Malignancy after solid organ transplantation

INTRODUCTION — In recipients of a solid organ transplant, the chronic use of immunosuppressive agents to prevent allograft rejection increases the long-term risk of malignancy compared with that of the general population.

This topic will review the general issue of malignancy following solid organ transplantation. Malignancy following hematopoietic cell transplantation, skin cancer following solid organ transplantation, and lymphoproliferative disorders following solid organ transplantation are discussed separately:

●(See "Secondary cancers after hematopoietic cell transplantation".)

●(See "Epidemiology and risk factors for skin cancer in solid organ transplant recipients".)

●(See "Prevention and management of skin cancer in solid organ transplant recipients".)

●(See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders".)

●(See "Treatment and prevention of post-transplant lymphoproliferative disorders".)

EPIDEMIOLOGY AND RISK FACTORS

Incidence — Solid organ transplantation is associated with an increased risk of a wide range of cancers [1-8]. The most extensive data come from a large cohort study that analyzed the frequency of malignancy in over 175,000 solid organ transplant recipients during the period 1987 to 2008 [1]. The most common organs transplanted included kidney, liver, heart, and lung (in 58, 22, 10, and 4 percent of cases, respectively). Overall, malignancy was identified in 10,656 cases, which correlated with a standardized incidence ratio (SIR) of 2.1 (95% CI 2.06-2.14) compared with the general population and an excess absolute risk of 719 cases per 100,000 person years.

A significantly increased risk of malignancy was associated with more than 30 different primary sites. Tumor sites with a fivefold or greater increase, compared with the general population, included the following:

●Kaposi sarcoma (KS; SIR 61.5)

●Skin (nonmelanoma, nonepithelial; SIR 13.9)

●Non-Hodgkin lymphoma (SIR 7.5)

●Liver (SIR 11.6)

●Anus (SIR 5.8)

●Vulva (SIR 7.6)

●Lip (SIR 16.8)

Of note, these malignancies are associated with viral infections. (See 'Coexisting viral infection' below.)

Other common malignancies with an increased risk included the following:

●Kidney (SIR 4.7)

●Hodgkin lymphoma (SIR 3.6)

●Melanoma (SIR 2.4)

●Lung (SIR 2.0)

●Pancreas (SIR 1.5)

●Colon and rectum (SIR 1.2)

Other primary malignancies that were increased, but to a lesser extent, included stomach, oral cavity, larynx, pharynx, vulva, penis, thyroid, urinary bladder, esophagus, salivary glands, soft tissue sarcomas, small intestine, testis, biliary tract, acute myeloid leukemia, plasma cell neoplasms, and chronic myeloid leukemia.

By contrast, the incidence of breast cancer was decreased (SIR 0.85), as was the risk of prostate cancer (SIR 0.92).

This analysis also found that the incidence of specific malignancies varied depending upon the organ transplanted [1]. As an example, the frequency of non-Hodgkin lymphoma was approximately twofold greater in recipients of lung transplants compared with those who received a kidney, liver, or heart transplant. Conversely, there was an approximately threefold increase in lung cancer among lung transplant recipients, and the frequency of liver and kidney cancer was increased in liver and kidney transplant recipients, respectively.

Similar patterns of increased incidence have been observed in other studies of both adults and children [2-8].

Risk factors for malignancy — Several factors have been linked to the increased incidence of secondary malignancies among transplant recipients, including sun exposure; type, extent, and duration of immunosuppression; and concomitant viral infection. In rare cases, malignancy has been transplanted from the donor.

The risk factors associated with an increased risk of skin cancer and posttransplant lymphoproliferative disorders (PTLDs) are discussed separately.

●(See "Epidemiology and risk factors for skin cancer in solid organ transplant recipients", section on 'Risk factors'.)

●(See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders", section on 'Risk factors'.)

Immunosuppression — The overall level of immunosuppression appears to be the principal factor that increases the risk of posttransplant malignancy [9]. The relationship between an increased level of immunosuppression and the likelihood of malignancy can be illustrated by the following data:

●In a study of over 50,000 kidney and heart transplants from centers in Europe and North America, the incidence of PTLD was highest in the first year, the time of most intense immunosuppression, and fell by approximately 80 percent thereafter (figure 1) [10]. The incidence was significantly greater in heart transplant recipients, a finding consistent with the greater degree of immunosuppression in these patients.

●Episodes of graft rejection in the first year after transplantation increase the likelihood of developing a secondary malignancy, possibly because of the greater level of immunosuppression that is required to treat rejection [11].

●In one trial, 231 kidney allograft recipients were randomly assigned after 12 months of standard immunosuppressive therapy to receive cyclosporine doses adjusted to yield trough blood concentrations between 75 to 125 ng/mL (low-dose group) or doses that yielded trough concentrations between 150 to 250 ng/mL (normal-dose group) [12]. At a median of 66 months, patients receiving the low-dose cyclosporine regimen had a lower incidence of all secondary cancers (23 versus 37 cancers), particularly skin cancers (17 versus 26 cancers).

The risk of malignancy appears to vary depending upon the agents used for immunosuppression:

●Antibody therapy – Antibody therapy directed against T lymphocytes (as with OKT3 or antilymphocyte serum) specifically predisposes to PTLD induced by Epstein-Barr virus (EBV). By contrast, antibody therapy targeting B lymphocytes (as with rituximab) may reduce the incidence of lymphoproliferative disorders and is regarded by many as appropriate first-line therapy for these disorders. This is discussed in more detail elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders", section on 'Degree of immunosuppression'.)

●Calcineurin inhibitors – Limited evidence from animal models suggests that cyclosporine may promote cancer progression, principally via the production of transforming growth factor-beta (TGF-beta). In vitro, cyclosporine induces invasive behavior of nontransformed cells in association with striking morphologic changes; in addition, cyclosporine administration promotes tumor growth in immunodeficient animals [13]. Both the in vitro and in vivo changes were prevented by the administration of anti-TGF-beta antibodies.

An increase in proangiogenic effect due to elevated expression of vascular endothelial growth factor has been reported with cyclosporine [14-16]. Another notable cytokine with increased levels is interleukin-6, which may help EBV-induced B-cell growth [16].

Data from one series suggest that the use of tacrolimus increases the risk of malignancy following kidney transplantation [17]. Tacrolimus appears to increase TGF-beta levels [18], an effect clearly associated with tumor growth with cyclosporine.

●Azathioprine – The use of azathioprine has been associated with malignancy posttransplantation, particularly an increased risk of cutaneous squamous cell carcinoma [9]. The mechanism of action is postulated via intercalation of DNA to be the inhibition of repair splicing and induction of codon misreads [19].

●Mycophenolate mofetil – Mycophenolate mofetil impairs lymphocyte function by blocking purine biosynthesis via inhibition of the enzyme, inosine monophosphate dehydrogenase. Some malignancies, including some solid tumors, have dramatic elevations of this enzyme, suggesting that this agent may have some antiproliferative activity [9,20].

Some population studies also suggest that the risk of developing a malignancy is not higher with mycophenolate mofetil and may actually be associated with a decreased risk [9,21,22]. In a study using data from two large registries, there was a nonsignificant trend to a decreased risk with mycophenolate- versus non-mycophenolate-based therapy [21]. A principal mechanism of a lower malignancy risk with mycophenolate mofetil, to the degree that it occurs, may be due to the decreased incidence of acute rejection. This results in a reduced need for increased doses of immunosuppressive agents.

●Sirolimus – Some data suggest that sirolimus, an inhibitor of the mammalian (mechanistic) target of rapamycin (mTOR), suppresses the growth and proliferation of tumors in various animal models [14,16,23]. Possible mechanisms of actions include inhibition of p70 S6K (thereby decreasing cell proliferation), interleukin-10 (decreasing tumor cell Jak/STATs activity), and cyclins (blocking cell cycle activity). Lymphangiogenesis also appears to be impeded via impaired signaling of vascular endothelial growth factors A and C [24].

In humans, evidence also suggests that sirolimus may confer a decreased risk of malignancy compared with other immunosuppressive medications [16,25-32]. The best data are from a systematic review and meta-analysis of randomized trials that compared immunosuppressive regimens with and without sirolimus using patient-level data from kidney and kidney-pancreas transplant recipients [30]. Compared with controls, sirolimus was associated with a 40 percent decrease in the overall risk of malignancy and a 56 percent decrease in the risk of nonmelanoma skin cancer. This result was most striking among patients who converted to sirolimus from another immunosuppressive regimen with an overall decrease in malignancy risk (hazard ratio [HR] 0.34, 95% CI 0.28-0.41), nonmelanoma skin cancer (HR 0.32, 95% CI 0.24-0.42), and other cancers (HR 0.52, 95% CI 0.38-0.69). By contrast, analysis of de novo sirolimus trials revealed no difference in malignancy risk between sirolimus and controls. However, sirolimus was associated with an increased mortality risk (HR 1.43, 95% CI 1.21-1.71), driven by increased cardiovascular and infection-related deaths in the sirolimus group. Some studies have found a higher incidence of prostate cancer associated with sirolimus use among transplant recipients [31,32]. (See "Prevention and management of skin cancer in solid organ transplant recipients", section on 'mTOR inhibitors'.)

Coexisting viral infection — At least four viruses may be cocarcinogenic in transplanted patients: EBV, human herpesvirus 8 (HHV-8), human papillomavirus (HPV), and the Merkel cell polyomavirus (MCV).

●Epstein-Barr virus and lymphoma – Lymphomas are among the most common complications of transplantation; many are related to EBV infection. This topic is discussed in detail elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders", section on 'Pathogenesis'.)

●Human herpesvirus 8 and Kaposi sarcoma – The presence of HHV-8 in tumor tissue has been recognized in all forms of KS: classic KS, endemic KS, acquired immune deficiency syndrome (AIDS) KS, and posttransplant KS, with serologic evidence of infection also being common [33,34]. (See "Human herpesvirus-8 infection".)

•A study of kidney transplant recipients from Saudi Arabia, in whom the incidence of KS is approximately 10-fold higher than in patients from Western countries, found a markedly higher incidence of specific anti-HHV-8 antibodies in patients with KS compared with those without it (92 versus 28 percent) [35].

•In a report of 400 consecutive kidney transplant recipients, 32 had antibodies to HHV-8 at the time of transplantation [36]. Three years after surgery, 28 percent of antibody-positive patients had developed KS compared with no cases in antibody-negative patients.

•There is convincing evidence of transmission of HHV-8 from the donor to kidney and cardiac transplant recipients [37-40]. Not only is the virus transmitted, but, in at least one series, the tumor cells are also commonly (five of eight) donor derived.

HHV-8 infection is necessary but not sufficient for the development of KS. Transplanted-related immune dysfunction is an important contributing cofactor. Pretransplant antibody screening would appear to be useful for identifying high-risk patients; it is not routinely performed in the United States but may be performed in endemic areas [41]. If pursued, donor testing is warranted as well, particularly in areas with high seroprevalence.

●Human papillomavirus and squamous skin cancers – The potential role of HPV infection in the pathogenesis of squamous cell skin cancers is discussed separately. (See "Epidemiology and risk factors for skin cancer in solid organ transplant recipients", section on 'Risk factors'.)

●Merkel cell polyomavirus and Merkel cell carcinoma – MCV is believed to be a contributing factor to Merkel cell carcinoma. The data supporting this relationship are discussed separately. (See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma", section on 'Pathogenesis'.)

Donor transmission — Unintended transmission of malignant cells from a donor is rare but may result in metastatic cancer in the immunosuppressed transplant recipient [42-48]. In a survey of a single kidney transplant center's experience, the risks of having a donor with an undetected malignancy and of transmitting the cancer were 1.3 and 0.2 percent, respectively [44].

This was also illustrated by a series from the Cincinnati Tumor Registry that included 22 patients who received donor hearts and/or lungs from patients who had a history of malignancy; malignant tumors subsequently developed in 45 percent of the recipients [48]. Almost all of these tumors were believed to have occurred because of the presence of occult malignant cells in the transplanted organ.

The risk of inadvertent transplantation of malignant cells appears to depend upon the type and extent of the donor's cancer. In the Cincinnati Tumor Registry report, although the numbers were small, the authors concluded that a history of renal cell cancer without capsular invasion appeared to be safe, but not if vascular invasion was present. No malignancy transmission was noted with central nervous system (CNS) tumors, with the exception of one medulloblastoma. By contrast, a history of melanoma or choriocarcinoma was associated with high rates of transmission, with early and almost universal death.

A variety of donor-transmitted malignancies have been documented including melanoma and cancers of the lung, breast, colon, rectum, and kidney, KS, and glioblastoma multiforme. In one review, malignancy developed in 78 of 142 (45 percent) patients who received a cadaver graft from a donor subsequently found to have a tumor. Metastatic disease occurred in 36, while complete remission occurred in 9 of the 20 patients treated with cessation of immunosuppression with or without graft nephrectomy. In comparison, transmission of nonmelanoma skin cancer and some CNS tumors appears to be rare, and the risk appears very low in donors with a past history of cancer but no evidence of current disease [49].

Cancer mortality — Cancer is one of the leading causes of death among solid organ transplant recipients, accounting for 13 to 20 percent of deaths in various studies [50-53]. Overall cancer mortality is approximately 2.3- to 2.8-fold higher among solid organ transplant recipients compared with the general population, and mortality is increased for most individual cancer sites, particularly non-Hodgkin lymphoma, kidney cancer, melanoma, and, among liver recipients, liver cancer [50-53]. Most of this increased risk is driven by de novo malignancies. (See "Kidney transplantation in adults: Patient survival after kidney transplantation", section on 'Causes of death'.)

COMMON CANCER TYPES IN TRANSPLANT RECIPIENTS

Skin cancers — Skin cancers, especially squamous cell and basal cell carcinomas, but also melanoma, Merkel cell carcinoma, and Kaposi sarcoma (KS), are more common than in the nontransplant population. The issues surrounding these malignancies are discussed separately:

●(See "Epidemiology and risk factors for skin cancer in solid organ transplant recipients".)

●(See "Prevention and management of skin cancer in solid organ transplant recipients".)

Kaposi sarcoma — Most cases of posttransplant KS occur in individuals of Mediterranean, Jewish, Arabic, Caribbean, or African descent [54]. This is a function of the geographic distribution of human herpesvirus 8 (HHV-8, also known as KS-associated herpesvirus). There is a male predilection (male to female ratio 3.3:1), and the average age at diagnosis is 43 years, younger than for patients with classic KS [55,56]. The average time to presentation is 13 to 21 months following transplantation [57]. (See 'Coexisting viral infection' above.)

The clinical presentation is similar to that of classic KS, manifested as angiomatous lesions predominantly affecting the legs and causing lymphedema. Although the incidence varies by population, approximately 90 percent of patients have cutaneous and/or mucosal lesions, while 10 percent have disease that is limited to the viscera [58,59]. For unclear reasons, visceral involvement is less common in patients with kidney as compared with liver or heart allografts (25 to 30 versus 50 percent). At least partly because of this, patients who develop KS after a liver or heart transplant have shorter survival than those who have undergone kidney transplantation [58,60].

KS may respond to reduction or discontinuation of the immunosuppressive regimen, and this should be the first therapeutic maneuver [57]. Among patients listed in the Cincinnati registry, for example, reduction in immunosuppressive therapy was associated with the disappearance of KS in 17 and 16 percent of patients with mucocutaneous disease and visceral involvement, respectively [61,62]. In addition, the substitution of sirolimus for cyclosporine in a total of 17 kidney transplant recipients has been associated with complete regression of KS [27,63]. Given these results, converting to sirolimus from a calcineurin inhibitor in this setting may be reasonable if there are no contraindications for this strategy. (See 'Reduction in immunosuppression' below.)

Additional treatment options, which may be required for cases that do not regress spontaneously, are similar to those considered for patients without immunosuppression. (See "AIDS-related Kaposi sarcoma: Staging and treatment".)

Lymphoproliferative disorders — The majority of malignant lymphoproliferative disorders occurring following solid organ transplantation are of B cell origin, most commonly non-Hodgkin lymphoma. T cell lymphoproliferative disorders have been described but are rare. These disorders are discussed in greater detail separately. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders".)

Anogenital cancers — Cancers involving the anogenital region (ie, anus, vulva, perianal region, penis, scrotum, or perineum) account for 2 to 3 percent of cancers in transplant recipients [64-66]. Lesions tend to be multiple and/or extensive, particularly in women, one-third of whom have concurrent cervical cancer. Clinically, these lesions often appear as pigmented papular lesions, but they may resemble genital warts.

Anogenital cancers present an average of 84 to 112 months following transplantation [57]. The latency is even longer among patients who received allografts as children, in whom the lesions often develop during adulthood (mean interval after transplantation was 142 months for carcinomas of the vulva and perineum in one series [67]).

In situ anogenital cancers can be treated with laser therapy, electrocautery, or topical fluorouracil. Topical imiquimod, which is available for the treatment of anogenital warts, has not been systematically studied in transplant recipients. Tapering the immunosuppressive regimen is beneficial and may lead to resolution of in situ carcinomas [68]. (See "Anal squamous intraepithelial lesions: Epidemiology, clinical presentation, diagnosis, screening, prevention, and treatment", section on 'Treatment' and "Vulvar squamous intraepithelial lesions (vulvar intraepithelial neoplasia)", section on 'Treatment'.)

Invasive tumors require wide local excision (eg, radical vulvectomy), with inguinal lymphadenectomy for tumors >1 mm thick and adjuvant therapy in selected patients (see "Vulvar cancer: Epidemiology, diagnosis, histopathology, and treatment"). The management of anal margin and anal canal lesions is discussed in detail elsewhere. (See "Clinical features and staging of anal cancer".)

Lung cancer — The incidence of lung cancer has been noted to be particularly increased in recipients of heart and lung transplants, and this may be related to the high incidence of cigarette smoking leading to heart and lung disease [69-72]. However, the incidence also appears to be increased following kidney and liver transplants [73].

Lung transplants are frequently carried out in patients with chronic obstructive lung disease secondary to smoking. In this setting, the incidence of lung cancer is markedly increased and frequently arises in the residual native lung in recipients of a single-lung transplant [74]. As an example, in a series of 520 lung transplants conducted at a single institution over a 17-year period, 12 patients developed lung cancer, 11 of which occurred in the residual native lung [72].

The increased incidence of lung cancer compared with the general population is similar to that seen in patients infected with HIV and thus may be a reflection of the role of chronic, prolonged immunosuppression. (See "HIV infection and malignancy: Management considerations", section on 'Lung cancer'.)

The management of lung cancer in recipients of heart or lung transplants is generally similar to that in nontransplant patients with lung cancer. The use of immune checkpoint inhibitors should be avoided, if possible, given the potential increased risk of organ rejection with this class of agents. (See 'Avoidance of immune checkpoint inhibitors' below.)

Liver cancer — The risk of liver cancer is markedly higher in liver transplant recipients compared with the general population [1]. The vast majority of these cancers are diagnosed within the first six months after transplantation. However, the risk of liver cancer does not appear to be higher in other solid organ transplant recipients. A more detailed discussion of liver cancer following liver transplantation is presented elsewhere. (See "Liver transplantation for hepatocellular carcinoma", section on 'Post-transplantation surveillance' and "Liver transplantation in adults: Long-term management of transplant recipients", section on 'Screening and prevention'.)

Kidney cancer — In kidney transplant recipients, kidney cancer can develop in both the remaining native kidney and in the transplanted kidney [75]:

●Kidney transplant recipients are at increased risk of developing carcinoma of the native kidneys, particularly if they have undergone prolonged periods of dialysis [76,77]. The incidence is approximately 100 times greater than expected [78,79]. Why this might occur is not known. It may be related in part to the factors that, during the period of advanced kidney failure, lead to tubular hyperplasia, cyst formation, and, in some cases, malignant transformation. (See "Acquired cystic disease of the kidney in adults".)

●Kidney tumors are rare in transplanted kidneys. A retrospective, multicenter study identified 20 patients with histologically confirmed tumors in a survey of 11 European centers [80]. Tumors were small (0.6 to 4 cm in diameter). Pathologically, 17 were papillary, and 3 were clear cell, in contrast to the predominance of clear cell tumors in other populations. All patients were successfully managed with either radiofrequency ablation or cryoablation and without a change in immunosuppression, although one patient developed a new tumor (clear cell carcinoma).

A number of options are available in the management of renal cell carcinoma (RCC) that emerges from a transplanted kidney [75,81]. In those without metastatic disease, total transplant nephrectomy may be curative, although a return to dialysis is required. Some have suggested that consideration may be given to nephron-sparing surgery in those with nonmetastatic RCC that is less than 4 cm in size and located peripherally [77,82]. This approach has been reported thus far in only a few cases [82]. Metastatic disease should be treated with cessation of immunosuppression, transplant nephrectomy, and immune therapy [77].

CANCER SCREENING — The ability to prevent and detect solid organ malignancies in the transplant patient, particularly early-stage cancers, relies upon periodic screening examinations and strict adherence to prophylactic measures. However, direct evidence to support specific screening practices in solid organ transplant recipients is lacking [83]. In general, we, and most transplant centers, perform age-appropriate cancer screening in solid organ transplant recipients that is similar to cancer screening recommended for the general population. For certain malignancies, such as skin cancer, liver cancer, cervical cancer, and anogenital cancers, more frequent screening than what is advised for the general population is suggested for solid organ transplant recipients. Screening recommendations for specific cancers are discussed in more detail separately:

●Screening recommendations similar to those for the general population:

•Breast cancer (see "Screening for breast cancer: Strategies and recommendations")

•Lung cancer (see "Screening for lung cancer")

•Prostate cancer (see "Screening for prostate cancer")

•Colon cancer (see "Screening for colorectal cancer: Strategies in patients at average risk" and "Screening for colorectal cancer in patients with a family history of colorectal cancer or advanced polyp")

●Screening recommendations tailored to solid organ transplant recipients:

•Skin cancer (see "Prevention and management of skin cancer in solid organ transplant recipients", section on 'Post-transplantation surveillance')

•Cervical cancer (see "Screening for cervical cancer in patients with HIV infection and other immunocompromised states", section on 'Immunosuppressed patients without HIV')

•Liver cancer (in liver transplant recipients) (see "Liver transplantation for hepatocellular carcinoma", section on 'Post-transplantation surveillance' and "Liver transplantation in adults: Long-term management of transplant recipients", section on 'Screening and prevention')

•Anal intraepithelial neoplasia (see "Anal squamous intraepithelial lesions: Epidemiology, clinical presentation, diagnosis, screening, prevention, and treatment", section on 'Who should be screened for anal SIL?')

MANAGEMENT

General preventive measures — The approach to posttransplant malignancies begins with general preventive measures, which include the following:

●Careful screening of the patient and donor prior to transplantation to help detect an underlying preexisting malignancy. (See "Kidney transplantation in adults: Evaluation of the potential kidney transplant recipient" and "Kidney transplantation in adults: Evaluation of the living kidney donor candidate", section on 'Malignancy'.)

●Avoidance of excess immunosuppression, especially with calcineurin inhibitors (CNIs), or repeated exposure to agents that selectively target T lymphocytes such as antithymocyte globulin (ATG) or OKT3. (See 'Immunosuppression' above and "Treatment and prevention of post-transplant lymphoproliferative disorders", section on 'Tapering immunosuppressive therapy'.)

●Sun-protective measures, such as sun avoidance and regular use of sunscreens and sun-protective clothing. These and other issues related to the prevention of skin cancer among solid organ transplant recipients are discussed in more detail elsewhere. (See "Prevention and management of skin cancer in solid organ transplant recipients", section on 'Prevention'.)

●Vaccination against human papillomavirus (HPV) for patients who have an age-based indication for HPV vaccination. (See 'Coexisting viral infection' above and "Immunizations in solid organ transplant candidates and recipients", section on 'Human papillomavirus' and "Human papillomavirus vaccination", section on 'Indications and age range'.)

●Some centers administer antiviral prophylaxis with acyclovir or valacyclovir to solid organ transplant recipients who are seronegative for Epstein-Barr virus but who receive organs from seropositive donors. Supportive evidence for this practice as well as other issues related to the prevention of posttransplant lymphoproliferative disorder (PTLD) are discussed in more detail separately. (See "Treatment and prevention of post-transplant lymphoproliferative disorders", section on 'Antiviral prophylaxis'.)

Patients with a de novo cancer after transplant

Reduction in immunosuppression — Reduction or cessation of immunosuppressive therapy is useful primarily for patients who have undergone kidney transplantation since loss of the graft to rejection is not a fatal event in these patients. However, a reduction in immunosuppression may also be tolerated in heart, lung, or liver recipients. Such measures may result in tumor regression in some cases of lymphoma; some skin cancers; Kaposi sarcoma (KS), in which reducing the CNI exposure may be particularly important [62,65,84,85]; and donor-derived malignancies. (See "Treatment and prevention of post-transplant lymphoproliferative disorders", section on 'Treatment' and 'Kaposi sarcoma' above.)

For most solid organ transplant recipients with a de novo cancer after transplant, we suggest a reduction in immunosuppression rather than continuing standard immunosuppression. The optimal approach to reducing immunosuppression in this setting is uncertain, and strategies vary depending upon the cancer type and type of organ transplant. We take the following approach:

●For transplant recipients with a de novo cancer other than KS or PTLD, we suggest discontinuing the antimetabolite rather than discontinuing the CNI or switching from a CNI to a mammalian (mechanistic) target of rapamycin (mTOR) inhibitor. Despite the association of the CNIs with increased transforming growth factor-beta levels and the risk of malignancy, rejection is less likely to occur with double therapy with a CNI and prednisone than the combination of an antimetabolite with prednisone. In addition, substituting mTOR inhibitor therapy in place of CNIs has fallen into disfavor for most cancers due to the adverse impact on overall survival [31,86]. (See 'Immunosuppression' above.)

An exception to this approach is in very well-matched human leukocyte antigen (HLA) transplant recipients, such as 0-HLA or 0-B, 0-DR mismatched recipients, in whom the risk of rejection is low with the combination of an antimetabolite and prednisone. In such patients, discontinuing the CNI, rather than the antimetabolite, may be reasonable. This combination also avoids the nephrotoxicity and malignancy potential associated with a CNI.

●For transplant recipients with posttransplant KS, we suggest switching from a CNI to an mTOR inhibitor rather than discontinuing the antimetabolite. In such patients, switching from a CNI to an mTOR inhibitor has been associated with disease regression in one observational study [27,63]. Some experts switch from a CNI to an mTOR inhibitor in transplant recipients receiving checkpoint inhibitor immunotherapy, although there is no high-quality evidence to support this approach. (See 'Immunosuppression' above and 'Avoidance of immune checkpoint inhibitors' below.)

●The reduction of immunosuppression in transplant recipients with PTLD is discussed separately. (See "Treatment and prevention of post-transplant lymphoproliferative disorders", section on 'Reduction in immunosuppression'.)

Data evaluating the efficacy and safety of reducing immunosuppression in transplant recipients with a de novo cancer are limited to mostly observational studies. These data are presented elsewhere. (See "Prevention and management of skin cancer in solid organ transplant recipients", section on 'Reduction of immunosuppressive therapy' and "Treatment and prevention of post-transplant lymphoproliferative disorders", section on 'Reduction in immunosuppression'.)

If evaluation of the tumor reveals it to be of donor origin, reduction of immunosuppression may theoretically lead to rejection of the tumor. Although this has been effective in PTLD, there is little evidence that this is effective in other tumors [56].

Avoidance of immune checkpoint inhibitors — In general, solid organ transplant recipients with a de novo cancer after transplant can be managed with the same therapeutic approaches used to treat nontransplant patients with cancer, without concern that such therapies may lead to organ rejection or loss of the transplant. One exception, however, is the use of checkpoint inhibitor immunotherapy (ie, cytotoxic T-lymphocyte antigen 4 and programmed cell death 1 antibodies), which should be avoided, if possible, in solid organ transplant recipients due to the increased risk of organ rejection with this class of agents. If checkpoint inhibitors are used, adjustment of the maintenance immunosuppression regimen may be warranted, although the optimal approach to this is not known. Some experts prefer to use low-dose tacrolimus (target trough level 3 to 5 ng/mL) and prednisone; other experts favor switching to an mTOR inhibitor and prednisone. (See 'Reduction in immunosuppression' above.)

Several studies have shown that the use of immune checkpoint inhibitors in solid organ transplant recipients with cancer has been associated with an increased risk of rejection [87-90]. As examples:

●In a systematic review of case series and reports that included 64 solid organ transplant recipients (39 kidney, 19 liver, and 5 heart) treated with checkpoint inhibitors, the overall rate of graft rejection was 41 percent [90]. Graft rejection occurred in 44, 39, and 20 percent of kidney, liver, and heart transplant recipients, respectively.

●In a multicenter retrospective analysis of 69 kidney transplant recipients who received a checkpoint inhibitor (mostly for cutaneous squamous cell carcinoma and melanoma), 29 patients (42 percent) developed acute rejection and 19 lost their allograft [88]. By comparison, rejection occurred in only 5 percent of cancer stage-matched transplant recipients who were not treated with a checkpoint inhibitor.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kidney transplantation".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology and risk factors – There is an increased risk of a wide range of cancers associated with solid organ transplantation. The incidence of specific malignancies appears to vary depending upon the organ transplanted. Several factors have been linked to the increased incidence of secondary malignancies among transplant recipients, including sun exposure; type, extent, and duration of immunosuppression; and concomitant viral infection. In rare cases, malignancy has been transplanted from the donor. (See 'Incidence' above and 'Risk factors for malignancy' above.)

●Common cancer types – Common cancer types among solid organ transplant recipients include skin cancers, Kaposi sarcoma (KS), lymphoproliferative disorders, anogenital cancers, lung cancer, liver cancer (in liver transplant recipients), and kidney cancer (in kidney transplant recipients). (See 'Common cancer types in transplant recipients' above.)

●Cancer screening – The ability to prevent and detect solid organ malignancies in the transplant patient, particularly early-stage cancers, relies upon periodic screening examinations and strict adherence to prophylactic measures. However, direct evidence to support specific screening practices in this population is lacking. In general, we, and most transplant centers, perform age-appropriate cancer screening in solid organ transplant recipients that is similar to cancer screening recommended for the general population. For certain malignancies, such as skin cancer, liver cancer, cervical cancer, and anogenital cancers, more frequent screening than what is advised for the general population is suggested for solid organ transplant recipients. (See 'Cancer screening' above.)

●Management

•Preventive measures – The approach to posttransplant malignancies begins with general preventive measures. In particular, excess immunosuppression or repeated exposure to antilymphocyte drugs should be avoided. Careful screening of the patient and donor prior to transplantation to help detect an underlying, preexisting malignancy should also be performed. (See 'General preventive measures' above.)

•Reduction in immunosuppression – For most solid organ transplant recipients with a de novo cancer after transplant, we suggest a reduction in immunosuppression rather than continuing standard immunosuppression (Grade 2C). For transplant recipients with a de novo cancer other than KS or posttransplant lymphoproliferative disorder (PTLD), we suggest discontinuing the antimetabolite rather than discontinuing the calcineurin inhibitor (CNI) or switching from a CNI to a mammalian (mechanistic) target of rapamycin (mTOR) inhibitor (Grade 2C). For transplant recipients with posttransplant KS, we suggest switching from a CNI to an mTOR inhibitor rather than discontinuing the antimetabolite (Grade 2C). The management of immunosuppression among those with PTLD is presented separately. (See 'Reduction in immunosuppression' above and "Treatment and prevention of post-transplant lymphoproliferative disorders", section on 'Reduction in immunosuppression'.)

•Other transplant-specific considerations – In general, transplant recipients with a de novo cancer after transplant can be managed with the same therapeutic approaches used to treat nontransplant patients with cancer, without concern that such therapies may lead to organ rejection or loss of the transplant. However, the use of checkpoint inhibitor immunotherapy should be avoided, if possible, due to the increased risk of organ rejection with this class of agents. (See 'Avoidance of immune checkpoint inhibitors' above.)