Early Onset Colorectal Cancer in Arabs, Are We Dealing with a Distinct Disease?

Simple Summary The recent alarming increase in EOCRC incidence globally calls for research to understand the disease and its epidemiology from different geographical regions. Therefore, experts call for the inclusion of CRC patients from different geographical regions to understand the clinicopathological and molecular features of the disease. Our study is among the very few studies that evaluate the epidemiology and clinicopathological signatures and survival of EOCRC in the Arab population. Despite the reported significant difference in stage, molecular signature, and survival of EOCRC compared to LOCRC, our study showed no differences between the two groups. This could be explained either by a unique entity of the EOCRC in Arabs or the absence of a screening program for those above 50 years old. Abstract Early-onset colorectal cancer (EOCRC) incidence is increasing worldwide. Efforts are directed to understand the biological and clinical signatures of EOCRC compared to late-onset colorectal cancer (LOCRC). EOCRC is thought to present differently across different ethnic groups and geographical regions. This study was an attempt to contribute with data from the Arab world toward the understanding of the clinicopathological parameters of EOCRC compared to LOCRC. Data from 254 CRC patients diagnosed at Sultan Qaboos University Hospital from the period 2015–2020 were studied. About 32.6% of all diagnosed CRC patients are below 50 years old, with no differences in gender distribution between EOCRC and LOCRC (p-value 0.417). Rectal involvement and tumor laterality were comparable among the two groups. Adenocarcinoma accounts for 83.3% and 94.2% of EOCRC and LOCRC, respectively. More mucinous and signet ring adenocarcinoma (8.3% each) were reported in EOCRC than LOCRC (2.9% and 2.2%, respectively). MLH1 and PMS2 loss are more common among LOCRC, but MSH6 loss is more frequent in EOCRC. The overall survival of EOCRC and LOCRC was comparable (median survival 64.88 and 67.24 months, respectively). This study showed comparable clinicopathological parameters between EOCRC and LOCRC from Arabs, which adds to the bigger picture of understand the disease.


Introduction
A plethora of published works have highlighted the alarming increasing trend of colorectal cancer among those younger than 50 years old, what is called Early-onset colorectal cancer (EOCRC) [1][2][3][4][5]. Colorectal cancer (CRC) is considered the third most common cancer and the leading cause of death worldwide in both genders [6]. Despite the slow The average age was 40 years (range 19 to 49) year for the EOCRC and 63 years (range 50 to 86) for the LOCRC. In the EOCRC population, 50.6% were males, and 49.4% were females, whereas, among old patients, 56.3% were males and 43.7% were females (p-value 0.4) Table 2. There were no differences in gender distribution between the two age groups of CRC or rectal cancer (p-value 0.417 and 0.70, respectively). While young patients with rectal cancer had an almost equal gender distribution (58% young men vs. 42% young women), more men in the old group had rectal cancer (62% elderly men vs. 38% elderly women) (p-value < 0.065). There was no significant difference between EOCRC and LOCRC in terms of BMI or family history of colorectal cancer (p-value > 0.05). There was a significant difference in the rate of comorbid diseases such as diabetes mellitus, heart disease, and hypertension among LOCRC compared with EOCRC and the medication taken for such diseases (p-value < 0.05).

Disease Stage and the Anatomical Location at Diagnosis
The majority of EOCRC and LOCRC presented in stage IV, which is an advanced stage (48% and 42% respectively), followed by stage II (19%, 23%) and stage III (15%, 21%) Table 3. Only one young patient (age 47) was diagnosed with carcinoma in situ who did a colonoscopy test abroad per his request for abdominal bloating. There were six young patients and four old patients diagnosed with stage I disease. Considering rectal cancer, there were no differences in the proportions of stages between young and old patients (p-value = 0.08) Table 3.   Table 4 shows the details of the tumor location and the histopathological findings of both EOCRC and LOCRC. In the EOCRC group, colon tumors were relatively more often located in the sigmoid colon (18, 23%) followed by rectosigmoid (12,15.2%) and then transverse colon (8, 10.4%). There were no significant differences between rectal involvement among the EOCRC and the LOCRC (p-value 0.68). There is no difference in the tumor laterality between the two groups where the proportion of left-sided tumors is more than the right-sided tumors Table 4. When stratified by gender, old males tend to present with left-sided tumors compared to old females (p-value = 0.016). There is no gender difference seen in the sidedness of the tumor in the EOCRC group (p-value 0.369) Table 5.

Tumor Location and Histopathology
As indicated in the table, the histologic subtype of EOCRC and LOCRC do not differ significantly (p-Value = 0.045). The most prevalent type in both categories was adenocarcinoma (NOS), accounting for 83.3% and 94.2% of EOCRC and LOCRC, respectively. EOCRC demonstrated a greater proportion of mucinous and signet ring adenocarcinoma (8.3% each) compared to LOCRC (2.9% and 2.2%, respectively).
Even though a higher pathological grade (G3) is more prevalent in EOCRC (10.2%) compared with 2.3% in LOCRC, this did not reach statistical significance (p-Value = 0.064). Both groups often have moderate tumor differentiation (G2).
Similarly, EOCRC and LOCRC do not differ much in terms of the pT stage, with the majority of cases presenting with pT3 followed by pT4.
Although EOCRC has a greater incidence of lymph node metastasis than LOCRC, the difference is not statistically significant (p-Value = 0.146).
There is no substantial difference between the two age groups concerning the prevalence of MMRP deficiency. In this study, we found that MLH1 and PMS2 loss is more common among older patients, but MSH6 loss is more frequent in younger patients.

Remission and Survival
There is no difference in the overall survival of EOCRC compared to the LOCRC (median survival 64.88 months and 67.24 months, respectively) 95% CI; p = 0.684 Table 6, Figure 1A.
The free overall survival was comparable between the two age groups with no significant difference (57.06 and 55.58 months, respectively, 95% CI; p = 0.653) Figure 1B.

Subcategories of EOCRC
Knowing that the literature is not consistent in defining the cut-off age for the EOCRC, different subcategories have been reported. Most of the published work defines it as CRC below the screening age, i.e., <50 years old, while others consider it as below 35 years old [19]. This unidentified age-group subdivision is considered one of the limitations for interpreting available published molecular and clinical data. Considering the reported findings that the major increase in the EOCRC in the USA was among those 20-35 years old who were found to have the worst prognosis [23], we have subdivided the EOCRC group into those <35 years old, and those 35-50 years old and run the comparison as shown in Table 7. Table 7 showed no significant differences between the three subcategories in any of the clinicopathological determinants (p-value > 0.5). In Figure 2, the overall survival of those <35 is less than the other two subgroups (46.197, 66.059, 67.985, respectively, 95% CI; p-value 0.49) Table 8. This difference was not statistically significant considering the difference in the sample size of those <35 (14 patients) and those 35-50 years old (72 patients).

Subcategories of EOCRC
Knowing that the literature is not consistent in defining the cut-off age for the EOCRC, different subcategories have been reported. Most of the published work defines it as CRC below the screening age, i.e., <50 years old, while others consider it as below 35 years old [19]. This unidentified age-group subdivision is considered one of the limitations for interpreting available published molecular and clinical data. Considering the reported findings that the major increase in the EOCRC in the USA was among those 20-35 years old who were found to have the worst prognosis [23], we have subdivided the EOCRC group into those <35 years old, and those 35-50 years old and run the comparison as shown in Table 7.  Table 7 showed no significant differences between the three subcategories in any of the clinicopathological determinants (p-value > 0.5). In Figure 2, the overall survival of those <35 is less than the other two subgroups (46.197

Discussion
It is not yet understood whether EOCRC represents a distinct disease entity from LOCRC. Efforts are directed toward deciphering the clinicopathological and molecular features of the disease across different geographical and ethnic areas. Experts are calling to include data from across the globe to understand the disease, which subsequently will improve its management. This study was an attempt to contribute with data from the Arab world toward the understanding of EOCRC, which is increasing at an alarming pace globally. Very few data are published on the molecular and clinical status of EOCRC from the middle east.
The present study showed that an average of 30% of all diagnosed CRC are younger than 50 years old, which is higher than what was reported earlier [3,14,24] but almost similar to some reports from the region [15,25,26]. There is no definite explanation for this high proportion of EOCRC in the region, but it is thought to be due to the general young population pyramid of these countries and the rapid adoption of a westernized lifestyle [23,24]. Smoking is becoming more common in the Gulf Cooperation Council countries, especially among the young [25,26], which could contribute to this high percentage of EOCRC. Data on the smoking and alcohol consumption of patients is incomplete, which

Discussion
It is not yet understood whether EOCRC represents a distinct disease entity from LOCRC. Efforts are directed toward deciphering the clinicopathological and molecular features of the disease across different geographical and ethnic areas. Experts are calling to include data from across the globe to understand the disease, which subsequently will improve its management. This study was an attempt to contribute with data from the Arab world toward the understanding of EOCRC, which is increasing at an alarming pace globally. Very few data are published on the molecular and clinical status of EOCRC from the middle east.
The present study showed that an average of 30% of all diagnosed CRC are younger than 50 years old, which is higher than what was reported earlier [3,14,24] but almost similar to some reports from the region [15,25,26]. There is no definite explanation for this high proportion of EOCRC in the region, but it is thought to be due to the general young population pyramid of these countries and the rapid adoption of a westernized lifestyle [23,24]. Smoking is becoming more common in the Gulf Cooperation Council countries, especially among the young [25,26], which could contribute to this high percentage of EOCRC. Data on the smoking and alcohol consumption of patients is incomplete, which prevented inferring an association. Another modifiable risk factor that could explain the high proportion of EOCRC in the region is the inactive lifestyle and the increase in the prevalence of obesity in the young population to an alarming level in the region [27]. The widespread use of prebiotics and probiotics in the region might explain the findings. Studies showed an increase in the consumption and availability of pro/prebiotics products in the Arabian peninsula in the past few years [20]. The epigenetic changes should never be underestimated in this content. Antibiotic overuse, climate change, environmental pollutants, and dysbiosis are all interrelated factors that need to be studied to better understand the disease and its increased incidence [28].
It is thought that COVID-19 might affect the cancer incidence and stage of the disease in the coming years due to the sudden disruption in cancer care services. Experts expect that such disturbances might lead to an upscale in cancer diagnosis and death post-COVID-19, called a "Tsunami of cancer". There are also concerns that a "stage shift" will be seen in the post-COVID-19 era, where the delay in diagnosis and interrupted screening can lead to be patients diagnosed at advanced stages, which subsequently will impact survival negatively.
The government of the Sultanate of Oman took early and practical approaches and measures to tackle the pandemic and reduce its impact. For example, at Sultan Qaboos University Hospital, a tertiary center in Muscat, all non-urgent elective surgeries were temporarily suspended. Cancer-related diagnostic and surgical procedures were reduced from March to August 2020. Diagnostic gastroscopies and colonoscopies decreased by almost 80% during and after the first wave of COVID-19, and the numbers of colorectal surgeries were 50% lower than those recorded before March 2020. The data presented here did not show a significant difference in the number and stage of diagnosed CRC patients in 2020 compared to earlier years. The COVID-19 impact is thought to be more prominent a few years post-pandemic.
Prior studies have shown a significant association between EOCRC and metabolic diseases [29], which was not obvious in our study. Here metabolic diseases were significantly more common among LOCRC than EOCRC, which is mainly due to their direct link with age [26].
Previous studies showed that EOCRC significantly differs from LOCRC in being more left sided and with predominant rectal involvement [30], which was not prominent here since the proportions of right-sided and left-sided tumors were similar in both age groups with old males are more likely to present with left-sided tumors. The most prevalent anatomical location was rectosigmoid which is similar to previous reports [19,31]. There is no gender predominance in EOCRC compared to male predominance in LOCRC [31][32][33].
Here young males and females have an equal risk of getting diagnosed with CRC, but older males are significantly more prone to get the disease compared to old females. Males were also predominant in rectal cancer in the young age group. It is worth mentioning that rectal cancer constitutes up to 46% of all EOCRC cases in this study which is higher than reported earlier [4].
The majority of patients in both age groups presented with stage IV disease which is consistent with earlier data from Arab region [34]. This is most likely due to the absence of a national screening program in the country where the majority of patients are diagnosed after developing symptoms. It is even worse for younger patients because of the known delay in diagnosis that results from system, patient and physician related factors [35]. The majority of patients in both age groups presented with stage IV disease. This is most likely due to the absence of a national screening program in the country, where the majority of patients are diagnosed after developing symptoms. Prior studies have assumed that EOCRC presents in a more advanced stage due to its distinct aggressive molecular biology [5,8,[36][37][38][39]. As a result, EOCRC patients are usually receiving aggressive treatments, which were not translated into an improvement in survival [5,11,40]. The survival of patients in this study did not show any differences, with a mean survival of 64.4 months and 67.2 for EOCRC and LOCRC, respectively. Interestingly those below 35 years of age are found to have a worse survival in this study. Considering prior reports from different geographical areas, the survival of this group of patients is significantly lower than their older counterparts [41][42][43] which might indicate a distinct biological signature that is worth studying. It is worth noting that only 14 patients in this study were in this age group which might not be reasonable to draw a statistical significance.
This study failed to find any statistically significant difference between EOCRC and LOCRC in terms of histopathological subtypes, tumor grade, pT stage, pN stage, as well as MMRP status.
The SEER analysis  found that 2.6% of colorectal carcinomas in young patients had signet ring histology [5], which is lower than the 8.3% of tumors with signet ring histology observed in our study. One reason for this difference is that we excluded neuroendocrine carcinoma cases which were included in SEER data. With regards to tumor differentiation, data from the SEER registry  demonstrated that colorectal carcinoma in young patients was more frequently higher grade compared to older patients [44]. We observed a similar finding, but it is not statistically significant. No difference was demonstrated between the two groups concerning the tumor stage pT or the number of lymph node metastases pN. This was similarly demonstrated in other studies [45]. Several reports showed that the proportion of MMRd tumors among early-onset CRC ranges from 19.7% to 41.0% 43, which is significantly higher than LOCRC [42,46]. However, in our current study, only 7.8% of EOCRC were classified as MMRd, with a similar proportion observed in LOCRC.

Limitation
Although our study is one of the few studies from the region that represents a five years description of EOCRC and LOCRC clinicopathological parameters, some limitations impact the comprehension of the study. First of all, this is a single institute study that prevents the generalization of the reported findings. Second, the amount of missing data, especially in the histopathology of the disease, affected the statistical analysis and the statistical conclusion from the presented data.

Conclusions
This study adds to the pre-existing literature to understand EOCRC. The most recent clinical and molecular studies revealed that EOCRC and LOCR are not biologically distinct diseases, but they do have different clinical presentations. Although few studies have shown that EOCRC has different clinical and molecular features when compared with LOCRC, this was not observed in our patient population, as there were no significant differences in the overall characteristics, tumor sidedness, or molecular profile of both EOCRC and LOCRC. This could be, in effect, a result of a smaller sample size and selection bias as we function as a referral center to specific parts of the country. Colorectal cancer cases are also managed in different centers in the country, and perhaps the pooling of all data will strengthen the results and help draw different results.  Institutional Review Board Statement: The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of College of Medicine and Health Sciences (E.C2943, 2020).

Informed Consent Statement: Not applicable.
Data Availability Statement: The data presented in this study are available on request from the corresponding author.

Conflicts of Interest:
The authors declare no conflict of interest.