Pediatric Colorectal Carcinoma: A Series of Seven Cases.

Introduction: Colorectal carcinoma (CRC) accounts for <1% of all the neoplasms of children. Unfavorable histology and delayed diagnosis often result in poor outcome. This study aimed to investigate the clinical characteristic and prognosis of pediatric patients with CRC. Materials and
Methods: A retrospective review of medical records of all patients diagnosed of CRC between 2015 and 2020 was performed. Data regarding gender, age, location, and histopathology were collected.
Results: Seven children (5 males and 2 females) were included in the study. Age ranged between 8.6 and 11.8 years. Abdominal pain was the most common symptom. The duration between onset of symptoms to the diagnosis ranged from 5 days to 8 months. Right-sided tumors were more common than the left side. Histopathological examination showed mucinous adenocarcinoma in four/seven patients and signet cell variant was seen in 2/7. Immunohistochemistry was positive for cytokeratin and beta-catenin, however, all microsatellite instability markers were found negative. Despite surgical treatment and chemotherapy, four of our cases faced mortality and one patient was lost to follow-up.
Conclusion: CRC can present in first decade of life and often misdiagnosed. Pediatric CRC has distinct tumor biology and shares a poor prognosis. Paucity of literature from the Indian subcontinent should urge further clinicopathological trials for establishing etiology and for refining treatment recommendations in these children. Copyright:

INTRODUCTION

Colorectal carcinomas (CRC) are one of the most common cancers worldwide in adults, with a peak at the age of 65 years.[1] Very rarely, does it affect adolescents and is extremely rare in the first decade of life, constituting only 1% of all pediatric neoplasms. An estimated annual incidence of about 1 case/million individuals has been reported.[2] The incidence rate of colorectal cancer in the US pediatric population is about 1.3/1 million.[2] As per the Indian Council of Medical Research; the annual incidence of colorectal malignancy is about 8.5/million in India and pediatric population is 1:1,000,000 of all the malignancies.[3]

The clinical presentation is nonspecific, making it difficult to differentiate from other commoner benign and infectious etiologies seen in children. The prognosis is grave, owing to the advanced stage at the time of diagnosis and commonly seen poorly differentiated histopathological forms in this age group. With our brief case reviews, we wish to draw the attention to the rising number of patients of CRC within the first decade of life, its varied symptomatology mimicking infectious diseases, and the need to understand biology behind the poorer histopathological forms in children.

MATERIALS AND METHODS

We retrospectively reviewed the medical records of all patients of CRC managed over a period of 5 years (January 2015–January 2020) after obtaining institutional ethical clearance. Demographic details including family history of cancer and duration of delay in presentation were collected through our records. Tumor characteristics including site, histopathology type, immune-histochemistry (cytokeratin, beta-catenin, and microsatellite instability (MSI) markers-MLH1, MSH2, MSH6), and tumor markers (serum CEA levels) were evaluated. We defined the location as follows; right colon (cecum to splenic flexure), left colon (descending and sigmoid colon), and rectum. Treatment modalities and outcomes were also recorded.

RESULTS

A total of seven cases (5 males, 2 females) were identified. The mean age of presentation was 9.84 ± 1.17 years (range: 8.6–11.8). None of the patients had a family history of CRC in the first degree relatives. The clinical presentation was variable and is highlighted in Table 1. Abdominal pain was the most common symptom among the patients. Two patients presented with features of acute intestinal obstruction. The lag time between the onset of symptoms and diagnosis ranged from 5 days to 8 months. Right side carcinoma was seen in four patients and two patients had rectal carcinoma. Perianal fistulae and blood discharge was the primary complaint in one of the latter cases [Figure 1]. Contrast-enhanced computed tomography abdomen was performed in all cases and was able to establish a heterogeneously enhancing hypodense mass lesion in five cases with thickened bowel wall in two cases [Figure 2]. One case showed foci of calcification. Biopsy was performed in all patients. Open biopsy was performed in three patients. Ultrasound-guided trucut biopsy was performed in two patients. Staging of tumor could be done only in 2 cases. Gross specimen of intestine was received in one case, which showed circumferential wall thickening [Figure 3a]. Histopathological examination showed mucinous adenocarcinoma [Figure 3b] in four/seven patients and signet cell variant [Figure 3c] was seen in 2/7. Special stains like Mucicarmine highlighted the extracellular mucin [Figure 3d]. Immunohistochemistry was positive for Cytokeratin and beta-Catenin, however, all MSI markers were found negative (control-normal lining mucosa being positive). Complete resection was accomplished in only one patient. Five of the seven patients received chemotherapy (5 Flurouracil and Oxaliplatin). Despite surgical treatment and chemotherapy, four of our cases faced mortality and one patient was lost to follow up. Of the two survivors, one is undergoing treatment and the other has shown no signs of recurrence to date.

Table 1

Clinical features of pediatric CRC patients.

Case No.	Age (years)	Gender	Presenting symptoms with duration	Site	Modified Duke’s Stage	Histopathology	Management	Outcome
1	10.2	Male	Abdominal pain, vomiting, fever (15 day)	Right	C	Mucinous	Laprotomy with ileostomy with biopsy, neo-adjuvant chemotherapy, R1 resection, adjuvant chemotherapy	Disease free at 1.8 year follow up
2	9	Male	Intestinal obstruction (7 day)	Left	C	Signet cell	Laprotomy with biopsy, adjuvant chemotherapy. Re-exploration with ileostomy	Expired after 2 month
3	9.9	Male	Abdominal lump, lower limb swelling (4 month)	Right	-	NOS	Guided biopsy, neoadjuvant chemotherapy	On treatment
4	9.4	Female	Multiple perineal abscess (3 month)	Rectum	-	Mucinous	Per rectal biopsy	Expired after 5 days
5	8.6	Male	Per rectal bleeding (7 month)	Rectum	-	Mucinous	Per rectal biopsy, chemotherapy	Expired after 3.5 month
6	9	Male	Abdominal pain, low grade fever (8 month)	Right	-	Signet cell	Biopsy, refused surgery	Expired after 1 month
7	11.8	Female	Intestinal obstruction (5 day)	Right	-	Mucinous	Open laparotomy with biopsy, ileostomy, adjuvant chemotherapy	Lost to follow up

Figure 1

Clinical picture showing perianal fissures and abscesses

Figure 2

Computed tomography image showing diffusely thickened bowel wall

Figure 3

(a) Gross specimen of colon showing thickened bowel wall and cut section of which is grey white firm and glistening. (b) Photomicrograph showing mucinous adenocarcinoma. Tumor cells are seen floating in pools of extracellular mucin (H and E, ×100). (c) Microscopic section show features of signet ring cell carcinoma. Tumor cells show intracellular mucin (H and E, ×100). (d) Special stain Mucicarmine showing both intra and extracellular mucin. (Mucicarmine Stain, ×100)

DISCUSSION

The incidence of CRC is variable in-between countries, being highest in Australia, New Zealand, Europe and North America and lowest in Africa and South Central Asia.[4] This difference can be attributed to the differences in dietary habits and environmental exposure. CRCs are an extensively studied and researched entity in adults, however, in children they are a definite rarity. Such a low incidence is responsible for the lack of suspicion and leads to delayed diagnosis, untimely management, and a very dismal prognosis.

In children, the usual age of diagnosis is in the second decade, however, all cases except one in the current study are <10 years, wherein it is considered an absolute exception. There is scant Literature on children presenting with carcinoma colon within the first decade of life, both from India and overseas.[567] Rahman et al. reported a series of seven cases wherein the age ranged from 7.5 to 19 years.[8] Males are usually affected more than the females, similar finding was seen in our study too.[9] Nair et al. though found that rectal carcinoma affected females more than the males and in the present study too, perineal abscess and rectal involvement was seen in a female.[10]

Familial adenomatous polyposis (FAP), hereditary nonpolyposis colon cancer (HNPCC/Lynch Syndrome), familial juvenile polyposis, ulcerative colitis and other familial cancer syndromes are strongly associated with CRC in adults but they account for only <5% of all bowel carcinomas arising during childhood.[11] Studies from the Indian population to date have not reported any child with the presence of either of the above predisposing factors.[1213]

The clinical presentation is also quite variable with only few overlapping features as seen in adults. Typical symptoms of CRC in adults include vomiting, abdominal pain, lump, altered bowel habits, malena and anorexia. However, in children, the symptoms may be restricted to altered bowel habits or vague abdominal pain which leads to the loss of precious time in establishing diagnosis during which this lethal disease upstages. Changes in the bowel habits like calibre of stools, constipation, or diarrhea may be observed before the development of tarry stools due to rectal bleeding. Advanced stages may present as soft tissue mass causing bowel obstruction along with other complications like perforation, abscess or fistula. Presenting complaints may hint primary site of the tumor like rectal tumors may present with change in caliber of stools, hematochezia, dyschezia, and anemia whereas tumors of caecum and ascending colon may become bulky and present as a mass lesion. One of the cases in the current series presented with multiple perineal fistulae and abscesses, mimicking inflammatory bowel disease and Tubercular proctitis. The recurrent perineal abscess has been rarely reported as a presenting symptom of colonic carcinoma in children and can be easily missed.[10] Abdominal TB is endemic in developing countries and presents with pain abdomen, fever, and weight loss. One of the cases in the present study was treated with antitubercular drugs (ATT) by a physician and was referred to us with persisting symptoms despite completing treatment. World Gastroenterology Organization has identified symptoms such as constipation, diarrhea, rectal bleeding, abdominal pain, vomiting to be associated with inflammation in the gastrointestinal tract.[14]

Two different genetic pathways have been found to be involved in the pathogenesis of CRC. These include the APC/beta-catenin pathway and the MSI pathway. The majority of CRCs occur sporadically. A mere 10%–30% of the reported childhood CRCs has been found to arise in the setting of hereditary cancer syndromes, more commonly FAP and HNPCC. Other associated polyposis syndromes include Peutz-Jegher's and Juvenile Polyposis coli. The most important genetic mutation observed in childhood CRC if any is high MSI (MSI-H).[15] Tumor that shows mutations of two or more of the five microsatellite sequences (enlisted by the National Cancer Institute) is labeled as MSI-H, which is the hallmark of early-onset CRC.

Approximately 15% of CRC show MSI-H, of which 3% are related with Lynch syndrome. It is the most prevalent familial colorectal cancer syndrome and shows an autosomal dominant pattern of inheritance. They do not present clinically as polyposis, but with a few adenomas like sporadic CRC. Polyps can progress to cancer more rapidly (1–3 years) when compared to polyps seen in the general population.[16] Histologically, these tumors are characterized by young age at onset, involvement of right colon, a heavy infiltration of lymphocytes, a medullary growth pattern, a mucinous or signet ring cell differentiation, and a better prognosis.[1617] It is also associated with an increased risk of extra-colonic cancers like cancer of the endometrium, ovary, stomach, urinary tract, biliary tract, pancreas, small bowel, brain, and skin. Muir-Torre and Turcot syndromes are unusual variants of Lynch syndrome and are associated with cutaneous sebaceous neoplasms and brain tumors (glioblastoma), respectively.

FAP, on the other hand, is an autosomal dominant disorder caused by the mutational inactivation of the APC (adenomatous polyposis coli) gene and is also reported to be higher in adolescents. CRC develops in 100% of untreated FAP patients, usually before 3rd decade and nearly always by the fifth decade.[17]

Per abdomen, examination is helpful only in case of a palpable lump. On the contrary, digital rectal examination (DRE) plays an important role in the diagnosis of colorectal cancers. Palpation of any hard mass in the rectal wall or mass lesion obstructing the lumen should generate a suspicion toward malignancy. DRE proved useful in two of our cases by picking rectal thickening.

Tumor markers such as CEA have also been found to be associated with CRC and help suspect them early; however, their role in pediatric CRC has not been completely established. They are less sensitive when compared to radiological examination and may be raised in some benign tumors leading to a poorer diagnostic ability. CEA levels were raised in only two of our cases. CEA levels of over 5 ng/mL predict a worse prognosis than lower levels.

Mucinous adenocarcinoma is a rare subtype of CRC and has an aggressive clinical course and poorer outcome. Majority of colorectal cancers in adults are moderately differentiated or well-differentiated with only <5% of cases being mucinous. In contrast, more than 50% of pediatric patients are diagnosed with poorer histological subtypes such as mucinous and signet ring cell type. The latter may be diagnosed signet ring cells constitute more than 50% of tumor.

The management of childhood CRC is an extrapolation of the adult treatment protocols.[18] Surgical resection of the tumor along with the lymphatic basin is the mainstay of treatment. Advanced stage disease or high-risk localized disease requires adjuvant multi-agent chemotherapy based on a fluorouracil backbone, though its role in pediatric CRC is controversial. In the present series, majority of the patients presented with unresectable masses. Case 1 of the present series received 3 cycles of neoadjuvant FOLFOX therapy, following which R 1 resection was performed. The patient was administered the remaining 8 cycles of adjuvant chemotherapy and is under close follow-up.

CONCLUSION

CRC can present in the first decade of life. Its different biology is responsible for its atypical presentation, advanced stage at diagnosis, aggressive histological subtypes and poorer survival. Increasing awareness of this entity at such young age amongst pediatricians and family practitioners would aid early diagnosis, prompt management, and also prevent side effects of wrong treatments such as ATT or steroids. Poorer outcome in children warrants a need for pediatric CRC trials both to establish etiology and for refining treatment recommendations in these children.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.