12.7), and use of ATG (RR = 6.4) or anti-CD3 monoclonal antibody (RR = 43.2) for prophylaxis or treatment of acute GVHD.12
In our analysis, TCD clearly contributed as a significant risk factor for the development of LPD. Since the most frequent malignancies/lymphoproliferative disorders reported in non-transplanted patients with PIDD are LPD,15,16
it is difficult to assess the relative contributions of the underlying immune deficiency, the preparative regimen and the TCD to LPD development. However, the median time of 3 months between the HCT and the LPD is very similar to the findings of Curtis et al.12
and suggests that the TCD was an important contributory risk factor. There was no correlation between incidence of PTLD and year of transplant (data not shown). EBV monitoring was not routinely available for the majority of patients transplanted during the period covered by this report. Of the 52 patients reported here, 40 died after developing a malignancy/ lymphoproliferative disorder with the majority of the deaths being attributed to the malignancy. With routine monitoring for EBV reactivation with EBV PCR and pre-emptive therapy, future analyses may allow us to assess the impact of these approaches on the incidence and survival of post-transplant lymphoproliferative disorders in these patients.
An analysis of 19,229 patients who had received allogeneic or syngeneic transplants for acute and chronic leukemias and a number of non-malignant diseases identified a cumulative incidence of new solid cancers of 2.2 % at 10 years and 6.7 % at 15 years. The use of TBI and the presence of chronic GVHD were associated with a higher risk of solid cancers and there was a trend toward an increased risk of solid cancers over time with younger patients having the greatest risk of developing solid cancers post-HCT.17
However, patients with Fanconi anemia and primary immune deficiencies were excluded from this analysis because of their inborn susceptibility to cancer. In a separate analysis of 700 patients with severe aplastic anemia including 79 with Fanconi anemia, Deeg et al. reported 23 malignancies post-HCT. There were 5 cases of lymphoid malignancies at a median of 3 months post-transplant and 18 cases of solid tumors at a median of 99 months post-HCT. In this analysis, the most significant risk factor for solid tumors was Fanconi anemia, consistent with the known risk of solid tumors in non-transplanted Fanconi anemia patients.18
There are a number of limitations to our analysis that need to be acknowledged. Centralized histopathologic examination of archived tissue or slides on each of the patients would have been the ideal way to confirm the occurrence of a malignancy. Since a large number of these patients had been diagnosed over 20 years earlier, it was considered impracticable to retrieve these specimens and we chose to review clinical and pathology reports to confirm the malignancy. Secondly, although data are available for the risk of malignancy in a cohort of age-matched healthy children, the true comparator for our cohort of patients with primary immune deficiencies would have been a similarly sized cohort of patients with PIDD who have not undergone transplantation. Unfortunately, reliable data on such a cohort are not available. For assessment of the impact of HCT on the risk of malignancy in PIDD, one has to thus rely on early data from the Immunodeficiency-Cancer Registry and data compiled through multi-institutional surveys of patients with Wiskott-Aldrich syndrome.
We conclude from this analysis that patients with primary immune deficiencies who undergo hematopoietic cell transplantation appear to be at a relatively low risk of developing malignancies compared to the historical risk of cancer in these patients. The most frequent malignancy/lymphoproliferative disorder seen in this cohort of patients is that of early-onset PTLD and as has been noted for other HCT recipients, the use of TCD appears to correlate with the development of PTLD post-transplantation.