Adenocarcinomas

Adenocarcinomas are the most common malignant tumors in the small bowel, accounting for approximately 30–50% of all malignant small bowel tumors.^{30, 31} They most commonly arise in the seventh decade of life and are seen slightly more often in men than in women.³² Cohort studies suggest that increased body mass index and alcohol use may increase risk of small bowel cancer.³³ While primary tumors arise most often in the duodenum (48–52%) and jejunum (23–25%) and less commonly in the ileum (13–16%), the reason for this distribution is unclear.^{34, 35} Some have postulated that the richness of IgA-secreting cells in the ileum accounts for its relative sparing from adenocarcinoma by neutralizing luminal carcinogens.⁴ Others have noted that the abundance of the enzyme benzopyrene hydroxylase may play a protective role by detoxifying potential carcinogens.³⁶ Adenocarcinoma is staged using the American Joint Committee on Cancer (AJCC) TNM system, and as expected small bowel carcinomas that are well differentiated with only local invasion and no lymph node metastasis tend to have the best prognosis. Unfortunately, little progress has been made in the treatment of small bowel adenocarcinoma. There have been improvements in diagnostic modalities and insights into the molecular basis, but the prognosis is still generally poor.

The histogenesis of small bowel adenocarcinoma most likely follows the adenoma–carcinoma sequence described initially for large bowel cancer.³⁷ As a result, the single most important risk factor for small bowel adenocarcinoma is preexisting adenoma, either single or multiple, as associated with multiple polyposis syndromes.³⁸ Small bowel adenocarcinomas have also been associated with alcohol (but not tobacco), nontropical sprue, regional enteritis, celiac disease, and urinary diversion procedures such as ileal conduit.^39–43

Familial adenomatous polyposis (FAP) is known to be a powerful risk factor for adenocarcinoma, with small bowel cancer being the most common cancer after colon cancer itself.⁴⁴ The relative risk (RR) of small bowel carcinoma in these patients has been described as being greater than 100.⁴⁵ Other hereditary syndromes associated with small bowel tumors include Peutz–Jeghers (PJ) syndrome (increased incidence of hamartomatous polyps in the jejunum and ileum), Gardner syndrome (adenoma and adenocarcinoma), and von Recklinghausen disease (paraganglioma). Small bowel inflammatory disorders are associated with increased malignancy, including, most notably, Crohn’s disease.⁴⁶ Crohn’s disease is a risk factor for future small bowel adenocarcinoma. An RR of 33 (95% CI: 15.9–60.9) was reported in a 2006 meta-analysis.⁴⁷ As with ulcerative colitis (UC) and tumors of the colon, the diagnosis of Crohn’s disease precedes small bowel tumors by about 10 years. Several risk factors have been identified in patients with Crohn’s disease who develop adenocarcinoma of the small bowel: duration of Crohn’s disease, male gender, fistulization, presence of strictures, and surgical creation of blind excluded loops of intestines.^{48, 49} Other disorders associated with increased risk of malignancy are celiac disease (lymphoma and adenocarcinoma) and immunoproliferative disease (diffuse intestinal lymphoma and immunoproliferative small intestinal disease.⁵

Celiac sprue, while well known to predispose to intestinal lymphoma, is also associated with adenocarcinoma of the small bowel.⁴⁰ The numbers cited in case reports are few, but the presence of disease in otherwise noncharacteristic locations seems to lend credence to the theory that gluten-mediated jejunoileitis is also an independent risk factor for the development of adenocarcinoma of the small bowel as well as lymphomas.³¹ Adenocarcinoma of the small intestine, often aggressive, can affect children and is usually associated with degeneration of a PJ hamartoma.³⁸

The genetic mechanisms involved in the carcinogenesis of the small bowel remain unknown, most likely because of the small number of cases. Blaker and colleagues from Germany showed that although small intestinal carcinomas reveal complex genetic changes, a significant number of tumors share karyotypic instability and losses of chromosome 18q21-q22. 18q deletions often target the SMAD4 gene and disrupt tumor suppression through TGFβ-signaling.⁵⁰ Svrcek and colleagues, using tissue microarray analysis, determined that inactivation of the SMAD4/DPC4 gene is involved in small intestinal adenocarcinoma tumorigenesis and that overexpression of TP53 and abnormal expression of β-catenin are two common events in small intestinal adenocarcinoma.⁵¹ Other pathways include Notch3 signaling associated with MUC5AC expression.⁵² There is also recent evidence suggesting DNA mismatch repair genes are involved; the frequency of the dMMR phenotype is variable, ranging from 5% to 35% of cases.⁵³

Symptoms of adenocarcinoma of the small bowel range from obstructive symptoms, such as vomiting and jaundice for those with duodenal tumors, to indistinct abdominal pain, weight loss, and anemia for more distal lesions. Weight loss is also common, occurring in more than 50% of patients. Obstruction is found in 40% to 70% of patients prior to presentation. In the collected Mayo series, 71% of patients had either overt or clinical evidence of blood loss.⁵⁴ Adenocarcinomas, especially duodenal tumors, usually become symptomatic earlier than other small bowel tumors, allowing for earlier diagnosis and intervention. Despite this, 30–35% of small bowel adenocarcinomas are metastatic at the time of diagnosis.^{34, 35}

In a recent study conducted by the American College of Surgeons on 5000 small bowel adenocarcinomas, the overall 5-year disease-free survival (DFS) was 30.5%.⁵⁵ The median survival in this series was 19.7 months. The primary treatment of adenocarcinomas is wide surgical resection, with removal of lymph nodes and the vascular pedicle. Margins of 5 cm are considered acceptable. Recent reports indicate that even this treatment does not yield good survival rates for node-positive patients. In a recent study examining 217 patients with small bowel adenocarcinoma followed over a 10-year period at MD Anderson Cancer Center, patients with stage IV disease had a shorter 5-year overall survival (OS) than those with I–III disease (5% vs 36%).³⁵ The 5-year survival was significantly shorter if the positive lymph node ratio (number of positive lymph nodes/number of total lymph nodes) was greater than 75% versus <75% (12% vs 51%).

All attempts should be made to resect the primary lesion to prevent mucosal bleeding. For patients deemed unresectable at the time of laparotomy, some have advocated the use of intraoperative radiation therapy.^56–58 The lack of clinical trials makes this therapy difficult to recommend in a setting other than specialized centers. Data regarding the role of adjuvant chemotherapy are limited, with no evidence of significant benefit in survival in patients with adenocarcinoma of the small intestine treated with adjuvant chemotherapy. An attempted Cochrane review in 2007 failed to find any studies eligible for meta-analysis.⁵⁹ Despite this, adjuvant chemotherapy is frequently used because small bowel cancer tends to recur systemically, similar to CRC, and because colon cancers respond to adjuvant therapy. A 2009 retrospective multicenter study suggested that an adjuvant folinic acid, 5-FU, and oxaliplatin (FOLFOX) regimen prolonged OS by around 5 months compared to patients treated with other regimens, but the findings of this small study were not statistically significant.⁵³ For advanced unresectable disease, a recent phase II study of modified FOLFOX as first-line chemotherapy in advanced small bowel adenocarcinoma reported an objective response rate of 48.5% [95% confidence interval (95% CI): 31–67%], with one complete response in patients with advanced small bowel adenocarcinomas.⁶⁰

Carcinoid tumors

Carcinoid tumors represent approximately 25–30% of malignant tumors of the small bowel.^{58, 61} Obendorfer used the term “karzinoide” in 1907, but the exact nature of the tumor was not determined until 1928 when Masson described its origin as the chromaffin cell.^{62, 63} The frequency of carcinoid in large autopsy series, before the era of increased detection by CT and endoscopy, indicated that about 85% were undiagnosed during life.⁶⁴ US data show that the incidence of GI carcinoid has increased at a rate of 3%–10% per year over the past three decades.^{64, 65} The most frequent sites for carcinoids were the GI tract (54.5%) and the bronchopulmonary system (30.1%). Within the GI tract, most occurred in the small bowel (44.7%), rectum (19.6%), and appendix (16.7%). In contradistinction to adenocarcinoma, the carcinoid tends to arise in the distal small intestine rather than in more proximal sites. In the series reported by Moertel, all surgically confirmed, 3% were in the duodenum, 5% in the jejunum, 32% in the proximal ileum, and 60% in the distal ileum.⁶⁶ The median age at discovery is 60.9 years, and females constitute 54.2% of patients.⁶⁷ The overall 5-year survival rate for patients with GI carcinoid is about 58%, with little change over the past 30 years.⁶⁴ However, in the subgroup of patients with well-differentiated carcinoid with distant spread, the 5-year survival rate has improved from 15% to 52% over this time period.⁶⁴

The most useful marker of neuroendocrine cells in tissue sections is chromogranin A (CgA), a glycoprotein stored in secretory granules of neuroendocrine cells. Plasma CgA levels correlate with tumor burden and may be useful for monitoring treatment.⁶⁸ Twenty-four-hour measurement of urinary 5-hydroxyindole-3-acetic acid (5-HIAA), the degradation product of serotonin, can also aid in diagnosis. The specificity of 5-HIAA as a marker for these carcinoids is 88%, although tryptophan/serotonin-rich foods (bananas, avocados, plums, eggplants, tomatoes, plantains, pineapples, and walnuts) can provide false elevations, and several drugs can result in increased or decreased 5-HIAA levels.⁶⁹ Higher concentrations of 5-HIAA in urine are consistent with a worse prognosis, while persistently low levels predict a more favorable outcome in disseminated disease.⁶⁸ Mitotic count and Ki-67 index [a marker of cell proliferation] provide some indication of prognosis.⁶⁸

A unique feature of carcinoid tumors is their ability to produce a variety of protein and peptide products, the most characteristic of which is serotonin. Systemic serotonin is thought to cause most of the symptoms of the carcinoid syndrome, including diarrhea, flushing, wheezing, and right-sided heart disease. Carcinoid syndrome is seen in 5–7% of patients with large tumor burdens and metastatic disease.⁵⁴ It is believed that the metastatic component is necessary to ensure drainage of the compounds involved in the syndrome into the systemic circulation and to provide an adequate tumor mass to produce large amounts of peptidergic products.

The clinical manifestations of carcinoid are often vague or absent, and the definitive diagnosis is often not made prior to surgery. Patients with small intestine carcinoid often present at a late stage, and the prognosis is poor once tumors have spread beyond the intestine. In a series of 145 patients with GI carcinoid tumors, only 12 had a proper diagnosis before surgery, and those 12 had definite symptoms of carcinoid syndrome.^{54, 70} Most often, patients are operated on for signs of bowel obstruction, not by the tumor itself but by a desmoplastic reaction that leads to shrinking of the mesentery as a result of fibrosis and kinking of the bowel.⁷¹ Scintigraphy with radiolabeled octreotide has been successfully used to localize undetected primary and metastatic lesions.⁷² Two large European studies show carcinoid lesion detection with a sensitivity of 89% by using this diagnostic tool.⁷³

The metastatic potential of a carcinoid tumor correlates closely with its size. In the Moertel series, there were no metastases in tumors <0.5 cm in diameter, 15% in tumors 0.5 to 0.9 cm in diameter, 72% in tumors 1.0 to 1.9 cm in diameter, and 95% metastases in tumors larger than 2 cm.⁶⁶ However, small bowel carcinoids may still metastasize when <1 cm. Recent evidence based on 5-HIAA levels suggests that most cases of metastatic carcinoid of unknown primary probably arise from small ileal tumors.^{74, 75} Extent of disease, which mainly comprises either lymph node (regional) or liver (metastatic) involvement, is a definite predictor of outcome. In Maggard’s analysis of 11,427 carcinoids, 5-year survival for localized, regional, and distant disease of the small intestine was 70.4%, 64.1%, and 32.4%, respectively.⁶⁵

Primary surgical resection of the tumor and regional lymph nodes is the only curative treatment for GI NETs; this is usually possible in about 20% of patients. Surgery remains the only approach that allows definitive histopathologic staging, resection of occult lymph node metastasis, and prevention of local complications caused by a desmoplastic resection.⁷⁶ Referral for surgical management should not be influenced by the inability to localize the primary tumor. As midgut tumors are difficult to localize on imaging, one study found the primary tumor could be identified intraoperatively in a majority of patients with metastatic NETs, irrespective of preoperative localization status.⁷⁷ Careful intraoperative examination is mandatory, because most series report that 30% of these tumors are multicentric.⁶⁶ Primary duodenal carcinoids account for only 2.6% of carcinoid tumors in the United States; although they are increasingly recognized with the more widespread use of upper GI endoscopy.⁷⁸ Because of the rarity of this disease, management recommendations for duodenal carcinoids have been extrapolated from the experience with midgut and hindgut carcinoids. A recent study by Mullen and colleagues however demonstrated successful margin negative endoscopic resection in six patients with tumors <1.5 cm.⁷⁸ Interestingly, this study found lymph node metastases to be present in 54% of patients with duodenal carcinoid, including two patients with tumors smaller than 1 cm and limited to the submucosa. The impact of lymph node metastasis in duodenal carcinoids is uncertain, however, in that no patient developed distant metastases or carcinoid syndrome in this series. In the case of advanced disease, there may be some benefit to debulking procedures, but this remains controversial, because the absolute size of the tumor does not correspond well with the degree of symptoms.^{54, 79, 80} Some authors recommend aggressive treatment even in patients with widely metastatic disease, including resection of all intra-abdominal tumor deposits, segmental liver resection as needed, and hepatic arterial embolization. Cholecystectomy also has been performed to prevent gallbladder necrosis during hepatic embolization. Although it has not been proven whether this aggressive surgical approach increases survival, it has yielded biochemical remission in up to 25% of patients and regression of hepatic metastases for long periods.^{69, 81} In the MD Anderson experience of 81 patients with carcinoid disease metastatic to the liver who underwent hepatic artery embolization or chemoembolization, 67% experienced a partial response with a mean duration of response of 17 months. Overall, 63% of patients had reduction in their tumor-related symptoms and the OS time was 31 months.⁸² Importantly, many patients diagnosed with carcinoid have other malignancies. Using the surveillance, epidemiology, and end results (SEER) database to identify patients diagnosed with small intestine carcinoids between 1973 and 2007, almost one-third of patients with small bowel carcinoid had an associated metachronous primary tumor. The most common sites were prostate (26.2%), breast (14.3%), colon (9.1%), lung/bronchus (6.3%), and bladder (5.3%).⁸³

Medical therapy in the form of somatostatin analogues is effective in relieving symptoms of the carcinoid syndrome, though demonstrated tumor regression is rare. Octreotide is an eight amino acid, long-acting somatostatin analogue that binds to receptor subtypes 2, 3, and 5 and has been widely used for both detection and treatment of carcinoid tumors.⁸⁴ The currently available SSAs—Sandostatin LAR (octreotide; Novartis) and Somatuline Autogel (lanreotide; Ipsen)—display high-affinity binding for receptor subtypes 2 and 5, low affinity for subtypes 1 and 4, and medium affinity for subtype 3. SOM230 (pasireotide; Novartis), a more recently developed SSA, now in phase III trials, has a wider range of activity against somatostatin receptors and may offer a therapeutic advantage, especially in resistant disease.⁸⁵ In one study, octreotide was delivered subcutaneously at a dosage of 150 µg three times a day, showing improved symptoms in 88% of patients and decreased urinary 5-HIAA in 72% of patients.⁸⁶ Advances in the understanding of the mechanisms underlying tumor progression have led to the identification of several potential therapeutic targets (including the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) signaling pathways). In a randomized phase 3 trial of everolimus plus octreotide LAR compared with placebo plus octreotide LAR improved progression-free survival in patients with advanced neuroendocrine tumors. However, progression-free survival was still poor at 16.4 (95% CI 13.7–21.2) months in the everolimus plus octreotide LAR group and 11.3 (8.4–14.6) months in the placebo plus octreotide LAR group.⁸⁷ Several other agents are being studied, including the use of novel SSTa, VEGF and mTOR inhibitors, and agents that interfere with insulin growth factor 1 receptor and AKT signaling. Another treatment modality is peptide receptor radionuclide therapy. Peptide receptor radionuclide therapy delivers tumoricidal doses of radiation to carcinoid cells highly selectively, with few adverse effects (nausea and occasional bone marrow and renal toxicity). By linking a radioactive isotope (111Indium, 90Yttrium, or 177Lutetium) to a somatostatin analogue, carcinoid cells, with their often high density of somatostatin receptors, may be specifically targeted. Tumor regression rates of up to 50%, with a disease-free response approaching 3 years, have been reported in some studies.⁸⁸

Prognosis of patients with carcinoid disease varies according to several factors. Size of the primary tumor is an important predictor of metastasis and survival. Carcinoid tumors >2 cm in diameter portend a worse prognosis than those <2 cm.⁸⁹ In a recent series of 603 patients, lymph node metastasis was also not surprisingly prognostic.⁹⁰ In the Maggard series, increased tumor size was associated with a greater likelihood of lymph node involvement.⁶⁷ In the carcinoid series at Duke University, a direct correlation was found between size of the primary tumor and extent of disease at presentation.⁹¹ In addition, after controlling for stage of disease, region of origin of primary tumor predicted prognosis in this series of patients. In patients with distant metastases at presentation, those with midgut tumors had markedly better prognosis than did patients with foregut or hindgut tumors. In addition to traditional pathologic determinants, expression of cocaine- and amphetamine-regulated transcript (CART) in small bowel carcinoid tumors is associated with worse survival.⁹²

Composite tumors, those that display characteristics of both carcinoid tumors and adenocarcinomas, are well described in the appendix but are less well known in the small intestine. These tumors are relatively rare, with most reports to date encompassing only one or two cases. They are aggressive tumors with a metastatic potential similar to that of adenocarcinoma and should be treated as adenocarcinomas. Lymphatic metastasis appeared histologically to be adenocarcinoma in two cases and carcinoid in one; thus, it seems that these tumors may arise from cells with pluripotential patterns of differentiation.⁹³

Gastrointestinal stromal tumors

Gastrointestinal stromal tumor (GIST) is the current nomenclature for a diverse group of benign or malignant GI neoplasms derived from embryonic mesoderm. There are three histologic subtypes of GIST. The spindle cell form is the most common (70%) and consists of uniform, intersecting fascicles with eosinophilic cytoplasm. The epithelioid (20%) and the rare mixed type (10%) forms show more rounded cells with nuclear atypia.⁹⁴ Malignant GISTs constitute 15–20% of the malignant tumors found in the small bowel.⁹⁵ The annual incidence in the United States is reported to be approximately 5000 cases per year which seems to be rising due to increased awareness and histopathologic diagnosis.^{96, 97} GISTs affect men and women equally.⁹⁸ Most patients diagnosed with GIST are between 40–80 years old with a median age at diagnosis of 60.⁹⁹ The most commonly encountered GIST is the sporadic form. Familial GISTs occur and result from a germline mutation in either the KIT or platelet-derived growth factor receptor alpha (PDGFRα) proto-oncogenes.^{100, 101} The cellular origin of GIST is proposed to be the interstitial cell of Cajal, an intestinal pacemaker cell.⁹⁵ GISTs are characterized by mutations in the proto-oncogene C-kit that lead to constitutive activation of its glycoprotein product KIT and the subsequent tyrosine kinase activity.¹⁰² The tyrosine kinase inhibitor, imatinib, has revolutionized the treatment of GIST tumors. More than 95% of GISTs express KIT and biochemical evidence of KIT can be found in almost all GISTs.¹⁰³ The most common sites of KIT mutation include exon 11 (70%) and exon 9 (10%) although other regions have been described.^{104, 105} Other commonly expressed markers include CD34 (70%), smooth muscle actin (30%), and desmin (<5%).¹⁰⁶ Because other malignancies can stain positive for KIT include metastatic melanoma, angiosarcoma, and Ewing’s sarcoma, IHC alone is not sufficient for diagnosis.⁹⁴ The diagnosis of GIST is based on both morphology and IHC. GIST can also occur in patients with neurofibromatosis type-1 (NF1) and in young women as part of a syndrome that includes, paragangliomas, pulmonary chondromas, and gastric GISTs.^{107, 108}

GISTs can occur anywhere in the GI tract from the esophagus to the rectum. Stomach represents the most common site (60%), followed by the small bowel (30%), rectum (∼5%), and esophagus (∼5%).⁹⁹ Up to 50% of patients will present with metastatic disease at the time of diagnosis, with the liver and peritoneum being the two most common sites.¹⁰⁹ Most GISTs present as an abdominal mass causing bowel obstruction evidenced as nausea, vomiting and abdominal pain, or as GI bleeding. GISTs usually grow rapidly, with masses 5 cm in diameter or greater being common.¹¹⁰ This rapid rate of growth explains the propensity for GI blood loss, because these tumors may outgrow their blood supply, become necrotic, and ulcerate. Blood loss is usually chronic, with laboratory studies revealing a microcytic anemia.¹¹⁰ Fistulas and abscesses are also caused by tumor necrosis. The primary mode of diagnosis and assessment of extent of disease is by contrast-enhanced CT scan of the abdomen and pelvis. Characteristic findings on CT scan include an enhancing, exophytic mass in close association with the stomach or bowel wall. Like other sarcomas, GISTs tend to displace rather than invade adjacent structures. While positron emission tomography (PET) is not used to diagnose GIST, it can be used to assess the response to tyrosine kinase therapy. GIST appears as a submucosal mass on endoscopic evaluation. Endoscopic or percutaneous biopsy is recommended in cases in which neoadjuvant therapy is planned or metastasis is suspected.¹¹¹

The primary treatment of GIST is surgical resection with wide margins. However, there is current debate about the management of tumors <2 cm. Current National Comprehensive Cancer Network (NCCN) guidelines for the management of gastric GISTs <2 cm without high-risk features on EUS include surveillance endoscopy every 6–12 months.¹¹² For tumors >2 cm, surgical resection included en bloc resection when other organs are involved is advocated. Because lymph node involvement is not common, extensive lymphadenectomy appears to provide no added survival benefit. The role of laparoscopy in the management of patients with GIST continues to expand. Those undergoing laparoscopic resection of GIST up to 8 cm at MSKCC had equivalent perioperative and oncologic outcomes when compared with case-matched controls undergoing open resection.¹¹³ With a median follow-up of 34 months, oncologic outcomes were similar with no positive microscopic margins and one recurrence in each group. Bischof et al. also reported that a minimally invasive approach for gastric GIST was associated with low morbidity, and a high rate of R0 resection, based on their review of nearly 400 patients undergoing surgical resection for GIST.¹¹⁴ Periampullary GIST tumors of the duodenum represent a more challenging surgical approach. A meta-analysis demonstrated that local resection should be the procedure of choice for duodenal GIST whenever technically feasible, because it is associated with good oncologic outcomes and lower morbidity compared with pancreaticoduodenectomy (PD). The use of imatinib in patients with duodenal GIST may potentially allow a proportion of patients who would otherwise require a PD to undergo local resection instead.¹¹⁵

Even after surgical resection, may tumors recur. One study analyzing 200 cases of GIST over a 16-year period found that in patients with primary disease who underwent complete resection of gross disease, the 5-year actuarial survival rate was 54%.⁹⁹ Even with complete surgical resection, the majority of tumors recurred, often involving the liver and peritoneal surface. In the largest series of GIST recurrences, the group from Memorial Sloan Kettering Cancer Center retrospectively analyzed 69 such patients.⁹⁹ Local recurrence was seen in 76% of patients, of which half had synchronous liver lesions. Surgical resection for recurrent disease was completed in one-third of cases with median survival of 15 months. The advent of tyrosine kinase inhibitors has revolutionized treatment of GIST. Although the mechanism of tumor response was believed to be predominantly inhibition of KIT-driven cells, recent data suggest the immune system contributes substantially to the antitumor effect. Imatinib therapy was shown to induce regulatory T cell apoptosis within the tumor by reducing tumor cell expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase.¹¹⁶ This data is critical to devising future treatment strategies that may involve immune modulators to increase response.

Due to high recurrence rates, adjuvant imatinib has been explored in several trials. There have been two American College of Surgeons Oncology Group (ACOSOG) trials looking at the role of adjuvant imatinib mesylate after resection for those patients at intermediate or high risk of recurrence. ACOSOG Z9000 was the first phase II trial studying the efficacy of adjuvant imatinib following complete resection of GIST at high risk of recurrence.¹¹⁷ Patients underwent complete gross resection of a KIT-expressing primary GIST that was at high risk of recurrence (tumor size >10 cm, tumor rupture, or <5 peritoneal metastases). Following resection, patients received oral imatinib 400 mg/day for 1 year. At a median follow-up of 4 years, the 1-, 2-, and 3-year OS rates were 99%, 97%, and 97%, respectively. The 1, 2, and 3-year recurrence-free survival rates were 94%, 73%, and 61%, respectively. These results compared favorably with historical controls for both recurrence-free survival and OS. ACOSOG Z79001 was a follow-up phase III trial in which patients were randomized to 1 year of oral imatinib or placebo following resection.¹¹⁸ Imatinib taken once a day for 1 year following surgery for localized, primary GIST (≥3 cm) was compared with placebo in 713 patients. Recurrence-free survival was significantly higher in the imatinib arm (98%) when compared with the control group (83%) while there was no difference in OS. Subsequently, disease survival was found to be longer with 3 years versus 1 year of adjuvant imatinib.¹¹⁹ However, only a few percent of low-risk patients developed recurrence, and more than 70% of patients appeared to be cured by surgery alone based on recurrence-free survival in the placebo arm. Thus, the value of adjuvant imatinib in patients with resected primary GIST 3 cm should be considered carefully. Risk stratification systems can be used to identify patients who have a low likelihood of recurrence in whom adjuvant therapy is not indicated; risk stratification can also identify patients who should get therapy.¹²⁰ For example, patients with KIT exon 11 deletions assigned to 1 year of adjuvant imatinib had a longer regression-free survival.¹²¹ Furthermore, specific mutations have been found to be resistant to imatinib; patients with PDGFRA D842V mutations do not respond to imatinib. Another risk stratification score showed that patients with nongastric GIST with a high mitotic count are at a particularly high risk for recurrence.¹²¹

The future focus of research for the use of adjuvant imatinib is which patients should be treated and what is the optimal duration.¹²² The PERSIST5 trial is an ongoing phase II trial testing 5 years of adjuvant imatinib therapy in patients at moderate to high risk of recurrence (NCT00867113). Expert opinion suggests that currently mutation testing of the tumor should be performed to exclude patients with a PDGFRA D842V mutation or wild-type tumor. In the remaining patients, a discussion should ensue about the goals and current results of adjuvant therapy.¹²³

The role of neoadjuvant imatinib in the setting of locally advanced disease has been investigated. Neoadjuvant imatinib mesylate holds much promise because it can lead to marked shrinkage in tumor size, which can frequently be predicted within 2 to 4 weeks of initiating therapy using PET scans. The cytoreductive potential of imatinib in the preoperative setting may enable surgeons to obtain R0 resections with less extensive resections. This is most applicable to GIST tumors near the gastroesophageal junction, ampulla, and in the rectum. Recent results from a phase II trial led by the Radiation Therapy Oncology Group (RTOG) revealed that imatinib is well tolerated in the neoadjuvant setting.¹²⁴ The groups were divided into whether disease was locally advanced and >5 cm (Group A) or recurrent/metastatic and >2 cm (Group B). Imatinib administered at 600 mg per day for 8 weeks preoperatively was followed by surgery and an additional 2 years of imatinib. Response rates after 8 weeks of preoperative imatinib were similar between groups A and B (4–7% partial response, 83–90% stable disease, and 4–5% progressive disease).¹²⁴ Another phase II trial from MD Anderson Cancer Center investigated either 3, 5, or 7 days of neoadjuvant imatinib in 19 patients.¹²⁵ This regimen was tolerated well and response rates by FDG-PET were 69%. The duration of neoadjuvant therapy and patient selection remain to be defined. Current NCCN guidelines suggest that in patients on neoadjuvant imatinib, once two successive CT scans fail to show any radiographic response, surgical resection should be considered.¹¹²

In the metastatic setting, there is strong evidence of the effectiveness of imatinib mesylate. Up to 80% of patients with metastatic GIST attain a partial or complete response with imatinib.¹¹⁸ A recent meta-analysis of two, large, randomized studies^{126, 127} comparing the efficacy of imatinib given either once (400 mg) or twice daily revealed that the higher dose confers a progression-free survival advantage among patients with exon 9 mutations.¹²⁸ The second-line agent for patients with imatinib-resistant disease is sunitinib.¹²⁹ Sunitinib targets KIT and PDGFRα, as well as the vascular endothelial cell growth factor receptor (VEGFR). In patients with advanced disease resistant to imatinib, sunitinib is a safe and effective second-line agent.¹³⁰ Molecular studies suggest that imatinib is most effective in patients with exon 11 C-kit tyrosine kinase mutations, and sunitinib may be more effective in patients with exon 9 mutations.¹²⁸ Other studies have recently been completed examining third-line agents. Regorafenib was shown to significantly improve progression-free survival compared with placebo in patients with metastatic GIST after progression on standard treatments.¹³¹ Although a relatively rare clinical entity, the treatment of GIST is continually evolving and represents an area of active developments.

Lymphoma

Lymphoma accounts for 15–20% of all malignant small bowel tumors.¹³² The stomach is the most common site of GI lymphoma (>60%), followed by an equal distribution between the large and small intestines.¹³³ There is a slight male predominance of approximately 1.5 : 1, and the median age is lower than that of persons with other small bowel tumors (49 years in one large series).^{134, 135} Lymphomas are the most frequent malignant neoplasms in transplant recipients, appearing on average 20 months after the initiation of cyclosporine.¹³⁵ Prognosis is better than for other forms of intestinal lymphomas with two-thirds cured with resection, radiotherapy, acyclovir, and reduction of immunosuppression.^{136, 137} Small bowel lymphomas also occur in AIDS. Virtually all lesions are B lymphocyte in origin. The prognosis is poor but is dominated by the HIV-related disease such that life expectancy for these patients is not significantly inferior to similar HIV-positive patients without lymphoma.¹³⁶

The clinical presentation of GI lymphoma includes abdominal pain, nausea, vomiting, fatigue, weight loss, and GI bleeding, which may be occult. A mass with bulky adenopathy on CT scan is highly suggestive of abdominal lymphoma.¹³⁸ Multiple staging systems have been proposed for GI lymphomas, including the Ann Arbor, Musshoff, and the European–American classification system. Each of these major staging systems recognizes four major stages of small bowel lymphoma: stage I for local disease, stage II for regional involvement, and stages III and IV for advanced disease with metastasis. Imaging is also now included in some staging systems after the 11th International Conference on Malignant Lymphomas (ICML) in 2011.¹³⁹

Resection of small bowel lymphoma is important for local control but rarely eradicates the disease. Disease is often advanced so that fewer than 30% of intestinal tumors are amenable to primary curative resection.¹⁴⁰ Adjuvant therapy is an essential part of the treatment. Surgical resection should be attempted for localized disease and should involve removal of the bowel segments, with wide margins, and the involved mesenteric lymph nodes, if possible. Margins need to be completely clear of tumor since lymphomas may spread for long distances in the submucosal plane. Adjuvant chemotherapy in patients after potential curative resection is advocated.¹⁴¹ In patients with unresectable lymphoma, radiation therapy and chemotherapy are recommended.¹⁴² Additionally, rituximab, the chimeric monoclonal antibody against the protein CD20, has also shown some promise in B cell lymphomas.¹⁴³

Forty years ago, an unusual immunoproliferative small intestinal disease was reported to be particularly common in the Middle East, especially in southern Iran. This Mediterranean lymphoma is found in children and young adults and carried a poop prognosis.¹⁴⁴ Patients tend to be from lower socioeconomic groups with a background of malnutrition. The tumor progenitor cell is believed to be the perifollicular B cell, which produces IgA. The tumor releases an excess of alpha heavy chains, which are detectable in the serum.¹⁴⁵ However, recent epidemiologic reports from southern Iran suggest that distribution of NHL in the GI tract is similar to Western countries.¹⁴⁶

Metastatic neoplasms

Metastatic neoplasm involvement of the small bowel is more frequent than primary small intestinal neoplasia. Primary tumors of the colon, ovary, uterus, and stomach involve the small bowel, most often by direct invasion or peritoneal spread. Primaries from the breast, lung, and melanoma metastasize to the small intestine hematogenously. A large review of autopsies from Memorial Sloan Kettering Cancer Center previously found the incidence of GI metastases from metastatic melanoma was 58% small bowel.¹⁴⁷ Within the GI tract, the small bowel is the most frequent site of metastasis of melanoma most likely because of its rich blood supply. A retrospective study of 103 cases of malignant melanoma performed by the Armed Forces Institute of Pathology stated that small bowel involvement by melanoma, even in the absence of a known primary, is usually metastatic.¹⁴⁸ If possible, surgery to remove disease should be offered. Ollila et al. reported on a retrospective review of 124 of 6509 melanoma patients who had GI tract metastases at the John Wayne Cancer Institute from 1971 through 1994.¹⁴⁹ Of these 124 patients, 69 (56%) underwent surgical exploration of the abdomen, of which 46 (67%) had curative resection and 23 (33%) had a palliative procedure only. Almost all (97%) of the 69 surgical patients experienced symptomatic relief postoperatively. The median survival of patients undergoing curative resection was 48.9 months compared with only 5.4 months in patients undergoing palliative procedures and 5.7 months in patients undergoing nonsurgical interventions. Metastatic lesions to the small bowel can be treated with resection in selected cases and/or tumor-specific systemic therapy.

Age and racial background

Age is a known risk factor for CRC. The vast majority of cases of CRC occur in people over age 50, with incidence continuing to increase thereafter.¹⁹⁸ In fact, fewer than 10% of all new CRC diagnoses and deaths occur in patients younger than 50.¹⁹² As discussed previously, African-American individuals have a higher incidence and mortality rate of CRC compared to other racial and ethnic populations.^{195, 198, 199.}

Personal or family history

Patients with a personal history of adenomatous polyps or previous CRC have an increased risk of developing colon cancer in the future. Size, number, and histology of polyps are important prognostic factors, with size >1 cm, villous or tubulovillous histology, and multiple polyps conferring a greater risk for CRC.²⁰³ Patients with an isolated tubular adenoma of <1 cm do not appear to be at an increased risk of developing CRC.²⁰³ In patients with previous CRC, the incidence of metachronous CRC is 6%, and the incidence of metachronous adenomas is 25%.²⁰⁴

Family history of CRC in a first-degree relative increases the risk of developing CRC two- to threefold, while cancer in a second-degree relative increases the risk of CRC by 25–50%.^{205, 206} In addition, risk increases if there are more than one first-degree relative with colon cancer or if they are diagnosed before age 55.²⁰⁷ Family history of colonic adenoma also increases the risk of CRC, especially if the adenoma is diagnosed early.

Inflammatory bowel disease

UC and Crohn’s disease are well-known risk factors for colorectal carcinoma. For UC, the extent of disease and the duration of disease are the primary prognostic factors. Patients with pancolitis have a 5- to 15-fold increased risk of developing CRC compared to a threefold increased risk with colitis limited to the left colon.²⁰⁸ The risk also increases the longer the disease is present.²⁰⁹ Similar characteristics and incidence of CRC have been reported in Crohn’s disease.^210–212

Diet and lifestyle

Westernized dietary habits, including an increased consumption of red meat and fat with a decreased consumption of fruits and vegetables, are associated with CRC. There is conflicting evidence regarding the effect of diets high in fruits and vegetables, but the general consensus is that while there may not be a protection associated with increased consumption, very low consumption does increase risk of developing CRC.^213–215 A high-fat diet containing mixed lipids and saturated fat has been shown to promote colon carcinogenesis.^{216, 217} Alternatively, high intake of poultry and fish appears to be protective.²¹⁸

Obesity has been associated with an increased risk of CRC in both men and women, and people with a BMI ≥30 kg/m² appear to have nearly a 20% increased risk of CRC compared to nonobese patients.^{219, 220} In contrast, physical activity and exercise are correlated with a decreased risk of CRC.²²¹

Diabetes mellitus and hyperinsulinemia

There is increasing evidence that diabetes mellitus and insulin resistance are risk factors for CRC. A meta-analysis of 15 studies found the estimated risk of CRC in diabetics was 30% higher than nondiabetics.^{222, 223} A possible explanation is the hyperinsulinemia associated with diabetes or even chronic insulin treatment for diabetes, resulting in growth signals to colonic mucosal cells via insulin-like growth factor 1.^{223, 224}

Alcohol and tobacco

Heavy alcohol consumption is correlated with a moderately increased risk of CRC. The association is dose dependent and is irrespective of the type of alcoholic beverage consumed.^{225, 226} The association between smoking and CRC is not as straightforward, and cigarette smoking may have a greater impact depending on specific somatic polymorphisms.²²⁷

APC gene

The APC gene is located on the long arm of chromosome 5 (5q). It is mutated in FAP and Gardner syndrome and in most cases of Turcot syndrome. A mutated APC gene is detected in 63% of adenoma and carcinoma, but not in the surrounding tissues, indicating that this is a somatic mutation. Because APC is a tumor suppressor gene, inactivation of the second allele must occur for the cell to lose the tumor-suppressing activity of the APC protein. There is considerable evidence that APC mutations occur early and may be the first event in sporadic colorectal mutagenesis.

DCC gene

The DCC gene is located on the long arm of chromosome 18 (18q). The gene product is involved in cell–cell adhesion and cell–matrix interactions, which may be important in preventing tumor growth, invasion, and metastasis. In sporadic CRC, DCC seems to play a critical role in the ability of a tumor to metastasize.

p53 gene

The p53 is located on the short arm of chromosome 17 (17p). p53 seems to be the most important determinant of malignancy during colorectal tumorigenesis. As a tetramer, p53 binds sequences of DNA in the promoter region of other genes to enhance their transcription.²³⁰ Most genes activated by p53 are thought to be involved in the inhibition of growth. Mutations of p53 can be found in more than half of all human cancers.²³¹

K-ras proto-oncogene

K-ras is an oncogene, which acts in a classic dominant fashion and is located on the short arm of chromosome 12 (12p). The K-ras protein interacts with putative effector molecules, conveying a growth response. The signal transduction process is perturbed with a mutant K-ras protein leading to tumor formation. In sporadic colorectal tumors, K-ras mutations have been found in approximately 50% of carcinomas and large adenomas.²³²

Mismatch repair gene

Mismatch repair genes are needed for cells to repair DNA RERs and spontaneous base repair loss. The four DNA mismatch repair genes found in humans are hMSH2 (chromosome 2p), hMSH6 (chromosome 2p), hMLH1 (chromosome 3p), hPMS1 (chromosome 2q), and hPMS2 (chromosome 7p). They are regarded to contribute to hereditary nonpolyposis syndrome in various percentages.²³³

Signs and symptoms

The presentation of large bowel malignancy generally falls into three categories: insidious onset of chronic symptoms, acute onset of intestinal obstruction, or acute perforation. The most common presentation is that of an insidious onset of chronic symptoms (77–92%), followed by obstruction (6–16%), and then perforation (2–7%).^254–256

Bleeding is the most common symptom of colorectal malignancy.²⁵⁷ Unfortunately, patient and physician alike often attribute the bleeding to benign conditions. Bleeding may be occult or it may be seen as stool that is black, maroon, or bright red depending on the location of the malignancy.

Change in bowel habits is the second most common complaint, with patients noting either diarrhea or constipation.^{257, 258} Constipation is more often associated with left-sided lesions because the diameter of the colon is smaller and the stool is more formed than on the right side. Patients may report a gradual change in the caliber of the stool or may have diarrhea if the narrowing has progressed sufficiently to cause obstruction. Carcinomas of the right side of the colon do not typically present with changes in bowel habits, but large amounts of mucus generated by a tumor may cause diarrhea, and large right-sided lesions or lesions involving the ileocecal valve may cause obstruction.

Abdominal pain is as common a presentation as change in bowel habits.²⁵⁹ Left-sided obstructing lesions may present with cramping abdominal pain, associated with nausea and vomiting, and relieved with bowel movements. Right-sided malignancies may result in vague pain that is difficult to localize. Rectal lesions may present with tenesmus, but pelvic pain is generally associated with advanced disease after the tumor has involved the sacral or sciatic nerves. Less common symptoms include weight loss, malaise, fever, abdominal mass, and symptoms of urinary tract involvement. Bacteremia with Streptococcus bovis is highly suggestive of colorectal malignancy.^{260, 261}

Physical exam is often unrevealing because the abdomen is distended, and masses, primary or metastatic, are not palpable. Tympany, ascites, and distention may be all that is noted on abdominal exam. Rectal exam will only rarely reveal an obstructing tumor. Colorectal malignancy should always be considered when patients present with large bowel obstruction. The diagnosis may be confirmed with contrast enema, rigid or flexible endoscopy, or CT scans of the abdomen and pelvis.

Perforation may result in localized or generalized peritonitis or, if walled off, it may present with obstruction or fistula to an adjacent structure such as the bladder. Perforation occurs in 12–19% of patients with obstruction due to CRC.^{262, 263} When the perforation occurs proximal to the obstructing lesion, the patients present with diffuse peritonitis and sepsis. Emergent surgical intervention after adequate fluid resuscitation is clearly indicated. However, perforation at the tumor, possibly secondary to tumor necrosis, may follow a more indolent course, and thus may be confused with alternative diagnoses such as appendicitis, diverticulitis, or Crohn’s disease.

Stool-based screening methods

The advantage of fecal occult blood testing includes availability, convenience, and low cost. Limitations include low sensitivity, low specificity, low compliance, and inability to detect adenomas. Sensitivity is affected by slide storage, ascorbic acid, lesions not bleeding at the time of testing, and degradation of hemoglobin by colonic bacteria. Specificity is adversely affected by exogenous peroxidase activity by red meat and uncooked vegetables and medications that may induce bleeding from noncolonic sources such as aspirin and other nonsteroidal anti-inflammatory drugs. In five large controlled studies including more than 300,000 patients, an increased detection of CRC at earlier stages was demonstrated with the proper use of stool-based screening,^{264, 265} and testing was also associated with a significant reduction in mortality.^264–268 Stool-based screening techniques include high-sensitivity guaiac-based testing, immunochemical-based testing, and most recently stool DNA tests. DNA testing detects the presence of genomic alterations that are known to occur in CRC oncogenesis; the best tests have demonstrated sensitivities as high as 95%.²⁶⁹ Currently, DNA tests have not yet been FDA approved, and thus they do not represent a first-line option for screening. As of 2014, high-sensitivity guaiac-based and immunochemical-based stool testing as standalone screening methods are considered appropriate so long as they are performed annually by a healthcare provider and a prescribed diet is followed. Any abnormal test requires follow-up invasive screening. Recently, immunochemical-based testing has proven to have increased sensitivity compared to guaiac-based tests.²⁷⁰ Stool-based screening is a particularly good option for those who refuse more invasive options.²⁷¹

Flexible sigmoidoscopy

Both rigid and flexible sigmoidoscopies are inexpensive, require no conscious sedation, and afford direct visualization and biopsy of polyps and cancers.²⁷² The advantage of the flexible sigmoidoscope over the rigid is that it can reach the descending colon and even the splenic flexure. The disadvantage of sigmoidoscopy is that the entire colon is not visualized, and lesions may be missed in the proximal colon. Current National Comprehensive Cancer Network and American Cancer Society Guidelines recommend sigmoidoscopy with or without stool-based screening every 5 years, with subsequent full colonoscopy if adenomatous disease is found.²⁷³

Barium enema

Barium enema combined with sigmoidoscopy allows for evaluation of the entire colon and rectum. Single-contrast barium enema is significantly less sensitive and specific than double-contrast barium enema (DCBE) and should not be used as a screening tool. DCBE has a sensitivity of 50–80% for polyps <1 cm, 70–90% for polyps >1 cm, and 55–85% for stage I and II carcinomas.^274–276 When combined with sigmoidoscopy, the sensitivity reaches 98% and 99% for carcinomas and adenomas, respectively.²⁷⁷ Perforation as a result of DCBE has been reported at a rate of 1 per 25,000 studies.²⁷⁸ Current ACS screening recommendations are for a barium enema every 5 years with subsequent colonoscopy if test results are positive. The NCCN does not include barium enema as a screening option.²⁷³

Colonoscopy

Examination of the entire colon by colonoscopy is the gold standard screening method. When performed by trained endoscopists, colonoscopy with polypectomy is a safe procedure with a perforation incidence of 0.1%, hemorrhage incidence of 0.3%, and a mortality of 0.01–0.03%. The cecum is visualized in up to 98.6% of patients, and a DCBE may be performed when the cecum is not reached.^279–284 Studies have shown that detecting and removing polyps reduce the incidence of colorectal malignancy, that detecting earlier lesions decreases disease-related mortality, and that fewer carcinomas develop in patients who have colonoscopy and polypectomy.^{285, 286} Colonoscopy is better than DCBE in detecting lesions <1 cm.²⁷⁶ Furthermore, a tissue diagnosis or therapeutic intervention may be made at the time of initial evaluation. Colonoscopy also compares favorably with sigmoidoscopy because the entire colon may be directly visualized. In one study, a prevalence of 24% of new adenomas was found when 226 patients underwent colonoscopy within 1 year of flexible sigmoidoscopy. Advanced lesions proximal to the descending colon were found in 6% of these patients.²⁸⁷ Current ACS screening recommendations are for a colonoscopy every 10 years.

CT colonography

CT colonography (virtual colonoscopy) is an emerging technique that uses three-dimensional reconstruction of the air-distended colon. At the National Naval Medical Center, in 1223 average-risk adults who underwent CT colonography followed by conventional colonoscopy, virtual colonoscopy was as good or better at detecting relevant lesions.²⁸⁸ However, it may be less accurate in surveillance populations, and subsequent multi-institutional studies have failed to confirm the excellent results from this series. The major limitations include uncertain accuracy, need for full bowel preparation, and follow-up colonoscopy for tissue diagnosis of radiographic abnormalities. CT colonography as the primary method of screening also results in repeated radiation exposure to the patient. Because virtual colonoscopy is considerably time and labor intensive from the standpoint of the radiologist, active investigations into methods of automating the evaluation process are ongoing. Current ACS screening recommendations are for a virtual colonoscopy every 5 years with subsequent colonoscopy if a lesion is found. The NCCN does not include CT colonography as a screening option.²⁷³

Routine laboratory work

A complete blood count (CBC) may reveal the presence of anemia. Liver function tests (LFTs) may be abnormal in the case of liver metastases. Carcinoembryonic antigen (CEA) levels should be obtained as a baseline against which further values may be compared. Metastatic disease to the liver is often accompanied with very high levels of CEA, and levels surpassing 10 to 20 ng/mL are associated with increased chances of treatment failure.²⁸⁹

Colonoscopy

Colonoscopy remains the single most important investigation in the evaluation of colonic diseases. It allows assessment of tumor size, but not depth of invasion, as well as localization in the colon. Further histology from the tumor can be obtained, synchronous tumors are detected, and synchronous polyps may be removed. Synchronous carcinomas occur in 2–7% of patients and synchronous polyps 29.7% of the time.²⁹⁰ It has been suggested that preoperative colonoscopy alters the operative procedure in 30% of patients.²⁹¹

Radiologic evaluation

A chest X-ray evaluates for pulmonary lesions and serves as a rough guideline for cardiac as well as pulmonary status. The use of CT of the abdomen and pelvis in the preoperative evaluation of patients with colon cancer is controversial. It is our practice to obtain a CT in order to detect involvement of contiguous organs, paraaortic lymph nodes, and the liver. Abnormal LFT’s are present in only 15% of patients with liver metastases and may be elevated without liver metastases in up to 40%.²⁹² Therefore, we do not believe LFT’s are a useful screening tool for determining the need for obtaining a CT scan. Abdominal ultrasound can be used in select patient to identify liver metastases, ascites, and gross adenopathy.

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