Overall Bottom Line

Due to long-term immunosuppression therapy, the post-LT recipient is at risk for disease conditions (e.g. infection, malignancy) that are generally regulated by the body’s immune system.
Skin cancer is the most common type of de novo malignancy after LT.
Malignancy, either de novo type or recurrent HCC, may occur after LT.
PTLD is a malignancy unique to the transplant recipient.
Specific screening guidelines have not yet been established for LT recipients; the current ones for immunocompetent persons remain in use. Increased surveillance may be prudent in view of the recipient’s immunosuppressed state.
Treatment can be tailored according to the particular tumor, along with reduction of the immunosuppression regimen to strengthen the individual’s immune system.
Molecular markers may shed more light in the future on risk estimation of HCC recurrence post-transplantation.

Section 1: Background

Definition of disease

De novo malignancy is the second cause of mortality after LT, with cardiovascular disease as the primary reason; cumulative incidence ranges up to 26%.

There is a higher incidence of developing malignancy in post-transplant (i.e. immunosuppressed) recipients when compared with the immunocompetent population.
The cumulative incidence of de novo malignancies range up to 26%, with 0.5% for the general non-transplant population.

Comparison of the incidence of the common types of malignancy after LT and the incidence in the general population

The etiology of malignancy after LT is related to long-term immunosuppression use.

Immunosuppression results in the weakening of the body’s natural defenses (e.g. cytotoxic T cells, macrophages, natural killer cells) that generally inhibit oncogenic viral growth and destroy malignant cells in vitro.
Azathioprine use is an independent risk factor for the increased incidence of de novo malignancies. By inhibiting purine synthesis, it affects T cell and B cell production.

Bottom Line/Clinical Pearls

Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor, and in a different drug category from tacrolimus and cyclosporine (calcineurin inhibitors). It has anti-angiogenic properties and has been reported to decrease skin cancer incidence in kidney transplant recipients.
mTOR is upregulated in HCC, therefore allowing sirolimus to have a potential effect on HCC recurrence. A recent meta-analysis demonstrated that sirolimus use to reduce HCC recurrence rates post-LT resulted in a lower recurrence rate, longer recurrence-free survival and overall survival, and lower recurrence-related mortality when compared with patients receiving calcineurin inhibitors.

There are currently no guidelines on the surveillance schedule for HCC post-LT.
At Mount Sinai Hospital, the recipients’ explants are assessed and classified as either low-risk or high-risk for recurrence, depending on the HCC histology, number of tumors and presence/absence of lymphovascular invasion.

Surveillance imaging protocol for patients who undergo LT for HCC at Mount Sinai Hospital

Imaging schedule*	Low-risk HCC	High-risk HCC
Year 1	At 3 months post-transplantation	Every 3 months
Year 2	At 12 months post-transplantation	Every 6 months
Year 3	End	Every 6 months
Year 4	N/A	Every 12 months
Year 5	N/A	Every 12 months
Year 6	N/A	End

* Imaging studies: chest CT scan (without contrast) and abdomen CT scan or MRI (with intravenous contrast)

Current guidelines for de novo malignancy screening have not yielded consistent benefits in both the liver and kidney transplantation populations to justify the cost-effectiveness of this approach, nonetheless various organizations recommend screening guidelines for the average-risk individual.

Organ/cancer type	Screening guidelines for average-risk individuals
Organ/cancer type	Onset	Interval
Breast	Starting age 50	Between 12–24 months
Cervix	Between ages 18 and 20, or when sexual activity begins	Annually
Colon	Fecal occult blood test and flexible sigmoidoscopy starting age of 50	Every 5 years
Skin	Self-examination	Monthly
Skin	Clinician examination	Every 6–12 months
Kidney	No guidelines	N/A
Lung	No guidelines	N/A
Prostate	PSA and DRE starting age of 50	Annually