Etiopathogenesis, Screening, Diagnosis and Management of Viral Origin Post-Transplant Malignancies

Kidney transplant is the treatment of choice for patients with end-stage renal disease as it has better survival outcomes and improved quality of life compared to dialysis [1]. The success of transplantation has dramatically improved over the decades due to advances in surgical techniques, organ preservation and immunosuppression therapies. Despite the one-year graft and patient survival having improved significantly, long-term survival of transplant recipients has not improved. Cardiovascular diseases, infections and cancers are the leading causes of mortality post Solid Organ Transplant (SOT) [2]. Malignancy following solid organ transplantation represents one of the most significant challenges in long-term post-transplant care with profound implications for patient survival and quality of life. The relationship between transplantation and malignancy is complex and multifactorial. Chronic immunosuppression impairs the body’s natural surveillance mechanisms, which would typically identify and eliminate neoplastic cells. Oncogenic viruses play a crucial role in the development of cancer after transplantation. Viruses such as Epstein-Barr virus (EBV), Human Papillomavirus (HPV), human herpes-virus 8 (HHV-8) and hepatitis B and C viruses play crucial roles in the pathogenesis of various post-transplant malignancies.

There is an overall increased risk of cancer in dialysis patients compared to the normal population. The types of cancers seen in dialysis patients were similar to the cancers seen in transplant patients [3]. The risk of malignancy post-transplant increases with the vintage time of dialysis pre-transplant [4]. Incidence of malignancy post SOT increase with the duration of the transplant from 4 to 5% after five years to more than 25% after 20 years [2]. The incidence of malignancy in Kidney Transplant Recipients (KTR) is more than 2-4 fold as compared to age and gender matched individuals in the general population [5]. The most common cancers occurring post renal transplant compared to the general population include: Kaposi Sarcoma (KS) (up to 300 times more compared to the general population, non-melanoma skin cancers (2-40 times), lip cancer (more than 10 times), and cancers whose etiology has been postulated to be due to viruses like post-transplant lymphoproliferative disorders [6].  Most data do not show an increase in breast and prostate malignancy post-kidney transplant as compared to the general population [7].

Cancer increases mortality significantly post-transplantation. The incidence of mortality is 56% in a study of 12,805 renal transplant recipients [8]. The median survival of transplant recipients who developed a malignancy was significantly lower than that of the age and gender matched controls, due to the aggressive nature of the tumour in transplant recipients [9].

Several risk factors have been identified which predispose an individual to developing malignancy post-transplant. These include increased age at transplant, male gender, Caucasian ethnicity, duration on dialysis, degree of HLA mismatches, and type, intensity, and duration of immunosuppression. 

a. Age and gender 

Increased age at transplantation increases the risk of malignancy. Age of more than 55 years was associated with a threefold higher increase in developing cancer as compared to recipients less than 35 years [10]. Younger transplant recipients (< 30 years) have a higher incidence of developing malignancy compared to age-matched controls. This is due to the general low incidence of cancer in the younger non-transplant population. The risk of developing cancer is higher among male recipients by 20-30% compared to female transplant recipients [11]. 

b. Ethnicity 

Caucasians who have undergone a kidney transplant have a 20-35% higher risk of developing cancer post-transplant than non-Caucasians who have undergone a kidney transplant. This could be due to a higher risk of developing melanoma cancer in the Caucasian population and increased survival, which increases exposure time to immunosuppression [12]. 

c. Vintage time on dialysis 

The risk of malignancy post-transplant increases with increased time on dialysis pre-transplant. Compared to transplant patients who had been on dialysis for 4.5 years versus those who had been on dialysis for less than 1.5 years, the cumulative incidence of malignancy was 0.23 and 0.15, respectively [4]. 

d. Immunosuppression 

Calcineurin Inhibitors (CNIs), especially cyclosporin, have a higher incidence of causing cancers in transplant recipients, mainly if used at higher doses for maintenance therapy [14]. T-cell-depleting agents, such as anti-thymocyte globulin, have a higher incidence of developing Non-Hodgkin Lymphoma (NHL) compared to the propensity-matched general population. IL-2 receptor antibodies have not been shown to increase the risk of malignancies post-transplant. Mammalian Target Of Rapamycin (mTOR) inhibitors have been shown to reduce the risk of certain cancers, like non-melanoma skin cancers, compared to cyclosporine. A meta-analysis comparing regimens containing sirolimus and no sirolimus found that the regimen containing sirolimus had a 40% risk reduction of developing cancer [15]. 

e. Degree of HLA mismatch 

The number of HLA mismatches, especially at the HLA-DR locus, is associated with a higher risk of developing diffuse large B-cell lymphoma [16]. 

f. Oncogenic viruses 

Certain viruses have been known to cause malignancies, and the incidence of these malignancies increases in virus-endemic areas. The oncogenic viruses include Epstein-Barr virus (EBV), human papillomavirus (HPV), human herpesvirus 8 (HHV8), hepatitis B and C viruses, and Merkel Cell Polyomavirus (MCV).

Cancers occurring post-transplant occur mainly de novo but can also be donor-transmitted (< 2%) or occur as a result of the recurrence of the recipient’s pre-transplant cancer [17]. Several factors play a role in the pathogenesis of developing malignancy post-transplant and include:

• Impaired immune surveillance
• Oncogenic viruses
• Environmental factors
• Immunosuppression
• Chronic immune activation

Impaired immune surveillance

One of the functions of the immune system is to eliminate malignant cells and reduce viral-induced proliferation of cells. This immune surveillance is lost post-transplant due to the long-term effects of immune suppression, which allows the cancerous cells to proliferate unchecked, leading to the development of cancer [18]. The long-term immunosuppression impairs the function of Natural Killer (NK) cells, which are crucial in eliminating tumour cells and virally infected cells. 

Oncogenic viruses 

Transplant recipients have an increased risk of acquiring viral infections or reactivation of latent infections. Some of these viruses, such as EBV, HPV, HHV8, HBV, HCV, and MCV, have oncogenic potential. The immune-suppressive state leads to the replication of these viruses and the proliferation of virally infected cells [19]. 

Environmental factors  

Environmental factors play a significant role in the development of certain cancers, particularly skin cancers. UVA and UVB radiation lead to DNA damage, which is not repaired due to immunosuppression, thereby increasing the risk of skin cancer. Cyclosporine has been shown to impair the repair of UV-induced DNA damage via reduction in the transcription of xeroderma pigmentosum complementation A and G genes [20]. 

Immunosuppression 

Tacrolimus increases the levels of transforming growth factor beta, which promotes the proliferation of tumour cells and metastasis. CNIs activate the P53 gene due to inhibition of signalling via calcineurin. Its activation is responsible for many non-melanoma skin cancers (NMSCs) [21]. Cyclosporine has also been shown to inhibit DNA repair, which leads to the accumulation of mutations in the DNA that can lead to cancer. The antimetabolite, azathioprine, increases the sensitivity of the skin to ultraviolet radiation, leading to UV-radiation damage to the DNA [22]. T cell depleting agents used for induction therapy and treating rejection episodes have been known to increase the incidence of non-Hodgkin lymphoma and melanoma skin cancer. After T cell-depleting therapy, the T cells do not fully recover, and there is a long-term effect on immune surveillance. This can increase the risk of the development of subsequent malignancies [23]. mTOR inhibitors have been shown to reduce the risk of cancers post-transplantation, particularly melanoma and NMSCa [24]. The possible mechanisms by which the induction of factors lowers cancer risk include a reduction in cellular proliferation and inducing apoptosis in B-cell lymphoma lines by reducing cyclin and inhibiting P70S6K [25]. 

Chronic immune activation 

Prolonged immune system stimulation due to HLA mismatches can increase the risk of NHL [26]. The postulated mechanism is chronic stimulation of lymphoid tissue that leads to hyperplasia and subsequently the development of cancer (Figure 1). 

Figure 1: Pathogenesis of virus-induced posttransplant malignancy. VEGF: Vascular endothelial factor, TGF-β: Transforming growth factor-β, IL-6: Interleukin-6, RAS: Rat sarcoma-rapidly accelerated fibrosarcoma, PTLD: Posttransplant lymphoproliferative disease, EBV: Epstein–Barr virus. Adapted from Indian Journal of Transplantation - Postrenal Transplant Malignancy: An Update for Clinicians.

Several viruses have been known to increase the risk of cancer after a transplant. EBV was the first virus to be classified as a human carcinogen by the International Agency for Cancer Research in 1997. causes PTLD in the transplant recipients. PTLD is eight times more common in transplant patients than in the general population [27]. The incidence is higher in children as compared to adults due to a lack of exposure to T-cells in childhood. The risk factors   include donor+/recipient- status, use of T cell depleting agents, CMV co-infection and graft-versus-host disease. PTLD commonly occurs in the first year post-SOT ith a median onset of six months. The symptoms of EBV are very non-specific and include fever, generalised body malaise and anorexia [28]. It has been recommended that the EBV load be used to detect the likelihood of a recipient having PTLD. Studies have shown that transplant patients who develop PTLD have a higher viral load than recipients without PTLD. High EBV levels prior to the onset of signs and symptoms may be a harbinger of developing PTLD, which can allow interventions and prevent PTLD progression [29]. A rise in EBV levels is seen in all recipients post-transplant and unfortunately, there is no universally agreed cut-off level for a high EBV load. EBV testing should be done in high-risk patients to detect high viral loads. The frequency of monitoring should be weekly for three months, then monthly for one year. If the viral load is above the cut off set by the laboratory, PTLD should be actively looking for and the immunosuppression should be reduced [30]. For transplant recipients, who develop signs and symptoms of PTLD, like lymphadenopathy, splenomegaly, fever with suggestive laboratory parameters like leucopenia, quantitative EBV load testing should be carried out. If the quantitative EBV load is higher than the laboratory threshold, then preemptive therapy may be carried out while waiting for histological diagnosis of PTLD. Preemptive therapy includes reduction of immunosuppression and the use of rituximab. The success of preemptive therapy is assessed by the reduction of EBV load by at least one log unit [31].

• Reduction in immunosuppression
• Rituximab
• Chemotherapy
• Radiotherapy

HPV is it common cause of skin, lip, anal, vulvar, cervical, penile and head and neck malignancies in solid organ transplant recipients. It is a small DNA virus with approximately 7900 base pairs. There are more than 100 subtypes of HPV and are classified by their association in causing invasive cancer, into ‘high risk’ and ‘low risk’.

Anogenital cancers (affecting the anus, penis, vulva, perineum, scrotum) account for 2-3% of cancers in patients who have undergone solid organ transplantation [32]. The lesions can be multiple and cover large areas, especially in females and can occur concurrently with cervical cancer. HPV has been associated with head and neck cancers in the non-transplant population, although there have been limited studies of solid organ transplant recipients. One study showed that transplant patients had a 3-fold increased risk of head and neck cancer [33]. 

Diagnosis of HPV associated cancers requires a thorough examination of the skin during each clinic visit to assess for warts, which can be premalignant. The anogenital tract should also be examined for any warts. Any external lesions in the anogenital region should raise suspicion for internal lesions, and a speculum exam is warranted. All lesions with an abnormal appearance should be biopsied. Lymph nodes in the head and neck region should also be assessed carefully in each visit. The Pap smear is the gold standard for detecting cervical lesions. It should be carried out in all female transplant recipients every six months after the transplant for one year and then annually if no suspicious lesion is detected. The anal pap test can also be used to screen for anal cancer. Abnormal cytological results should prompt visualisation and biopsy of any visualised lesions. All transplant candidates who are between the ages of 11 and 26 years should be offered the HPV vaccine. In situ anogenital cancers can be treated with localized therapies like laser therapy, electrocautery, topical imiquimod or fluorouracil. Invasive tumors will require radical excisions with adjuvant chemotherapy and radiation therapy.

HHV8 is an oncogenic virus that causes KS, Multicentric Castleman disease and primary effusion lymphoma. Like all herpes viruses, HHV8 establishes a latent phase in the host after primary infection, facilitating immune evasion. The lytic phase of the virus becomes predominant when the host's immunity is reduced. KS is the most common malignancy occurring post-solid organ transplant [6]. The highest prevalence of KS post-transplant occurs in recipients who are of Mediterranean, Jewish, Arabic or African descent, reflecting the high HHV8 prevalence in these geographic regions [34]. The majority of patients, approximately 90%, present with cutaneous and/or mucosal lesions, while only 10% have visceral lesions, particularly in KTRs. The lesions present as angiomatous nodules, most commonly affecting the lower limbs. A careful dermatological examination is critical at every clinic visit. Biopsy of the suspected lesion is the gold standard for diagnosing KS. KS may respond to a reduction in immune suppression. In one study, mucocutaneous KS lesions were treated in 17% post-transplant patients by reducing immunosuppression [35]. Substitution of a CNI for an mTOR inhibitor has also been associated with complete resolution of KS lesions. For extensive disease, chemotherapy and radiotherapy may be needed.

MCV belongs to the family of polyoma viruses. It was originally discovered in Merkel cell carcinoma (MCC), which is a neuroendocrine tumour. MCCs are more common in the fair-skinned, post-transplant individuals and occur as asymptomatic, rapidly expanding lesions on the sun-exposed areas of the skin. Patients treated with cyclosporine and azathioprine have a higher risk of developing MCC [36]. Biopsy is required for the diagnosis of MCC. Surgical excision of the lesion is the treatment of choice for MCC with adjuvant radiotherapy. Reduction of immunosuppression may lead to regression of the lesions.

Post-transplant malignancy is the second leading cause of death among SOT recipients. Therefore, it is important to identify high-risk individuals who are predisposed to malignancies to prevent the development of cancer in these individuals. Careful pretransplant screening is mandatory to detect any occult malignancies. Any malignancies detected pre-transplant should be treated, and the transplant done after the appropriate waiting time, which is normally 2-5 years after successful treatment. The patient should be advised to apply sunscreen and to avoid sun exposure to reduce the risk of NMSC. Patients should also be taught to perform skin self-examinations and report any new lesions to their doctor. Careful skin examination for high-risk individuals is important at every clinic visit. Using mTOR inhibitors may reduce the risk of skin malignancies in SOT recipients [37]. SCC is normally managed depending on the staging of the disease, from surgical excision to topical treatment to systemic chemotherapy and radiotherapy. Cancer screening for other malignancies should follow the general population-based guidelines. Any cancer detected should be treated aggressively, and the decision weighed whether to reduce immunosuppression and to change from CNI to mTOR inhibitors (Table 1).

This is the infusion of T-cells or NK cells with antitumor or antiviral activity into a patient with cancer or chronic viral infections. Individuals naturally have the ability to kill viruses in cancer cells via T-cells and NK cells. The principle of adoptive immunotherapy is to utilise these T-cells and NK cells with antitumor and antiviral effects for the treatment of chronic viral infection and cancer. The cells utilised for adoptive immunotherapy can be obtained via: 

• Isolating the cancer-specific T-cells from tumours
• Genetically modifying T-cells with a specific T-cell receptor to allow them to recognise the tumour or viral antigens specifically
• Adding a chimeric antigen receptor (CAR) to the T-cells, which can also identify cancer antigens that are not present on the cell surface.
• Modifying NK cells with tumour-targeting CAR.

The clinical utility of adaptive immunotherapy includes:

• Treatment of cancer
• Treatment of chronic viral infections in immunosuppressed patients, like cytomegalovirus, EBV and adenovirus
• Attenuating severe, uncontrolled allergic responses.

The future of adoptive immunotherapy will also include the treatment of autoimmune conditions, like myasthenia gravis, where genetically modified T-cells will be used to eliminate the autoimmune B cells.

The side effects of adoptive immunotherapy include:

• Stimulating an overactive immune response, leading to cytokine release syndrome
• Graft versus host disease
• Triggering acute rejection episodes in SOT recipients
• Immunosuppression leading to febrile neutropenia and sepsis. 

Table 1: Summary of viral infections leading to malignancies.

There are very few studies examining the factors that determine the waiting period after successful treatment of malignancy for retransplantation. Available guidelines recommend a waiting period of 2-5 years, depending on the stage and type of malignancy. Any metastatic disease is a contraindication for re-transplant. Several factors need to be considered prior to re-transplantation: 

• Type of malignancy – Patients with successfully treated PTLD have been retransplanted after a waiting period of 1-2 years, provided the EBV load is undetectable. The EBV load was closely monitored post-transplant, and most patients got basiliximab as the induction agent 

• Medical suitability of the recipient 

• Optimum immunosuppression – Avoidance of T-cell depleting agents and use of mTOR inhibitors needs to be discussed before the transplant 

• Prior response to cancer treatment 

For breast, colon and prostate cancer, a waiting period of 2 years for early-stage and 5 years for late-stage disease is recommended after successful treatment. The waiting periods for the various cutaneous malignancies are also 2-5 years, except for low-risk SCC and melanoma in situ, where no waiting period is necessary after surgical excision [38].

There is a significantly elevated malignancy risk in transplant recipients compared to the general population, with standardised incidence ratios ranging from 2 to 4-fold overall but much higher for specific malignancies such as non-melanoma skin cancer. Cancer is the second leading cause of morbidity and mortality in SOT recipients. It can also lead to graft dysfunction and graft loss. Several viruses have oncogenic potential and have been known to cause cancers in solid organ transplant recipients. It is important to screen recipients pre-transplant for any malignancies and precancerous lesions, which will determine the frequency of organ-appropriate screening for cancer. The management of established malignancies in transplant recipients presents unique challenges, requiring a delicate balance between oncologic efficacy and allograft preservation. Reduction of immunosuppression and switching to mTOR inhibitors play a crucial role in the treatment of most malignancies. Adoptive immunotherapy is an upcoming field for the treatment of malignancy and chronic viral infections. Prevention represents the cornerstone of reducing the cancer burden in transplant recipients. Strategies include optimisation of immunosuppression regimens, vaccination against oncogenic viruses, antiviral prophylaxis and comprehensive lifestyle modifications.

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