Copyright
©The Author(s) 2023.
World J Meta-Anal. Dec 18, 2023; 11(7): 317-339
Published online Dec 18, 2023. doi: 10.13105/wjma.v11.i7.317
Published online Dec 18, 2023. doi: 10.13105/wjma.v11.i7.317
Table 1 Post-transplant cancers standardized incidence ratio compared to general population[12]
| Standardized incidence ratio compared to general population | Post-transplant cancers |
| > 5 | NMSC, PTLD, lip, RCC and KS |
| 2-5 | Melanoma, thyroid cancer, leukemia and multiple myeloma |
| < 2 | Breast, brain, lung and prostate cancer |
| Cancers associated with post-transplant viral infections | Meta-analysis SIR |
| EBV-associated | |
| Hodgkin’s lymphoma | 3.89 (2.42-6.26) |
| NHL | 8.07 (6.40-10.2) |
| HHV8-associated | |
| Kaposi’s sarcoma | 208 (114-369) |
| HBV/HCV-associated | |
| Hepatocellular | 2.13 (1.16-3.91) |
| HPV-associated | |
| Cervical | 2.13 (1.37-3.30) |
| Vulva & vagina | 22.8 (15.8-32.7) |
| Penis | 15.8 (5.79-34.4) |
| Anus | 4.85 (1.36-17.3) |
| Oropharynx | 3.23 (2.4-4.35) |
| Non-melanocytic skin cancer | 28.6 (9.39-87.2) |
Table 3 Different viruses associated/related to post-kidney transplant tumours/cancers
| Virus | Associated/related post-kidney transplant tumours/cancers |
| EBV | PTLD, smooth muscle tumours |
| HPV | Squamous cell carcinoma |
| HHV8 | Kaposi’s sarcoma, multiple myeloma |
| HIV | Plasmablastic lymphoma, Merkel cell carcinoma |
| HBV/HCV | Hepatocellular carcinoma |
| BK polyomavirus | Urothelial, renal cell and collecting duct carcinoma |
| CMV | Gastrointestinal tumours, nephrogenic adenoma |
| Risk factors of PTLD in KT | Likely cause/association |
| Recipient age < 10 yr | A greater likelihood of being seronegative for EBV |
| Recipient age > 60 yr | Associated finding in various studies |
| EBV seropositive donor to EBV seronegative negative recipient (EBV D+/R-) | 90% are donor derived and 10–76-fold higher incidence of early PTLD |
| Bimodal peak | First peak (with higher incidence) in first 2 years and 2nd peak between 5 to 10 years post-transplant |
| Intensity of immunosuppression and use of T cell depleting antibodies (ATG and/or OKT3), belatacept | Reduction in cancer immunosurveillance |
| Treated acute rejection within first year after transplantation with depleting antibodies | Reduction in cancer immunosurveillance |
| Simultaneous pancreas–kidney transplantation | Association |
| HLA mismatches (especially HLA B and DR mismatches) | Likely, due to higher associated risk of rejection and use of increased net immunosuppression |
Table 5 Viruses and their specific carcinogenic mechanisms
| Virus | Carcinogenic mechanisms |
| EBV | EBV-infected cells generates more interleukin-6, which promotes the proliferation of B-cells, and interleukin-10, an immunosuppressive cytokine that promotes tumour development |
| HPV | E6 and E7 proteins expressed by HPV suppress p53-mediated apoptosis and increase malignant growth in infected cells |
| HHV8 | Viral proteins encoded by HHV8 inhibit the activation of pro-caspase-8, promotes Ras-PI3K-Akt survival pathway and enhances antiapoptotic Bcl-2 (B-cell lymphoma 2) expression, thereby inhibiting apoptosis and promoting uncontrolled proliferation of infected and endothelial cells |
| HBV | HBx proteins produced by virus activate the Ras-PI3K-Akt survival pathway and change EGFR signalling. In addition, it modifies the transcriptional activity of c-Myc, c-Fos, and c-Jun and promotes the expression of angiogenic factors, including VEGF and angiopoietin-1. Consequently, this stimulates proliferation and angiogenesis |
| HCV | Virus-produced non-structural proteins (NS3 and NS5A) promote the Ras-PI3K-Akt survival pathway. NS5A also modulates the signalling mediated by. Consequently, this stimulates proliferation and angiogenesis |
| Immuno-suppressive agents | Mechanisms in carcinogenesis | Cancer risk |
| Polyclonal lymphocyte depleting agents (OKT3/rATG) | Interfere with T-cells, B-cells, NK and DC functions[143-145] | Increased risk of PTLD |
| Alemtuzumab | Depletes B and T cells | Increased risk[146] |
| NHL (2.5-fold rise) | ||
| Colorectal cancer (2.5-fold rise) | ||
| Thyroid cancer (3-fold rise) | ||
| Mixed results with PTLD association[147,148] | ||
| Cyclosporine A | Downregulate T-bet dependent immunosurveillance[149] | Suppress immune response against melanomas |
| Inhibit antigen presentation by DC[150] | Impairs elimination of oncogenic viruses and overall increased risk of cancer[151] | |
| Tacrolimus | Inhibit antigen presentation by DC[150] | Impairs elimination of oncogenic viruses |
| Overall increase risk of PTLD and reduced trough levels substantially decline the risk[152] | ||
| Azathioprine | selectively depletion of memory T-cells[153] | Linked to late SCC (of skin) and myelodysplastic syndrome [154] |
| Mycophenolate (MMF/MPA) | Antiproliferative and antioncogenic potential[155] | Protective and reduce the risk of PTLD |
| mTOR inhibitors | Promotion of CD8+ central memory T cells[156] | Enhance antiviral immunity |
| Upregulate transcription factor T-bet[157] | T-bet regulates cross-talk of innate and adaptive immune cells and has tumour-suppressive activities[158] | |
| Antioncogenic and antiproliferative role | Overall cancer risk reduction and even regress KS[159] | |
| Belatacept | Inhibitor of T cell proliferation | Unclear though postulated as slight increased risk of oncogenicity[160] |
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 |
Table 8 Post-transplant virus associated malignancy and their diagnosis
| Post-transplant viral associated malignancy | Diagnosis |
| CIN and cervical cancer and (HPV- associated) | Abnormal cervical Pap test/cytology on screening: Colposcopy biopsy of any suspicious lesion[28,161] |
| AIN and anal cancer (HPV-associated) | Abnormal anal Pap test/cytology on screening: High-resolution anoscopy ± biopsy of any suspicious lesion[28,161] |
| EBV associated PTLD | Identify “B” symptoms (fever, night sweats and weight-loss) |
| Excision biopsy/core biopsy (in allograft PTLD as excision in not practical) is gold standard for diagnosis[46] | |
| Stage PTLD with CT imaging of the chest, abdomen, and pelvis, as well as MRI brain imaging before initiating treatment as in immunocompetent host[166] | |
| PET-CT may help in diagnosing occult PTLD, accurate staging in occult cases and sometime evaluating treatment response[167-169] | |
| PT-KS | Examine for cutaneous or mucosal lesions, visceral involvement and haematological manifestations |
| Diagnostic gold standard: HHV8 confirmation in biopsy of KS lesions[170] | |
| HPE characteristic of PT-KS: Spindle-shaped cells and immunostaining confirmation with latency-associated nuclear antigen and CD34 positive staining[171,172] | |
| Quantitative PCR load of HHV8: Role in supporting diagnosis and monitoring treatment response | |
| Confirmation of diagnosis by HPE and HHV8 DNAemia | |
| Depending on site involved, disease staging by imaging and invasive procedures (e.g., bronchoscopy, esophago-gastroduodenoscopy, colonoscopy)[173] | |
| MCD | Watch for lymph node enlargement, systemic inflammatory symptoms |
| Gold standard for diagnosis: Lymphnode biopsy confirmation of HHV8[170] | |
| HPE: HHV8+ plasmablasts in follicular mantle zone and vascular hyperplasia | |
| Quantitative PCR load of HHV8: Role in supporting diagnosis and monitoring treatment response | |
| Confirmation of diagnosis by HPE and HHV8 DNAemia | |
| PEL | Watch for effusion (pleural, peritoneal, pericardial) |
| Gold standard: Confirmation of HHV8 in pleural/ascitic fluid[170] | |
| HPE characteristic: HHV8+ plasmablasts displaying immunoblastic and anaplastic characteristics | |
| Quantitative PCR load of HHV8: Role in supporting diagnosis and monitoring treatment response | |
| Confirmation of diagnosis by HPE and HHV8 DNAemia |
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] |
Table 10 Post-transplant malignancy: surveillance protocols[30]
| Cancer | Post-transplant surveillance |
| Skin | Self-skin examination monthly; examination by dermatologist: 6 to 12 monthly[162] (expert opinion) |
| PTLD (EBV+) | Routine screening of EBV D+/R- by EBV NAAT: once first week, monthly for next 3–6 mo, and every 3 mo till 1 yr after transplantation[162] (expert opinion) |
| Cervical | Age 25–74 yr: yearly cervical Pap test and pelvic examination[195]; in higher risk category, more frequent Pap test |
| Hepatocellular | Every 6 mo screening with USG ± α-fetoprotein in high risk (i.e. with cirrhosis) (extrapolation from general population) |
| Renal | USG screen every 6–12 mo in high risk (i.e. acquired cystic kidney)[196] |
| Breast | Females < 50 yr: individual decision when to start screening; Females 50–74 yr: every 2 yr screening mammography[197]; [extrapolation from immunocompetent (general) population] |
| Prostate | Men 55–69 yr: individualized screening approach after discussing potential benefits and harm; Men > 70 yr, avoid routine screening[198] [extrapolation from immunocompetent (general) population] |
| Bowel | All 45–75 yr: stool immunochemical testing every 2 yr, 5-yearly FEGD and sigmoidoscopy, or 5–10-yearly colonoscopy[199] |
| Lung | All 55–79 yr who have smoked 1 pack/day for 30 yr or its equivalent (2 packs/day for 15 yr, 3 packs/day 10 yr): yearly low dose CT chest [200] [extrapolation from immunocompetent (general) population] |
- Citation: Yadav R, El Kossi M, Belal D, Sharma A, Halawa A. Post-transplant malignancy: Focusing on virus-associated etiologies, pathogenesis, evidence-based management algorithms, present status of adoptive immunotherapy and future directions. World J Meta-Anal 2023; 11(7): 317-339
- URL: https://www.wjgnet.com/2308-3840/full/v11/i7/317.htm
- DOI: https://dx.doi.org/10.13105/wjma.v11.i7.317