Posttransplantation Cancer

Etiology

The risk factors for post-transplant malignancy are the patient, transplant, and medication-related.

Patient-related Risk Factors

The advanced age of the patient is a well-described risk factor, and it is an established risk factor for the development of skin cancer. Sun exposure, prior history of cancer in a transplant recipient are also strong risk factors. Acuna et al. in their meta-analysis showed that pre-transplant malignancy correlates with an increased risk of cancer-specific mortality and of developing de novo malignancies after transplantation, compared with solid organ transplant recipients without a pretransplant malignancy.[4]  Smoking and alcohol consumption are risk factors for carcinogenesis and carry a high risk of mortality.[5] Viruses implicated in carcinogenesis include Epstein-Barr virus (EBV), human herpesvirus 8 (HHV-8), human papillomavirus (HPV), the Merkel cell polyomavirus, hepatitis B, and hepatitis C. EBV is implicated in the development of Hodgkin disease, Non-Hodgkin lymphoma, and other manifestations of PTLD, nasopharyngeal cancers and leiomyosarcomas.[6]

Transplant-related Risk Factors

Differences in the type of transplant (living versus deceased) correlate with cancer risk. Patients who receive kidneys from a living donor have a lower risk for genitourinary cancer and PTLD.[7] Donor transmission as a cause of post-transplant malignancy is a rare but is a documented way of carcinogenesis; melanoma, cancer of lung, breast, colon, rectum, kidney, Kaposi sarcoma, and glioblastoma multiforme all have been reported to be transmittable from donors.[8] 

Medication-related Risk Factors

The immunosuppressive drugs impair immunosurveillance of neoplastic cells and increase the incidence of virally induced malignancies. The type, intensity, and duration of immunosuppressive therapy all influence the rate of carcinogenesis. These immunosuppressive drugs, for example, biologic agents (anti-thymocyte globulin, basiliximab), corticosteroids, antimetabolites (azathioprine, mycophenolate mofetil), calcineurin inhibitors (cyclosporine, tacrolimus), and mTOR inhibitors (rapamycin [sirolimus], everolimus) all have been implicated.[9]

Epidemiology

The Israel Penn International Transplant Tumor Registry (IPITTR),[10] the largest and most comprehensive registry in the world records non-melanoma skin cancers (NMSCs) as the most prevalent cancer in post organ transplant state. Following is the list of various cancers associated with the organ transplant:

• Kaposi sarcoma
• Skin (nonmelanoma, nonepithelial)
• Non-Hodgkin lymphoma 
• Liver 
• Anus 
• Vulva 
• Lip 

Other common malignancies with a statistically significant (p<0.001) increase included 

• Lung 
• Kidney 
• Colon and rectum 
• Pancreas 
• Hodgkin's lymphoma 
• Melanoma 

Pathophysiology

Transplant-related malignancies arise from an interplay of immunologic and nonimmunologic risk factors. The following is a brief description of the various pathways for the oncogenesis:

1. Immunosuppressive agents and oncogenesis: calcineurin inhibitors stimulate carcinogenesis by inhibiting DNA repair mechanisms, apoptosis, and enhancing the production of interleukin 2 (IL-2), transforming growth factor (TGF), and vascular endothelial growth factor (VEGF). Transforming growth factor promotes tumor growth by regulating tumor cell invasion, metastatic potential, and VEGF stimulates neo-angiogenesis. Azathioprine increases cancer risk by causing post-replicative DNA mismatch repair. Sirolimus, everolimus and mycophenolate mofetil are not associated with an increased risk of cancer; they actually have antiproliferative properties.
2. Viral Infection and oncogenesis: Transplant patients are vulnerable to viral infection or reactivation of latent infection. EBV promotes the oncogenesis by reduced lymphocyte regulation, a lack of control of the oncogenic virus by EBV-specific CD81 cytotoxic T-cells, and proliferation of EBV-infected B cells. The mechanism by which HHV-8 induces oncogenesis has not been completely elucidated. HHV-8’s proinflammatory proteins might directly inhibit apoptosis and promote cell transformation.[11]

History and Physical

Although early cancer diagnosis may show improvement of cancer outcomes in the cancer population, the reduced life expectancy and multiple comorbidities that exist in organ transplant recipients regular physical examination and history are of paramount importance. On average, the age at diagnosis of post-transplant cancer is 40 years and the time from transplantation is the 3 to 5 years.[12] However, these numbers vary according to the cancer subtype, with lymphoma and Kaposi sarcoma occurring early after transplantation and epithelial cancers later on. The specific questions on history taking that are of paramount importance are the amount of high sun exposure, any skin health concerns, and the onset of irregular skin lesions, as they all point towards the onset of skin malignancy. Studies have shown that continued consumption of alcohol and smoking lead to early and aggressive squamous cell malignancy and urinary bladder cancer. If there is a concern for fever, weight loss or any neurological disturbance, then radiological investigations should be performed to rule out PTLD. If the patient endorses lower GI bleed, then threshold to examine colon to rule out malignancy should be low. The history taking in patients with solid organ transplant is more vigorous and frequent than the general population. Physical examination should be carried out keeping in mind all the secondary cancers that may arise. Regular skin and breast examination should be performed in the office, a digital rectal exam to detect early prostate cancer, and neurological examination to clinically rule out CNS lymphoma and PTLD.[13]

Treatment / Management

Screening and early detection of cancers is the best form of treatment. Below are the recommendations for the screening of the specific malignancy.[14](A1)

1. Breast cancer: Women 50 to 69 years: annual screening mammography with or without clinical breast examination is the current recommendation. At age 40 to 49 years: the benefit of screening is less certain and the ultimate decision is up to the clinician and patient. In females above 70 years of age: annual screening is appropriate as long as estimated life expectancy is about 8 years.
2. Liver cancer: Patients with chronic hepatitis B or C and cirrhosis, serum AFP and liver ultrasound should be performed every 6 to 12 months.
3. PTLD: Complete history and physical examination should take place every three months, particularly in the first posttransplant year.
4. Anogenital: Early physical examination of the anogenital area, including a pelvic examination and cytologic studies for women. There is insufficient evidence to recommend either for or against screening anoscopy and biopsies of the anal epithelium.
5. Cervical: All women aged above 18 years and sexually active girls <18 years old should undergo an annual pelvic examination and Pap smear.
6. Skin cancers: Examination of skin, conjunctivae, and oropharyngeal mucosa annually; patients at higher risk (ethnicity, geographic area of residence or serologic positivity for HHV) may benefit from more frequent screening.

 Careful screening of the patient and donor before transplantation to help detect an underlying pre-existing malignancy is one of the effective ways to avoid dealing with this enigmatic problem later on. We have tried to summarize the broad topic of management and cancer in solid organ recipients into general recommendations;

Reduction of immunosuppression: Reduction or cessation of immunosuppressive therapy is useful primarily in patients who had a renal transplant since the loss of the graft to rejection is not a fatal event in these patients. Such measures may cause tumor regression sometimes such as  PTLD, some skin cancers, Kaposi sarcoma (KS).[15] The reduction in calcineurin inhibitor exposure may be important.

Anogenital cancers: In situ anogenital cancers can be treated with laser therapy, electrocautery, or topical fluorouracil. Invasive tumors require wide local excision (e.g., APR), with inguinal lymphadenectomy.

Visceral malignancy: Visceral malignancies are to receive treatment by standard surgical, radiotherapeutic, or chemotherapeutic modalities. 

Post-transplant lymphoproliferative disorder (PTLD): Management of PTLD deserves special mention as the treatment has undergone major changes over time. The main options for initial treatment are the reduction of immunosuppression, immunotherapy with the CD20 monoclonal antibody (rituximab), chemotherapy, radiation therapy, or a combination of these. The PTLD classifies into four types and treatment varies according to the type.

• Early lesions:  Reduction of immunosuppression alone suffices.
• Polymorphic PTLD: They express CD20, so besides the reduction in immunosuppression rituximab is advised. Surgery is reserved for patients with minimal localized residual disease.
• Monomorphic PTLD: For CD20+ PTLD, reduction in immunosuppression with rituximab and combination of systemic chemotherapy such as CHOP (cyclophosphamide, vincristine, prednisone) is the therapeutic recommendation. If the tumor is CD20 negative, then systemic chemotherapy is administered along with the reduction in immunosuppression. Surgery is only for patients with complications such as perforation or obstruction of the hollow viscus such as the bowel. 
• Classic Hodgkin lymphoma-like PTLD–Classic Hodgkin lymphoma-like PTLD is the least common form. Data regarding its management is lacking. Treatment is according to the protocols used for classic Hodgkin lymphoma.[16][17]
(B3)

Differential Diagnosis

Differential diagnosis:

• PTLD: Infectious complications streptococcal pharyngitis and Infectious mononucleosis in an immunosuppressed individual presenting with fever, pharyngitis, and cervical lymphadenopathy closely mimic PTLD. Solid-organ recipients with opportunistic pulmonary infections such as aspergillosis and acute graft-versus-host disease may develop multiple lung parenchymal nodules and alveolar opacities that mimic PTLD on imaging studies. 
• Melanoma: Mucosal fungal lesions closely mimic mucosal melanoma, so the progression of lesion and cytology may be necessary to treat.
• Skin cancers: keratoacanthoma and solar (actinic) keratosis closely mimic squamous cell carcinoma; an excisional biopsy can differentiate between the two. 
• CNS Lymphoma: CMV or Toxoplasma are common viral and parasitic infections in an immunosuppressed individual, they present as ring-enhancing lesions in the brain and may be mistaken for primary or secondary CNS lymphoma.
• Benign conditions of the transplanted kidney, liver, and lungs can manifest as space-occupying lesions and mimic posttransplant malignancies. Renal pathologic conditions such as transplant-related fibrosis, acute pyelonephritis, and subcapsular hematoma may mimic malignancies un ultrasound and CT.
• Ischemia and reperfusion injury to the liver transplant may cause biliary necrosis and hepatic infarcts or micro-abscesses that may mimic recurrent HCCs at imaging studies.[18]

Prognosis

Malignant neoplasms after transplantation have different clinical features that are responsible for higher mortality. The Israel Penn International Transplant Tumor Registry showed that the stage-specific survival for cancer of colon, lung, breast, prostate, and bladder, was lower in patients after solid organ transplant compared with those without it. The 1-year adjusted survival of recipients with colorectal, prostate and non-small-cell lung cancer were 10%, 40%, and 20%, respectively, compared with 40%, 80%, and 30% in the general population.[19] Farrugia et al. reported that the overall risk of cancer death after transplantation was tenfold as compared to age- and sex-matched population.[20]

Complications

Complications because of post-transplant cancer are decreased quality of life, death, and increased healthcare spending.