eMedicine Specialties > Pediatrics: General Medicine > Oncology

Colorectal Tumors

Author: Jaime Shalkow, MD, Head of Surgical Oncology, Division of Surgery, National Institute of Pediatrics, Mexico; Head-Professor of Pediatric Surgical Oncology, Universidad Nacional Autonoma de Mexico
Coauthor(s): Leonard H Wexler, MD, Associate Professor of Pediatrics, Weill Medical College of Cornell University; Associate Attending, Department of Pediatrics, Memorial Sloan-Kettering Cancer Center; Michael La Quaglia, MD, Chief of Pediatric Surgical Service, Memorial Sloan-Kettering Cancer Center; Professor, Department of Surgery, Weill-Cornell University Medical School
Contributor Information and Disclosures

Updated: Oct 1, 2009

Introduction

At least 50% of the Western population develops a colorectal tumor by age 70 years. In 10% of these individuals, the tumor progresses to malignancy. In adults, colorectal cancer is the second leading cancer that causes death worldwide.¹ This article discusses the classification, etiology, genetics, clinical presentation, and management of colonic tumors seen in the children. These include polyps, sporadic colorectal carcinoma (CRC) and familial colon cancer (familial adenomatous polyposis [FAP]), and hereditary nonpolyposis colorectal cancer (HNPCC).

Polypoid Disease of the Gastrointestinal Tract

Not all polyposis syndromes are familial. Familial polyposis syndromes are divided into 2 major groups based on the presence of adenomas or hamartomas. The inherited adenomatous polyposis syndromes include familial adenomatous polyposis (FAP) and Turcot syndrome; the familial hamartomatous polyposis syndromes include Peutz-Jeghers syndrome and juvenile polyposis.

Although juvenile polyps are common in children, adenomas are quite unusual. The latter are considered dysplastic precancerous lesions that are commonly seen in late adulthood. When discovered in children, they suggest one of several types of inherited colorectal cancer.²

Although the nomenclature is confusing, diffuse juvenile polyposis differs from juvenile polyposis coli. Diffuse juvenile polyposis is a syndrome with multiple polyps spread throughout the GI tract and presents in younger children (aged 6 months to 5 years); in juvenile polyposis coli, the polyps are confined to the rectosigmoid area and are typically found in older patients (aged 5-15 y). Hamartomatous polyps may also be found in patients with Cowden disease, Cronkhite-Canada syndrome, Bannayan-Riley-Ruvalcaba syndrome, and basal cell nevus syndrome.³

Colonic polyposis syndromes

• Nonfamilial polyposis - Isolated juvenile polyps (inflammatory polyps) 
• Familial polyposis
  • Adenomas
    • FAP
    • Gardner syndrome
    • Turcot syndrome
  • Hamartomas
    • Juvenile polyposis
    • Peutz-Jeghers syndrome
    • Cowden disease
    • Cronkhite-Canada syndrome

The lesions can be isolated to the intestine (eg, juvenile, lymphoid, familial adenomatous) or can involve other areas of the body (eg, Peutz-Jeghers syndrome, Gardner syndrome, Turcot syndrome). Most polyps of the GI tract are benign and result from hamartomas of the mucosa or lymphoid hyperplasia of the submucosal layer. However, adenomatous polyps represent a genetic alteration in the mucosa and have substantial malignant potential.

For study purposes, only the hamartomatous lesions and other nonfamilial lesions are discussed in this section. FAP is presented in detail below, with other cancer-predisposing entities.

Polyps occur in 1% of preschool-aged and school-aged children⁴ and are the most frequent cause of rectal bleeding in toddlers and infants aged 2-5 years. Juvenile polyps are the most common (80%), followed by lymphoid polyps (15%).

Juvenile polyposis syndromes are classified as follows:⁵

• Isolated juvenile polyps (nonmalignant) - No family history of juvenile polyposis; fewer than 5 polyps confined to the colon
• Juvenile polyposis syndromes (malignant potential)
  • Diffuse juvenile polyposis of infancy - Widespread polyposis of the entire GI tract in patients younger than 6 months.
  • Diffuse juvenile polyposis - Multiple polyps throughout the GI tract but concentrated in the stomach, distal colon, and rectum; usually occurs in patients aged 6 months to 5 years
  • Juvenile polyposis coli - Multiple polyps confined to the distal colon and rectum in patients aged 5-15 years

Lymphoid polyps (lymphoid nodular hyperplasia)

Lymphoid polyps (present in 15% of patients) are hyperplastic submucosal lymphoid aggregates, most likely due to a nonspecific infection (exposure to bacteria and viruses). Submucosal lymphoid tissue is prominent in children, particularly in the distal ileum (Peyer patches). These non-neoplastic polyps may occur in the rectum, colon, and terminal ileum. Macroscopically, they appear as firm, round, submucosal nodules that are smooth or lobulated. They are never pedunculated. They often have a volcano-like appearance with mucosal ulceration, which leads to occult blood loss. Histologically, they are hyperplastic lymphoid follicles with a large germinal center covered by colonic mucosa. They develop in young children, with a peak incidence at age 4 years.

Patients present with anemia or, less frequently, with severe rectal bleeding. Barium enema and colonoscopy findings are helpful (in 50% of patients), and biopsy findings confirm the diagnosis.

Surgery is indicated only for uncontrolled bleeding and intussusception that does not respond to enema treatment. Otherwise, expectant measures are adequate because these polyps are benign and spontaneously regress.

Isolated juvenile polyps

Also known as retention, inflammatory, or cystic polyps, isolated juvenile polyps are the most common types of polyps found in children (80%) and represent one of the most common sources of lower GI bleeding in this population. They are considered hamartomas and lack malignant potential.^6,7 Juvenile polyps occur in approximately 1% of preschool-aged children. The peak incidence is in children aged 3-5 years; boys seek medical attention twice as often as girls do.⁷ The polyps are solitary in 50% of patients; the remaining patients have 2-5 polyps. Approximately 40-60% of polyps are found in the rectosigmoid area; the remaining polyps are distributed throughout the proximal colon.⁴ Isolated juvenile polyps are rarely seen after adolescence.

These polyps are smooth, reddish, and range from 2 mm to several centimeters in diameter. They often have an ulcerated surface, which accounts for the rectal bleeding. On cross-section analysis, cystic spaces filled with mucus are revealed. Some data suggest that that these polyps may result from structural rearrangement of the mucosa secondary to an inflammatory process.⁸

Patients most often present with hematochezia due to superficial ulceration of the polyp (93%), pain (10%), or rectal and/or polyp prolapse and encopresis.⁴ Ten percent of juvenile polyps autoamputate with spontaneous cessation of rectal bleeding.^5,7,9 Colonoscopy of the entire colon is performed to eliminate juvenile polyposis (ie, >5 polyps).¹⁰ The polyps can be endoscopically removed. When managing a prolapsed polyp, controlling the polyp stalk prior to resection is mandatory. Failure to control the polyp stalk can result in retraction, which makes hemostatic control very difficult.⁷

Juvenile polyposis syndromes

• Diffuse juvenile polyposis of infancy
  • This entity occurs within the first months of life and is not familial.¹¹ Patients may present with diarrhea, rectal bleeding, intussusception, prolapse, bowel obstruction, protein-losing enteropathy, macrocephaly, clubbing of fingers and toes, and hypotonia.⁶
  • The entire GI tract is involved. One third of these patients have other congenital abnormalities such as Meckel diverticulum, malrotation, and heart lesions.⁵
  • Patients require total parenteral nutrition (TPN) and bowel rest, followed by selective resection.
  • Despite appropriate treatment, this disease is almost universally fatal; only 2 patients have been reported to survive after age 2 years.^6,12
• Diffuse juvenile polyposis
  • Diffuse or familial juvenile polyposis was originally identified as isolated or multiple hamartomatous polyps that occur in the colon and rectum of children aged 6 months to 5 years.¹³
  • Patients present with bright red blood per rectum, anemia, abdominal pain, and rectal prolapse. Diffuse juvenile polyposis is inherited as an autosomal dominant trait;⁵ thus, if a parent has the condition, the chance of having an affected child is 50%.
  • Hamartomas are malformed colonic mucosa arranged in a bizarre fashion. Typically, these are not considered premalignant unless they are part of a polyposis syndrome.
  • Patients with diffuse juvenile polyposis have a 50% lifetime risk of colorectal carcinoma (CRC).¹⁴ This may be due to chronic inflammation that produces reactive hyperplasia, which then progresses to dysplasia or adenomatous changes. These polyps often have an ulcerated surface and demonstrate more epithelium with a villous or papillary configuration.
  • In addition to the aforementioned epithelial dysplasia occurring in juvenile polyps, adenomas are also often present. Thus, the approach to these patients is similar to that taken in patients with FAP. Some authors recommend monitoring these patients with an annual CBC count (to detect anemia due to GI bleeding), semiannual pancolonoscopy, and subsequent colectomy if severe dysplasia, bleeding, or rapid polyp formation occurs. Others advocate for prophylactic colectomy.
  • Associated congenital defects include cleft palate, malrotation, polydactyly, and cranial abnormalities.
• Juvenile polyposis coli
  • A child with at least 5 polyps, polyps throughout the GI tract, or one polyp and a family history of juvenile polyposis is considered to have the syndrome.
  • Most patients have 50-100 colorectal polyps; they may also have gastric and small intestinal polyps.
  • Identifying patients with this syndrome is fundamental because of the high risk for carcinoma (17%) at an early age; the mean age at diagnosis of carcinoma is 35.5 years.¹¹
  • Close long-term surveillance is important. The amount of polyps increases the risk of chronic bleeding, which subsequently leads to iron deficiency anemia, hypoproteinemia, and failure to thrive.^7,12

Macroscopically, these polyps resemble the isolated juvenile polyps; however, histologically, they have more epithelium with a villous or papillary configuration. Epithelial dysplasia can occur. Adenomas can also be found in conjunction with juvenile polyps.⁶ Lobular polyps have a higher propensity for a more severe dysplasia (47%) than nonlobular polyps (10%).¹⁵

According to the St. Mark's Polyposis Registry in London, the cumulative risk for cancer in patients with a juvenile polyposis syndrome is 68% by age 60 years.¹⁶ Because the entity is transmitted in an autosomal dominant fashion, patients with a juvenile polyposis syndrome and their families must receive long-term follow-up.¹⁷

Some authors advocate prophylactic total colectomy and rectal mucosectomy with an endorectal pull-through (ERPT),¹⁵ whereas others recommend regular screening with colonoscopy and subsequent colectomy if severe dysplasia, rapid polyp formation, or bleeding occurs.¹⁸

When intussusception occurs in children older than 2 years, the discovery of a specific lead point is not uncommon (22%); however, lead points are only found in 2-8% of children within the usual age range (6-18 mo). When a polyp is demonstrated as a lead point in a patient with intussusception, an evaluation may be indicated to identify polyposis syndromes.

Some hamartomas do not appear to have any malignant potential. However, germline mutations and somatic inactivation of STK11, SMAD4, BMPR1A, and PTEN genes in hamartomatous polyposis syndromes create an epithelial environment favorable for neoplastic transformation.¹⁹

Peutz-Jeghers syndrome

In 1921, Peutz reported on the association of intestinal polyps with mucocutaneous pigmented spots of the mouth, hands, and feet.²⁰ From 1944-1949, in a study of 20 patients, Jeghers defined the 2 main features of the syndrome as melanotic spots on the buccal mucosa and lips (with variable melanin pigmentation on the face and digits) and polyposis of the intestinal tract.⁶ The melanotic spots range from brown to black and occur in the rectum, around the mouth, and on the lips, buccal mucosa, feet, nasal mucosa, and conjunctivae. These spots are typically present at puberty.⁶

The polyps most commonly appear in the small intestine (55%), followed by stomach and duodenum (30%) and the colorectal area (15%). Dramatic advances have occurred in the understanding of the genetic and molecular basis of the disease that apply to these polyps. A germline mutation involving the genes LKB1 and STK11 (10-70% of cases) has been identified in this syndrome.^21,22

Also, the ENG gene, which may play a role in the pathogenesis of the mucosal defects, has been identified in a subgroup of these patients, as well as in patients with hereditary hemorrhagic telangiectasia (HHT).²² Although adenomas can occur concurrently in the syndrome, these polyps are mostly hamartomas of the muscularis mucosa. They appear as pedunculated lobulated lesions, measuring from a few millimeters to several centimeters. Peutz-Jeghers syndrome is inherited as an autosomal dominant trait,²⁰ but de novo cases can also develop. It affects all ethnic groups with equal sex distribution;⁶ however, symptoms appear earlier in males (5-10 y) than in females (10-15 y).²⁰

GI disturbances become apparent later. Patients usually present during early adolescence. Some patients present with an increased frequency of defecation, rectal bleeding, anemia, abdominal pain, vomiting, or recurrent episodes of intussusception.²⁰ Prolapse of rectal polyps in the first year of life, even in the absence of pigmentation, may indicate Peutz-Jeghers syndrome, at least in the familial cases.

Compared with the general population, patients with Peutz-Jeghers syndrome have a 13-fold increased risk of death due to GI cancer and a 9-fold increased risk for all other cancers.⁶ The risk of death due to cancer by age 60 years is 50%. Adenomatous and carcinomatous changes in the hamartomas have been reported.²³

Screening tests to detect all these forms of cancer are recommended in children who present with abdominal pain or occult anemia and melanotic-pigmented spots. An aggressive screening and biopsy program should be undertaken, including an annual examination with CBC count, breast and pelvic examinations (with cervical smears and pelvic ultrasonography) in females, mammography at age 25 years, testicular examination in males, pancreatic ultrasonography, and biennial upper and lower endoscopy.

Extensive intestinal resections are contraindicated because of the recurrent nature of the polyps and the ensuing short-bowel syndrome that may result. Rapid growth, induration, severe dysplasia, villous changes, or polyps larger than 15 mm (which presents a much higher chance of having malignant transformation) suggest the need for a more aggressive intervention.⁶

Gardner syndrome

In 1962, Gardner and colleagues noticed extracolonic manifestations in some kindred with polyposis. In this syndrome, the polyps are adenomatous rather than hamartomas. The associated extraintestinal tumors include desmoid cysts, cysts of the mandible, fibromas, osteomas, and hypertrophy of the retinal pigmented epithelium.²⁴ Bone tumors are most common (80%), followed by inclusion cysts (35%) and desmoid tumors (18%).⁷ The syndrome is inherited in an autosomal dominant pattern. The osteomas are most frequently found in the skull and facial bones. Abnormal dentition is common.⁶ Periampullary malignancies may develop during the third or fourth decades of life at rates much more common than in the general population.⁷

Gardner syndrome is considered a phenotypic variant of FAP, and different mutations on the adenomatous polyposis coli (APC) gene have been shown to be associated with this syndrome (APC polymorphism in exons 13 and 15).²⁵ Intestinal polyps have a 100% likelihood of undergoing malignant transformation.²⁶

The natural history and treatment of patients with colonic polyps is the same as in those with FAP. Desmoid tumors of the abdominal wall and mesentery occur in 20% of patients with Gardner syndrome, usually appear 6-30 months after surgery for intestinal manifestations, and are the leading cause of death in patients who have undergone colectomy. Desmoid tumors are dense fibroplastic proliferations but can present with dysplasia and even fibrosarcoma. Treatment is challenging. When these tumors are small and well defined, excision is feasible with a recurrence rate of 10%; however, some are not identified until they become unresectable. Desmoids that involve the small bowel mesentery should be treated according to their symptoms and growth rate. Sulindac, tamoxifen, or vinblastine and methotrexate are adequate for slow-growing, mildly symptomatic tumors. Aggressive tumors require high-dose tamoxifen, or antisarcoma chemotherapy (doxorubicin and dacarbazine), and possibly radiation therapy.^22,19

Turcot syndrome

This syndrome, also considered a variant of FAP, includes multiple pediatric brain tumors (eg, gliomas, ependymomas) in families that also have an increased risk for polyposis and colon cancer. All patients with this syndrome develop carcinoma of the colon as young adults.⁷ Colonic adenocarcinomas occur in the colonic polyps and in the mucosa between the polyps. Patients may present with chronic bloody diarrhea, hypoproteinemia, weight loss, anemia, malnutrition, bowel obstruction, and intussusception. Hamilton found that families with Turcot syndrome have mutations in APC or HNPCC genes.²⁷ The type of brain tumor correlates with the mutations, medulloblastomas in APC -related mutations, and microsatellite instability in families with glioblastoma multiforme.⁶ In patients with a strong family history, begin diagnostic investigation during the second decade of life and continue annually.

Cronkhite-Canada syndrome

This is a variant of juvenile polyposis in which the GI polyps are associated with skin hyperpigmentation, alopecia, and nail changes (Cronkhite, 1955). Hair loss and skin and nail changes may be evident long before GI symptoms appear. The hamartomatous polyps appear in the stomach and colon. Chronic diarrhea results in malabsorption, hypovitaminosis, hypoproteinemia, and fluid and electrolyte imbalance. Because patients with Cronkhite-Canada syndrome may develop colonic malignancy, close follow-up is recommended (see Syndromes associated with CRC).⁷

Typically, in all syndromes with increased risk of cancer, the author recommends following a screening schedule like the one used for patients with Peutz-Jeghers syndrome to identify malignancies at an earlier stage.

Bloom syndrome

This is a rare, recessively inherited disease in which growth retardation, accelerated aging, immunodeficiency, susceptibility to chromosome breaks, and a high frequency of malignant tumors are observed.²⁸ Patients with Bloom syndrome appear hypersensitive to various different DNA-damaging agents, such as UV light and irradiation. A generalized DNA repair defect is present, likely a defect in DNA ligation; thus, this process has been encompassed in diseases of DNA repair defects such as xeroderma pigmentosum, ataxia-telangiectasia, and Fanconi anemia.

The Bloom syndrome gene has been cloned and has been found to code for a putative helicase on chromosome 15. In this regard, genes involved in DNA repair may be considered tumor suppressor genes.²⁹ Only 0.8% of individuals with Bloom syndrome and colorectal neoplasia carry the BLM(Ash) mutation,³⁰ and this appears to have little clinical effect on the number of neoplasms, patient age at detection, or tumor location within the colon.³¹ No specific incidence of colorectal cancer in patients with Bloom syndrome has been described in the literature.

Cowden syndrome

This is an autosomal dominant transmitted disease with hamartomas of all 3 embryonal layers. Facial tricholemmomas, oral papillomas, multinodular goiter, and GI polyps with occasional GI cancer may also be found in patients with this syndrome. Fibrocystic breast disease and esophageal glycogenic acanthosis have been described.¹⁹ These patients have a higher breast and thyroid cancer risk. Germline mutations have been identified in the PTEN gene.

Treatment is directed toward alleviating symptoms of pain, bleeding, or obstruction. Polyps should be removed when symptomatic, and screening to detect subsequent development of more polyps is warranted.

Ruvalcaba-Myhre-Smith syndrome

This syndrome includes developmental abnormalities, microcephaly, and juvenile polyposis. It is a rare disease that occurs in males. No cancer has been reported in these patients. The polyps are removed when symptomatic, and family screening is advised.

Osler-Weber-Rendu syndrome

Also termed HHT, Osler-Weber-Rendu syndrome is an autosomal dominant familial disorder characterized by telangiectases and vascular malformations of the skin and mucous membranes and recurrent GI bleeding. It may also affect the brain, lungs, and liver.³² The lesions are typically noticed in the first few years of life, and 50% of patients aged 10 years have had a GI bleed. A family history of the disease is reported in 80% of patients.

The pathogenesis may relate to mutations of the ENG and ALK1 genes, which play an important role in determining the properties of endothelial cells during angiogenesis.³³ Telangiectases are usually present on the lips, oral and nasopharyngeal membranes, tongue, and perlingual areas. They also occur in the colon but are more common in the stomach and small bowel, where they tend to cause significant bleeding.³⁴

In one study, 6 of 24 patients (25%) evaluated with HHT developed a colonic neoplasia, 3 had adenocarcinoma of the colon, and 3 more had multiple colonic polyps.³⁵ Elinav et al recommend lower GI tract evaluation for all patients with new-onset anemia or GI bleeding, even if blood loss may be a manifestation of GI HHT.

Oldfield syndrome

This syndrome refers to the association between sebaceous cysts and FAP. Patients present during adolescence with subcutaneous lesions typically located on the extremities, scalp, and face; they develop during adolescence.³⁶ These patients share the same chromosomal derangements as those with FAP (ie, germline mutations of the APC gene on band 5q21).

The most recently described adenomatous polyposis syndrome, MutYH-associated polyposis, is autosomal recessive and requires an inherited mutation from each parent for the development of the disease.²

Colorectal carcinoma

Syndromes associated with CRC include the following:

• Gardner syndrome - Polyposis, osteomas, and multiple sebaceous cysts
• Turcot syndrome - Polyposis and brain tumors (gliomas, ependymomas)
• Peutz-Jeghers syndrome - Colonic polyposis, ovarian tumors, and mucocutaneous pigmentation of lips, oral mucosa, and perioral region
• Cronkhite-Canada syndrome - GI polyposis, skin hyperpigmentation, alopecia, and nail changes
• Osler-Weber-Rendu syndrome - Juvenile polyps and hepatic telangiectasia
• Oldfield syndrome - Polyposis and multiple sebaceous cysts
• Bloom syndrome - Growth retardation, accelerated aging, immune deficiency, and malignant tumors
• Cowden syndrome - Hamartomas, GI polyps, breast, thyroid, and GI cancer
• Ruvalcaba-Myhre-Smith syndrome - Microcephaly and juvenile polyposis in males; no cancer

The screening schedule for patients with polyposis syndromes and increased risk of malignancy is as follows:

• Symptoms related to polyps - Annually
• Blood count to detect anemia - Annually
• Breast and pelvic examinations with cervical smears and pelvic ultrasonography in girls - Annually
• Testicular examination with ultrasonography in boys - Annually
• Pancreatic ultrasonography - Annually
• Esophagogastroduodenoscopy and colonoscopy - Biennially
• Mammography - Recommended at ages 25, 30, 35, and 38 years; biennially until age 50 years; annually thereafter

Familial colon cancer

Familial colon cancer syndromes are divided into those associated with polyposis (familial polyposis coli) and HNPCC. To provide a better description of the genesis of these 2 entities and their differences, their genetic principles are briefly discussed below.

Colorectal Carcinoma Genetics (Defects in Mismatch Recognition and Repair)

The unwinding and copying enzymes that replicate DNA form a highly efficient and accurate replicative complex; however, this process is not perfect. Mistakes in base pairing occasionally occur, depending on the organism, the accuracy of DNA polymerases, and the peculiarities of the local environment, which may make such mistakes more or less likely. Some stretches of DNA are more likely to accumulate errors than others, particularly stretches of DNA that consist of tandem-repeat units. These areas are termed microsatellite regions. Certain patients have marked instability in the microsatellite repeats throughout their genomes; this instability leads to a failure to recognize and repair these nucleotide mismatches. Mismatch repair defects are an early step in the process leading to malignant transformation in some cancers.

The progression from normal colon epithelium to dysplastic epithelium begins with hyperplasia, followed by the development of adenomas and, finally, invasive carcinomas. Most mutations that occur in colon cancer develop after birth in single cells as a result of exposures to environmental influences or perhaps as a result of mistakes that cells make when they copy their DNA during cell division. Approximately 80% of annual cases of colorectal carcinoma (CRC) are not associated with hereditary factors.

The pathological progression of adenoma to carcinoma depends on reproducible genetic alterations such as APC gene inactivation, K-ras oncogene activation, and p53 mutation.

Familial Adenomatous Polyposis

As mentioned, adenomatous polyps represent a disturbing alteration in the mucosa and have substantial malignant potential. Adenomatous polyps occur in less than 3% of children with polyps.⁶ However, familial adenomatous polyposis (FAP) accounts for less than 1% of all colorectal cancer.¹⁹ The criteria for a diagnosis of FAP and, thus, for an increased risk of cancer in children with polyps include the following:

• More than 5 polyps in the colon
• Polyps throughout the GI tract
• Any number of polyps associated with a family history of juvenile polyposis

FAP occurs in approximately 1 per 7000 individuals.³⁷ The major feature of the syndrome is extensive polyposis, which is defined by at least 100 visible adenomatous polyps in the large intestine.⁶ Some patients have thousands of polyps. The rate of development of colorectal carcinoma (CRC) in the third decade of life and after is nearly 90%.³⁸

These patients also have a greatly increased risk of upper GI malignancies (eg, duodenal and periampullary adenocarcinomas), thyroid cancer (occurring in 1% of patients with FAP),⁴⁰ and hepatoblastoma (occurring in 1 case per 250 persons with FAP, compared with 1 case per 100,000 persons in the general population).^41,42

FAP has been divided into 2 types: the sparse type and the profuse type. A relationship between the location of mutations in the gene and the phenotypic expression of FAP has been established.⁴³ The sparse type of FAP is characterized by hundreds of polyps; the profuse type is characterized by thousands of polyps. Patients with the profuse type tend to have adenocarcinoma at an earlier age.⁶ In addition, depending on the codons that are mutated within the gene, patients may develop desmoid tumors or congenital hypertrophy of retinal pigment epithelium (CHRPE).⁴³ Environmental factors may affect manifestations of FAP; identical mutations may result in different phenotypes in different patients.⁴³

Adenomatous polyps progress through dysplasia to complete transformation. Extension of the neoplastic cells into the basement membrane of the colonic epithelium represents carcinoma in situ. Because the colonic mucosa does not contain lymphatics, metastasis does not occur until the tumor invades the submucosa through the muscularis mucosa. The duodenal mucosa may also be involved with adenomatous polyps; periampullary adenocarcinoma develops in the duodenal mucosa in 2.9% of patients with FAP.⁴⁴ Although gastric polyps may occur in patients with FAP, the polyps are usually benign hamartomas, and no evidence of neoplastic transformation has been reported.⁶ The use of capsule endoscopy may play a role in the screening for small intestinal polyps.

FAP is inherited as an autosomal dominant trait; a 10% incidence of new mutations is reported. FAP is caused by a deletion in the APC gene on the long arm of chromosome 5. The APC gene codes for a protein product that acts as a tumor suppressor.³⁹ Specific genetic alterations have been identified in most of the 30% of patients who do not test positive for mutations in the APC gene with routine testing.²² Recent studies indicate the presence of mosaicism in approximately 15% of such cases.⁴⁵

All untreated patients with FAP develop colon cancer. The average age at which these patients develop cancer is 39 years; malignant transformation occurs by age 20 years in 7% of patients and by age 25 years in 15% of patients.⁶

Patients usually present during early adolescence. Approximately 90% are asymptomatic but are identified during routine surveillance because of a family history of FAP. Some patients present with an increased frequency of defecation, rectal bleeding, anemia, and abdominal pain. The diagnosis is confirmed by endoscopic biopsy findings. Most who present with symptoms already have a malignant condition.⁶ Because many FAP carriers have few polyps but still develop early colorectal cancer, surgery is indicated even if polyposis does not develop. After prophylactic surgery, carriers require screening of their upper GI tracts and rectums (if rectal mucosa is left in place) to evaluate for malignancy.³⁸ Surgical removal of the entire colonic mucosa prevents the development of CRC.⁹

Total proctocolectomy with permanent ileostomy is not advocated because of the physiologic and psychologic impact of a permanent stoma in a young patient and because of the risk of bladder atony, impotence, and retrograde ejaculation due to destruction of nervi erigentes during the pelvic dissection.³⁸ Total abdominal colectomy with ileorectal anastomosis is also not ideal because 44% of patients require subsequent treatment for rectal polyps that develop in the remaining mucosa and because the cumulative risk of developing rectal cancer is 10% at age 50 years and 29% by age 60 years.⁶

In a 30-year review of FAP, Nikitin et al found that coloproctectomy with preservation of the anal sphincter and coloproctectomy with ileoanal pull-through resulted in the development of anal canal cancer in 4.1% of patients, whereas 10.7% of patients developed cancer after colectomy with preservation of various colonic segments.⁴⁶ They found that occurrence of cancer is not related to sex, age, length of preserved colonic segment, presence of cancer in the removed colonic segment, or postoperative follow-up period. Presence of polyps in the colonic segments preserved during surgery significantly increased the risk of cancer at a later time.

Total colectomy with a rectal mucosectomy and endorectal pull-through (ERPT) is the procedure of choice.⁷ Some authors suggest that an ileal reservoir is not absolutely necessary because it increases the risk of pouchitis (23%) and that patients who undergo straight (nonreservoir) pull-through develop a neoreservoir within 24 months, which decreases the frequency of stools.⁶

Laparoscopic techniques for total abdominal colectomy with ileorectal anastomosis have been described as safe and effective.⁴⁷ Gastroduodenoscopy and flexible endoscopic surveillance of the pelvic pouch must be performed annually in these patients.¹⁹ Rapid growth, induration, severe dysplasia, villous changes, or polyps larger than 1 cm (which presents a much higher chance of having malignant transformation) suggest the need for more aggressive intervention.

Sulindac (Clinoril), a nonsteroidal anti-inflammatory drug (NSAID), was found to reduce the number of polyps in patients with FAP.⁴⁸ However, later studies demonstrated that the effect was only partial and that CRC may still develop. Apparently, the mechanism of action is induction of apoptosis in the abnormally proliferating colony of epithelial cells. Studies with the more specific cyclooxygenase-2 (COX-2) inhibitors (eg, celecoxib [Celebrex]) have also shown some efficacy.⁴⁹

The American Society of Colon and Rectal Surgeons have published management guidelines and practice parameters for patients with FAP. Patients with FAP or people with personal or family risk factors for FAP should be referred to center registries and genetic counselors with experience in the multidisciplinary management of these individuals.⁵⁰

Hereditary Nonpolyposis Colon Cancer (Lynch Syndrome)

Hereditary nonpolyposis colon cancer (HNPCC) describes a clinical syndrome of colorectal cancer that occurs with early onset and in multiple family members. In contrast to familial adenomatous polyposis (FAP), HNPCC does not have a specific phenotype, and malignancy develops in the absence of adenomatosis of the colon and rectum. Lynch syndrome is the most common hereditary colon cancer syndrome and accounts for about 2-3% of all colorectal cancer cases.⁴⁵ The lifetime risk of developing colorectal cancer for patients with Lynch syndrome is 60-80%.⁴⁵

The expression of the disease may be limited to the colon (Lynch syndrome I) or mat coexist with extracolonic tumors (Lynch syndrome II).⁵¹ These other tumors include endometrial (the second most common after colorectal carcinoma [CRC]), uterine, ovarian, stomach, pancreatic, and genitourinary cancers.⁵² They usually manifest in the second decade of life.³⁸ Patients with Lynch syndrome have a 50% lifetime risk of developing cancer and a 3-fold increased incidence of CRC compared with the general population. Female patients with Lynch II syndrome should also undergo vaginal ultrasonography, endometrial aspiration, and serum CA-125 assessment annually beginning at age 30 years.¹⁹

Most CRCs in patients with HNPCC demonstrate microsatellite instability. Lynch used the term replication error positive to describe such tumors.^43,19 The first genetic cause of the syndrome was identified in chromosome 2; since then, additional loci have been described. More than 90% of these mutations are in 2 genes, MSH2 and MLH1, which are located on chromosome arms 2p and 3p, respectively. These genes are inherited in a dominant fashion, with 90% penetrance.⁵¹ Patients suspected of carrying the mutation may be tested for mismatch repair gene mutations in commercial laboratories.

HNPCC accounts for approximately 2-5% of all colorectal cancer cases,^43,19 but these patients reportedly have a better prognosis than those with sporadic CRC.⁵³ The average age of colorectal cancer onset among HNPCC gene carriers was reported to be 45 years, but recent studies have shown that it appears to be at age 69 years.⁵⁴ Synchronous and metachronous tumors are frequent.

Patients present with lower stage disease at diagnosis than patients with sporadic CRC, and distant metastases at diagnosis are also less frequent. One possible explanation is that the large number of mutations that accumulate in these cells results in production of abnormal products recognized as foreign by the host. Alternatively, a high mutation rate may actually hinder tumor dissemination through derangement of functions critical to that process.⁵³

The Amsterdam criteria for defining HNPCC include the following:⁵⁵

• Onset of colorectal cancer in at least 3 individuals spanning 2 generations
• At least one of these individuals is a first-degree relative of the other two
• At least one of these individuals must have a diagnosis prior to age 50 years

The stringency of the Amsterdam criteria likely excludes a number of individuals with an inherited predisposition to colorectal cancer. FAP must be excluded. Some patients with this syndrome satisfy the Amsterdam criteria for HNPCC, but their cancer cells do not display MSI-2. These patients seem to have a distinct form of the syndrome recently referred to as "familial colorectal cancer type X." They have a lesser risk for colorectal cancer and a later onset. They do not carry the risk for extracolonic malignancies.^56,19

HNPCC malignancies occur in the cecum and ascending colon more often than in other colorectal sites (70%); they have a higher incidence of poorly differentiated and mucin-producing tumors (signet cell). Full colonoscopic screening is recommended biannually, beginning at age 25 years.^57,19,58,59 Lynch proposed treatment with subtotal colectomy rather than hemicolectomy or a segmental resection because the risk of a second or third primary cancer of the colon is 45% over 10 years. Patients who are poorly compliant with colonoscopic surveillance may be candidates for prophylactic colectomy. Patients who have undergone subtotal colectomy must be informed that they require lifelong endoscopic evaluation of their remaining rectal segment.⁴³ They also still face the risk of extracolonic cancers.

Lynch reported that colonic polyps can be identified in as many as 17% of first-degree relatives during colonoscopic screening. Adenomas are more likely to grow and progress to invasive cancer in this patient population than in the general population.

The optimal management strategy for HNPCC gene carriers has yet to be established. Evidence suggests that surveillance colonoscopy and polypectomy are effective in reducing the risk of invasive cancer in these patients.⁴⁵ It seems wise to advise biannual colonoscopy starting at age 25-30 years and annually after age 40 years. Currently, experts have not reached consensus regarding the role of prophylactic subtotal colectomy for patients with HNPCC. Given the high penetrance of the disorder and the high rate of synchronous and metachronous disease among mutation carriers, a strong case may be made for prophylactic colectomy in these patients.

Subtotal colectomy with a rectal mucosectomy and endorectal pull-through (ERPT) has not been studied in this population. Patients who elect to undergo a subtotal colectomy require colonoscopic surveillance of the remaining rectum. Patients who elect not to consider prophylactic surgery must commit to lifelong surveillance. At present, both of these are reasonable management strategies.

Sporadic Colorectal Carcinoma

¹

Multimedia

(Enlarge Image)

Media file 1: This picture depicts an abdominal CT scan of a 7 year-old boy with a mucinous adenocarcinoma of the ascending colon. Note the thickness and increased vascularity of the colonic wall, as well as irregularities on the serosal surface. This cut also shows severe tumor infiltration of the colonic mesentery surrounding the mesenteric and retroperitoneal vessels.

(Enlarge Image)

Media file 2: Coronal CT scan of the same patient as in Media file 1 demonstrating the profuse tumoral infiltration of the ascending colonic mesentery surrounding mesenteric and portal vessels. Also note the thickness of the colonic hepatic flexure.

(Enlarge Image)

Media file 3: Surgical specimen after right hemicolectomy, including the terminal ileum up to the transverse colon. Mesenteric fat, vessels and lymph nodes were resected en block with the ascending colon. The large intestine has been opened longitudinally. Note the tumor on the right lower quadrant of the image, with severe thickness of the wall, areas of necrosis and hemorrhage, and some stippled calcifications.

Keywords

colorectal tumors, malignancy, cancer, colon cancer, colonic tumors, polyps, sporadic colorectal carcinoma, CRC, familial colon cancer, nonfamilial polyposis, isolated juvenile polyps, inflammatory polyps, familial polyposis, adenomas, familial adenomatous polyposis, FAP, Gardner syndrome, Gardner's syndrome, Turcot syndrome, Turcot's syndrome, hamartomas, juvenile polyposis, Peutz-Jeghers syndrome, Cowden disease, Cowden syndrome, Cronkhite-Canada syndrome, Lynch syndrome, Lynch's syndrome, hereditary nonpolyposis colorectal cancer, HNPCC, Peyer patches, intussusception, bowel obstruction, protein-losing enteropathy, macrocephaly, clubbing of fingers and toes, hypotonia, Meckel diverticulum, malrotation, heart lesions, bright red blood per rectum, anemia, rectal prolapse, cleft palate, polydactyly, failure to thrive, iron deficiency anemia, malabsorption, hypovitaminosis, hypoproteinemia, fluid and electrolyte imbalance, Bloom syndrome, xeroderma pigmentosum, ataxia-telangiectasia, Fanconi anemia, Ruvalcaba-Myhre-Smith syndrome, Osler-Weber-Rendu syndrome, Oldfield syndrome, treatment, diagnosis

• Search for CME/CE on This Topic »

• Fecal DNA Test May Help Detect Gastrointestinal Tumors

• Epidermal Growth Factor Receptor (EGFR) Status and K-Ras Mutations in Colorectal Cancer
• Report of a Case: Primary Mucinous Carcinoma of the Skin
• Digestive Cancer in the Elderly