Abstract
Recipients of liver transplantation (LT) remain at higher risk (adjusted for other risk factors) of de novo malignancies (DNMs). The higher risk can be attributed to the effect of immunosuppression and patient-related risk factors (age, tobacco, alcohol, etiology of liver disease). DNMs are an important cause of late mortality in liver transplant recipients. The pattern (type) of posttransplant malignancies reflects pattern in local population. The common types include skin cancers, solid organ malignancies, and post-transplant lymphoproliferative disorders. Counseling of patients about risk factors and surveillance protocols may help in the prevention and diagnosis at early stage. We also discuss the results of LT in patients with a history of extrahepatic malignancy in the pretransplant period.
Keywords: de novo malignancy, recurrence, risk factors, smoking, surveillance
Abbreviations: DNM, de novo malignancy; EBV, Epstein–Barr virus; HR, hazard ratio; LT, liver transplantation; MPD, myeloproliferative disorder; PTLD, posttransplant lymphoproliferative disorder; SIR, standardized incidence ratios
Patients with solid organ transplant including liver transplantation (LT) remain at a higher risk of developing DNMs due to prolonged immunosuppression. As outcomes of LT have been improved considerably, long-term survival is common, and there is increased likelihood of long-term complications like cardiovascular events, disease recurrence and de novo malignancies (DNMs). DNMs, although not very common, remain an important cause of long-term morbidity and mortality. The risk of DNM is two- to threefolds higher (with significantly elevated standardized incidence ratios [SIRs]) after LT, and patients with de novo cancers have a lower long-term survival.1, 2, 3, 4, 5 At times, decision to LT is made difficult by the presence of history/concurrent extrahepatic malignancy. We discuss the incidence and risk factors of DNM after LT. We also discuss the outcomes of LT in the presence of history/concurrent extrahepatic malignancy before LT. We will not be discussing hepatic malignancies before or after LT in this article.
Incidence of de novo malignancy after liver transplantation
In a study of French national registry of 11,226 LT recipients, 1200 (10.7%) developed DNM. The risk of death and SIR for all de novo solid organ malignancies was approximately 2 and 2.20, respectively, with higher risks in men and alcoholics.5 The studies with >1000 LT recipients are shown in Table 1.4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 The incidence of DNMs varies with follow-up of patients, with studies having a higher follow-up noting higher incidence of DNM. Several things can be noted from Table 1. Various studies have found different incidence rates due to different population profiles (risk factors, demographics) and varying follow-ups. Two studies with long-term follow-up are discussed below. Finkestedt et al. showed that 96/779 (12.3%) patients developed 105 malignancies. The cumulative risk of DNM was 10% at 5 years, 24% at 10 years, 32% at 15 years, and 42% at 20 years after LT. The patients with skin cancers and solid tumors (diagnosed at early stages) had good outcome.20 In another study of 1616 LT recipients with a median follow-up of 14.1 years, 322 DNMs developed in 266 (16.5%) patients. The probability of developing any DNM was 12.9% at 10 years and 23% at 25 years.15
Table 1.
Incidence of de Novo Malignancy in Studies with ≥1000 Liver Transplantation (LT) Recipients.
| Author,ref. year, country | Number of LT recipients | Recipients with de novo malignancy | Common malignancies |
|---|---|---|---|
| Frezza,6 1997, USA | 1657 | 50 (3%) | Basal cell carcinoma 16, squamous cell carcinoma 13 |
| Jain,7 1998, USA | 1000 | 57 (5.7%) | Skin 22, respiratory 8, oropharyngeal 7 |
| Saigal,8 2002, UK | 1140 | 30 (2.6%) | Skin cancer 13, oropharyngeal, bladder, breast, leukemia 2 each |
| Sanchez,9 2002, USA | 1421 | 125 (8.8%) | Skin 41, lymphomas 35, lung 11 |
| Oo,10 2005, UK | 1778 | 141 (7.9%) | Skin (51 excluding melanoma), large bowel and rectal 21, hematological 18, lung 14, breast 11 |
| Yao,11 2006 USA | 1043 | 50 (4.8%) | Skin 17, gastrointestinal 11 |
| Jiang,12 2008, Canada | 2034 | 113 (5.5%) | Hematological 44, colorectal 14, lung 10 |
| Ettorre,13 2013 Italy | 1675 | 98 (5.9%) | PTLD 18, head and neck 19, lung 13, colorectal 11, Kaposi's sarcoma 6 |
| Schrem,4 2013, Germany | 2000 | 115 (6%) | PTLD 23, lung 14, colorectal 13, gynaecological 10, breast 8, gastric/esophageal 7 |
| Mangus,14 2015, USA | 1275 | 180 (14.1%) | Skin 107, gastrointestinal 19, hematologic 18, lung 15 |
| Rademacher, 2017,15 Germany | 1616 | 266 (16.5%) | Skin 83, hematological 49 |
| Sérée,5 2018, France | 11,226 | 1200 (10.7%) | Lung 188, esophagus, stomach, colorectal 141, larynx 76, oral/pharynx 72, |
| Studies from the East | |||
| Park,16 2012, Korea | 1952 | 44 (2.3%) | Stomach 11, colorectal 9, breast 4, predominantly living donor series |
| Sanaei,17 2015, Iran | 1700 | 38 (2.2%) | PTLD 24 (20 children), gastrointestinal 4, Kaposi's sarcoma 3, pancreatic 2 |
| Tiwari,18 2020, India | 2100 | 21 (1%) | 7 oropharyngeal, 4 lung, predominantly LDLT series |
| Yeh,19 2020, Taiwan | 2127 | 111 (5.2%) | Digestive most common |
PTLD: posttransplant lymphoproliferative disorder.
A review of literature by Mukthinuthalapati et al. found following SIR for DNM: nonmelanoma skin cancer, 2.1–70, posttransplant lymphoproliferative disorder (PTLD) 3.9–21 and solid organ cancers 1.4–3.1. DNMs have been reported from 1% to 16.5% in studies with ≥1000 recipients as shown in Table 1.21 The types of DNMs in LT recipients reflect common malignancies prevalent in the given community. Thus, nonmelanotic skin cancer is the most common malignancy in the western world;6, 7, 8, 9, 10, 11,22 however, aerodigestive malignancies are the most common DNM in Asia. In the series of 1952 LT recipients from Korea, 2.3% developed DNM. Stomach cancer (25%) was the most common form of DNM followed by colorectal (20%).16 Similar results have been shown from China; digestive system malignancies accounted for 57% of total DNMs in the study by Gao et al.23 In a study from our center, a total of 21/2100 adult LT recipients (1%) developed DNMs at a median follow-up of 42 (32–73) months. The oropharyngeal (n = 7, 33%) and lung (n = 4, 19%) malignancies were the most common forms.18 Other malignancies included squamous cell carcinoma of skin (n = 2), lymphoma (n = 2), and one each of brain, colonic, gastric; ovary, pancreatic, and prostate malignancies. Of 21 patients, 6 (28.5%) died (2 with lung malignancies, one each with lymphoma, ovarian, brain and stomach) at median 38 months after the diagnosis of DNM. Prognosis remains better for nonmelanoma skin cancers compared with other solid organ DNM.11
Risk factors for de novo malignancy
The increased incidence of DNMs in transplant patients is attributed to immunosuppression, which affects the tumor development and progression in several ways. The duration of exposure and intensity of immunosuppressive therapy are related to the risk of DNM. Also, after the development of DNM, intense immunosuppression may result in aggressive cancer progression and lower patient survival.24 The mechanisms causing higher risk of malignancy in LT recipients include a permissive environment for proliferation of tumor cells, infection or reactivation of oncogenic viruses, chronic antigen stimulation leading to a cytokine-rich milieu, and impaired immune surveillance. Also, insulin resistance caused by immunosuppressive agents contributes to the development of DNM.24,25 Other risk factors are shown in Table 2 (references 8,10,13,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36). Several viruses can lead to malignancies: Epstein–Barr virus (EBV) is related to PTLD, human papilloma virus is related to cervical, skin, oropharyngeal, and anal cancers. The Kaposi's sarcoma-associated herpes virus is related to Kaposi's sarcoma and Castleman's disease. Hepatitis B and hepatitis C can lead to de novo HCC.37
Table 2.
Risk Factors for de Novo Solid Organ Malignancies.
| Risk factors | Type of malignancy | References |
|---|---|---|
| Alcohol, smoking | Lung, head and neck, esophageal | 8,10,13,26, 27, 28,29,30 |
| Barrett's esophagus | Esophageal | 31 |
| Primary sclerosing cholangitis, inflammatory bowel disease | Colorectal | 10,32 |
| Higher age, male gender, red hair, brown eyes, primary sclerosing cholangitis, alcohol, and cyclosporine | Skin | 6,8,33 |
| Epstein–Barr virus seronegative status Age of donor and recipient Number and severity of rejection episodes Cytokine gene polymorphisms Pediatric age Hepatitis C as etiology Transplant for acute liver failure Use of induction |
Posttransplant lymphoproliferative disorder | 17,34, 35, 36 |
Common types of de novo malignancy
Table 3 shows the common types of DNM after LT (adapted from reference 38).
Table 3.
Common Types of Malignancies after Liver Transplantation (Adapted From Reference 38).
| Type of malignancy | Incidence % | Estimated standardized incidence ratio |
|---|---|---|
| Nonmelanoma skin | 0.9–3.2 | >30 |
| Kaposi's sarcoma | 0.14–2.8 | >100 |
| Posttransplant lymphoproliferative disorder | 0.9–2.6 | 6–20 |
| Oropharyngeal, head, and neck | 0.1–2 | 5–14 |
| Esophagus | 0.5–1.19 | 12–18.7 |
| Colorectal (in IBD/PSC) | 0.7–7.9 | 3–5 |
| Stomach | 0.25–3 | 3 |
| Lung | 0.6–1.2 | 2–8 |
| Vulva, renal, thyroid | <1% | 8–23.8, 2–2.65, 4.6 |
Skin malignancies are the most common type of DNM after LT in the western world (Table 1).
Patients on cyclosporine and azathioprine are at higher risk for the development of skin cancers after transplant.39,40 PTLD occurs in 1–3% of adult population. The incidence of PTLD is more in the pediatric population (likely secondary to the absence of previous EBV exposure).41, 42, 43 The study by Soriano-Lopez et al. showed that monitoring of EBV load and reduction of immunosuppression lead to markedly decreased incidence of PTLD (14.9% versus 1.9%) without increasing the incidence of rejection.44 The common solid organ DNMs after LT include head and neck malignancies, gastrointestinal malignancies, lung tumors, genitourinary, breast, and pancreatic malignancies. Table 2 shows risk factors for these malignancies. Alcohol and smoking are the important risk factors for head and neck, and lung tumors. In a study of 1275 LT patients by Mangus et al., current (n = 279) and previous smokers (n = 323) were more likely to have hepatocellular carcinoma (at transplant) and HCC recurrence. DNM was higher for current and previous smokers, compared with nonsmokers and survival was worse for current smokers.14 Watt et al. showed that increased age by decade (hazard ratio [HR] = 1.33, history of smoking [HR = 1.6], primary sclerosing cholangitis [HR = 2.5], and alcoholic liver disease [HR = 2.1]) were important factors on multivariate analysis for the development of solid organ DNM.45 One more important factor for oral malignancies is use of smokeless tobacco, which is a common cause of these malignancies in South Asia.46 The prognosis of solid organ malignancies remain poor in long term unless diagnosed early. The probability of death after diagnosis of hematologic malignancy was 44.0% at 1 year and 57.6% at 5 years in the study by Watt et al. The probabilities of death in patients with solid organ DNM at 1 and 5 years were 38% and 53.1%, respectively.45
Impact of screening protocols
There are not much data on the impact of surveillance strategies on outcomes of DNM after LT. It is necessary to maintain a high level of suspicion and consider surveillance strategies that include common DNM in patients at risk. Patients with risk factors (alcohol, smoking) may be screened more frequently. Standard cancer screening surveillance strategies used in the general population should, at a minimum, otherwise be followed. In the nonimmunosuppressed population, alcoholism and smoking are associated with an increased risk for several malignancies, including lung and head/neck and esophageal malignancies. A suggested algorithm for surveillance is shown as Table 4. Two studies have looked at impact of surveillance strategies on outcomes of DNM. Herrero et al. compared DNM (excluding skin, hepatobiliary carcinomas, and lymphoproliferative diseases) in 9 patients (due to active screening) with 24 patients where DN diagnosis was based on symptoms or incidental. All the nine patients were alive (median follow-up 25 months and all free of tumor) compared with 18/24 deaths (median survival was 13.5 months) in other group, with a significant difference in survival, p = 0.002.47 After introduction of an intensified surveillance protocol, Finkestedt et al. noted improved diagnosis of DNM (rate increased from 4.9% to 13%), also more DNM could be diagnosed at an early stage. The authors noted improved survival in the intensive group.20
Table 4.
| Site specific | Tests | Applicable to transplant recipients |
|---|---|---|
| Skin cancer | Annual examination, early in patients with risk factors | All recipients |
| Colon cancer | Annual colonoscopy with random surveillance biopsy | Patients with inflammatory bowel disease, primary sclerosing cholangitis |
| Lung cancer | Annual chest X-ray, yearly CT chest if chronic symptoms or active smoking | All |
| Oropharyngeal/laryngeal cancer | Annual otolaryngology evaluation by specialist | Ethanol, current or ex-smokers, tobacco chewing |
| Cervical cancer | Pelvic examination with gynecologist and Papanicolaou smear | Female recipients |
| Breast cancer | Annual mammography starting at the age of 45 years | Female recipients |
| Prostate cancer | Annual prostate-specific antigen testing starting at the age of 50 years | Male recipients |
| RCC | Annual USG abdomen |
Liver transplant in the presence of history of pre–liver transplantation extrahepatic malignancy
Penn showed a recurrence of pretransplant malignancies in 21% recipients in the setting of renal transplant (Cincinnati, USA). The recurrence rates were 54% for malignancies treated within 2 years of transplantation, 33% for treatment 2–5 years before transplantation and 13% with history of treatment >5 years before transplantation. The highest recurrence rates happened with the following malignancies: breast (23%), symptomatic renal carcinomas (27%), sarcomas (29%), bladder (29%), nonmelanoma skin cancers (53%), and multiple myeloma (67%).48 This study led to recommendations of postponement of transplantation for 2–5 years depending on the type of cancer. LT differs from kidney transplantation in several ways. The need of immunosuppression is less in LT. While kidney patients can be maintained on dialysis (thus delaying transplant), sick patients with decompensated cirrhosis are unlikely to survive for several years. Although, pretransplant malignancy is associated with the risk of recurrence and of development of DNMs after transplantation, most of data regarding recurrence are available from kidney transplantation setting. The risk of recurrence is more for kidney transplant recipients compared with LT recipients.49 Ideally, a similar period of waiting is desirable in elective LT patients with a history of preexisting malignancy. However, in carefully selected sick patients, one can proceed to LT if malignancy is proven to be or can be eradicated at the time of LT and type/stage of neoplasm is not associated with poor prognosis. There are limited data available regarding impact of pretransplant extrahepatic malignancies on outcomes of LT as shown in Table 550, 51, 52, 53, 54, 55, 56.
Table 5.
Liver Transplantation in the Presence of Extrahepatic Malignancies.
| Author (year) | N, free of malignancy from (months) | Recurrence, follow-up |
|---|---|---|
| Penn,50 1996 | 44, mean 26 months | 24% at mean 16 months |
| Kelly,51 1998 | 29, 104 months | 4 (13.8%) at mean 29 months |
| Saigal,52 2001 | 18, median 12 months, 4 surgeries at time of liver transplantation | 11% at 71 median months |
| Benten,53 2008 | 37, except for 3 patients, recipients were tumor-free at OLT, median 44 months | 1 (2.7%) recurrence at median 66 months |
| Jain,54 2009 | 30, median 86 months | 1 at mean follow-up 34 months |
| Desai,55 2013 (abstract form) | 16, time period not provided | 2 (melanoma, leiomyosarcoma), time not provided |
| Tiwari,56 2017 (abstract form) | 13, some malignancies detected at time of pre-LT workup | None at mean 51 months |
Saigal et al. analyzed the data of 18 patients with a history of pretransplant malignancy including six cases of myeloproliferative disorder (MPD). One patient had recurrence of non-Hodgkin's lymphoma after 27 months, and one patient with MPD developed acute leukemia 6 years after LT. Four patients had an incidental diagnosis of malignancy at time of LT (two renal carcinomas, one colon carcinoma, and one bladder carcinoma). One of these patients died due to sepsis, there was no recurrence in remaining recipients.52 Benten et al. analyzed the data of 37 patients with pretransplant malignancies (26 solid tumors and 11 hematological malignancies). All but three were tumor-free at the time of LT. Only one recipient had recurrence of colon carcinoma. No patient with MPD had leukemic transformation; a patient with neurofibromatosis experienced growth of skin fibromas.53 Jain et al. analyzed the data of 30 LT recipients with a history of extrahepatic malignancy. Only one patient had recurrence of oropharyngeal malignancy, which was free of pretransplant malignancy for 77 months.54
Two studies are available as abstracts. In the study from our center, 13 patients with history of pretransplant extrahepatic malignancies underwent LDLT. These patients were accepted for transplant if the extrahepatic malignancy either was curable prior to/at the time of liver transplant or was in complete remission. Among the 13 patients, (7 males, 6 females), aged 44 ± 20 years, the malignancies included hematologic malignancies (n = 5, Langerhans cell histiocytosis in 2, leukemia in 1, multiple myeloma in 1 and Hodgkin's lymphoma in 1), renal carcinoma (n = 3, two had radicle nephrectomy of affected site, one had partial nephrectomy), breast carcinoma (n = 2, wide local excision in one, mastectomy in one), thyroid carcinoma (n = 1, underwent total thyroidectomy), endometrial carcinoma (n = 1, underwent total abdominal hysterectomy) and bilateral salpingo-oophorectomy, and squamous cell cancer of skin (n = 1, underwent wide local excision). The median remission time of hematological malignancies before LT was 11 months. Thus, eight of these patients underwent additional surgery for the extrahepatic malignancy at the time of LDLT, and all but one had stage T1 disease. A patient with breast carcinoma had T2 disease at excision specimen. None of the patients had nodal disease or metastasis at the time of surgery. One patient died in postoperative period due to sepsis, rests were alive at a mean follow-up of 51 ± 25 months without recurrence.56 One of these patients had recurrence of renal carcinoma after 5 years of LDLT. In another study published as abstract, Desai et al. analyzed the data of 16 LT recipients. The pretransplant malignancies included lymphoma (4), breast (3), and one each of cervix, colon, leiomyosarcoma, leukemia, kidney, prostate, melanoma, thyroid, and uterus. Two recipients developed cancer recurrence (melanoma and leiomyosarcoma).55 Budd–Chiari syndrome is often associated with myelodysplastic syndromes and is associated with good prognosis after LT. Leukemic transformation after LT happened in 1/11 patients after LT in the study by Srinivasan et al.57
DNMs contribute significantly to morbidity and mortality in the long-term after LT. LT recipients should be advised about avoidance of risk factors like alcohol, smoking, and tobacco. All LT recipients should be kept under posttransplant surveillance for DNM as per the center's protocol. Good outcomes after LT can be obtained in selected patients with a history of pretransplant extrahepatic malignancy.
Credit authorship contribution statement
Narender Singh Chaudhary, Sanjiv Saigal: Conceptualization; writing - original draft. Narender Singh Chaudhary: writing - review and editing. Sanjiv Saigal, Arvinder Singh Soin: critical revision.
Conflicts of interest
All authors have none to declare.
Funding
None.
References
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