De novo malignancies after liver transplantation: The effect of immunosuppression-personal data and review of literature

Table 1 Incidence of de novo malignancies in adult orthotopic liver transplant patients

				Number and % incidence of de novo malignancy types in all orthotopic liver transplant recipients
Author	Yr	Number of patients	Number of DNM	PTLD	Skin and Kaposi	Head and Neck	Lung	Renal	Colon	Prostate	Breast	Gynecological	Others
Jonas et al[72]	1997	458	33	7 (1.5)	8 (1.7)	2 (0.4)	3 (0.7)	0	0	0	3 (0.7)	7 (1.5)	3 (0.6)
Jain et al[134]	1998	1000	57	NA	24 (2.4)	7 (0.7)	8 (0.8)	2 (0.2)	4 (0.4)	3 (0.3)	3 (0.3)	0	6 (0.6)
Kelly et al[135]	1998	888	31	NA	8 (0.9)	6 (0.7)	1 (0.1)	0	3 (0.3)	0	2 (0.2)	1 (0.1)	10 (1.1)
Jimenez et al[136]	2002	505	62	13 (2.6)	16 (3.2)	10 (2.0)	6 (1.2)	NA	NA	NA	NA	NA	17 (3.3)
Saigal et al[73]	2002	1140	30	NA	14 (1.2)	3 (0.3)	0	3 (0.3)	1 (0.1)	0	2 (0.2)	1 (0.1)	6 (0.5)
Sanchez et al[137]	2002	1421	125	35 (2.5)	42 (3.0)	4 (0.3)	11 (0.8)	3 (0.2)	9 (0.6)	0	7 (0.5)	2 (0.1)	13 (0.8)
Benlloch et al[17]	2004	772	41	10 (1.3)	NA	9 (1.2)	8 (1.0)	3 (0.4)	2 (0.3)	1 (0.1)	2 (0.3)	2 (0.3)	4 (0.5)
Oo et al[138]	2005	1778	141	18 (1.0)	51 (2.9)	NA	14 (0.8)	NA	18 (1.0)	NA	11 (0.6)	1 (0.06)	28 (1.6)
Yao et al[12]	2006	1043	53	9 (0.9)	17 (0.6)	3 (0.3)	5 (0.5)	2 (0.2)	6 (0.6)	0	4 (0.4)	2 (0.2)	5 (0.5)
Aberg et al[81]	2008	540	39	9 (1.7)	11 (2.0)	2 (0.3)	NA	2 (0.3)	2 (0.3)	2 (0.3)	1 (0.1)	NA	10 (1.8)
Jiang et al[20]	2008	2034	113	44 (2.1)	NA	3 (0.1)	10 (0.5)	4 (0.2)	14 (0.7)	5 (0.2)	5 (0.2)	NA	24 (1.2)
Baccarani et al[139]	2010	417	43	9 (2.1)	8 (1.9)	8 (1.9)	4 (0.9)	0	2 (0.5)	0	1 (0.2)	3 (0.7)	8 (1.9)
Engels et al[5]	2011	37888	1563	365 (1.0)	NA	NA	300 (0.8)	67 (1.8)	NA	NA	NA	NA	831 (2.2)
Chatrath et al[140]	2013	534	80	16 (3.0)	24 (4.5)	9 (1.7)	13 (2.4)	1 (0.2)	1 (0.2)	1 (0.2)	NA	1 (0.2)	14 (2.6)
Schrem et al[141]	2013	2000	120	23 (1.1)	NA	11 (0.5)	14 (0.7)	7 (0.3)	13 (0.6)	5 (0.2)	8 (0.4)	10 (0.5)	29 (1.4)
Krynitz et al[32]	2013	1221	150	27 (2.2)	58 (4.7)	4 (0.3)	6 (0.5)	2 (0.1)	6 (0.5)	4 (0.3)	7 (0.6)	10 (0.8)	26 (2.1)
Mouchli et al[62]	2017	373	64	22 (5.9)	5 (1.3)	NA	NA	11 (2.9)	11 (2.9)	7 (1.9)	5 (1.3)	3 (0.8)	0
Egeli et al[142]	2017	429	9	NA	1 (0.2)	2 (0.4)	5 (1.1)	NA	NA	NA	NA	NA	1 (0.2)
Taborelli et al[143]	2018	2832	266	37 (1.3)	72 (2.5)	34 (1.2)	28 (1.0)	4 (0.2)	21 (0.7)	2 (0.1)	4 (0.2)	3 (0.1)	65 (2.1)

NA: Not available; DNM: De novo malignancy; PTLD: Post-transplant lymphoproliferative disease.

Table 2 Clinical operational tolerance literature and clinical trials in adult orthotopic liver transplant recipients[9,90]

First authors	Yr/Trial start	Number of patients	Complete IS weaning, %	Median follow-up mo from IS withdrawal	Rejection rate, for acute, %	Weaned patients due to DNM diagnosis
Ramos et al[110]	1995	39	41	15	38.4	None
Devlin et al[144]	1998	18	27.8	> 36	44.4	None
Eason et al[145]	2005	18	5.5	9	61.1	None
Girlanda et al[146]	2005	18	11	84	5.5	None
Tisone et al[109]	2006	34	23.4	45.5 ± 5.8	21.0	None
Assy et al[147]	2007	26	42	6	58.0	None
Pons et al[148]	2008	12	38.0	10-30	58.0	None
Tryphonopoulos et al[149]	2010	23	22.0	87 ± 3.0	5.0	None
Manzia et al[106]	2013	28	21.4	113 ± 20.0	21.0	None
De la Garza et al[150]	2013	24	62.5	14.0	37.5	None
Benitez et al[151]	2014	102	40.2	48.9	59.8	None
Bohne et al[152]	2014	34	50	12	44.1	None
Todo et al[153]	2016	10	70	NA	30.0	None
Manzia et al[107]	2018	75	42.6	78.5	0	None
Shaked[154]	2005 (clinical trial)	275	20.3	NA	5.5	None
Markman[155]	2016 (ongoing trial)	60	NA	NA	NA	NA
Markman et al[156]	2019 (ongoing trial)	NA	NA	NA	NA	NA

NA: Not available; IS: Immunosuppression: DNM: De novo malignancy.

Table 3 De novo malignancy features in orthotopic liver transplant recipients: The Tor Vergata experience between April 1998 and December 2014

	Patients under standard IS,n = 234Median age: 53.6 ± 7.1 yr	Tolerant patients,n = 22Median age: 52.3 ± 6.0 yr	Non-tolerant patients, n = 43Median age: 51.5 ± 9.6 yr
Number of patients	234	22	43
Median follow-up time from OLT to IS weaning, mo	-	112.9	59.8
Median follow-up time from weaning start to IS withdrawal, mo	-	6.0	4.9
Median follow-up time with no IS, mo	-	92.3	2.3
Median follow-up time after IS resumption, mo	-	-	149.1
Patients who developed DNMs, %	13.7	0	6.4
Median time from OLT to DNM development, mo	44.5	-	113.0
Incidence and type of DNMs	(n = 32) Lung (7) Head and neck (5) Colon (4) Oral cavity (4) PTLD (4) Genito-urinary (3) Esophagus (2) Liver (1) Mesothelioma (1) KS (1)	None	Bladder (1) Larynx (1) Lung (1)

DNM: De novo malignancy; OLT: Orthotopic liver transplant; IS: Immunosuppression; PTLD: Post-transplant lymphoproliferative diseases; KS: Kaposi’s sarcoma.

Table 4 Clinical operational tolerance trials in pediatric orthotopic liver transplant recipients

First author	Yr	Type of study	Number of patients	DNM-Patients indicated to withdraw IS	Complete IS weaning, %	Time interval: OLT to withdrawal, mo/yr	Rejection rate, for acute, %
Ramos et al[110]	1995	Prospective	20 (12-20 yr at entry) (59 total patients)	2	27.10%	> 5 yr	20.3%
Mazariegos et al[157]	1997	Historical cohort (self-weaned) and prospective cases	31 (≤ 20 yr) (100 total patients)	12	Pediatric cohort: 29%	> 5 yr	10%
Takatsuki et al[111]	2001	Prospective	63	NA	38.1%	≥ 2 yr	25.4%
Oike et al[112]	2002	Prospective	115	NA	42.6%	≥ 2 yr	20%
Koshiba et al[113]	2007	Retrospective	581	NA	15%	≥ 2 yr	1.5%
Ohe et al[114]	2012	Historical cohort	190	NA	44.2%	≥ 2 yr	26.3%
Hurwitz et al[116]	2004	Retrospective	38	19 (PTLD)	21% (n = 4 PTLD; n = 4 EBV)	Mean time to PTLD onset: 1.8 ± 2.3 yr; Mean time to EBV infection onset: 1.1 ± 1.1 yr	55.2%
Lee et al[117]	2009	Prospective	5	1 (PTLD)	100%	1.2-2 yr	0%
Feng et al[118,158] (WISP-R trial)	2012	Prospective	20	NA	60%	≥ 4 yr	35%
Feng et al[159] (iWITH trial, partial results, 2016)	2012	Prospective	88	NA	60%	≥ 4 yr	40%
Waki et al[120]	2013	Retrospective	52	NA	42.5%	> 2 yr	57.5%
Lin et al[121]	2015	Prospective	16	NA	40%	> 2 yr	40%

OLT: Orthotopic liver transplant; DNM: De novo malignancy; IS: Immunosuppression; PTLD: Post-transplant lymphoproliferative diseases; EBV: Epstein-Barr virus; NA: Not available.