Hereditary and Inflammatory Bowel Disease-Related Early Onset Colorectal Cancer Have Unique Characteristics and Clinical Course Compared with Sporadic Disease

This article is featured in Highlights of This Issue, p. 1767

There is an increasing incidence of colorectal cancer among adults <50 years of age (1). Colorectal cancer in the young can be separated into hereditary, inflammatory bowel disease (IBD)–related, or sporadic. Hereditary syndromes account for 5% of all colorectal cancer diagnoses (2), and occur due to germline mutations that predispose patients to developing colorectal cancer. Lynch syndrome is a defect in mismatch repair (MMR) proteins and is the most common cause of hereditary colorectal cancer (3). It is the most well characterized in young patients, accounting for 4%–13.5% of early onset colorectal cancer (EoCRC; refs. 4–6). Additional genetic conditions associated with EoCRC are familial adenomatous polyposis (FAP), MUTYH-associated polyposis, Li-fraumeni syndrome (TP53 loss), and others (7, 8). IBD is composed of two diseases, ulcerative colitis (UC) and Crohn's disease (CD) and is associated with colorectal malignancy (9).

Individual comparisons between sporadic and hereditary (10, 11) or IBD-related colorectal cancer (12) have been conducted. Decreased survival in IBD-related colorectal cancer has been noted (13), whereas hereditary conditions, such as Lynch syndrome, are associated with improved survival over sporadic colorectal cancer (10, 11). However, most of the outlined reports are small, not population-based, and do not compare IBD-related colorectal cancer, hereditary colorectal cancer, and sporadic colorectal cancer specifically in early onset patients together in one study. We aimed to compare EoCRC as separated by predisposing conditions and identify clinicopathologic characteristics and prognostic changes that differentiate the clinical course of colorectal cancer related to predisposing conditions specific to EoCRC.

BC Cancer is a province-wide agency that delivers comprehensive publicly funded cancer care to nearly 5 million people in British Columbia, Canada. It consists of 6 regional cancer centers. Within BC Cancer, the Gastrointestinal Cancer Outcomes Unit (GICOU) prospectively collects demographic, disease, treatment, and outcome data on all patients with colorectal cancer. After receiving institutional review board approval, the GICOU database was queried to identify patients <50 diagnosed with colorectal cancer between 1990 and 2016. A waiver of consent was obtained as this was a retrospective administrative database review. The study was conducted with recognized ethical guidelines per the Declaration of Helsinki.

Patient charts were retrospectively reviewed for a diagnosis of a hereditary syndrome or IBD. Patients with hereditary EoCRC were identified by medical genetics and confirmed with sequencing or nucleic acid amplification as Lynch syndrome, FAP, MUTYH, or other hereditary malignancy syndrome. In British Columbia, guidelines recommend all patients diagnosed with a colorectal cancer <40 years of age, those with MSI-H colorectal cancer, patients with 2 Lynch syndrome-related cancers with one of them being diagnosed at age <50, and patients with a strong family history be referred for hereditary counseling and testing. IBD-related colorectal cancer was identified by endoscopy, clinical exam, imaging, or a combination of modalities. The remaining patients were considered sporadic EoCRC. Demographic and clinicopathologic data were available from the GICOU and compared between groups. Survival was compared between sporadic, hereditary, and IBD-related using disease-specific survival (DSS), defined as the time interval from diagnosis to cancer-related death. Patients were censored at the time of last contact if an event had not occurred.

Baseline characteristics were compared using the χ² test for categorical variables and un-paired t tests for continuous variables. For binary categorical variables, we obtained odds ratios (OR) and corresponding 95% confidence intervals (CI) from contingency tables. Comparisons with more than two categories were conducted using the χ² test for trend. After satisfying that all included variables met the proportional hazards assumption, a Cox-regression analysis was performed with pre-specified variables entered into the model based on known prognostic factors. In multivariate analysis, a total of 1,183 patients (1,065 sporadic, 73 hereditary, 45 IBD-related) were included with 952 patients excluded due to missing values for a variable (ECOG 57.3% known, stage 98.0% known, remaining variables all >98% known). Variables assessed for the final model included gender, age, site of disease, histology, stage at diagnosis, ECOG, IBD/hereditary status. The largest group within each variable was made the reference group. Outcomes representing survival were summarized using Kaplan–Meier curves and compared with the Log-rank test. P < 0.05 was regarded as statistically significant for all analyses. Statistical analyses were conducted using GraphPad Prism v8.3.0 or IBM SPSS 21.0.0.

A total of 2,135 patients <50 years old with colorectal cancer were reviewed. The minority of cases had a hereditary colorectal cancer syndrome (n = 146, 6.8%) or IBD (n = 87, 4.1%) and most patients had no predisposing hereditary or inflammatory condition (n = 1,902, 89.1%). Baseline characteristics are compared in Table 1. Patients with sporadic EoCRC were the oldest [median 45, interquartile range (IQR), 40–47], followed by patients with IBD (median 41; IQR, 34–45), then patients with hereditary syndromes (median 40; IQR, 33–45; P < 0.0001). The proportions of patients with predisposing conditions were unchanged over the time course of our study from 1990 to 2016 (Supplementary Fig. S1). Patients with sporadic EoCRC were more commonly female than hereditary or IBD groups (P = 0.005). IBD-CRC was associated with poor ECOG performance status, whereas hereditary had the best, and sporadic was intermediate (P = 0.0014). Sporadic colorectal cancer had the highest BMI with a mean of 25.9, standard deviation (SD)±6.0, followed by hereditary (mean 24.5, SD±5.0) then IBD (mean 23.7, SD±4.6; P = 0.040). IBD-associated cancers occurred predominantly in Caucasians (82.1%, P < 0.0001). The IBD group had the highest proportions of synchronous metastatic disease (39.8%), whereas hereditary had the lowest (14.7%) and sporadic had an intermediate proportion (30.3%, P < 0.0001). Similarly, the IBD group had the highest proportions of poorly differentiated disease (46.4%), whereas hereditary had the lowest (16.8%) and sporadic was intermediate (19.0%, P < 0.0001). The majority of sporadic colorectal cancer malignancies were adenocarcinomas (92.9%) whereas IBD had the highest rate of mucinous and signet-ring cell tumors (20.0%, P < 0.0001). IBD-related EoCRC displayed increased lymphovascular (LVI, 58.5%) and perineural invasion (PNI, 40%) on resection specimens, whereas hereditary colorectal cancer had the least (LVI: 23.6%, PNI: 17.6%) and sporadic being intermediate (LVI: 39.3%, P < 0.0001, PNI: 29.6%, P = 0.043). Microsatellite instability (MSI) was noted to be highest in the hereditary group (77.2%, P < 0.0001), but comparable in IBD (6.9%) and sporadic EoCRC (7.4%). Resections in patients with IBD had the highest rate of positive margins (18.2%) followed by sporadic (14.4%) then hereditary (8.7%) but this did not reach significance (P = 0.19).

We separated patients by age deciles and determined the proportion of hereditary and IBD patients within each group (Fig. 1A). Just over a third (34.3%) of patients <30 with EoCRC had a cause attributed to either hereditary (23.2%) or IBD (11.1%). A proportion that decreased with increasing age decile (Fig. 1A, P < 0.0001). Of hereditary patients, the largest contributing groups were confirmed Lynch syndrome (77.7%), FAP (10.8%), MUTYH and Li-Fraumeni (both 2.7%). Other conditions occurred in <2% of hereditary cases (Fig. 1B). In IBD-related EoCRC, 56.7% of patients had UC, whereas 26.7% had CD, and 14.9% were indeterminate or unidentified (Fig. 1C).

Sporadic and IBD-related EoCRC had a preference for the left colon and rectum, whereas hereditary EoCRC had predilection to the right colon (Fig. 2A). The likelihood of a tumor at each site of the colon and rectum comparing sporadic and IBD groups were unchanged with the exception of increased tumors in the sigmoid of sporadic cases (OR, 2.83; 95% CI, 1.36–5.92; P = 0.0039) and decreased tumors in the splenic flexure of sporadic EoCRC compared with IBD-related EoCRC (OR, 0.25; 95% CI, 0.11–0.54; P = 0.0001). Sporadic EoCRC was less likely to have disease in right colon compared with hereditary EoCRC (cecum OR, 0.50; 95% CI, 0.31–0.81; P = 0.0041, hepatic flexure OR, 0.36; 95% CI, 0.17–0.76; P = 0.0053, transverse colon OR, 0.21; 95% CI, 0.12–0.35; P < 0.0001), and more likely to be in the rectum (OR, 2.16; 95% CI, 1.47–3.16; P < 0.0001; Fig. 2B).

Compared with sporadic EoCRC, patients with IBD had the worst DSS, with a median survival of 36.0 months (HR, 1.80; 95% CI, 1.54–3.13; P < 0.0001) whereas hereditary EoCRC had the best DSS (HR, 0.47; 95% CI, 0.45–0.73; P < 0.0001; Fig. 3A).

Patients with UC and CD did not differ in survival (Fig. 3B, median survival UC: 43.9 months, CD: 44.5 month, P = 0.99). Undifferentiated IBD survival was reduced from UC and CD (HR, 1.87; 95% CI, 1.01–4.05; P = 0.049; Fig. 3B). Hereditary subgroups were identified for survival analysis as Lynch syndrome, FAP, and other. Lynch syndrome had improved survival over FAP (HR, 0.31; 95% CI, 0.054–0.57; P = 0.0037; Fig. 3C), and other hereditary syndrome (HR, 0.43; 95% CI, 0.11–0.99; P = 0.049). FAP and other hereditary patients did not differ by survival (P = 0.46).

A multivariate cox-regression analysis was performed to identify outcomes while controlling for the following variables: gender, age, site of disease, histology, stage, ECOG, and IBD/hereditary status. Controlling for these variables, using sporadic EoCRC as the reference population, patients with hereditary EoCRC no longer experienced significantly improved survival (HR, 0.79; 95% CI, 0.49–1.25; P = 0.31). However, survival in patients with IBD-related EoCRC remained poor compared with sporadic (HR, 2.21; 95% CI, 1.55–3.16; P < 0.0001; Table 2). Multivariate analysis of survival for only patients with metastatic disease using the same variables above identified a similar result. Survival of patients with hereditary EoCRC was not changed from sporadic EoCRC (HR, 1.45; 95% CI, 0.67–3.16; P = 0.35); however, the IBD-related EoCRC group remained with poor survival (HR, 3.47; 95% CI, 1.84–6.55; P < 0.0001).

We investigated 2,135 patients with colorectal cancer diagnosed at age <50 and compared features based on the presence of predisposing conditions. Hereditary syndromes accounted for 6.3%, and IBD-related for 4.1% of EoCRC, comparable with prior similar reports (10, 14). The proportions of EoCRC attributed to hereditary and IBD were highest in the youngest groups, representing a third of patients under 30. Consistent with this, studies using younger age cutoffs of 35 or 40 to define EoCRC reported larger proportions of patients with hereditary causes of 35% (5) and 22.7% (15), respectively. IBD-related colorectal cancer in the young is less well studied, but in the general population, IBD-CRC diagnoses occur on average 7.7 years before sporadic colorectal cancer (16), and patients with IBD-CRC were found younger at diagnosis (13).

Stage, grade, histology, PNI, LVI, and positive resection margin that are disease and histologic characteristics associated with poor outcome were associated with IBD-related EoCRC, were intermediate in sporadic, and lowest in hereditary cases. These findings agree with our results of disease specific survival, which also showed a similar pattern of worse outcome in IBD-related colorectal cancer, intermediate in sporadic and best in hereditary young patients. Pooled studies have shown IBD-related colorectal cancer tumors to have poor differentiation but no difference in tumor or nodal stage, and patients have equal overall survival at 5-years compared with sporadic colorectal cancer (12, 17); however, when separating patients by age, IBD-related colorectal cancer confers worse survival in young patients ages <50 years (13). Our results concur and IBD-related EoCRC may be distinct and carry a worse prognosis compared with sporadic EoCRC, whereas average age onset IBD-CRC may be more similar to average age onset sporadic colorectal cancer in prognosis. Improved survival in hereditary colorectal cancer has been reported in patients with Lynch syndrome (18, 19), which comprise the majority of our hereditary group and was found to have improved survival over sporadic EoCRC. These results highlight that EoCRC associated with predisposing features are fundamentally different in presentation, disease characteristics, and outcomes.

Despite controlling for other poor prognostic markers, IBD-associated EoCRC was associated with a worse prognosis as compared with sporadic EoCRC both in all patients and those with metastatic disease. This suggests that either there are extrinsic factors not encountered in our study that may be influencing the outcome, or IBD-related EoCRC carries an intrinsically poor prognosis. The chronic inflammation associated with IBD may result in acquisition of genetic or clinical features associated with this poor prognosis. For example, we observed significantly more mucinous and signet ring histology in the IBD population, both negative prognostic markers. As well, there were higher rates of positive margins in patients who underwent resection with IBD. This could be due to the ongoing regional inflammation that would make surgical clearance more challenging. Patients with hereditary EoCRC no longer experienced significantly improved survival when compared in our multivariate model. These results signify that hereditary EoCRC may be similar in outcome to sporadic EoCRC when patient and disease characteristics are controlled. Indeed, hereditary EoCRC were also diagnosed with earlier disease stage. A concerning family history may be increasing suspicion for clinicians and driving earlier diagnosis. In addition, the outcome was likely influenced by the MSI-H status of many of the tumors that fell into the category and is associated with a good prognosis in early-stage disease (20).

We expanded our analysis of survival in of EoCRC to include sub-groups of IBD and hereditary patients where sufficient numbers allowed. Although we found no differences in IBD-EoCRC subgroups of UC and CD, which has been reported previously in all ages (12, 21), others report worse outcomes for CD in IBD-related EoCRC (13). Survival in undifferentiated or unreported IBD subtype appears lower that may represent overly morbid patients that did not receive a diagnostic work-up to discern the IBD subtype. Alternatively, these patients may have indeterminate colitis, a third subtype of IBD that is histologically uncategorizable upon colectomy as UC and CD (22). Indeterminate colitis occurs in 10%–15% of colitis (22), which is similar to our proportion of IBD-CRC that is undifferentiated (14.9%), and often associated with poor outcomes post-colectomy (23). Among the hereditary group, young Lynch syndrome patients had improved survival compared with FAP and other patients with hereditary EoCRC, a feature well described in the literature for early-stage tumors (20).

Our study limitations include those inherent to observational retrospective studies such as misclassification bias in chart review and confounding variables not included in our studies. In addition, variables not available to study are length of IBD and severity of disease, both which have been associated with development of colorectal cancer (16, 24), as well as presence of primary sclerosing cholangitis (25). Despite these, this study represents an important overview of colorectal cancer in young adults in a population-based cohort in British Columbia, Canada.

EoCRC is not a uniform disease. Predisposing syndromes contribute to distinct clinical presentation and outcomes. We report differences between IBD and hereditary syndrome associated EoCRC and sporadic EoCRC.

G. Rosenfeld reports grants, personal fees, and non-financial support from Abbvie, grants and personal fees from Pfizer, Ferring, Takeda, and personal fees from Janssen, Merck, fresnius Kabi, Roche, Viatris, and grants from Crohn's and Colitis Canada outside the submitted work. J.M. Loree reports grants and personal fees from Amgen and Ipsen, and personal fees from Novartis, Bayer, Eisai, non-financial support from Foundation Medicine, and non-financial support from AstraZeneca outside the submitted work. No disclosures were reported by the other authors.

A.A. Arif: Data curation, formal analysis, investigation, visualization, methodology, writing–original draft, writing–review and editing. D. Chahal: Conceptualization, data curation, formal analysis, writing–original draft, writing–review and editing. G.K. Ladua: Data curation, formal analysis. E. Bhang: Data curation, formal analysis. B. Salh: Formal analysis, methodology, writing–review and editing. G. Rosenfeld: Formal analysis, methodology, writing–review and editing. J.M. Loree: Conceptualization, formal analysis, supervision, investigation, methodology, writing–original draft, writing–review and editing. F. Donnellan: Conceptualization, formal analysis, supervision, investigation, methodology, writing–review and editing.

J.M. Loree was the recipient of a Michael Smith Health Professional Investigator Award. The authors thank the BC Cancer Foundation that provided funds to help support this project.

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