Posttransplantation Malignancies

Jeffrey M. Miller

Basmah Abdalla

Phuong-Thu T. Pham

GENERAL OVERVIEW

Recipients of organ transplants are at increased risk for developing certain neoplasms compared with the general population.
Posttransplant malignancy is an important cause of death in long-term kidney transplant recipients.
The overall incidence of de novo malignancies is two- to fourfold greater in solid organ transplant recipients compared with that of the general population.¹
Compared with the general population, kidney transplant recipients have a substantially higher risk for
- Nonmelanoma skin cancers.
- Kaposi sarcoma (KS).
- Posttransplant lymphoproliferative disorder (PTLD).
- Note: Nonmelanoma skin cancers (particularly squamous cell carcinoma [SCC]) have the highest standardized incidence ratios in transplant recipients.
The mean time to diagnosis of different neoplasms varies with the type of organ involved.
- KS, PTLD, testicular cancer, cancer of the small intestine, and thyroid cancer occur early after transplantation (defined as <800 days after transplantation in one study).²
- By 20 years after kidney transplant, nearly 50% have one or more skin cancers, and 10% to 27% have nonskin cancers.³
Common cancers in the general population, including breast, colon, prostate, lung, bladder, stomach, and pancreas were found to occur more frequently in kidney transplant recipients in some but not all studies.

Suggested risk factors

Duration and intensity of immunosuppressive agents due to their presumed ability to promote replication of oncogenic viruses.

The Australia and New Zealand Dialysis and Transplantation Registry analysis demonstrated that among all cancers known to occur at increased rates in kidney transplant recipients, the pattern of incidence after allograft failure was highly variable. Nonetheless, risk reversal was generally observed for cancers known to be associated with an infectious cause.⁴ Examples include
- KS and human herpes type 8.
- Non-Hodgkin lymphoma and Epstein-Barr virus (EBV).
Well-described virus-associated cancers are shown in Table 15-1.

TABLE 15-1 Virus-Associated Cancers

Oncogenic viruses	Specific virus-associated cancers
Epstein-Barr virus	PTLD, non-Hodgkin lymphomas, Hodgkin lymphoma, and plasma cell neoplasms
Human herpes virus 8	Kaposi sarcoma
Hepatitis B and hepatitis C	Hepatocellular carcinoma
Human papillomavirus (HPV)	Vulva, vagina, cervix, penis, anus, oral cavity, and pharynx
Possibly HPV related	Non-melanocytic-related skin cancer
Abbreviation: PTLD, posttransplant lymphoproliferative disorder.

The precise cause of increased risk of lip cancer has not been well-defined. The Transplant Center Match Study database demonstrated a strong association of lip cancer with white race and prior history of skin cancer, suggesting that ultraviolet radiation exposure is an important risk factor. A higher incidence of lip cancer was also found among transplant recipients receiving cyclosporine/azathioprine compared with tacrolimus/mycophenolate mofetil maintenance immunosuppression. The contributory role of cyclosporine and azathioprine was thought to be due to their photosensitizing or DNA damaging effects.⁵
Although melanoma has no known infectious etiology, a causal relationship between immunosuppression and its development in recipients of kidney transplants has been suggested.
Others: older age, male gender, Caucasian race, pretransplant dialysis duration, smoking history, deceased donor organ, cumulative exposure to radiation from repeated medical imaging studies, antecedent use of immunosuppressive agents to treat primary kidney diseases

SKIN CANCERS

Most common de novo posttransplant malignancy in the adult transplant population
Incidence of SCC > basal cell carcinoma (BCC)
SCC in organ transplant recipients
- Most common cutaneous malignancies in solid organ transplant recipients, with a 65- to 100-fold greater incidence compared with the general population⁶
- More clinically aggressive disease and worse tumor histology compared with that of the general population⁷
- Metastatic disease occurs in 3% to 8% of patients.
Risk factors for skin cancers
- Pretransplant history of SCC
- Actinic keratoses and viral warts (increased risk for keratinocyte carcinoma)
- Duration of follow-up after transplant
- Light-skin color (easily sunburned)
- Intensity of sun (ultraviolet radiation) exposure (eg, high-altitude residence)
- Older age at transplant
- Patients who develop SCC after transplantation are at increased risk for subsequent SCC, whereas those with a first posttransplant BCC are at risk for subsequent BCC.
- Azathioprine-based immunosuppression was found to be associated with a significantly increased risk for subsequent SCC but not subsequent BCC.
- Note: Voriconazole (a commonly used antifungal agent to treat invasive fungal infection in organ transplantation) use is associated with increased cutaneous SCC
  risk in organ transplant recipients, particularly in recipients of lung transplants. Voriconazole-associated increased risk of skin malignancy has been suggested to be due to increased skin photosensitivity.⁸
Mammalian target of rapamycin (mTOR) inhibitor in posttransplant cutaneous malignancies
- The mTOR inhibitors sirolimus and everolimus have antiproliferative and antitumoral effects.
- The Sirolimus Renal Conversion Trial (CONVERT) in which patients were randomized to sirolimus conversion or calcineurin inhibitor (CNI) continuation demonstrated that⁹
  - Sirolimus-based, CNI-free immunosuppression was associated with a significant reduction in nonmelanoma skin cancers at 2 years postconversion (1.2 vs 4.3, P < .001).
  - Sirolimus-treated patients had a significantly lower incidence of melanoma, although the incidence of melanoma was low (1.1% in the CNI continuation group and 0% in the sirolimus conversion group, P = .06).
  - There was a nonstatistically significant lower rate of all other cancers (1.0 vs 2.1, P = .058).
- Both “de novo” mTOR inhibitor use and CNI to mTOR inhibitor “conversion therapy” were found to be associated with decreased nonmelanoma skin cancer risks. Its use is effective in both primary and secondary skin cancer prevention. Furthermore, the earlier the conversion after an initial diagnosis of cutaneous SCC, the greater the efficacy.¹⁰
- Meta-analyses and randomized trials evaluating mTOR inhibitor use in secondary prevention of SCC showed a reduction in cumulative tumor load, suggesting that most benefit is gained by early conversion to an mTOR inhibitor-based maintenance regimen.¹¹
- It is suggested that the protective effect of mTOR inhibitors against skin cancer is a result of its inhibition of several ultraviolet-induced mechanisms involved in skin carcinogenesis.
Dermatology surveillance (guidelines drawn from evidence-based skin cancer surveillance program, United Kingdom)
- High risk (aged older than 55 years at transplant and light-skin color): annually for the first 2 years and then every 6 months thereafter
- Low risk (Asian or black): every 2 years
- Increased surveillance recommended after first cancer
- Authors’ center practice (see chapter 20)

POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER (PTLD)

PTLD encompasses a wide spectrum of lymphoid proliferations ranging from reactive polyclonal lesions to frank malignant monoclonal lymphomas.
The World Health Organization (WHO) histologic classification of PTLD can be divided into four subtypes based on morphology, clonality, and molecular criteria (for a detailed discussion, see chapter 9).
- Early lesions
- Polymorphic PTLD
- Monomorphic PTLD
- Classical Hodgkin lymphoma-type PTLD
Most common type of posttransplantation malignancy in children
Second or third most common posttransplantation malignancy in adults (follows only nonmelanoma skin cancers and KS)
Incidence: varies with the type of organ transplanted¹²
- Kidney (1%-2%); liver (1%-4%); simultaneous kidney pancreas (2%-3%); heart, lung, and heart-lung transplants (2%-10%); small bowel and multivisceral transplantation (up to 33%)
- The high incidence of PTLD in intestinal and multiorgan transplants has been attributed to the use of more intensive immunosuppression and the amount of donorderived lymphoid tissue transferred at organ transplantation.
The majority of PTLD are non-Hodgkin lymphoma of B-cell origin and are CD20-positive.
Although PTLD was originally thought to be uniformly linked to EBV infection, an increased incidence of EBV-negative PTLD has been reported. In some series, EBV-negative PTLD may occur in up to 30% to 50% of cases. EBV-associated PTLD appear to vary with PTLD subtypes (Table 15-2).
EBV-positive versus EBV-negative PTLD¹³
- Pathogenesis
  - Immunosuppression-related decrease in T-cell immune surveillance has been suggested to play a major contributory role in EBV-positive PTLD. In immunocompetent hosts, EBV-specific CD8⁺ effector and memory T cells are responsible for controlling EBV-infected B cells from uncontrolled proliferation and transformation.
  - The pathogenesis of EBV-negative PTLD remains speculative. Proposed hypotheses include hit-and-run EBV infection (disappearance of EBV following an initial infection that leads to PTLD), viral infection other than EBV (eg, cytomegalovirus [CMV]), persistent antigen stimulation by the graft, and long-term immunosuppression.
- Molecular-genomic studies revealed that EBV-negative PTLD share many genomic and transcriptomic features with diffuse large B-cell lymphoma (DLBCL) in immunocompetent patients, whereas EBV-positive PTLD have fewer genomic abnormalities.
- Although the molecular genetic separation between EBV-positive and EBV-negative PTLD is well-defined, EBV status is not prognostic or predictive with respect to treatment response. In a subset of patients, reduction in immunosuppression alone is effective regardless of EBV status.
EBV-positive PTLD is typically considered to result from EBV infection of recipient B cells but may be of donor origin.
PTLD may also develop in donor organs (allograft PTLD).
- Generally occurs in the first 2 years after transplant
- Suggested pathogenic mechanisms: development of lymphoproliferations from donor passenger lymphocytes, chronic antigenic stimulation, EBV proliferation

Mortality is greater with PTLD than with lymphomas in the general population.

TABLE 15-2 Incidence of Epstein-Barr Virus-Associated Posttransplant Lymphoproliferative Disorder by Posttransplant Lymphoproliferative Disorder Subtypes and Time of Onset After Transplant

PTLD subtypes	EBV association	Onset after transplant
Early lesions	Almost 100% EBV positive	Most early PTLD
Polymorphic PTLD	>90% EBV positive	Variable
Monomorphic PTLD	Both EBV positive and EBV negative	EBV positive: Most occur within the first 3 y after transplantation. EBV negative: late-occurring PTLD (>5 y after transplant)
Hodgkin lymphoma-like PTLD	>90%
Abbreviations: EBV, Epstein-Barr virus; PTLD, posttransplant lymphoproliferative disorder.

Risk factors¹²

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