Tubular Adenoma

Etiology

Community-based estimates reveal an increased prevalence with age and male gender while several studies have also reported a higher risk of colon cancer in patients with a first-degree relative family history, smoking history, excess alcohol intake, diabetes mellitus, and higher body-mass index, which can be a reflection of high-fat, low-fiber diet, and limited physical activity. Historically, research has reported the prevalence of colonic adenoma and colorectal cancer to be higher in blacks versus white populations. However, several recent studies have had conflicting results.[4][5] This entity also represents a lower prevalence in developing countries compared to North America, Australia, and Europe; however, its prevalence is on the increase in recent years worldwide due to the westernization of diet and lifestyle.[6]

Epidemiology

Colorectal cancer is the fourth most common cancer and the second leading cause of cancer-related death in the United States (US), representing a significant public health problem. Adenoma detection rate (ADR) evaluated by colonoscopy has been used to estimate colorectal cancer risk, which is defined as the percentage of patients aged above 50 years who undergo colonoscopy for colorectal cancer screening for the first time and have at least one detected adenoma. ADR is reportedly approximately 12% by the fifth decade of life, which increases to 50% throughout a lifetime. ADR is also profoundly different among populations, reaching about 22% in a large screening population. ADR is a vital risk estimation score and is inversely associated with the risk of cancer as each 1% increase in ADR corresponds to a 3% decrease in cancer risk.[7]

Pathophysiology

Adenocarcinoma Development

Adenoma-carcinoma sequence explains the molecular changes that lead to the formation of carcinoma from adenomas. More than 95% of colon adenocarcinomas arise from colonic polyps, while approximately 1.5% to 9.4% of adenomas turn to a malignant lesion within an interval of 8 to 10 years. The length of the adenoma-adenocarcinoma interval depends on the size of the adenoma, its morphological features, and the pathological type.[8][9] In patients with reported advanced adenoma, i.e., higher dysplasia grade and higher villosity in the first colonoscopy, the probability of advanced adenocarcinomas is higher later in life. Thus, they need more aggressive and frequent colonoscopic surveillance. In general, the size of adenoma correlates with both its histopathological type and degree of dysplasia. Tubular adenomas comprise smaller adenomas (less than 1 cm) mainly, in contrast to villous adenomas that tend to have a larger polyp size. The small tubular adenomas have a lower incidence of high-grade dysplasia.[10] Excluding the cases with a diagnosis of juvenile polyps, there are still reports of coexisting adenoma-adenocarcinomas in 2 to 15% of children and teenagers who had an initial diagnosis of polyp in colonoscopy.[11]

Adenoma-Carcinoma Transformation

Two main molecular pathways lead to adenocarcinoma of the colon. The chromosomal instability (CIN) pathway is the most attributed pathway and accounts for almost 80% of colorectal adenocarcinomas in the U.S. In this pathway, cancer develops within adenomas through a series of progressive mutations in several genes, including adenomatous polyposis coli (APC), K-ras, SMAD4, and p53, as follows: The first step in the adenoma-carcinoma sequence is sporadic or germline inactivation of the tumor suppressor gene, APC, that increases the likelihood of developing a polyp due to β-catenin accumulation, which can then translocate to the nucleus and drive cell proliferation. K-ras mutation occurs afterward and leads to the formation of the polyp. Inactivation of the other tumor suppressor gene, p53, and increased expression of COX allow for progression to carcinoma. Aspirin may play a role in this process by impeding the progression from adenoma to carcinoma, which leads to improved survival outcomes in colorectal cancer. Carcinomas that develop in this pathway exhibit CIN are microsatellite stable (MSS) and mismatch repair proficient (MMR-P). In the second pathway, called the serrated pathway, cancer develops through the malignant transformation of sessile serrated adenoma/polyp (SSA/P) precursor lesions. This pathway is not the focus of the present report.[10]

Histopathology

Colonic tubular adenomas characteristically demonstrate nuclear hyperchromatism (i.e., dark purple nuclei), nuclear crowding (i.e., nuclei are bunched-up), elliptical/cigar-shaped nuclei, and loss or reduction in the number of goblet cells. They may not show dysplasia at first but will gradually develop dysplastic features and may eventually transform into colorectal cancer.[3]

History and Physical

Adenomas are primarily located in the rectosigmoid region of the colon and might occasionally present in the proximal colon. Patients are commonly asymptomatic, and these growths are usually found on screening colonoscopies. If symptomatic, the most frequent symptom is hematochezia, i.e., painless bright or dark red blood per rectum on wiping or with bowel movements mixed with stools or dripping. Occasionally patients might have a history of alterations in bowel movements (either diarrhea or constipation), weight loss, loss of appetite, abdominal pain, symptoms of partial bowel occlusion, or iron deficiency anemia due to bleeding. A physical exam is usually non-contributory; however, clinicians may rarely find rectal polyps on the digital rectal exam.[1]

Evaluation

Based on the latest U.S. Preventive Services Task Force, the recommendation is to initiate the screening at age 50 in all individuals and continuing until age 75 years. For adults aged 76 to 85 years, the decision should be individualized, considering the patient’s overall health and screening history. Screening for polyps is usually performed by testing for fecal occult blood and the gold-standard colonoscopy. As mentioned earlier, polyps are mostly asymptomatic but can bleed. Colorectal polyps can be detected using a fecal occult blood test, digital rectal examination, flexible sigmoidoscopy, colonoscopy, virtual colonoscopy, barium enema, or a pill camera. Colonoscopy and the subsequent pathological examination are necessary for a definitive diagnosis of the type of the tumor. Apart from the screening, surveillance colonoscopy should continue for the previously detected polyps.[12]

If no polyps appear on the initial colonoscopic evaluation, the suggested follow-up colonoscopy is within ten years. Surveillance of previously detected polyps includes follow-up colonoscopy in three to five years based on the initial resected polyp size and microscopic dysplastic features. If the examiner detects more than ten adenomas or even an adenoma showed villous features, screening is recommended in less than three years, while for 3 to 10 adenomas, repeat screening should take place in 3 years. If only 1 to 2 small tubular adenomas are present, the interval can extend for 5 to 10 years.[13][14][15] Recent studies have revealed that despite these surveillance guidelines, adherence to follow-up evaluations is low, and more must be done to increase this value.[3]

There have been reports of up to 25% of missed adenomas during colonoscopy because of poor colon preparation and suboptimal visualization behind mucosal folds. Flat lesions on the right side of the colon can be particularly difficult to detect. Recent studies have aimed to detect more cases using accessory diagnostic devices (cap assistance, third eye retro-scope, endo-cuff) and by improving the endoscope design with a full spectrum endoscopy system, balloon-assisted colonoscopy, and confocal laser endo-microscopy.[16]

Treatment / Management

The goal is to remove the adenomatous polyps before progression to adenocarcinoma. Hyperplastic and adenomatous polyps cannot be differentiated without pathological evaluation. Thus all polyps are usually resected during colonoscopy and examined microscopically. Total colectomy is necessary if there is evidence of malignancy or lymph node metastasis.[13](B2)

Pseudopolyps, which harbor an intermediate risk of malignancy, might present with bleeding or cause additional complications such as obstruction. Although a broad spectrum of medical and surgical treatment approaches have gotten introduced, debate still exists about the treatment of choice.[17]

Treatment of familial juvenile polyposis is the surgical approach and depends in part on the degree of rectal involvement. If the rectum is relatively spared, total abdominal colectomy with ileorectal anastomosis may be performed with subsequent close surveillance of the retained rectum. If the rectum is carpeted with polyps, a total proctocolectomy is a more appropriate operation. These patients are candidates for ileal pouch-anal reconstruction to avoid a permanent stoma.[18]

There are three different main surgical approaches known for the definitive treatment of those affected with familial adenomatous polyposis: total colectomy plus ileorectal anastomosis, total proctocolectomy with ileostomy, and restorative proctocolectomy with or without mucosectomy and ileal-pouch anal anastomosis.[19]

Differential Diagnosis

1. Inflammatory polyps (pseudopolyps): There is a well-defined association between identifying pseudopolyps and the spectrum of inflammatory bowel disease. However, a variety of other infectious and non-infectious colitis, including amoebic, ischemic, and schistosomal colitis, might be attributed. The larger lesions with greater than 1.5 cm diameter, classifying as giant pseudopolyps, might present as an extensive polyposis syndrome.[17]
2. Familial juvenile polyposis is inherited via an autosomal dominant pattern. The colon and rectum are most commonly involved. Malignant degeneration through the adenoma and carcinoma transformation is possible. Due to the high malignant yield, annual screening should merit consideration from 10 to 12 years. Although it is an uncommon polyposis syndrome in adults, it has a remarkable significant percentage of polyposis syndrome in the pediatric population.[18]
3. Hyperplastic polyps: The colon is most commonly affected by hyperplastic polyps. Although the hyperplastic polyps do not classify as premalignant lesions, due to the similarities with adenomatous polyps in colonoscopy, once diagnosed, they require removal. They may occur as a polyposis syndrome with multiple or giant polyps harboring the significantly increased risk of malignancy.[20]
4. Familial polyposis coli: Familial adenomatous polyposis (FAP) or familial polyposis coli is considered one of the rare causes of colorectal adenocarcinomas. Specific mutation of APC and positive family history are evident in the majority of patients. There is already an extremely significant value of timely screening and surveillance in positive family and personal history of FAP, respectively. Among those affected with FAP, the risk of colorectal cancer goes way up to 100% by the age of 50.[21]
5. Turcot syndrome: Familial colorectal adenocarcinomas, including FAP and HNPCC, may accompany with variety of central nervous system tumors known as Turcot syndrome. Moreover, Turcot syndrome categorizes according to the type of CNS tumor and number of colonic polyps in a couple of subgroups; type I, attributes to the glial tumors and a small number of colonic polyps, while a significant number of polyps and greater risk of medulloblastoma have been well-documented in type II.[22]
6. Cowden syndrome and PTEN hamartoma: PTEN acts as a tumor suppressor gene. Cowden syndrome, as an autosomal dominant syndrome and related to PTEN hamartoma tumor syndrome (PHTS), has a broad range of clinical manifestations, including trichilemmomas in the face, malignant pathologies in the breast, thyroid, and gastrointestinal polyps. Obtaining timely screening schedules to exclude malignancies in these patients is crucial. Traditionally, there was a remarkable 80% germline PTEN mutation in patients affected by Cowden syndrome; however, recently, the specificity of these criteria has been questioned.[23]
7. Peutz-Jeghers syndrome: Peutz-Jeghers syndrome, or mucocutaneous pigmentation and polyposis syndrome, is classified as an autosomal dominant hamartomatous polyposis. Although evidence of the remarkable malignant potential is lacking, stepwise screening plans are generally the recommended approach to evaluate not only the GI tract but also other possible sites for malignancies, including breast, upper gastrointestinal tract, pancreas, cervix, ovaries, and testicles.[24]
8. Cronkite-Canada syndrome: Cronkite-Canada syndrome is a rare non-inherited disorder in which patients develop gastrointestinal polyposis in correlation with alopecia, cutaneous pigmentation, and fingernail/toenail atrophy. Diarrhea is a prominent symptom, and malabsorption, vomiting, and protein-losing enteropathy may occur. Most patients die of this disease despite maximal medical therapy, and surgery is only for complications of polyposis such as obstruction. Cowden syndrome is an autosomal dominant disorder with hamartomas of all three of the embryonal cell layers. Facial trichilemmomas, breast cancer, thyroid disease, and gastrointestinal polyps are typical of the syndrome. Patients should have screening for cancers.[25]
9. Attenuated familial adenomatous polyposis (AFAP) is a recognized variant of FAP. Patients present later in life with fewer polyps (usually 10 to 100) predominantly located in the right colon compared to classic FAP. Colorectal carcinoma develops in more than 50% of these patients but occurs later (average age, 55 years). Patients are also at risk for duodenal polyposis. However, in contrast to FAP, APC gene mutations are present in only about 30% of patients with AFAP. When present, these mutations express in an autosomal dominant pattern. Mutations in MYH, a gene involved in the repair of DNA, also result in the AFAP phenotype but are expressed in an autosomal recessive pattern.[26]
10. Serrated polyps, including sessile serrated adenomas and traditional serrated adenomas, are a recently recognized, histologically distinct group of neoplastic polyps. Endoscopically they are flat lesions and frequently difficult to visualize. These lesions were long thought to be similar to hyperplastic polyps with minimal malignant potential. However, it has become clear that some of these polyps will develop into invasive cancers. Additionally, research has described a familial serrated polyposis syndrome.[27]

Complications

Several complications have been reported after colonoscopy and polypectomy, including but not limited to: perforation, post-polypectomy syndrome, and bleeding. The overall complication rate after colonoscopy for adenomas and cancer is below 4%.[28][29]