The incidence of CRC is increasing in young patients with seemingly few risk factors(9). Currently, the notion that younger age of onset is related to a poor prognosis is controversial; survival data is rather ambiguous and tumour characteristics are not consistently described for this subgroup of yCRC patients(2,8,9). Furthermore, no such study has been completed in Scotland. By establishing survival and characterising clinico-pathological features of this Scottish cohort, current knowledge and practice relating to yCRC may improve on both a local and international level.
In this retrospective study, survival in yCRC was found to be better than that in later onset CRC despite higher rates of advanced disease. Spanning an 11 year period up to December 2015, follow-up and survival data from 345 CRC patients aged under 55 years was collected. Despite a significant number of patients were diagnosed at late stage disease, the cohort had a greater overall five year survival of 63%, compared to 59% - the latest five year survival statistic for CRC across all age groups(15). This may reflect the fitness and relative lack of co-morbidities of these younger patients, making them better candidates for surgery, chemotherapy and radiotherapy. We found the five year survival of stage III and IV patients to be 67% and 18%, respectively. Across all age groups, five year survival in patients stage III disease is estimated at 63%, and stage IV is 7%(15). This suggests, contrary to popular belief, that the young-onset cohort actually had similar or better outcomes than colorectal cancer patients overall. This superior stage-specific survival is also reflected in other multi-national studies(2,4,9,12). However, in contrast, these studies did not find survival outcomes to be greater even when unadjusted to stage. This is likely to be because these studies tended to focus on patient groups aged between 20 and 40 years, rather than aged under 55 years. When our results are adjusted to age-specific survival, those less than 40 years of age were also found to have a poorer prognosis. Interestingly, one study consistent with this result by Ballester et al. also found that - despite an overall better prognosis - yCRC patients had a higher incidence of recurrence and development of metastasis than later-onset disease. In this study, tumour recurrence occurred in 22.6% of patients. In a Korean study considering CRC across all ages, recurrent disease was found to occur in 18.3%(16). Although inconclusive, this is potentially an area for further investigation to detemine why yCRC patients may have a higher incidence of tumour recurrence.
This study also characterised the cohort in terms of clinicopathological features, which found locally advanced rectosigmoid disease to be typical of yCRC. Tumours were commonly located in the left side of the bowel, with a greater proportion of tumours (42.6%) occurring in the rectum – concurring with previous literature describing young-onset disease(7). Although our cohort is relatively small, it includes all the patients in a geographical area, including both urban & rural populations. Over 60% of patients presented with late stage (III or IV) disease. According to cancer research statistics, in Scotland approximately 23% of CRC patients present with stage IV disease and 25% with stage III disease(17). In this cohort, perhaps surprisingly, fewer patients presented with stage IV disease (18%), although there were nearly 70% more patients (42%) diagnosed initially with stage III disease compared to the national incidence across all ages. Advanced disease prior to diagnosis may be explained by delays in patient presentation and diagnosis due to the relative rarity of the condition in comparison to the older population, as well as a lack of screening. In Scotland, population screening does not begin until the age of 50. In contrast with previous studies investigating yCRC(12,18), incidence of poorly differentiated – or high-grade – histology was not found to be overrepresented in our patient group. An Australian study concurs with this finding, putting this discrepancy down to the subjective nature of determining tumour grade across the world(2).
Of those referred to genetic services, a significant proportion (18%) were found to be MSI positive. FH was often not documented sufficiently or, in some cases, not at all. FH is a major determining factor for referral to genetic services given the autosomal dominant inheritance pattern of Lynch syndrome. SIGN 2003 guidelines state that a ‘three generation family history should be taken from all patients with colorectal cancer’(14). This was not adhered to and hindered the assessment of whether a patient required genetic referral, both for the purposes of this audit and in clinical practice. The audit found that only 46% of patients categorised as requiring referral had indeed been referred to genetics as part of their cancer management. However, given the poor FH records, there were potentially more unidentified patients who required referral. This falls far below the audit standard; 54% of the unseen patients requiring referral potentially have an unidentified underlying genetic risk implicating not only their future health, but also their families. Failure to identify these high or medium risk families may have grave repercussions on the mortality and morbidity of these patients, as having knowledge of this risk allows access to the appropriate screening and counselling. Interestingly, four of the 18 patients categorised as not requiring referral (therefore were aged over 50 years and had no known FH of CRC documented) who were seen and tested by genetics services were actually found to be carriers of Lynch syndrome, and as such fell into the high risk category. Perhaps insufficient FH documentation is responsible for these unexpected results. The findings of this study are in accordance with the published literature. A similar multi-centred English audit was conducted in 2011. Although using a different referral criteria in line with their own clinical practice, findings showed that the referral rate ranged from between only 35%-55%(10). The findings have also been echoed internationally; a Dutch study found that documentation of family history was sub-optimal, being correctly documented in only 16% of cases. 34% of patients with a complete FHrecorded were referred genetics services(19). In 2009, an Australian study showed even poorer outcomes with only 54% of patients having FH documented, and only 12% of patients being referred for formal genetic testing(20). Another 2012 study from Australia claimed only 38% of CRC patients were asked about their family by a health care provider(21). The reason behind these findings may have been due to documentation errors; perhaps if a negative FH was found on enquiry, no FH documentation was made at all. However, even if this were the case, opportunities for patient referral to genetic services are almost certain to have been missed.
Despite meticulous data collection from an 11 year time period with at least two years survival follow-up, this study does have its limitations. Firstly, the cohort size of 345 patients is relatively small. When considering the division of patients into further lesser subgroups (for example, by age), this has obtained results often with a low power. Only 80.6% of patients had at least five years of follow-up at data collection. When the 67 individuals diagnosed after August 2013 (since data was collected in August 2018) who did not have 5 years follow-up are excluded, the values in table 2 remain consistent. The data collection process introduced a degree of bias since most patient information was collected from oncology notes and other hospital notes including ward clerking. Pathology reports were less often accessed as this was more time consuming. Where patient notes were deemed unavailable, it was likely that these patients did not receive any oncology treatment due to early stage disease requiring only surgical intervention. Two separate researchers collated the data; one gathered data from 2005-2009 and the other gathered data from 2010-2015. Despite efforts to ensure data collection was identical both times, there may have been minor discrepancies in methods, recording and benchmarks. As the SIGN (2003) guidelines were in use during 2005-2009, they were also used as the guideline standards for the 2010-2015 cohort accepting that the SIGN guidelines were updated in December 2011. These new guidelines aimed to further improve the uptake of genetic referrals, although differences between the 2003 and 2011 standards were negligible regarding young-onset CRC and did not affect this study(13)(14). Routine assessment for Lynch syndrome is now the standard assessment of a tumour, and patient referral is no longer required. Re-audit will allow ascertainment in change of policy. ARI’s pathology dataset was updated in July 2014 to include immunohistochemistry (IHC) analysis looking at microsatellite mismatch proficiency on all specimens from patients aged less than 50 years. Since then, in 2015, all patients having a resection for a diagnosis of colorectal cancer in the North East of Scotland have had the KRAS, BRAF and MSI status assessed on their surgical specimen. As patients with rectal cancer may require pre-operative therapy, IHC for microsatellite proficiency is carried out on biopsy specimens, as this may influence therapeutic options. Therefore, significant improvements have been made with regard to identification of hereditary cancer syndromes.