Solid extraintestinal malignancies in patients with inflammatory bowel disease

Table 2 Studies on cervical neoplasia in patients with inflammatory bowel disease

Ref.	Country	Type of study	Patients	Results	Limitations
Connell et al[91], 1994	United Kingdom	Single centre-registry study, Prospective (1962-1991)	755 IBD patients taking AZA	CC: SIR 4.00	Small power of the study to detect an increased risk (expected 0.5). No variables analysed
Bhatia et al[110], 2006	United States	Single centre-cohort study, Retrospective	116 IBD patients 116 age-matched healthy controls	Abnormal Pap smears: 18% vs 5%; P = 0.004. Non association with IBD type or treatment exposure	Inter-observer variability in the smear interpretation. Recall bias (questionnaires)
Kane et al[111], 2008	United States	Single centre-cohort study (2004-2005)	8 UC; 32 CD. 120 controls (age, race, parity-matched). 58% exposed to ≥ 1 treatment (prednisone, AZA, 6-MP and/or IFX)	Abnormal Pap smear 42.5% IBD vs 7% controls; OR 3.4 (95%CI: 1.7-12.1, aP < 0.001), low-grade lesions OR 2.2 (95%CI: 1.7-4.4, aP < 0.001), high-grade lesions OR 3.1 (95%CI: 1.3-8.7, aP < 0.001). Exposed vs non-exposed: Abnormal Pap smear OR 1.5 (95%CI: 1.2-7.1, bP = 0.02), High-grade lesions OR 6.5 (95%CI: 1.43-30.1, bP < 0.05), IMMs > 6 mo OR 1.9 (1.1-12.1, bP < 0.001)	Small population study. Level of immune suppression not assessed
Hutfless et al[112], 2008	United States	Nested case- control study (1996-2006)	UC 778; CD 476; Controls 12124. TP monotherapy (AZA, 6-MP, MTX)	CC: aOR 1.45 (95%CI: 0.74-2.84), ASA: OR 1.65 (0.34-7.98), corticosteroids: OR 2.79 (0.71-11.00), IMMs: OR 3.45 (0.82-14.45)	Missing data for race, ethnicity, smoking status. No adjustment for therapy or disease severity. Diagnostic or screening Pap smears are not distinguishable
Marehbian et al[113], 2009	United States	Insurance claims-based United States population (2002-2005)	CD 22310; controls 111550	IBD vs controls: Cervical dysplasia/HPV: RR 1.35 (1.28, 1.43). Exposed vs non exposed to treatment: aHR Steroids 1.11 (0.59, 2.09), IS 1.77 (1.26, 2.49), anti-TNF 1.30 (0.68, 2.51), Combination 1.81 (1.10, 3.10)	Disease severity is a possible confounding factor. Limited amount of person-time on various treatments
Lees et al[114], 2009	Scotland	Tertiary centre, case-control study Retrospective	UC 178; CD 184; Healthy controls 1448	Abnormal Pap smear: IBD patients OR 0.82 (95%CI: 0.59-1.1.3), IBD patients current smokers vs ex or no smokers OR 2.95 (95%CI: 1.55-5.50); P = 0.001, Women < 20 yr at IBD diagnosis vs 20-39 yr vs > 40 yr: 27% vs 13.4% vs 5.0% (P = 0.001). No effect of IS therapy	No data on HPV status or exposure to corticosteroids. Small number of patients on MTX or anti-TNF. Median time exposed to IS 2.4 yr. Smoking may be a confounding factor
Singh et al[115], 2009	Canada	Population-nested case-control (2002-2006)	UC 233; CD 292; Controls 57898	Cervical abnormalities: OR 1.41 (1.09-1.81), IS+ steroids 1.41 (1.09-1.81). High risk lesions: IS monotherapy aOR 1.23 (0.57-2.63), IS + steroids aOR 1.28 (0.77-2.12), CD patients exposed to > 10 prescriptions of oral contraceptives OR, 1.66 (1.08-2.54), UC OR 1.03 (0.77-1.38)	Administrative databases. Possible bias is smoking, parity and sexual factors. Small number of patients exposed to IMMs alone. No data on HPV infection. CN confirmed histologically in 19% of cases
Jess et al[75], 2013	Denmark	Population-nested case-control (2002-2006)	1437 UC; 774 CD. UC median F.U. 15 yr (0-33); CD 14 yr (0-33). 1978-2010 Population-based cohort study (1978-2010). 25176 IBD patients; UC 1437; CD 774(UC median 15yrs/22 582 pt-yrsCD median 14yrs/11 261 pt-yrs)TP (18% of UC pts,45% of CD pts everused TP)	Cervical dysplasia/CC: SIR 1.65 (95%CI: 1.10-2.37), CD diagnosed at age 0-19 yr: SIR 2.52 (95%CI: 1.26-4.51), Smokers: SIR, 2.15 (95%CI: 1.27-3.40), 5-ASA: SIR, 1.69 (95%CI: 1.08-2.51), Thiopurines: SIR, 2.47; (95%CI: 1.54-3.73)	No detailed pharmaco-epidemiological analyses. Cervical dysplasia was analysed along with CC resulting in higher CC incidence
Rungoe et al[116], 2015	Denmark	Nationwide population-based cohort (1979-2011)	27408 IBD patients (UC 18691; CD 8717), controls 1508334, median F.U: UC. 7.8 yr; CD 8.3 yr	CD: CC IRR 1.53 (95%CI: 1.04-2.27), High grade lesions IRR, 1.28 (95%CI: 1.13-1.45), low grade lesions IRR, 1.26 (95%CI: 1.07-1.48), CN significantly higher risk in CD patients diagnosed at young age and treated with AZA. UC: CC IRR 0.78 (0.53-1.13), High-grade lesions IRR 1.12 (95%CI: 1.01-1.25), Low-grade lesions: IRR 1.15 (95%CI: 1.00-1.32)	Data for smoking not available. Possible confounding factor is disease severity. Vaccination policies and screening may influence risk estimation
Kim et al[119], 2015	United States	Cohort U.S. insurance data (2001-2008 and 2003-2012)	133333 SID patients, including 25176 IBD	High grade dysplasia/CC: aHR 1.72 (0.66-4.45). IS: aHR 1.72 (95%CI: 0.66-4.45)	Confounding factors (race, ethnicity, socioeconomic status, sexual behavioural, gynaecologic history). Study not designed to determine the comparative effect of IS drugs. Short follow-up (mean 2.1 yr)
Jung et al[31], 2017	Korea	National Health Insurance claims (2011-2014)	IBD (5595 CD and 10049 UC)	CC: UC 5.65 (2.44-11.13)	Did not focus on cancer occurred during IBD treatment. Missing data (disease diagnosis, phenotype). Short follow-up
Segal et al[117], 2021	United Kingdom	Hospital Episode Statistics database (1997-2012)	837 with IBD, 61648 control patients	IBD vs controls: CC: 5.2 of 100000 vs 4.6 of 100000; P = 0.042	Other possible mechanism of carcinogenesis (other than HPV) not evaluated. Database accuracy. HPV-related cancers were not considered separately in CD and UC
Li et al[118], 2019	China	Prospective study (2014-2017)	124 IBD patients and 372 controls	HPV 16/18 infection OR 29.035 (3.64-210.988) P = 0.001, HPV-infection rate: MTX OR 4.76 (1.471-15.402) P = 0.005, > 2 IS OR 3.64 (1.255-10.562) P = 0.013, CIN prevalence: 3.2 vs 0.0%, P = 0.004	No data on sexual behaviour in control group

^aP: Compared to controls.

^bP: Compared to non-exposed.

IBD: Inflammatory bowel disease; AZA: Azathioprine; Pap: Papanicolaou; CC: Cervical cancer; SIR: Standardized incidence ratio; IFX: Infliximab; 6-MP: 6-Mercaptopurine; UC: Ulcerative colitis; CD: Crohn’s disease; OR: Odds ratio; aOR: Adjusted odds ratio; CI: Confidence interval; IS: Immunosuppressant; TP: Thiopurine; MTX: Methotrexate; ASA: Amino-salicylate; IMMs: Immunomodulators; anti-TNF: Anti-tumour necrosis factor; SID: Systemic inflammatory disease; HPV: Human papilloma virus; HR: Hazard ratio; IRR: Incidence rate ratio; CIN: Cervical intraepithelial neoplasia.