Incidence, screening, and management of de novo malignancies in liver transplant patients: A review

Abstract

Liver transplantation (LT) is the definitive treatment for end-stage liver disease, acute liver failure, and liver cancer. Although advancements in surgical techniques, postoperative care, and immunosuppressive therapies have significantly improved outcomes, the long-term use of immunosuppression has increased the risk of complications, including infections, cardiovascular disease, and cancer. Among these, de novo malignancies (DNMs) are a major concern, accounting for 20%-25% of deaths in LT recipients surviving beyond the early post-transplant period. Non-melanoma skin cancers, particularly squamous cell carcinoma are the most prevalent DNMs. Other significant malignancies include Kaposi's sarcoma, post-transplant lymphoproliferative disorders, and various solid organ cancers, including head and neck cancers. Compared to the general population, LT patients face a twofold increase in solid organ malignancies and a 30-fold increase in lymphoproliferative disorders. Risk factors for DNM include chronic immunosuppression, alcohol or tobacco use, viral infections, and underlying liver disease. Emerging evidence emphasizes the importance of tailored cancer screening and prevention strategies, including regular dermatological examinations, targeted screenings for high-risk cancers, and patient education on lifestyle modifications. Early detection through enhanced surveillance protocols has been shown to improve outcomes. Management of DNMs involves a combination of standard oncological therapies and adjustments to immunosuppressive regimens, with promising results from the use of mTOR inhibitors in select patients. The review highlights the critical need for ongoing research to refine risk stratification, optimize screening protocols, and improve treatment approaches to mitigate the burden of DNMs in LT recipients. By implementing personalized preventive and therapeutic strategies, we can enhance long-term outcomes and quality of life for this vulnerable population.

Key Words: Liver transplant; De novo malignancy; Immunosuppression; Post-transplant lymphoproliferative disorder; Screening; Squamous cell cancer

Core Tip: Liver transplantation (LT) is crucial for treating severe liver conditions, but it increases the risk of new cancers, especially non-melanoma skin cancers like squamous cell carcinoma. LT recipients also have a higher chance of developing solid organ cancers and lymphoproliferative disorders compared to the general population. Key risk factors include chronic immunosuppression, alcohol or tobacco use, and viral infections. Effective management involves regular cancer screenings, early detection, and adjusting immunosuppressive treatments, particularly for Kaposi's sarcoma and post-transplant lymphoproliferative disorders.

INTRODUCTION

Liver transplant (LT) is the definitive treatment for decompensated end-stage liver disease, acute liver failure, and liver cancer. Advancements in LT techniques, postoperative care, and long-term immunosuppressive agents have significantly increased the number of recipients and markedly improved long-term survival. However, while long-term immunosuppression is required, it is associated with an increased risk of complications, such as infections, cardiovascular events, renal injury, and cancer. Notably, retrospective studies have highlighted that de novo malignancy (DNM) accounts for 20%-25% of deaths in patients who survive the early post-transplant period[1-3].

Compared to the general population, LT recipients face a two-fold increase in the incidence of solid organ malignancies and a dramatic 30-fold increase in the risk of lymphoproliferative disorders[4-8]. Risk factors for developing DNM in LT recipients include chronic immunosuppression, a history of alcohol or tobacco use, oncogenic viral infections, and underlying liver disease. This review aims to summarize the current literature on the incidence, risk factors, screening, and management of de novo malignancies following liver transplantation.

INCIDENCE

Skin malignancies

Non-melanoma skin cancers (NMSC) are the most prevalent type of cancer among Caucasian solid organ transplant recipients. The occurrence of NMSC in LT patients is more than 15 times higher than in the general population[9,10]. Squamous cell cancer (SCC) is the most prevalent type of skin cancer in LT recipients, whereas basal cell cancer (BCC) is more common in the general population. There have also been reports of Merkel cell carcinoma occurring following liver transplantation[11,12]. NMSCs often occur as a late complication following liver transplantation, with an average time from transplant to diagnosis of 50 months (Table 1)[13,14]. Fortunately, NMSCs generally do not impact mortality but can affect quality of life and require ongoing monitoring.

Table 1 Incidence of de novo malignancies in liver transplant recipients in various studies, n (%).

Ref.	Country	Study period	No. of LT patients included in the study	Follow up period	Interval to DNM	Overall Incidence of DNM	Common malignancies (%)	Overall SIR
Frezza et al[115]	United States	Before 1992	1657	-	-	64 (3.8)	Basalioma 25%, SCC 20.3%, melanoma 6.2%	-
Krynitz et al[116]	Sweden	1970-2008	1221	20	-	(27)	-	All cancer: 3.4 (2.9-4.0); non-SCC: 2.3 (1.9-2.8); all skin cancer: 16 (12-20); SCC: 32 (24-42)
Haagsma et al[117]	The Netherlands	1979-1996	174	5.9	5.1	23 (12)	Skin and lip cancers 52%	4.3
Oo et al[118]	United Kingdom	1982-2004	1778	6.5	-	141 (7.9)	Skin cancer excluding melanoma 36.1%, lymphoma 12.7%, large bowel cancer 12.7%, lung cancer 10%	2.1
Aberg et al[5]	Finland	1982-2005	540	6.3	5.1	39 (7.2)	Nonmelanoma skin cancer 25.6%, non-Hodgkin lymphoma 20.5%	2.59
Finkenstedt et al[51]	Austria	1982-2007	779	4.1	4.4	105 (12.3)	Skin cancer 17%, lung cancer16%, oropharyngeal carcinoma 11%	1.9
Jiang et al[119]	Canada	1983-1998	2034	3.5 ± 2.8	3.5 ± 2.8	113 (5.5)	Non-Hodgkins lymphoma 35.3, colorectal cancer 12.3, lung cancer 8.8%	2.5
Schrem et al[120]	Germany	1983-2010	2000	7.3	6.8	120 (6)	PTLD 19.12%, lung cancer 11.6%, colorectal cancer 10.8%, gynecological cancer 8.03%, breast cancer 6.6%, gastric/esophageal cancer 5.8%	2
Galve et al[121]	Spain	1984-1996	1827	-	2.5 ± 1.8	70 (3.83)	-	-
Mouchli et al[122]	United States	1984-2012	293	11.5	-	73 (25)	PTLD 30.1%, SOT 63%	-
Sanchez et al[123]	United States	1985-1999	1421	5.5 ± 3.7	-	123 (88)	Skin cancer 32.8%, lymphomas 25%, lung cancer 8%, colon cancer 5%	-
Wimmer et al[124]	Germany	1985-2007	609	4.8	5.7 ± 3.7	87 (14.2)	SCC 15%, BCC 27.6%	-
Taborelli et al[125]	Italy	1985-2014	2818	NA	NA	244 (8.6)	-	-
Shalaby et al[126]	Italy	1985-2014	2653	3.6 for HCC, 6.6 non-HCC	2.7 in HCC, 4.5 in non- HCC patients	62 (6.6) in HCC patients, 127 (7.4) in non-HCC patients	-	-
Jiménez et al[127]	Spain	1986-2000	505	-	-	62 (12.3)	Skin cancer and Kaposi sarcoma 25.8%, PTLD 21.6%, head and neck cancer 16%	-
Tjon et al[128]	Denmark	1986-2007	385	-	-	66 (17.1)	non-melanoma skin cancer 55%, PTLD 21%	2.2
Engels et al[7]	United States	1987-2008	37888	-	-	1563 (4.1)	PTLD- 23.3%	-
Jonas et al[129]	Germany	1988-1994	458	4.2	3.6	33 (7.2)	Skin cancer 24%, PTLD 21%, gynecological cancer 21%	-
Kelly et al[130]	United Kingdom	1988-1996	888	-	2 ± 1.5	31 (3.4)	Skin cancer and Kaposi sarcoma 25.8%, lung cancer 3%	-
Saigal et al[14]	United Kingdom	1988-1999	1140	-	3.8 ± 2.8	30 (2.6)	Skin cancer 43%, oropharyngeal cancer 6%, bladder cancer 6%, acute leukemia 6%	-
Yao et al[131]	United States	1988-2000	1043	6.7	-	53 (5)	Skin cancer 32%, GI cancer 21%, hematologic malignancies 17%	-
Rademacher et al[69]	Germany	1988-2006	1616	14	-	322 (19.9)	Skin 25.7%, hematological 15.2%, solid organ tumors 60%	-
Watt et al[37]	United States	1990-1994	798	10	-	271 (34)	Skin cancer 54.2%, hematologic malignancy 10.7%, solid organ cancer 35%	-
Herrero et al[15]	Spain	1990-2001	187	5.5	-	63 (33)	Cutaneous neoplasia 55.5%, non-cutaneous neoplasia 44.4%	-
Ettorre et al[132]	Italy	1990-2008	1675	5.2	3.2	98 (5.9)	PTLD 18.4%, head and neck cancer 19.3%, lung cancer 13.2%, colorectal cancer 11.2%, Kaposi's sarcoma 6.2%	-
Tajima et al[133]	Japan	1990-2020	1781	Approximately 12 years	-	153 (8.6)	PTLD 53%, colorectal 9.1%, lung 7.8%, gastric 7.8%	SIR1993-1995: 8.12, SIR1996-1998: 3.11, SIR2005-2007: 1.31, SIR2008-2010: 1.34, SIR2014-2016: 2.27, SIR2017-2019: 2.07
Benlloch et al[71]	Spain	1991-2001	772	4.3	-	41 (5.3)	Solid organ tumours 75.6%, hematologic cancer 24.3%	-
Baccarani et al[8]	Italy	1991-2005	417	6.7	4.2	43 (10.3)	Non-Hodgkin lymphoma 21%, head and neck cancer 18.6%, Kaposi sarcoma 14%	-
Sanaei et al[134]	Iran	1992-2012	1700	-	5.5	38 (2.2)	PTLD 63%, GI cancer 10.5%	-
Sérée et al[101]	France	1993-2012	11226	-	-	1200 (10.7)	Lung cancer 15.6%, esophagus, stomach, colorectal 11.8%, larynx 6.3%, oral/pharynx 6%	For all solid organ malignancies 2.2
Jain et al[87]	United States	1996-2006	1000	6.5 ± 1	3	57 (5.7)	Skin cancer including melanoma 38.6%, lung cancer14% oropharyngeal cancer 12.2%	-
Chatrath et al[1]	United States	1997-2004	534	5.7 ± 3.2	4 ± 2.2	80 (15)	Solid tumors 50%, skin cancer 30%, hematologic malignancy 20%	3.1
Yeh et al[135]	Taiwan	1997-2011	2127	4.2	-	111 (5.2)	-	1.5
Park et al[136]	South Korea	1998-2008	1952	3.5 ± 2.8	3.4 ± 2.4	44 (2.3)	Stomach 25%, colorectal cancer 20.4%, breast cancer 9%	7.7 for men and 7.3 for women
Egeli et al[137]	Türkiye	1998-2016	429	8.6	5.3	9 (2)	Lung cancer 44.4%	-
Kobayashi et al[138]	Japan	1999-2022	70	12.1	-	8 (11.4)	Lung cancer 50%, PTLD 37.5%, skin cancer 12.5%	-
Lucidi et al[139]	Italy	2000-2015	789	6.75	4	67 (5.5)	Lung 16.4%, head and neck 16.4%, PTLD 13.4%, breast 7.4%	-
Mangus et al[140]	United States	2001-2011	1275	-	-	180 (14)	Skin cancer 59.4%, GI malignancy 10.5%	-
Yu et al[141]	China	2005-2011	569	3.5 ± 2.2	-	18 (3.2)	PTLD 16.7%	-
Antinucci et al[142]	Argentina	2006-2014	159	1.1	1.3	12 (7.5)	Skin cancer 33.3%	-
Tiwari et al[143]	India	2006-2017	2100	3.5	-	21 (1)	Oropharyngeal cancer 33.3%, lung cancer 19%, SCC 9.5%	-

LT: Liver transplant; DNM: De novo Malignancies; SIR: Standardized incidence ratio; PTLD: Post-transplant lymphoproliferative disease; SCC: Squamous cell cancer; BCC: Basal cell cancer; HCC: Hepatocellular carcinoma; SOT: Solid organ tumors; NA: Not available; GI: Gastrointestinal.

In a retrospective study the reported rates of cutaneous neoplasia to be 14% at 5 years and 24% at 10 years, while the rates for non-cutaneous neoplasia were noted to be 11% at 5 years and 22% at 10 years[15]. In a study with 151 LT patient, the overall incidence of skin cancers in LT recipients was 22.5%, with SCC being the most frequently observed neoplasm[16]. In a prospective cohort study of 161 adults, the prevalence of pre-malignant and neoplastic skin lesions was noted to increase over time (5% at 2-3 years, 12% at 3-5 years, and 28% beyond 5 years)[17]. Meanwhile, the frequency of malignant lesions was 0% at 2-3 years, 9% at 3-5 years, and 12% after more than 5 years of follow-up post-transplantation.

Kaposi's sarcoma (KS) is a multifocal antiproliferative neoplasm that affects the mucous membranes and skin, driven by human herpesvirus 8 (HHV-8) infection, and comprises approximately 4% of all tumors seen post-transplant[18,19]. It exclusively manifests in immunocompromised hosts[20]. A higher prevalence of KS in specific ethnic groups corresponds with regions where HHV-8 seroprevalence is elevated, such as Central and South Africa, the Mediterranean, the Caribbean, and the Middle East[21]. Solid organ transplant recipients have a 500-fold increased risk of developing KS compared to the general population[19]. Nearly all documented cases of KS are found on the skin, although some visceral cases with poor prognosis have also been reported[22].

Hematological malignancies

Post-transplant lymphoproliferative disorders (PTLDs) are the next most common DNM in LT recipients. The overall incidence of PTLD in adults ranges from 1% to 5.5% in adults and up to 15% in children[4,23,24]. PTLD typically presents within one year of LT but may present as early as 20 days or as late as several decades after the transplant. Higher doses of immunosuppression after the LT are suspected to be the cause of higher incidence early on. Early-onset PTLDs are characterized by the outgrowth of Epstein-Barr Virus (EBV) infected B lymphocytes which occurs due to profound impairment of T lymphocytes applied to prevent graft rejection[25]. Late-onset PTLD usually presents as aggressive tumors with monoclonal proliferation and a lack of EBV genome tumor cells[26-28].

Solid organ malignancies

Approximately 1% of LT recipients develop solid organ cancers each year. The overall incidence of these malignancies ranges from 3% to 15% following transplantation[3,29]. Liver transplantation is associated with a two to five-fold increase in the risk of developing solid organ cancers compared to the general population[30]. In contrast to PTLD, solid organ cancers are more frequently observed after the first year following transplantation, do not particularly affect children, and are linked to older recipient age[3]. Higher risk has been noted in specific patient populations within the LT community, including those with a history of alcoholic liver disease (ALD) and primary sclerosing cholangitis (PSC)[31]. Recent studies show that solid organ tumors have become the most prevalent malignancies in LT recipients, surpassing skin cancers and PTLDs[32].

SKIN CANCER

Risk factors

Risk factors for developing skin cancer include advancing age, prolonged and intensive immunosuppressive therapy, infection with human papillomavirus (HPV), extensive ultraviolet exposure, skin that burns easily (particularly skin phototypes II and III), a history of actinic keratosis, previous history of neoplasia [hepatocellular carcinoma (HCC) or other non-skin cancer], CD4 Lymphocytopenia, and having blue or hazel eyes (Figure 1)[15-17,33,34]. Male sex, red hair, Caucasian background, and monoclonal antibody induction therapy are additional risk factors noted in LT recipients[3,16,35]. A heightened risk of developing skin cancer is seen in patients who undergo liver transplantation for PSC, or ALD compared to those with other underlying conditions[14,16,34,36,37].

Figure 1 Risk factors for de novo skin cancer development in liver transplant recipients. HPV: Human papilloma virus; ALD: Alcoholic liver disease; PSC: Primary sclerosing cholangitis; LT: Liver transplant.

Studies have noted that cyclosporine A (CsA) is one of the most significant predictor of skin malignancy. Patients receiving CsA developed skin cancer more rapidly than those treated with tacrolimus[16]. Thus, CsA is considered an independent and specific risk factor for skin cancer in post-LT patients[34,38]. Similarly, azathioprine has been postulated to elevate the risk of developing squamous cell carcinoma of the skin in organ transplant recipients, including LT patients[39-41]. Although immunosuppression with CsA and azathioprine is a significant risk factor for NMSC, the extent of immunosuppression likely represents the main risk rather than the specific agent chosen[20,42].

Primary risk factors for KS include viral infections such as hepatitis B virus (HBV), cytomegalovirus, and EBV, but the most significant risk factor is HHV-8[43,44]. Also, there is a strong association between immunosuppression and the development of KS[18]. Therefore, customizing immunosuppressive therapy and carefully managing chemotherapy is essential to prevent the onset of KS[34]. Although ongoing trials are exploring new treatments for KS, current evidence indicates that changing the immunosuppressive regimen from CsA/tacrolimus to mTOR inhibitors is the most effective strategy for reducing the progression of KS[34,45,46].

Screening and prevention

Currently, there is limited data regarding the effectiveness of surveillance strategies for skin cancers following liver transplantation. It's essential to remain vigilant and implement surveillance strategies that target common DNMs in patients who are at higher risk[47]. Individuals with risk factors like alcohol consumption and smoking might require more frequent screenings. At the very least, standard cancer screening protocols used for the general population should be applied[47]. It is advised that all transplant recipients have regular dermatological check-ups with their healthcare providers, who should maintain a low threshold for performing biopsies or removing any suspicious skin lesions[3,48]. All LT recipients should undergo a full-body skin examination by a dermatologist once yearly[29,47,49,50]. Earlier examination, i.e., dermatological assessments every three to six months is recommended in patients with risk factors, particularly in LT recipients with a previous history of skin cancer, or as advised by their dermatologist[17,32,47-49]. All LT recipients should be informed that they have a higher risk of developing skin cancer compared to the general population. They should also be educated on how to protect their skin, including using sunscreen, and wearing hats, protective clothing, and sunglasses[13,29,47].

In a prospective cohort study, 779 consecutive LT recipients were followed, among which 96 patients (12.3%) developed 105 malignancies. The most common types of tumors were skin cancer (17%), lung cancer (16%), oropharyngeal cancer (11%), and prostate cancer (11%). Patients who were diagnosed at early stages with skin cancers and solid tumors had excellent outcomes. After implementing a more intensive surveillance protocol, the detection rate of de novo cancers increased from 4.9% to 13%, leading to more early-stage diagnoses of de novo malignancies. This study concluded that an extensive tumor surveillance program was highly recommendable for LT recipients[51].

Screening for KS is challenging because the HHV-8 viral load in affected individuals is often very low, detectable in less than half of the cases. Moreover, there is a lack of standardized serological tests for this condition[41,52-54].

Management

Overall, the management of malignant neoplasms in LT recipients aligns with that of immunocompetent patients, utilizing surgery, chemotherapy, and radiotherapy. However, the management of these neoplasms differs as here the major focus is on modifying immunosuppressive therapy, particularly for tumors that are highly sensitive to immunosuppression, such as KS and PTLD[18].

SCC: Superficial SCC can be managed using cryotherapy, electrocautery, and curettage, while invasive SCC requires wide local excision[55,56]. These invasive forms are typically aggressive and carry a high risk of recurrence and metastasis at the time of diagnosis.

BCC: The standard treatment for BCC continues to be surgical excision. Reducing immunosuppression in patients with recurrent basal cell carcinomas can help prevent additional recurrences[55]. In older patient populations radiotherapy is a suitable alternative to surgical methods. Electrodesiccation and curettage are frequently employed as primary treatments for low-risk lesions. Photodynamic therapy, along with topical treatments such as imiquimod and 5-fluorouracil, are also viable options[56].

Malignant melanoma: Treatment for malignant melanoma includes reducing immunosuppression and performing surgical excision, with or without sentinel lymphadenectomy[55,56].

Merkel-cell carcinoma: Localized Merkel cell cancer in transplant recipients is treated similarly to how it is in patients who are not immunosuppressed. If there is distant metastasis, temporarily discontinuing cyclosporine may elicit a response. However, the overall prognosis for Merkel cell carcinoma in immunosuppressed patients is poor[55,56].

KS: There is no established consensus on the optimal treatment for post-transplant KS. Treatment decisions are typically guided by clinical experience and medical expertise. Various treatment modalities have been employed, including surgical excision, radiation therapy, intralesional chemotherapy injections, reducing immunosuppressive therapy, and systemic chemotherapy[57]. In transplant patients, full recovery from KS has been observed after reducing immunosuppressive therapy or changing the immunosuppressive regimen to sirolimus[31,58,59]. Research indicates that using immunosuppressive treatments such as Sirolimus or Everolimus may lead to the regression of iatrogenic KS due to their antiangiogenic effects[60,61]. These properties are linked to reduced production of vascular endothelial growth factor (VEGF) and a constrained proliferative response of endothelial cells to VEGF[60]. Furthermore, Nichols et al[62] has suggested that mTOR inhibitors might help prevent KS in immunosuppressed individuals by inhibiting HHV-8 production through the modulation of replication and transcription activator expression.

If reducing or stopping immunosuppressive therapy does not yield results, conventional chemotherapy may be necessary. Pegylated liposomal doxorubicin is often the preferred first-line treatment, with around 70% of patients experiencing a complete or significant response[56,63]. Other cytotoxic drugs that have shown effectiveness in treating KS include vinblastine, bleomycin, taxanes, etoposide, and gemcitabine. Some data suggests that prophylactic treatment with ganciclovir or other antiviral therapy against HHV-8, along with other treatments may benefit patients who are at high risk, as noted in some observational studies[56,64].

HEMATOLOGICAL (LYMPHOPROLIFERATIVE) MALIGNANCIES

Risk factors

Due to improvements in immunosuppression and supportive treatments, LT recipients have increased overall survival (OS), which increases the likelihood of developing de novo malignancies. Aggressive immunosuppression leads to stronger immune impairment and increases the risk of developing PTLD with cumulative incidence of PTLD over five years in LT recipients close to 1%-2%[65]. There is a significantly higher risk in the first year after transplantation. Moreover, the type of immunosuppression employed may play a role, with the use of tacrolimus resulting in a higher risk of PTLD compared to another calcineurin inhibitor (CNI), cyclosporine[66]. Agents suppressing T cell function have a greater likelihood of causing PTLD.

The majority of PTLDs have a B cell origin and are strongly associated with EBV infection. EBV-negative recipients receiving a LT from an EBV-positive donor have an exponentially greater risk of developing PTLD when compared to EBV-positive recipients due to no prior immunity to EBV[67]. Furthermore, CMV sero mismatch can potentially increase the risk. EBV-negative PTLD is less commonly encountered and found to be biologically different from EBV-positive disease. Some may arise from EBV infections which are undetectable now[68].

A single-center German study discovered a significantly higher incidence of hematological malignancies in recipients with hepatitis C virus (HCV) leading to LT[69]. Moreover, this relationship was observed in a systematic review, with the hypothesis being chronic stimulation of immune cells, primarily B cells, in patients with HCV infection[70,71]. Conversely, a large retrospective study out of France did not report any relationship between the HCV as the etiology of liver disease and a higher incidence of de novo hematological malignancies[72].

Clinical presentation

Most of the cases display constitutional symptoms of fevers, night sweats, weight loss, and lead to lymphadenopathy. Half of the cases present with extra-nodal involvement, affecting numerous organs including the liver, lungs, and central nervous system (CNS). Lab abnormalities can also aid in diagnosing PTLD which can present with unexplained cytopenias, elevated LDH, hyperuricemia, hypercalcemia, or the presence of monoclonal protein.

There are four different types of PTLD: Nondestructive (early stage), polymorphic, monomorphic, and classic Hodgkin lymphoma (cHL)[73]. Early-stage PTLD comprises benign polyclonal proliferation without destruction of the normal architecture of the involved tissue. The polymorphic type consists of lymphoid cells that do not fulfill the immunocompetent B cell or T/NK cell lymphoma criteria. The monomorphic type includes PTLD that fulfills the B cell or T/NK cell lymphomas criteria established in immunocompetent individuals. They include diffuse large B cell lymphoma, Burkitt lymphoma, Plasma cell myeloma, T cell lymphoma. cHL is the rarest PTLD type. Patients with high international prognostic index scores, bulky disease, EBV negativity, CNS and bone marrow involvement have a worse prognosis[74]. Moreover, earlier presentations after transplant confers a poor prognosis.

Screening and prevention

There are no screening guidelines in place for the detection of hematological malignancies after LT and the protocols are institution specific. Earlier tapering or withdrawal of immunosuppressants accompanied with anti-viral prophylaxis can reduce the risk of PTLD incidence. Lower targets of immunosuppressive agents’ serum concentrations without compromising the risk of transplanted liver rejection can lower the incidence. Seropositive donors should be avoided in seronegative recipients if possible. Routine monitoring of EBV DNA viremia and pre-emptive adjustment of immunosuppression in transplant recipients with rising viral loads can prevent overt PTLD emergence[75]. Some cases of viral reactivation alone may need initiation of anti-CD20 monoclonal antibody, rituximab. Since most of the cases occur in the first year after transplantation, aggressive monitoring of high-risk patients is warranted initially, and the frequency can be subsequently reduced with time.

Management

LT recipients presenting with constitutional symptoms without an explainable infectious etiology or without any concerns for organ rejection should have PTLD in the differential. Evaluation should involve LDH levels, positron emission tomography, and EBV viral load. Magnetic resonance imaging of the head and cerebrospinal fluid assessment should be performed if CNS PTLD is suspected.

The backbone of PTLD management rests on achieving complete remission with minimal toxicities. Antiviral therapy for EBV+ PTLD has not been shown to be effective. Most patients will respond to a reduction in immunosuppression, focusing on discontinuing antimetabolites such as azathioprine or mycophenolate, accompanied by decreasing the dose of CNIs like cyclosporine or tacrolimus, usually to 25%-50% of baseline. Close collaboration with the transplant team is vital as numerous factors, including transplant timing and previous rejection episodes, play a role in deciding the treatment modality. Moreover, different centers have different protocols in place for PTLD management. The subtype of PTLD will dictate the upfront treatment with early lesions responding to immunosuppression reduction alone. These lesions typically resolve in three to five weeks after immunosuppression reduction[76]. The polymorphic subtype requires rituximab along with reduced immunosuppression and chemotherapy for relapsed/refractory cases. Monomorphic PTLD patients will benefit from upfront chemo-immunotherapy. Some centers discontinue antimetabolites and CNIs completely while placing patients on low-dose prednisone and start mTOR inhibitors after chemotherapy completion to allow better tolerance to full-dose chemotherapy.

Combining rituximab (anti-CD20 monoclonal antibody) with reduced immunosuppression has shown significantly improved OS in PTLD patients at 73% vs 33% when compared to reduced immunosuppression only[77]. Another study, called the PTLD-1 trial, evaluating sequential treatment with four cycles of Rituximab followed by four cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), demonstrated a 57% complete response (CR)[78]. This study was followed by a risk-stratified chemoimmunotherapy approach where PTLD patients with rituximab induction who did not achieve CR received R-CHOP, whereas patients achieving CR got rituximab maintenance instead[79]. The study reported about 25% of patients not requiring chemotherapy with a median OS of 6.6 years. This sequential approach has become the standard treatment modality in newly diagnosed PTLD patients. R-EPOCH administration is another approach that can be considered in high-grade PTLD cases and BCL2/MYC rearrangements[80].

Other therapies, including combinations of rituximab/ibrutinib and rituximab/brentuximab vedotin (anti-CD30 antibody-drug conjugate), have not shown any improvements in responses and are associated with significant side effects, especially with brentuximab vedotin[81,82]. Resection of PTLD lesions is rarely performed except in patients with gastrointestinal involvement at risk for obstruction and perforation.

Relapsed PTLD after exposure to chemoimmunotherapy is challenging. A retrospective analysis of EBV+ relapsed PTLD patients demonstrated a median OS of 4.1 months after relapse[83]. HLA-matched EBV-stimulated T cells, named tabelecleucel, were studied in the relapsed setting in the phase 3 ALLELE study, which resulted in CR in 12 out of 43 enrolled patients, leading to regulatory approval by the European Medicine Agency in 2022[84]. Brentuximab can also be used in the relapsed setting. Epigenetic therapy combining the histone deacetylase inhibitor Nanatinostat with valganciclovir has been studied in relapsed/refractory EBV+ PTLD, with 1 CR achieved in 4 patients[85]. Platinum-based salvage chemotherapy, CAR-T, and autologous stem cell transplant are other modalities that can be employed in both EBV+ and EBV- PTLD patients, depending on the disease biology and patient characteristics.

SOLID ORGAN MALIGNANCIES

Risk factors

Head and neck cancers/upper aerodigestive cancers: These cancers are linked to smoking and alcohol consumption and develop from tissues within the aerodigestive tract which includes parts of both the respiratory and upper digestive systems, encompassing the lips, mouth, tongue, nose, throat, vocal cords, and portions of the esophagus and windpipe. Oropharyngeal cancer is more likely to develop in patients with alcoholic cirrhosis who undergo LT compared to those transplanted for other reasons[20,29]. A single-center study found that no cases of oropharyngeal cancer were reported in patients without a history of alcohol consumption or smoking[86]. Tongue and laryngeal cancers have been reported in smokers, and the carcinogenic effects of tobacco seen in the general population also apply to transplant recipients[87]. Determining the relative contribution of alcohol vs tobacco as risk factors for head and neck cancers is challenging, as alcohol is known to enhance the carcinogenic effects of smoking[18]. Additionally, individuals who smoke heavily are often also heavy drinkers.

Lung cancer: The primary risk factors for developing lung tumors after LT are a longer duration since the transplant, ALD as the indication for the transplant, and an extended history of tobacco use[44,88,89]. A 2 to 4 times increased risk of developing lung cancer is seen in patients with ALD who undergo LT[1,29]. In an analysis of the National Institute of Diabetes and Digestive and Kidney Disease’ LT database, patients with alcoholic cirrhosis had the highest risk of developing lung cancer, with 5- and 10-year risks of 2.0% and 4.8%, respectively, compared to non-alcoholic cirrhosis patients, whose risks were 0.15% and 1.3% over the same periods[37]. Similar to the link between smoking and lung cancer seen in the general population, smoking is associated with a higher risk of lung cancer in transplant recipients[1,18,44,87]. While this is likely due to an epidemiological correlation, as smokers are often heavy drinkers, a study found that patients who received LTs due to alcohol-related cirrhosis had higher rates of lung cancer compared to those who had LTs for other reasons[18,90].

Gastrointestinal cancers: The primary risk factors for gastrointestinal cancers after LT are duration, tobacco use/smoking, alcohol abuse, PSC [with/without inflammatory bowel disease (IBD)], obesity, diabetes and the presence of metabolic dysfunction-associated steatohepatitis (MASH). The colorectal cancer risk for PSC patients with LT was noted to rise above the 10-year general population rate for a 50-year-old with PSC at 5.75 years after LT for males and 3.25 years for females. Patients with IBD diagnosis were twice as likely to develop colorectal cancer as compared to those without IBD (hazard ratio 2.06, 95%CI: 1.03-4.15, P = 0.042)[91]. Diagnosis of PSC and MASH were also noted to be significant risk factors for pancreatic cancers. Additionally, it is suspected that the higher rates of gastric cancer in LT patients are related to immunosuppression and cirrhosis[92]. In a retrospective study of 9724 patients, it was noted that donor age > 60, donor history of diabetes, donor with body mass index of ≥ 35 kg/m² and severe graft steatosis, and organs obtained after cardiac death with prolonged warm ischemia were associated with increased risk of HCC recurrence[93]. Other risk factors for HCC recurrence included active HBV/HCV infection and exposure to environmental carcinogens.

Genitourinary: Previous studies have indicated an increased risk of renal and bladder cancer in patients with LT compared to the general population[6,7,94]. Patients with a previous history of renal cell carcinomas (RCC), von Hippel-Lindau (VHL) disease, concurrent chronic kidney disease, and polycystic kidney disease are noted to be at increased risk. Bladder cancer risk is noted to be increased in all transplant patients; however, it is noted to be more aggressive with worse clinical outcomes[95]. Importantly, LT patients do not have an increased risk of prostate cancer-specific mortality[96].

Gynecological cancers: LT patients are at an increased risk of developing cervical and vulvar cancers. This elevated risk is primarily associated with a history of cervical dysplasia and the presence of an HPV infection. Immunosuppression can contribute to the reactivation of latent HPV infections, including oncogenic HPV types, thereby heightening cancer risk[97]. Additionally, immunosuppression impairs the body's ability to clear HPV infections, further exacerbating this vulnerability.

Screening and prevention

All LT recipients should receive education on the importance of smoking and alcohol cessation after their transplant. For lung cancer screening, it is advised to follow the general population guidelines, as there is no evidence supporting improved survival with more frequent screening in LT patients[98,99]. Annual oral examinations are recommended for all LT patients. However, those at higher risk, such as active smokers or those with active HPV infection, should undergo a comprehensive ear, nose, and throat examination annually[49,100]. Patients with IBD should undergo annual colonoscopies for surveillance for colon cancer, while those with PSC without IBD may undergo a colonoscopy every 3-5 years[101,102]. Patients with a history of HCC or MASH can be considered for a colonoscopy every 5 years if they are over the age of 50 years[49,91]. For RCC screening, the European Association of Urology recommends annual ultrasound for patients with previous RCC, VHL disease, or autosomal dominant polycystic kidney disease[103]. Guidelines for cervical and vulvar cancer screening in immunosuppressed women should also be followed for LT patients[104].

Management

The initial management of de novo solid organ cancers in LT patients involves adjusting immunosuppressive regimens to the lowest effective dose that still preserves graft function. While various practice guidelines recommend initiating mTOR inhibitors, no randomized controlled trials have confirmed their benefit. However, retrospective studies suggest a reduction in mortality by approximately 55%-75% with CNI minimization or conversion to mTOR inhibitors[105,106]. Surgical approaches for solid organ de novo malignancies should follow the same principles as those for the general population, though it is important to note that LT patients are at higher risk for infections and increased 90-day postoperative mortality[107].

Early diagnosis of lung cancers allows for surgical resection in all transplant patients. If patients have significant comorbidity sublobar excisions with radiotherapy can be considered[108]. In advanced stages, the management is similar to that in the general population, with primary surgical resection in non-(small cell lung cancer) SCLC and chemotherapy/radiotherapy in SCLC patients[109]. In cases of esophageal and gastric cancers, esophagectomy and gastrectomy (type dependent upon the spread of the cancer) is recommended. Endoscopic resection can be an option in patients with early-stage malignancies[110,111]. Other options include resection (surgical vs endoscopic), radiation, and systemic chemotherapy[112,113]. Pancreatic cancer treatment typically involves surgical resection with or without neoadjuvant therapy, though survival rates are generally shorter compared to those with sporadic pancreatic cancer. For upper airway cancers (oral cavity, oropharynx, larynx) typically involves surgery, often combined with chemotherapy or radiotherapy. Early detection of these cancers is a key factor contributing to improved survival[114].

CONCLUSION

Skin cancer, PTLD, and solid organ tumors are common DNM in post-LT recipients and are the leading causes of morbidity and mortality. The primary factors driving these malignancies are immunosuppression and latent oncogenic viruses. Additional major risk factors include age, sex, history of smoking or alcohol abuse, and the presence of PSC/IBD. Recent efforts to develop screening guidelines have seen reasonable success. To further improve outcomes, it is essential to implement reduced or alternative immunosuppressive therapies and adhere to guideline-directed screening protocols. Screening strategies should be tailored to each patient, taking into account their specific risk factors.