An increased risk of developing malignancy has been observed following solid organ transplantation, with rates and malignancy type closely related to the transplanted organ. The most common neoplasms encountered are non-melanoma skin cancers (NMSC). Significant increases in incidence of other common malignancies such as lung, breast, and renal cell carcinomas are consistently reported as well 1 . While posttransplant lymphoproliferative disorder (PTLD) is one of the more common malignancies developing in solid organ transplant recipient, angiosarcoma is rare in this setting. We describe two patients diagnosed with concomitant PTLD and angiosarcoma following solid organ transplant.

An increased risk of developing malignancy has been consistently observed following solid organ transplantation, with rates and malignancy type varying on the transplanted organ 1 . Non-melanoma skin cancers (NMSCs) are the most common malignancy in transplant recipients and affect up to 10-45% of transplant recipients, depending on race and ultraviolet light exposure 1 . Squamous cell carcinoma is the most common NMSC. Recipients of renal transplants, the most common solid organ to be transplanted, are the best studied to date in the context of post-transplant malignancies. In renal transplant recipients, the incidences of the most common cancers (colon, lung, prostate and breast) are roughly two-fold higher in the first 3 years after kidney transplantation, when compared to the general population 2 . Kaposi’s sarcoma and non-Hodgkin’s lymphoma are more than 20-fold higher than in the general population. When compared to patients on transplant waiting lists, several malignancies rates are more common: NMSCs (2.6-fold), melanoma (2.2-fold), Kaposi’s sarcoma (9.0-fold) and non-Hodgkin’s lymphoma (3.3-fold). Angiosarcoma is not reported as a unique entity in these studies and is included in the non-skin malignancies not otherwise specified (NOS) category which accounts for about 3% of the malignancies developing in the first 3 years following kidney transplant.

The relative rate of each post-transplant malignancy varies depending on the transplanted solid organ. In 2011, the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients reported a 2% incidence of PTLD at 5 years post renal-transplant in EBV-negative adult recipients 3 . Following liver transplant, the rate of PTLD is 10.2% at 5 years, with slightly higher rates in EBV-negative recipients. In contrast, PTLD following heart transplant is relatively infrequent in adult recipients and closely linked to EBV status. Risk of malignancy of any kind is especially high following lung transplant and has been reported to be as high as 15.4% at 5 years post-transplant. These observed differences in risk may be due to variations in length and type of immunosuppression given to recipients of the various solid organs.

Immunosuppression is often cited as the etiology of the increased risk of malignancy, possibly by conferring susceptibility to viruses implicated in oncogenesis such as EBV, herpes simplex, herpes zoster, HHV8 and polyoma virus 4 . Other potential mechanisms include direct oncogenesis by the immunosuppressive agents themselves; for example, the chromosome breaks and nuclear abnormalities observed with azathioprine use 5 . Hepatic angiosarcoma developing following an extensive cyclophosphamide exposure was reported in a patient treated for polyarteritis nodosa 6 . In kidney transplant recipients, immunosuppression with cyclosporine did not confer added risk when compared with azathioprine/steroid treatment, whereas treatment with tacrolimus has been shown to increase the risk approximately two-fold. Induction or anti-rejection therapy with OKT3 or ATG increases the risk of lymphoma during the first post-transplant year 7 .

Sarcomas are uncommon mesenchymal malignancies and comprise less than 1% of malignant neoplasms in adults. 80% of them arise in soft tissues 8 9 . Angiosarcoma is an uncommon type of soft tissue sarcoma, which may rise in a variety of tissues or organs. A well-documented risk factor for developing angiosarcoma is therapeutic radiation, such as the risk observed 8–10 years after breast radiotherapy 10 . Angiosarcoma has a propensity for early metastases and often presents with an aggressive biologic behavior. In a series of 67 patients with angiosarcomas, the actuarial 5 year disease-free-survival is 35% and the 5 year overall survival is 24% 8 . In another series of 82 patients with angiosarcoma, the five-year disease-specific survival is found to be 60%, with negative prognostic variables including higher tumor grade and tumors arising in areas of lymphedema or prior irradiation 9 . Similar to the majority of soft tissue sarcomas, the mainstay of therapy is complete surgical resection of the tumor, if operable. Adjuvant therapies such as post-operative radiation to the tumor bed with wide margins are offered to patients with tumors larger than 5cm or to those with positive surgical margins 11 . The role of adjuvant chemotherapy remains controversial in soft tissue sarcoma due to lack of consistent survival benefit in studies published to date 12 . Newer studies evaluating paclitaxel and bevacizumab in patients with unresectable or metastatic angiosarcoma suggest a possible role for these to treat angiosarcoma 13 14 .

Post-transplant angiosarcomas are rare and, to date, have been reported in less than 20 solid organ transplant recipients. In a single-institution prospective database encompassing 1,570 liver transplantations in 1,421 patients from 1985 to 1999, 125 patients (8.8%) developed de novo tumors, one of them being angiosarcoma 15 . The majority of reported patients with post-transplant angiosarcoma have been renal transplant recipients with tumor frequently developing at the site of a previously placed arterio-venous fistula 16 . An association has been suggested between angiosarcoma and oncoviruses, such as HHV-8, following detection of a viral sequence in the DNA of a primary angiosarcoma 17 . This association remains controversial, as others have failed to detect similar sequences in either primary 18 or in post-transplant angiosarcoma 19 . In a series of 3 patients with PTLD reported by Webster et al., 2 of the patients have PTLD as well as angiosarcoma 16 . In this series, 1 patient has been identified with an EBV-positive tumor and a second with an elevated EBV titer at the time of diagnosis of disseminated angiosarcoma. The 2 patients in our paper both had angiosarcomas diagnosed following a prior diagnosis of PTLD, and 1 had a positive EBV titer detected at the time of angiosarcoma diagnosis. Both angiosarcomas were found to be negative for HHV-8 immunostaining.

In summary, the few reported patients with angiosarcoma and PTLD vary in type of transplanted organ, immunosuppression therapy and in seropositivity for a possible oncogenic virus. While the possible association of the rare post-transplant angiosarcomas with PTLD may suggest the presence of underlying host variables predisposing the recipients to develop post-transplant malignancies, these are yet to be defined. Assessment of genetic abnormalities in these tumors in the future may inform the possible susceptibility conferring host variables.

PTLD: Posttransplant lymphoproliferative disorder; EBV: Epstein-Barr virus; ATG: Anti-thymocyte globulins; STS: Soft tissue sarcoma; MRI: Magnetic resonance imaging; CT: Computed tomography; PET: Positron emission tomography; FDG: Fludeoxyglucose; PCR: Polymerase chain reaction; NMSC: Non-melanoma skin cancers.

The authors declare that they have no competing interests.

LB compiled the clinical data, reviewed the literature and drafted the manuscript. DS provided clinical data, reviewed, and edited the manuscript. HHH provided the pathologic data, reviewed and edited the manuscript. KK offered conceptual advice, guided the composition process, and reviewed and edited the manuscript. All authors read and approved the final manuscript.