Along with graft vasculopathy, malignancies com­prise a major complication after heart transplant, with a rate of occurrence of 39.1% in 10 years. Skin cancers and posttransplant lymphoproliferative disorder are more common in adults, whereas lymphoma is more often shown in children. A major cause of malignancies after heart transplant is the use of increased doses of prophylactics needed during immunosuppressive therapy. Data, however, are scarce regarding the association between a particular immunosuppressive drug and a post­transplant malignancy. Compared with the general population, recipients have a higher incidence of malignancies after heart transplant, with an early onset and more aggressive disease. Solid tumors known to occur in heart transplant recipients include lung cancer, bladder and prostate carcinoma, adenocarcinoma of the oral cavity, stomach cancer, and bowel cancer, although the incidence is rare. The risk factors for development of a malignancy after heart transplant are the same as for the nontransplant population.

Key words : Transplants, Lymphoma, Immunosuppression

Introduction

Heart transplant is the best treatment for patients of all ages with end-stage heart disease resistant to medical or conventional surgical therapy.^1,2 The first successful human heart transplant was performed in Australia in 1967.³ Heart transplants are the third most common organ transplant procedure conducted in any transplant center.^4,5 With the advent of potent immunosuppressive therapies and evolution of posttransplant patient care, the survival rates of recipients and grafts have improved significantly, turning concern to long-term complications.⁶

Posttransplant malignancies and graft vascu­lopathy are the two major long-term complications and causes of death in heart transplant patients. Advanced age, male sex, preexisting malignancy, immunosuppressive therapy, and oncogenic viral infection are causes of cancer in heart transplant recipients.^7-10 According to the International Society of Heart and Lung Transplant, the cumulative prevalence of malignancy in heart transplant patients at 1 year is 2.9% and at 10 years is 31.9%. Skin cancers and posttransplant lymphoproliferative disorder are the two most common malignancies shown in adults,11 whereas lymphoma is the only reported cancer in pediatric patients, with a likelihood of occurrence of 8% at 10 years after transplant.¹²

Here, the different types of cancers that occur in heart transplant patients are discussed to highlight their mechanisms and causes.

Indications for Heart Transplant
Rinaldi and associates13 and Goldstein and associates¹⁴ have both presented considerable data regarding neoplastic diseases in cardiac transplant patients. In light of their studies, cardiomyopathy was identified as the single most important pathology leading to cardiac transplant. However, the cause is varied, with dilated, ischemic, valvular, and idiopathic cardio­myopathy all possible reasons for heart failure.

According to the Scientific Registry of Transplant Recipients,¹⁵ indicators other than cardiomyopathy for transplant are ischemic heart disease, hypertrophic heart disease, severe decompensated inoperable valvular heart disease, congenital heart disease, and any other cardiac abnormality that would severely limit normal function and/or have a mortality risk of greater than 50% at 2 years.

Role of Immunosuppressive Therapy in Malig­nancies After Heart Transplant
Among the causes of malignancies after heart transplant, as already mentioned above,^7-10 immuno­suppression is the dominant cause and is largely responsible for the increased risk of malignancy development after heart transplant.¹³

Different types of drugs are used for immuno­suppressive therapy in heart transplant patients, each with a different role during treatment. As reported by Rinaldi and associates,¹³ the intensity of immunosuppression used to prevent and treat rejection is directly proportional to the adverse effects and posttransplant malignancies.

Tacrolimus
Tacrolimus has been shown to have an incidence rate and pathologic features regarding malignancies after transplant similar to other immunosuppressive regimens.¹⁵ In a univariate analysis that included data from the Spanish Post Heart-Transplant Tumor Registry, the incidence of skin cancer with the use of tacrolimus was lower in the first 3 months after heart transplant. However, these results were not sta­tistically significant in the multivariate analysis.¹⁶ In contrast, Chen and associates⁶ linked tacrolimus with an increased risk of posttransplant malignancies.

Cyclosporine
Cyclosporine acts by blocking calcium-activated calcineurin by binding to cyclophilin. Penn¹⁵ reported that there is little difference in prevalence of tumor and its subclassification in patients treated with cyclosporine versus those treated with tac­rolimus or azathioprine-based regimens. Several studies have even suggested that cyclosporine might produce a lower incidence of cancers.^17,18 In contrast, several groups have reported that cyclosporine use is associated with higher incidences of lymphoma and Kaposi sarcoma.^19,20 Similarly, Wilkinson and associates²¹ also reported increased incidence of cancers with high doses of cyclosporine.

Mycophenolate mofetil
Mycophenolate mofetil is an inhibitor of inosine monophosphate dehydrogenase and a selective inhibitor of lymphocyte proliferation. The Spanish Post Heart-Transplant Tumor Registry data showed that mycophenolate mofetil is associated with a lower incidence of skin cancer.¹⁶

Azathioprine
Azathioprine has known potential cancerous effects. The average dose of azathioprine is associated with an increased risk for cancer occurrence. The Spanish Post Heart-Transplant Tumor Registry data also showed that azathioprine increases the risk of cancers, particularly of skin.¹⁶

Muromonab-CD3
Induction with muromonab-CD3 increases the risk of skin and other nonlymphoma neoplasias.¹⁶ However the role of muromonab-CD3 in causing lymphoma is still debatable. Swinnen and associates²² and Rinaldi and associates¹³ reported an increase in lymphoma incidence with the use of muromonab-CD3, whereas Crespo-Leiro and associates¹⁶ and many others^23-25 found no significant difference.

Malignancies after heart transplant
The risk of malignancy is much higher in heart transplant recipients than in other types of solid organ transplant recipients owing to the greater intensity of immunosuppression used pro­phylactically.^13,14

Skin cancer
Skin cancers are the most common malignancies that occur in transplant recipients,²⁶ comprising about 42% to 50% of the overall malignancies seen after heart transplant.²⁷ The mean interval between transplant and diagnosis of a skin tumor correlates with the age at transplant. Overall, patients greater than 50 years old have an earlier onset versus those who are younger.⁹

The pathogenesis of skin cancer is multifactorial, with extrinsic and intrinsic factors both playing roles in malignancy development. Ultraviolet radiation appears to be the most important responsible factor,⁶ as skin cancers are likely to develop on sun-exposed areas and in transplant recipients with high sun exposure after transplant (> 10 000 hours).^28,29 The incidence of skin cancer is proportional to the level of immunosuppression, with rejection episodes in the first year resulting in higher incidence.⁸ They are more frequent in individuals with fair skin (Fitzpatrick scale type II), blue eyes, or blonde or red hair.^27,28,30 The probability of developing skin cancer in heart transplant patients increases with time,¹⁶ with no sex predominance.³¹

Carcinomas are the most common cancers seen in heart transplant patients, with squamous cell carcinoma being the most common form.³² Most lesions that develop as a result of squamous cell or basal cell carcinoma occur on the head and neck (70%), with the remainder on the trunk (9%), upper limbs (17%), and lower limbs (4%).³³ In heart transplant patients, squamous cell carcinoma occurs 65 to 250 times more frequently than in the general population, whereas the risk of developing basal cell carcinoma is 10 times more than the general population.³² The ratio of squamous cell to basal cell carcinoma in patients without transplant (1:4) is reversed in transplant recipients.³¹ Accordingly, squamous cell carcinoma is more aggressive in transplant recipients than in the general population, with transplant patients more likely to have an increased number of primary tumors. This tumor burden increases the disease severity, deep tissue spread, and perineural and lymphatic invasion and recurrence, owing to an infectious cause with higher level of human papillomavirus DNA in squamous cell carcinoma.^34,35 Also, solar keratosis and older age are more common in patients with squamous cell carcinoma versus those without the disease.³³

After carcinoma, another common skin cancer is melanoma, which occurs mainly in patients with fair complexion, light hair and eyes, and a tendency to freckle. After heart transplant, the risk of melanoma increases by a factor of 1.633. Also, early metastasis of melanoma is a cause of death in patients who develop this disease after heart transplant.³³

Kaposi sarcoma
The incidence of Kaposi sarcoma is much higher in transplant recipients than in those who have not had a transplant,³¹ with incidence ranging from 0.41% to 1.2%.¹³ For heart transplant recipients, the mean age of diagnosis is 43 to 47 years; which is still younger than those with classic Kaposi sarcoma.^8,14 Also, the log time of developing cancer after transplant is shorter, with a mean of 12 to 14 months.^13,14 Infection with human herpesvirus 8 has been established as the cause of this cancer, and immunosuppression plays a key role in this context.⁸ Penn found that 60% of Kaposi sarcoma cases were nonvisceral (98% skin lesions, 2% mouth or oropharyngeal), with the remaining 40% being visceral, mainly involving the gastrointestinal tract, lungs, and lymph nodes.³⁶

The prognosis of Kaposi sarcoma is very poor, with a mean survival of 23.6 months after diagnosis. Death occurs either directly from the disease or from acute rejection seen in its disseminated forms.³⁶

Posttransplant lymphoproliferative disorder
Posttransplant lymphoproliferative disorder is the second most common cancer in heart transplant recipients¹⁴ and the most common cancer in pediatric heart transplant recipients.¹² Most cases of post­transplant lymphoproliferative disorder occur within 1 year after heart transplant.¹⁵ The incidence of posttransplant lymphoproliferative disorder in heart transplant patients is 1.5% to 11.4%, which is higher than results shown in many other types of allografts.³⁷ However, this incidence is independent of factors like age and sex and does not increase with time, which is in contrast to other cancers seen after heart transplant.^22,38 Infection with Epstein-Barr virus plays a significant role in the pathogenesis of posttransplant lymphoproliferative disorder, and the reason for young age (< 5 y) being a risk factor for this disease is the naivety of the immune system to Epstein-Barr virus. In adults, transplant from an Epstein-Barr virus seropositive donor is a cause for this disease.^16,39 Aggressive immunotherapy with muromonab-CD3 is harmful for any age group as it increases the risk for posttransplant lympho­proliferative disorder.³⁸

In contrast to the general population, post­transplant lymphoproliferative disorder in transplant recipients involves both nodal and extranodal sites. Liver, lungs, central nervous system, intestines, kidneys, and spleen are the common extranodal sites involved, with gastrointestinal and respiratory tracts being the most common sites in pediatric heart transplant recipients.40 Survival rates in patients with posttransplant lymphoproliferative disorder are reassuring,⁴¹ with reduction in immunosuppression and use of rituximab being the factors responsible for better survival.³⁶

Solid tumors
Solid tumors are relatively uncommon compared with cutaneous cancers and lymphomas but are no less responsible for complications and death.

Lung cancer
Lung tumors are the most common solid-organ cancers occurring after heart transplant. The greatest risk factors for disease development are heavy smoking within 10 years of transplant and advanced age.⁴² It is thought that smoking causes alterations in the immune response, which along with pharmaco­logic immunosuppression results in cancer development. Carcinoma is the most common type of lung tumor seen after heart transplant, but mesothelioma and carcinoid tumors have also been reported.^13,14,43

The mean interval from transplant to a diagnosis of lung malignancy, as reported by Goldstein and associates,¹⁴ is 35.7 months. Prognosis for patients with lung cancer is poor, with most dying within the first year after diagnosis. Accelerated tumor growth and metastatic spread, with consequently advanced stage of the disease at time of diagnosis, are the main causes for this dramatic mortality rate.^14,44

Urologic malignancies
Regarding de novo solid malignancies after heart transplant, Goldstein and associates¹⁴ reported an incidence of 0.79% for prostate and bladder cancers in patients at risk. Bladder malignancies are one of the most aggressive in heart transplant patients, with a greater incidence among transplant recipients versus the general population⁴³ and heavy smoking after transplant being a risk factor. The increased risk of prostate cancers was found to be due to high circulating levels of testosterone along with high sexual activity.

Adenocarcinoma is the most common type of prostate cancer, whereas in cases of urinary tract involvement papilloma is more common.^13,14,43 The mean interval between transplant and diagnosis of tumor is 36.5 months, and mean survival rate after diagnosis and treatment is 27 months. Metastasis of prostate cancers further jeopardizes this survival rate.^13,14

Gastrointestinal tract malignancies
Oral cavity, stomach, and bowels are the common sites for gastrointestinal involvement; however, involve­ment of tongue and peritoneum also has been reported.

The incidence of tumors of the salivary gland and tongue is 0.47%. Carcinoma is the usual type of cancer seen at these sites. Salivary gland tumors show remarkable aggressiveness, with widespread metastasis along with invasion of the blood and lymphatic vessels. These tumors generally show late presentation.^13,14,43

Adenocarcinoma is the common presentation of cancers of the stomach and bowels in heart trans­plant recipients. Metastasis of these cancers results in poor survival for heart transplant patients with the disease.^11,13

Other tumors
Papillary renal cell carcinoma, adenocarcinomas of the breast and pancreas, carcinomas of the liver and uterus, and cholangiocarcinoma of the biliary tract are some other rare types of malignancies seen after heart transplant.

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