Post-transplant malignancy: Focusing on virus-associated etiologies, pathogenesis, evidence-based management algorithms, present status of adoptive immunotherapy and future directions

Table 9 Post-transplant malignancies: treatment and prevention

Post-transplant malignancy	Treatment	Prevention
CIN (HPV-associated)[28,161]	Loop electrosurgical excision procedure/cryotherapy/cold knife conization of the lesion	Vaccination as mentioned in Table 3 (screening of HPV)
Cervical cancer (HPV-associated)[28,161]	Microinvasive disease (< 3 mm): conization[174]	Known previous history: Assess for anogenital lesion for cervical/anal lesions prior to transplant
	Up to stage IIA: Chemoradiation[175]	Recommend condom use
	Locally advanced: Chemoradiation[176]	During laser surgery for HPV lesions, cover skin surface, mask and eye protection to prevent reimplantation of virus in electrocautery fumes
	Metastatic: Chemoradiation (palliation and symptoms alleviation)[177]
AIN (HPV-associated)[28,161]	AIN I (< 1 cm2 at base): Topical 80% TCA[178]/5-fluorouracil[179] or cryotherapy
	Larger size AIN I, AIN II and III: Infrared coagulation[180,181] or fulguration (anoscopy guided)[181]
Anal and penile cancer (HPV-associated)[28,161]	Invasive anal carcinoma: Combined-modality therapy [radiotherapy and chemotherapy (5-fluorouracil and mitomycin/cisplatin)][182]
	Penile cancer: Surgical resection ± chemotherapy (as per stage in immunocompetent)
PTLD[183]	Differentiate allograft dysfunction from PTLD, before initiating treatment using allograft biopsy	EBV viral load surveillance (for EBV D+/R-) as mentioned in screening of EBV
	RIS: Preferred pre-emptive intervention. Adjust to lowest tolerated immunosuppression, may switch to mTOR inhibitor. Lack of sufficient evidence to suggest any specific RIS protocol or switching to mTOR inhibitor
	Rituximab monotherapy for progressive disease following RIS and CD20+ PTLD	Patients (EBV D+/R-) with fluctuating immunosuppression, episodes of rejection, or who have not established a viral “set point” will be monitored for a period beyond the first year
	Cytotoxic chemotherapy if progression after rituximab and RIS. R-CHOP 21 regimen: Four sequential cycles of rituximab/ cyclophosphamide, doxorubicin, oncovin, and prednisone every 3 wK[184,185]
	Children with EBV + PTLD: the low-dose cyclophosphamide and prednisone regimen plus rituximab [186].	EBV viral loads becomes positive 4 to 16 wk prior to development of PTLD[189]
	CD20- Tcell PTLD, B cell, Burkitt and Hodgkin’s lymphoma: same chemotherapy regimen as immunocompetent host
	CNS PTLD: Chemotherapy regimens are same as used to treat primary CNS lymphoma (PCNSL) in general population/ immunocompetent individuals[187,188]. Regimen with systemic rituximab, dexamethasone and antivirals, if unable to tolerate chemotherapy or disease occurring early post-transplant	Monitor viral load in EBV seropositive recipients in re-transplantation after PTLD
	Start pneumocystis jirovecii prophylaxis: If PTLD treatment administered beyond RIS
KS	RIS (30% complete remission in few reports)[190]	Pre transplant “at risk” in endemic areas (D+/R- or R+ HHV8 status): Frequent viral load monitoring for 3–6 months and physical examination of skin and mucosal surfaces as a routine, post-transplant
	Switch to mTOR if using CNI (mTOR inhibitor is antiangiogenic, inhibit viral replication pathways)[191,192] and helps recovery of HHV-8-specific cytotoxic T cells[78,82]	RIS if viral loads rising while monitoring and switching to mTOR inhibitors early
	Antivirals (ganciclovir, foscarnet, cidofovir): Not routinely used, as in vivo efficacy is not demonstrated
	If no response or relapse after above: Oncology consultation and chemotherapy (CHT) (L-anthracyclines)
	If single skin lesion: Surgical excision or intralesional electrocautery or intralesional chemotherapy can be considered
MCD	RIS (limited evidence) and/or switch to mTOR from CNI (if possible)
	Rituximab[193]
	If aggressive disease, no response/relapse: chemotherapy [R-CHOP/R-CVP (rituximab- cyclophosphamide, doxorubicin, vincristine, prednisone)][82]
PCL	Primary therapy is CHT [cyclophosphamide, doxorubicin, vincristine, prednisone(CHOP)][194]
	RIS (limited evidence)
	If CHT contraindicated/no response or relapse: Intracavitary antivirals(cidofovir)[82]

CNS: Central nervous system; CHT: Chemotherapy; MCD: Multicentric Castleman disease; RIS: Reduction in immunosuppression; CIN: Cervical intraepithelial neoplasia; HPV: Human papilloma virus; PTLD: Post-transplant lymphoproliferative disorders; EBV: Epstein–Barr virus; KS: Kaposi’s sarcoma; CNI: Calcineurin inhibitor.