among HSCT recipients. The magnitude of risk of secondary malignancies after HSCT has been found to be increased four‐fold to 11‐fold compared to the general population. The estimated actuarial incidence is reported to be about 3–4% at 10 years, increasing to 10–12 % at 15 years after allogeneic HSCT [13, 14, 49‐53].
Risk factors for the development of secondary malignancies include exposure to chemotherapy and radiation before transplantation, use of TBI and high‐dose chemotherapy used in preparation for HSCT, infection with viruses such as Ebstein‐Barr virus (EBV) and Hepatitis B and C viruses (HBV and HCV), immunodeficiency after transplant, aggravated by the use of immunosuppressive drugs for prophylaxis and treatment of GVHD, including the use of monoclonal and polyclonal antibodies, HLA non‐identity, and T‐cell depletion, the type of transplant (autologous versus allogeneic), the source of hematopoietic stem cells used, and the primary malignancy. However, assessment of risk factors for all secondary malignancies in aggregate is somewhat artificial because of the heterogeneous nature of the secondary malignancies, with differing clinico‐pathological features, distinct pathogenesis, and hence very distinct risk factors associated with their development [13, 14].
Currently secondary malignancies after HSCT are categorized into three distinct groups: 1) myelodysplasia and acute myeloid leukemia, 2) lymphoma, including lymphoproliferative disorders and 3) solid tumors.
Secondary leukemia after allogeneic HSCT
Secondary leukemia in the setting of allogeneic HSCT refers to leukemia of donor cell origin or a new leukemia developing in surviving patient cells. Both are extremely rare complications, raising important questions on leukemogenesis. Recently, the Seattle team has suggested that transfer with the donor graft of otherwise silent malignant cells could also be responsible for leukemias arising from donor cells. However, no clear evidence links these secondary leukemias to cGVHD. Nevertheless, with increasing use of older donors (especially for patients receiving reduced intensity conditioning) special attention must be given to the search for hematological abnormalities in the donor and of clear need for donor’s surveillance.
The development of new leukemias in patient cells is most likely related to cytotoxic conditioning therapy; there is no evidence to support a role of cGVHD.
Lymphomas
Posttransplant lymphoproliferative disorders (PTLD) are the most common secondary malignancy in the first year after allogeneic HSCT. Most of these cases are related to compromise immune function and Epstein‐Barr virus (EBV) reactivation. The large majority of the PTLD have a B‐cell origin, though some T‐cell PTLDs have been described [54, 55].
Nevertheless, several cases of late‐occurring lymphomas have been reported in the literature. It is believed that these late‐occurring lymphomas represent an entity that is distinct from the early‐occurring B‐cell PTLD [56–59].
“Secondary” Hodgkin disease (HD) has also been observed among HSCT recipients. HSCT recipients followed as part of a large cohort study were at a six‐fold increased risk of developing HD when compared with the general population [60]. Most of the reported cases were of the mixed cellularity subtype, and most of these cases contained the EBV genome. These cases differed from the EBV‐associated PTLD by the absence of risk factors commonly associated with EBV‐associated PTLD, by a later onset (>2.5 years), and relatively good prognosis. The increased incidence of HD among HSCT recipients could possibly be explained by exposure to EBV and over‐stimulation of cell‐mediated immunity, but no clear evidence for a link with cGVHD has been established.
Solid Tumors[53]
Solid tumors have been described after syngeneic, allogeneic and autologous HSCT. The increase in the risk of solid tumors has ranged from 2.1‐fold to 2.7‐fold when compared to an age‐ and sex‐matched general population [61, 62]. The risk increased with increasing follow‐up, and, among those who survived 10 or more years after transplantation, was reported to be 8.3 times as high as expected in the general population. Types of solid tumors reported in excess among HSCT recipients, were those typically associated with exposure to radiation therapy, including melanoma, squamous cell carcinomas of the oral cavity and salivary glands, and cancers of the brain, liver, uterine cervix, thyroid, and breast, as well as sarcomas of the bone and connective tissues.
Pathogenesis
Little is known about the pathogenesis of solid tumors. An interaction of cytotoxic therapy, genetic predisposition, viral infection, and GvHD with the resulting antigenic stimulation and the use of immunosuppressive therapy, all appear to play a role in the development of new solid tumors [63,64].
Radiation‐related cancers generally have a long latency period, and the risk of such cancers is particularly high among patients undergoing irradiation at a young age. A large series reported an increased risk of brain and thyroid cancers after TBI given as part of myeloablative conditioning, though most of these patients had also received cranial irradiation prior to HSCT. Both thyroid cancer and brain tumors have been reported after exposure to radiation to the craniospinal axis and the neck when given as part of the conventional therapy for childhood acute lymphoblastic leukemia, HD and primary brain tumors. Similarly, osteogenic sarcoma and other connective tissue tumors have been recognized as secondary malignancies developing after radiation therapy in non‐transplanted patients. Those studies indicated a strong dose‐response relationship for radiation exposure, in addition to an increased risk with increasing exposure to alkylating chemotherapy agents. The increased risk of thyroid, breast, brain, bone and soft‐tissue malignancies seen after HSCT appear to be related, at least in part, to cumulative doses of radiation exposure, both as a result of the pretransplant treatment regimens, and the conditioning regimen used for transplantation.
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
