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

Table 7 Viral infections post-transplant (associated with the potential to develop a malignancy): Screening, diagnosis, and treatment

Post-transplant virus infections	Screening	Diagnosis	Treatment
HPV anogenital/cutaneous manifestation[28,161]	All 9–26-yr: Before transplant, receive 3 doses of HPV vaccine [nine-valent or quadrivalent vaccine (Gardasil 9 or Gardasil; Merck, Whitehouse Station, New Jersey)] or HPV-bivalent vaccine (Cervarix; GlaxoSmithKline, Rixensart, Belgium) in women	Examination and biopsy of atypical lesions	Cutaneous warts: Topicals (patient applied): Salicylic/lactic acid/imiquimod or cryotherapy (provider-applied)
	Males and females (up to age 45 yr): May also be vaccinated with 3 doses of HPV vaccine (nine-valent)	Anogenital, perianal warts/history of receptive anal intercourse warts: colposcopy/anoscopy	Anogenital warts: topicals (patient applied): podofilox/5% imiquimod cream or cryotherapy/TCA /BCA/podophyllin resin (provider-applied)
	Organ recipient’s (15–26 yr): Immunize even if they have anogenital warts		Not responding or extensive or resistant warts: refer to dermatologist
	At each visit: bright light skin examination (including feet)
	Cervical pap smear (with or without HPV PCR co-test): Every 6 mo in first year and then yearly, post-transplant, in females (> 30 yr), irrespective of HPV vaccination status
	If rejection treated with T cell depleting agents, resume above schedule
	Follow in all females irrespective of HPV vaccination status
EBV viremia/disease	Identify high risk recipients (i.e. EBV D+/R-): EBV viral load once first week, monthly first 3–6 mo, and every 3 mo until the end of the first post-transplant year; Additionally, after treatment of acute rejection[162]	Quantitative EBV load assay [calibrated to World Health Organization IS for EBV DNA) (EBV NAAT)	Reduce immunosuppression with rising EBV loads in EBV-seronegative patients
	EBV disease precedes detectable or rising EBV loads	Whole blood/lymphocyte samples are preferable to plasma (the EBV viral load is greater and becomes detectable sooner), thereby enhancing sensitivity and early detection/reactivation
	Watch for signs/symptoms: fever, diarrhoea, lymphadenopathy, and allograft dysfunction	Same sample type, assay and laboratory for assessing rise in EBV loads
HHV8 viremia	Post-transplantation, HHV8 serologic testing is not routinely recommended globally	Serological assays (IFA ELISA) which detect HHV8 antibodies against latent and lytic viral antigens (both)[163]: Issues with such assays are inadequate standardisation, variable sensitivity and specificity among tests (60%–100%), and poor agreement with a predefined reference standard. It is still preferable when compared with quantitative PCR in identifying “at risk” transplant patients in endemic regions	RIS if quantitative PCR elevated/rising and/or absent HHV antibodies in “at risk” post-transplant patient or with non-neoplastic KS diseases
	Identify “at risk” before transplant, for HHV8 related disease post-transplant, in endemic zone [i.e. R+ (HHV8 reactivation) and D+/R- (HHV8 primary infection)][163,164]	Serological assay which detect HHV8 DNA by quantitative PCR: Its role are: (1) Predicts the occurrence of non-neoplastic HHV8 related diseases (in HHV8 primary infections and high viral loads);	Strictly follow and monitor
		(2) Detect active HHV8 replication; and
		And (3) monitor response to treatment in post-transplant patients with HHV8 related diseases
		Issue of serological assays in HHV8 diagnosis: Lack of any serological gold standard assay
		Direct detection of HHV8 (HHV8 immunohistochemical staining) from involved site is still gold standard for diagnosis
		Histopathological confirmation and HHV8 DNAemia confirms the diagnosis
Plasmacytic B-cell proliferation (HHV8 associated)[82]	Watch for SIS	Biopsy: Shows polyclonal HHV8 B-cell proliferations in lymph nodes/visceral organs	RIS
	Exclude mimickers of signs/symptoms	HHV8 viral load (quantitative PCR)	Rituximab
			Trial of antiviral
Bone marrow failure/HPS (HHV8 associated)[82,165]	Watch for fever, jaundice, severe pancytopenia, plasmacytosis, hepatosplenomegaly, SIS, rash (maculopapular)	Biopsy confirmation of HHV8 in bone marrow/ lesions	RIS
	Exclude mimickers of signs/symptoms	HHV8 viral load (quantitative PCR)	Rituximab
			Trial of antiviral
Hepatitis (HHV8 associated)	Elevated liver enzymes, SIS, rash (maculopapular).	HHV8 viral load (quantitative PCR)	RIS
	Exclude mimickers of signs/symptoms	Biopsy confirmation of lesion/organ affected	Trial of antivirals

NAAT: Nucleic acid amplification test; RIS: Reduction in immunosuppression; IFA: Indirect immunofluorescence assay; ELISA: Enzyme-linked immunosorbent assay; PCR: Polymerase chain reaction; IHC: Immunohistochemical staining; TCA: Trichloroacetic acid; BCA: Bichloroacetic acid; SIS: Systemic inflammatory symptoms; HPS: Hemophagocytic syndrome; HPV: Human papilloma virus; HHV8: Human herpes virus 8; EBV: Epstein–Barr virus; IS: International Standard.