Pediatric CRC differs significantly from adult CRC in clinical symptoms, localization, staging, histopathologic findings, and prognosis. While factors like age, alcohol use, smoking, obesity, hypercaloric diet, red meat consumption, and sedentary living are associated with adult CRC, they are less relevant in pediatric cases. Predisposing factors also include polyposis syndromes, inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, and chemical or radiation exposure.

Most pediatric CRC cases are sporadic (65–90%), while a smaller percentage have a genetic basis [1, 5, 10,11,12,13,14,15,16,17]. The genetic causes can be classified into different types of polyposis, such as familial adenomatous polyp (FAP), MUTYH-associated polyposis, Peutz–Jeghers syndrome, juvenile polyposis syndrome, and juvenile hyperplastic polyposis syndrome. CRC can also occur as a result of the malignant transformation of IBD, specifically ulcerative colitis and Crohn's disease. Finally, Another genetic causative group is listed under hereditary non-polyposis CRC, which includes LS and the constitutional mismatch repair deficiency syndromes. Within our case series, a single case demonstrated signs of LS, whereas the remaining cases showed no indication of genetic, molecular, polyposis syndrome, or inflammatory bowel disease association.

Three mechanisms can generally explain CRC development [5, 18,19,20]. The first mechanism is chromosomal instability, which accounts for about 65–70% of sporadic cancers and cases of FAP. This mechanism involves the mutation of the tumor suppressor gene known as APC, leading to its inactivation. The dysregulation of e-cadherin homeostasis by the tumor suppressor gene inactivator (p53) and proto-oncogene activators (c-Myc and KRAS) initiates this mutation. The second mechanism is MSI, typically seen in LS. MSI occurs due to a mutation in the genetic line of mismatch repair (MMR) genes, with high-frequency microsatellite instability (MSI-H) being particularly significant. The third mechanism is the CpG island methylator phenotype (CIMP), which involves the hypermethylation and deletion of tumor suppressor genes like Human MLH-1 and MGMT. Abnormal methylation of MMR and MLH-1 leads to mutations in the BRAF gene at the transcription site, particularly in MSI-H cases. CIMP is observed in around 15% of sporadic CRC cases. Only one of our patients, who exhibited KRAS positivity, had MSI and demonstrated a favorable prognosis. He is in his fourth postoperative year, and his follow-up proceeds without any complications through annual laboratory, endoscopic, and radiologic examinations.

Symptoms observed in adults typically encompass changes in bowel habits, blood in stool, rectal bleeding, anemia, and weight loss. The presentation of these symptoms may differ depending on the location of the mass. In pediatric patients, the symptoms are less specific and may encompass abdominal pain, nausea, and vomiting, which can also serve as indicators for conditions, such as gastroenteritis, appendicitis, and intussusception. Advanced cases may exhibit acute abdominal conditions such as ileus or perforation. This phenomenon is more commonly observed in pediatric patients than adults, with a prevalence rate surpassing 20%. Among adults, the mass is predominantly situated in the left colon, particularly in the sigmoid and rectum regions. Children display a more equitable distribution of the mass [1, 11, 17]. In our series, three patients (60%) exhibited nonspecific symptoms, such as abdominal pain, fatigue, and nausea. Hospitalization with a diagnosis of ileus was necessary for the remaining two patients, representing 40% of the study population. Without exception, the mass was identified in the rectosigmoid colon in all our cases.

The World Health Organization (WHO) has delineated six subgroups of colorectal adenocarcinomas, which are as follows: cribriform-comedo, medullary, micropapillary, mucinous, serrated, and signet ring cell [13]. The grades of differentiation are classified into four categories: well-differentiated (Grade I), moderately differentiated (Grade II), poorly differentiated (Grade III), and undifferentiated/anaplastic (Grade IV).

Two cases exhibited mucinous characteristics in our series, and one displayed signet ring cell features. When the literature regarding CRC histology is reviewed, pediatric CRC is frequently mucinous (50% and over) and signet ring cell (48%). In contrast, adult cases have been reported to have less commonly mucinous (5–8%) and signet ring cell (1%) tumors histologically. When differentiation is considered, 32% of pediatric CRC is poorly differentiated, with a poor prognosis. Regarding differentiation grade, the ratio of poorly differentiated adult CRC cases is 18% [1, 4, 14, 18, 21]. In our series, one exhibited well-differentiated characteristics, and one exhibited moderately differentiated characteristics.

The initial investigations for the diagnosis of CRC have been recommended to include abdominal US, esophago-gastro-duodenoscopy, and colonoscopy, particularly in cases with predisposing genetic syndromes. Post-diagnosis staging investigations have been suggested to include computed thorax, abdomen, and pelvis tomographies, accompanied by Tc99 m bone scanning. Direct abdominal radiography, enema colon radiography, followed by PET, and MRI examinations provide valuable data for children. Tumor markers, such as CEA and CA 19–9, should be checked for monitoring treatment, particularly metastasis [5, 11, 22]. All our cases underwent direct abdominal radiography, US, CT, and MRI. Two patients underwent colonoscopy. Tumor markers were evaluated in all patients preoperatively, with only one exhibiting slightly elevated CA 19.9 and CA 125 levels. Postoperative follow-up of all three cases with recurrence, metastases, and poor prognosis revealed elevated CEA and CA 19–9 levels.

The most frequently employed approaches are the TNM system and Dukes'prognostic staging systems, which are recommended guidelines for CRC staging according to the American Joint Committee on Cancer (AJCC, 7 th edition) [5, 23]. Given the high frequency of regional or distant metastasis observed in children, the staging of CRC is defined as stage ≥ 3 in 86% based on the TNM system and as stages C and D in 62–86% according to Dukes'system [1, 4, 11, 14, 15]. Peritoneum (34%), liver (32%), lung (9%), ovaries (7%), and bones (7%) are the primary locations of metastasis in pediatric patients, whereas in adults, liver (30–70%), lung (20–40%), and bones (5–10%) are predominantly metastasized [1, 15].

From a histopathological perspective, mucinous or signet ring cell appearance, Stages 3 and 4 (Dukes C/D), and regional or distant metastasis indicate an unfavorable prognosis in pediatric patients. Likewise, factors including incomplete resection, presence of positive lymph nodes, and invasion of the serosa are also associated with an unfavorable prognosis. Pediatric patients'five-year survival rate varies between 23% and 65.6% [3, 5, 10, 12, 14], whereas the ten-year survival rate stands at 31% [1, 4, 5, 12]. In the adult population, the survival rate over five years ranges from 60 to 75% [3, 10, 12], whereas over ten years it is 54% [10, 12]. Based on the TNM system, all our patients were categorized as Stage 3. Nevertheless, three patients (representing 60% of the sample) displayed an unfavorable prognosis, with all three experiencing early recurrence. A combination of therapeutic modalities and multiple surgical procedures were utilized to manage diffuse metastases in the peritoneal, hepatic, and intra-abdominal regions. All three patients succumbed during the early postoperative period. Two cases of patients with a favorable prognosis (40%) have been observed, one in the fourth postoperative year and another in the tenth postoperative year, surviving without complications.

As per the literature, the treatment principles for children are recommended to align with those employed for adults. Consultation with medical oncologists with extensive experience treating adults is advised [3, 11, 13, 16, 24]. The consensus is strong regarding the pivotal role of surgery in CRC treatment, emphasizing the need for a radical surgical procedure. It is necessary to perform an extensive resection of the colon segment that harbors the tumor and its associated mesentery and draining lymphatics. Additionally, it is crucial to thoroughly explore the peritoneal surface, renal fascia, and diaphragm and to excise all peritoneal lymph nodes. Evidence in the literature supports the proficient execution of laparoscopic surgery [25].

It is advised to perform the excision of the ovary and omentum, as these areas are prone to metastatic spread. In cases of infiltration, it is recommended to perform a hysterectomy and excision of the upper vagina [11, 13, 16, 26]. It is recommended to resect at least 5 cm of normal bowel tissue on both sides to prevent potential recurrence and excise at least 12 lymph nodes to confirm the N0 stage [5, 24]. When the mass effect causes obstruction, carrying out a colostomy before radical surgery is paramount, and this approach offers a notable level of convenience when employed [13]. Resection of the mass was conducted in all our cases, including one that underwent intervention at an external center. The resection procedure involved the removal of a minimum of 5 cm of healthy bowel from both sides of the intestinal segment where the mass was situated. Additionally, all cases underwent omentectomy, appendectomy, and lymph node dissection.

Reports indicate that a considerable portion, approximately 17%, of pediatric cases cannot be surgically removed [17]. Thus, neoadjuvant radio-chemotherapy [13] or a combination of immunotherapy and chemotherapy [6] is being explored as promising treatments followed by radical surgery.

The need to tailor treatment to each patient's specific needs is emphasized. Moreover, the scarcity of experience in pediatric chemotherapy has led to using adult chemotherapy protocols [3, 5, 13, 24]. Given the predominantly advanced stage and grim prognosis of CRC in children, it is necessary to provide adjuvant chemotherapy after surgery [5]. The standard chemotherapy treatment involves the administration of 5-fluorouracil and folinic acid. The alternative agents used have been reported as capecitabine, oxaliplatin, and irinotecan [13, 24]. The effectiveness of recently developed targeted therapies based on molecular profiling has been demonstrated in several advanced cases. Bevacizumab, pembrolizumab, cetuximab, panitumumab, bortezomib, gefitinib, and cabozantinib are commonly employed agents [24, 25, 27,28,29,30,31,32,33]. The administration of the Folfox protocol, which included 5-fluorouracil, folinic acid, and oxaliplatin as chemotherapeutic agents [34], was implemented in all cases. Additionally, three patients with an unfavorable prognosis were augmented with methotrexate, capecitabine, and bevacizumab.

Another essential element of CRC treatment is post-surgery radiotherapy even though its applicability is limited. However, it may be deemed advisable as a preventative measure against potential reoccurrence. In addition, it has been found to have applicability before surgery in advanced-stage situations that entail obstruction or intestinal perforation [13, 26]. Radiotherapy was administered postoperatively to all the patients.

The three patients who expired during the early phases of the disease experienced several surgical procedures due to disease recurrence and ileus resulting from intra-abdominal dissemination. There is a viewpoint suggesting that hyperthermic intraperitoneal chemotherapy (HIPEC), widely utilized in successful adult surgical procedures, has the potential to be used in pediatric cases. The recent review conducted by David J. Byrwa et al. [35] has reported that the impact of HIPEC on overall survival, compared to systemic chemotherapy and mass reduction surgery, is still uncertain. This uncertainty arises from the absence of clinical trials, limited sample sizes within tumor subgroups, and the general pediatric population. Hence, elucidating the connection between the extent of tumor burden and the magnitude of surgical mass reduction is paramount. Future directions in this field encompass prospective clinical trials, establishing patient databases for standardized HIPEC in pediatric patients, and optimizing HIPEC.