Colorectal Tumors in Adolescents and Young Adults: Practice Essentials, Background, Polypoid Disease of the Gastrointestinal Tract (original) (raw)

Colorectal cancer (CRC) remains one of the top 3 carcinomas for both new diagnosis and mortality in the United States. More than a million Americans are estimated to be living with colon cancer. [42]

Epidemiology

In the general population, the lifetime risk of developing colorectal carcinoma is 5-6%. However, CRC is quite rare in children and adolescents, with a reported annual incidence of only one per million persons younger than 20 years in the United States. Only 1% of total CRC cases occur in patients younger than 30 years. [43]

Primary pediatric gastrointestinal (GI) malignancies represent fewer than 5% of all pediatric neoplasms. [43] Unfortunately, advanced stage at diagnosis, aggressive histology, and poor survival are the hallmarks of pediatric CRC. In fact, 80-90% of patients younger than 20 years present with Duke stage C/D or TNM stage III/IV. [44]

The incidence of CRC rises exponentially with increasing age from 15 to 40 years and affects both genders similarly. However, in children, the incidence of CRC is higher in males.

Although CRC rates in older adults have been dropping since 1976, the opposite trend has been observed in adolescents and young adults, in whom rates have been disproportionately higher; 18% of cases are diagnosed in persons younger than 50 years. The incidence of distal tumors has increased the most, with rectal cancer representing 44% of CRC cases in patients younger than 30 years. [1]

Risk factors

In adults, CRC is largely preventable by the adoption of a healthy lifestyle, including diet and physical activity. Obesity is a well-documented risk factor for many types of malignancies, including CRC. [45]

Diet affects the risk of developing CRC. Both red and processed meats could increase the risk, whereas fiber, fruit, and vegetables may decrease it. [46] Other dietary factors, such as fish, vitamins, minerals, and coffee, might have potential effects on the risk of developing CRC. However, factors responsible for adult CRC are unlikely to exert a major effect on children, in whom the majority of CRC cases occur spontaneously. [18]

CRC in adolescents and young adults may be associated with a familial cancer syndrome. However, whereas inherited cancer syndromes are more likely to affect a younger population, most CRC cases in adolescents and young adults are sporadic. Only 22% of adolescents and young adults with CRC have a family history of the disease. [3]

Several inherited polyposis syndromes predispose to CRC, including familial adenomatous polyposis (FAP), MutYH-associated polyposis, juvenile polyposis syndrome, Cowden syndrome, and Peutz-Jeghers syndrome. Colonoscopy with polypectomy of adenomatous polyps results in a 76-90% reduction in the incidence of colon cancer in appropriately screened individuals. Thus, for patients with inherited polyposis syndromes, colonoscopic surveillance is recommended between 10 and 15 years of age.

Proper polypectomy technique decreases the risk of residual polyps and, thus, reduces interval CRC rates. Advanced polypectomy techniques, such as endoscopic mucosal and submucosal resections, have a role in the nonsurgical management of large polyps. [47]

The timing of surgery depends on the burden of polyps, presence of dysplasia, genotype, and emotional maturity. It is often delayed until after age 18 years.

Several new syndromes have been defined that give rise to CRC. A rare form of hypermutated microsatellite-stable tumor results from mutation in the POLE gene, which plays a critical role in proofreading to identify and remove mispaired nucleotides during DNA replication. [48]

Other risk factors include prior abdominal radiation for the treatment of childhood malignancies, and inflammatory bowel disease, especially ulcerative colitis. The risk of CRC in ulcerative colitis increases with the extent of the disease and duration of inflammation. CRC risk is estimated at 2%, 8%, and 18% in the first, second, and third decades of active ulcerative colitis, respectively. [49]

By virtue of age alone, all adolescents and young adults with a new diagnosis of CRC should be referred for genetic counseling and testing.

Biology

In patients aged 21 years or younger, high-grade tumors are predominant, with signet-ring cell histology (a feature associated with advanced stage and poorer prognosis) reported in 45% of cases in one cohort. Mucinous histology was reported in 80% of adolescents and young adults and 62% of children with CRC in observational studies. [3]

Microsatellite instability among adolescents and young adults with CRC may be a favorable prognostic indicator.

CRC oncogenesis studies have shown tumors in adolescents and young adults to be more complex than those in patients 45 years and older, and often associated with P53 and PTEN mutations. Interestingly, no PIK3CA mutations have been found in patients younger than 50 years, whereas such mutations are seen in 4-7% of older patients.

Attention is currently directed toward precision medicine. Tumor and genomic mutational analyses are increasingly being used to guide treatment options for patients with malignancies. Nicholson et al studied more than 400 patients with CRC and found that loss of Bcl-2 expression is associated with decreased disease-specific and overall survival. This finding could help identify the subset of patients with a more aggressive phenotype and guide therapy choices. [50]

Particular molecular profiles may identify patients with higher-risk disease, who may benefit from more aggressive treatment or specific targeted therapies.

Pathology

Colon cancer is triggered by a series of point mutations and genetic alterations that cause normal cells to transform into adenomas that progressively become dysplastic, resulting in carcinoma foci. [51] These mutations occur in a certain sequence that determines the clinical characteristics of the tumor.

CRC arises from the mucosal surface of the bowel, generally at a site of an adenomatous overgrowth or polyp. The tumor may penetrate the bowel wall and even perforate the serosa into the omental fat, lymph nodes, liver, ovaries, and other loops of bowel. Some lesions cause bowel obstruction. Synchronous lesions may be present, with the same or different histology and stages of development. Carcinoma in situ may occur in one or more polyps. Patients with synchronous primary tumors have the same prognosis as patients with single colon cancers. [52]

The epidermal growth factor receptor (EGFR) is abnormally expressed in CRC cells (72-82%). It promotes cell division, migration, and angiogenesis and inhibits apoptosis. [53] Thus, EGFR plays an important role in the pathogenesis of CRC. Its expression is associated with poor survival and increased risk of metastasis. Italiano et al demonstrated EGFR expression in CRC metastatic cells. [54] Monoclonal antibodies and low molecular weight tyrosine kinase inhibitors may be useful in the therapeutic armamentarium for patients with CRC.

A rare "flat-type" colorectal tumor has been reported. This form tends to be more aggressive despite the small size of the tumor; it shows high-grade dysplasia and progresses rapidly to invasive cancer. Inactivation of p53 and 17p-LOH have been described in this tumor. [55] They are poorly differentiated and contain pools of mucin. Mucin-producing or signet ring adenocarcinoma is the predominant cell type; it occurs in 50% of pediatric cases compared with a 5% occurrence reported in adults. [56] These tumors may become huge. The differential diagnosis includes malignant carcinoid, leiomyosarcoma, malignant fibrous histiocytoma, and metastatic tumor from other sites.

In a series reported by La Quaglia et al, the interval from symptom onset to diagnosis was not a significant predictor of mortality; however, tumor grade was. [53] Signet ring tumors, which are more common in children and adolescents than adults, behave more aggressively and are associated with earlier penetration of the bowel wall and extension along peritoneal surfaces, which suggests more aggressive tumor biology. The mucin absorbs water, swells, and invades tissues, thus promoting spread of malignant cells. Mucin also interferes with the mucopolysaccharide-coating immune recognition of carcinoma cells. [57] Children have a worse prognosis than adult patients who are at the same disease stage. [58]

Clinical presentation

Although colorectal carcinomas constitute approximately 1% of all pediatric neoplasms, they are still the most common primary gastrointestinal malignancy. Most cases of pediatric colon cancer occur during late childhood and adolescence. [18] While the gender distribution is equal in adults, the incidence of CRC in children is higher in males, with a relative ratio of 2:1. [18, 44]

Because of its rarity, CRC is seldom suspected in children and adolescents with abdominal symptoms. Therefore, the diagnosis is often delayed. [18]

Presenting symptoms are nonspecific and include vague abdominal pain, weight loss, nausea, vomiting, anorexia, change in bowel habits (diarrhea or constipation), abdominal mass or distension, rectal bleeding, and/or intestinal obstruction. Left-sided tumors, most common among adolescents and young adults, may cause changes in stool caliber and bowel habits, whereas right-sided tumors are more likely to cause symptoms of anemia. Rectal tumors may lead to blood per rectum and tenesmus.

Advanced stage at presentation is more likely in adolescents and young adults than in older patients. The delay from symptom onset to diagnosis of CRC in adolescents and young adults often exceeds 6 months. A low suspicion rate for malignancy and a lack of screening may contribute to the delay.

Overall and event-free survival seem to be better for pediatric patients. In one study, 5-year survival rates for patients with stage 4 CRC were 18.1% for adolescents and young adults versus 6.2% for older adults. [18] Younger patients are more likely to receive systemic therapies and radiation because of sufficient functional reserve and limited comorbidity.

Clinical and laboratory investigation

In the absence of rectorrhagia or hematochezia, patients may test positive for occult blood in the stool; however, screening for fecal occult blood has not proven to be of significant value for the treatment of pediatric patients. [37] Hepatic function abnormalities may be related to metastatic involvement of the liver. Anemia is due to blood loss or malnutrition.

Although fewer than 75% of colon carcinomas in children produce carcinoembryonic antigen (CEA), levels of this protein should be determined. CEA may be a useful tool in identifying recurrent disease after resection, and an increase in CEA levels during follow-up is also related to a higher mortality rate. [12, 59] However, the role of CEA levels in the diagnosis and follow-up of CRC in children is not well established. [44]

A urine metabolites screening test for colonic adenomas is under development and may be a useful alternative to conventional fecal-based screening tests. Preliminary results show that this urine test has a sensitivity of 82.7% and a specificity of 51.2%, with a negative predictive value of 88.5%, making it a future alternative for excluding colonic polyps. [60]

A blood test that includes miRNA analysis of 5 genes implicated in CRC could constitute a new screening test. Preliminary reports show a predicted specificity of 70-95% and a predictive sensitivity of 83-91%, although more multicenter studies are required. [61]

Imaging studies

Conventional radiographic studies include barium enema with air contrast to define the tumor. Abdominal and chest computed tomography (CT) scans define spread to the liver, lungs, or enlarged lymph nodes, as well as pelvic metastases, especially to the ovaries. Colorectal cancer has the ability to metastasize through various routes, including transmural invasion and spread by continuity, intraluminal extension, and hematogenous, lymphatic, and transperitoneal routes. Kaste et al analyzed 32 patients with peritoneal metastatic implants from different primary tumors and found that 22% of these patients had colorectal cancer. [62]

CT scanning may be unable to detect intra-abdominal metastases because of lesion size, paucity of intra-abdominal fat, contiguity with the primary tumor, ascites, implant location, and adequacy of bowel opacification. Current CT scanners are able to detect implants as small as 5 mm in diameter. Magnetic resonance imaging (MRI) may further improve detection.

Colonoscopy is useful in locating the site of lesions within the large bowel. The entire length of the colon should be evaluated. Transrectal ultrasonography may help determine the extent of invasion and resectability of rectosigmoid cancer. Intraoperative ultrasonography of the liver may reveal metastases not observed in other imaging studies. [12] Radioisotope studies should include a bone scan; if the results are positive, bone marrow aspiration and biopsy are indicated to determine spread to the marrow.

Advanced imaging techniques are indicated for specific patient groups. The European Society of Gastrointestinal Endoscopy (ESGE) strongly recommends that conventional screening with white light colonoscopy in high-risk patients should be performed, as well as pancolonic conventional or virtual chromoendoscopy for patients suspected or known to have Lynch syndrome or serrated polyposis syndrome.

The ESGE also recommends that all patients with longstanding colitis undergo periodic pancolonic chromoendoscopies, with either 0.1% methylene blue or 0.1% to 0.5% indigo carmine and targeted biopsies, replacing the common practice of non-targeted 4-quadrant biopsies. [11]

Staging

In 1932, Cuthbert Esquire Dukes, the Director of the Research Laboratory at St. Mark's Hospital in London, indicated that growth of colorectal cancers followed an orderly and predictable fashion. He created a staging classification system that was later modified in 1954 by Astler and Coller. [63] The extent of the disease is determined using the modified Dukes staging scheme. According to this classification, in stage A, only the mucosa and submucosa are affected; in stage B, the disease is limited to the bowel wall; in stage C, the disease is limited to the lymph nodes; and in stage D, the patient has distant metastases, peritoneal implants, direct invasion of other viscera, or surgically unresectable tumors.

The American Joint Committee on Cancer (AJCC) published the most commonly used system to evaluate prognosis in colorectal cancer. [64] The AJCC TNM staging of colorectal cancer is described in the following table.

Table 1. American Joint Committee on Cancer TNM Staging of Colorectal Cancer (Open Table in a new window)

The AJCC prognostic stages are defined in the following table. [64]

Table 2. American Joint Committee on Cancer Prognostic Stages of Colorectal Cancer (Open Table in a new window)

Treatment

Surgical resection remains the mainstay of treatment for colorectal carcinoma in adult and adolescent patients, and the sole therapy required for patients with stage I and II disease. [42]

Open colectomy has been the standard of care for the past 100 years. Complete en bloc tumor resection, including the lymphatic basin of the affected segment, has the greatest impact on survival. [18]

Treatment guidelines are based largely on evidence from older adults. Multidisciplinary care is crucial, and prompt referral to centers experienced in the care of adolescents and young adults should be considered for young patients.

Surgical site infection complicates approximately 15% of colectomy procedures. Oral antibiotic bowel preparation before elective colorectal surgery is associated with shorter postoperative length of stay and lower 30-day readmission rates, primarily because of fewer readmissions for infections. [47] Moghadamyeghaneh et al demonstrated that a combination of mechanical and oral antibiotic preparations significantly decreased postoperative morbidity. [41]

Enhanced recovery protocols, which aim to streamline and standardize perioperative care, have demonstrated efficacy in reducing length of stay but have not resulted in reduced readmission rates. These protocols avoid the use of bowel preparation and epidurals, and encourage early ambulation, early feeding, and early transition to oral analgesia.

Restorative proctocolectomy with ileal pouch anal anastomosis (IPAA) is a viable procedure in pediatric patients, with acceptable morbidity and good long-term results with regard to gastrointestinal function, quality of life, and patient satisfaction. [65, 66] Concerning the type of anastomosis, these authors favor stapled IPAA for prophylactic colectomy, reserving hand-sewn IPAA for patients with neoplasia. The latter is a prudent approach, because earlier dysplasia and colorectal neoplasia are the most important risk factors for developing pouch-related cancer. [65]

An ileal J-pouch is easy to create and delivers acceptable outcomes. However, an S-pouch provides an extra 1-2 cm of length, allowing for tension-free IPAA. [66]

Because children have a long life expectancy, both functional outcomes and control of neoplastic activity of the anal canal and ileal reservoir are of utmost importance. [66]

Best results are obtained with stapled, tension-free anastomosis. Intact tissue rings, good hemostasis, and absence of air leak are imperative. Malnutrition (albumin level, < 3.5 g/dL), neoadjuvant drug toxicity, anemia (hemoglobin level, < 13.5 g/dL), and prolonged high-dose corticosteroid therapy (20 mg of prednisone daily for longer than 3 months) are prognostic factors for perioperative morbidity. Perioperative complications are not uncommon (10%); they include pelvic sepsis, anastomotic leak or stricture, pouchitis, pouch failure, bowel obstruction, and anastomotic stricture. [66]

Laparoscopic resection offers similar postoperative outcomes, pouch function, and long-term quality of life compared with open procedures. [66] However, the learning curve for laparoscopic colectomy remains steep. The need to retract multiple organs, identify complex anatomy, and control large vessels makes the operation difficult. [42]

Patient selection in minimally invasive surgery for colon cancer

Good surgical outcomes depend on careful patient selection. Historic contraindications to a minimally invasive approach include elderly or high-risk patients, multiple previous abdominal operations, technically challenging surgery, and patients with serious comorbidities. All these factors can add a level of difficulty to the performance of an operation, and they are certainly associated with increased morbidity and mortality. But clearly none of these factors are hard but rather are relative contraindications to minimally invasive surgery. The surgeon’s main goal is the performance of a safe and adequate operation. [42]

Laparoscopic surgery has been found to be equal to open surgery in terms of oncologic outcome, margins, lymph node sampling, recurrence, and disease-free survival. The ability to obtain an R0 resection with tumor-free margins is a keystone of oncologic colectomy. [42]

As of now, the following are the only 2 absolute contraindications to laparoscopic CRC surgery [42] :

• A tumor large enough that the extraction site to remove it would be of sufficient size to perform the entire operation.
• A high-grade large bowel obstruction leading to a reduced intra-abdominal domain. The impaired visibility coupled with the friability of the tissue associated with a cancer makes minimally invasive surgery an ill-advised approach in this setting.

Advantages of minimally invasive surgery in colon cancer

In adults, benefits of minimally invasive surgery include decreased length of stay, smaller incisions, less narcotic use, less blood loss and lower transfusion rates, and improved pulmonary function after surgery. No long-term differences have been demonstrated regarding oncologic outcomes. [42]

Surgical colon cancer guidelines widely cite consensus for a goal of at least 12 lymph nodes for an adequate staging. There is a positive correlation between the number of lymph nodes examined and survival for patients with stage II and III CRC. No difference has been shown between open and laparoscopic approaches regarding the number of lymph nodes examined, as well as local or distant recurrence rates. [42]

Early reports of a high rate (21%) of port site recurrence raised concerns about minimally invasive surgery. However, larger multicenter, randomized, controlled trials have not shown any significant increase in wound site recurrence. Both laparoscopic and open CRC resections have wound recurrence rates of less than 1%. [42]

Treatment of early-stage disease (non-metastatic)

Radical surgery is the pillar of curative treatment, including en bloc resection of adjacent organs infiltrated by the tumor. A margin of 5 cm of bowel both proximal and distal to the tumor should be removed (although this distal margin may not be feasible with a low-lying rectal tumor). Right hemicolectomy is indicated for tumors proximal to the splenic flexure, whereas left hemicolectomy is carried out for tumors of the descending colon.

Rectal cancer surgery should include total meso-rectal excision (TME) to minimize the risk of local recurrence. It also requires retrieving a minimum number of lymph nodes. The utility of this approach is still uncertain for adolescents and young adults.

Radical resection of low-lying rectal cancers has traditionally required abdominoperineal resection that involves permanent colostomy, which can have significant impact on the quality of life of adolescents and young adults. For very superficial tumors, mucosal resections might be adequate. Trans-anal TME allows for proper oncologic resection without permanent colostomy.

Indications should be made in the context of an integrated treatment strategy established by an interdisciplinary local or reference board. [67]

Treatment of metastatic disease

Metastatic disease occurs in half of patients with CRC. Metastasis can spread through hematogenous, lymphatic, transcoelomic, endoluminal, or contiguity routes, and it may occur in lymph nodes, liver, lung, peritoneum, brain, and bone. Synchronous presentation at diagnosis occurs in 21% of patients and is associated with worse survival than metachronous disease.

Although most cases of metastatic CRC are incurable, combination chemotherapy with improved surgical techniques and radiation therapy plays a role in prolonging survival and reducing cancer-related symptoms in the context of extensive metastatic disease. [2]

The staging work-up for metastatic disease includes CT of the chest, abdomen, and pelvis and consideration of positron emission tomography (PET)/CT for selected patients with indeterminate findings. Routine laboratory work-up, measurement of carcinoembryonic antigen (CEA) level, and determination of RAS and BRAF status at the primary tumor should be performed. Biopsy of metastases may be useful in the setting of first recurrence or in the case of indeterminate imaging findings.

A multidisciplinary evaluation is of critical importance for most patients with metastatic CRC, because the choice and order of therapies differ depending on presentation, number of sites and location of metastases, and potential for surgical resection. [2]

Research is focused on antiangiogenic agents, antibodies against EGFR (eg, cetuximab), and sequential lines of therapy. Median survival for patients with stage IV disease now exceeds 2.5 years.

Immune checkpoint inhibitors are a novel class of antineoplastic drugs that promote T-cell activation to overcome immune evasion of cancer cells. Other novel agents include monoclonal antibodies to block the programmed cell death protein. This class of therapeutics has shown promising activity for CRC with microsatellite instability, but not for microsatellite stable tumors.

Patients with type 2 diabetes who are being treated with metformin and in whom CRC develops have lower morbidity and better tumor-free survival than patients who are not receiving metformin. [68] .

Tumor debulking offers little survival benefit for patients with extensive metastatic disease. [44] However, in the case of a limited burden of cancer spread, surgical resection of metastatic deposits may result in a longer disease-free interval or even a cure in a minority of cases. [3]

Metastasis limited to the liver, lung, or peritoneum may be operable. Resection of peritoneal disease is often performed in conjunction with heated intraperitoneal chemotherapy (HIPEC), although the added value of this therapy compared with surgery alone remains uncertain.

Chemotherapy and radiation therapy

Radiation is often given with or without chemotherapy in the neoadjuvant setting for rectal cancer, to reduce the risk of local recurrence.

Adjuvant chemotherapy may be considered for recurrence risk reduction in stage III or high-risk stage II CRC. Features that indicate a high risk of recurrence in stage II CRC include the following:

• Peritoneal tumor infiltration (T4)
• High grade
• Perforation or obstruction at presentation
• Lymphovascular or perineural invasion
• Inadequate lymph node sampling

Combination chemotherapy with a fluoropyrimidine and oxaliplatin for 6 months remains the standard of care, although studies show little difference between 3 and 6 months of therapy in the absence of T4 or heavy lymph node involvement.

After surgery and adjuvant therapy, surveillance monitoring for recurrence includes periodic clinical assessment, CT, colonoscopy, and measurement of CEA levels.

Prognosis

Colorectal cancer during childhood is associated with a poor prognosis, mainly attributed to delayed diagnosis, greater tumor virulence, and the advanced stage of disease at presentation. Up to 50% of CRC cases that present during childhood are mucinous adenocarcinomas, and 60% have evidence of metastatic disease at presentation. [18]

Impact of treatment on fertility

Adhesions following pelvic surgery contribute to infertility risk in women. Pelvic radiation for rectal cancer is likely to cause premature ovarian failure. Options to prevent this complication include pre-radiation laparoscopic ovarian transposition or cryopreservation.

Chemotherapy can also impair reproductive health. Fluorouracil is not likely to cause infertility, but oxaliplatin has been associated with moderate infertility risk in animal studies.

Genetic testing and chemopreventive agents

Genetic testing for cancer susceptibility has positive attributes. Family members who test negative for the particular APC or MMR gene are spared the repeated medical and endoscopic examinations that otherwise would have to be performed. They are also spared the anxiety associated with not knowing whether they are affected. Surveillance can then be concentrated on those who have inherited a mutant gene.

Although genetic testing studies for screening are lacking, expert opinion recommends that genetic testing should be performed in every patient with newly diagnosed CRC, to prevent morbidity and mortality in direct relatives. Implementation of universal screening for Lynch syndrome has been declared as part of the 2020 objectives of the Office of Public Health Genomics in the United States. [15]

Future prospective studies should include a systematic family history and testing for potentially relevant genetic conditions if indicated. Trials should also address the risk of CRC in family members and promote sensible family screening guidelines. [69]

Most cancers have an increased glycolytic pathway (Warburg effect). Proteomic studies have demonstrated this pathway enhancement in CRC culture cells. Bi et al also reported on decreased gluconeogenesis, suppressed glucuronic acid pathway, and an impaired tricarboxylic acid cycle. [70] Their findings provide an insight into the tumorigenesis of CRC and possible specific targeted therapies to be developed.

Chemopreventive agents may one day inhibit the development of adenomas. Nonsteroidal anti-inflammatory drugs (NSAIDs) have a well-documented effect on shrinking existing adenomas in patients with familial adenomatous polyposis and potentially inhibit their formation. [36]

Although NSAIDs may have non–cyclooxygenase (COX)-mediated pathways, aspirin inhibits COX enzymes in the conversion of arachidonic acid to prostaglandins. COX-1 is thought to produce cytoprotective prostaglandins in the GI tract, whereas COX-2 is expressed in response to growth factors, mitogens, and cytokines and is found in 50% of colorectal adenomas and in 85% of cancers. [25] COX-2–specific inhibition is believed to be protective against epithelial transformation. Nuclear factor kappa B (NF-κB) transcription factor translocation that produces apoptosis is another mechanism of aspirin.

Specific COX-2 inhibitors are no longer used because of their cardiovascular adverse effects. Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor-A (VEGF-A), which is believed to be critical in cancer angiogenesis. Cetuximab is another monoclonal antibody that targets the EGFR, which is involved in cancer cell proliferation, degradation of the extracellular matrix (invasiveness), tumor migration, and endothelial proliferation. It may well become a good genetic target treatment for CRC. Collaborative multi-institutional pediatric clinical trials are needed to evaluate the prognosis, optimal treatment response, and basic biology of childhood-onset CRC.