Rare Colorectal Malignancies

Neuroendocrine Tumors

Carcinoid tumors are neuroendocrine cells in origin, and stain silver with an external reducing agent. They were first observed in 1907 by Oberndorfer, initially because they were observed to have a more indolent course and different behavior than adenocarcinomas. The neuroendocrine cells can take up various amine precursors and produce end products such as neuropeptides, neurotransmitters, as well as hormones that exhibit local and systemic effects.

Neuroendocrine tumor (NET) is the official umbrella term adopted by the World Health Organization (WHO) to represent different neuroendocrine neoplasms, including carcinoid tumors. According to the 2003 study based on the Surveillance, Epidemiology, and End Results (SEER) Program, NETs are most commonly seen within the gastrointestinal (GI) tract (67%) and bronchopulmonary system (25%). In the United States there is a significant correlation between tumor location and race, with primary lung NETs most commonly seen in white patients (30%), and primary rectal NETs more commonly seen in Asian/Pacific Islanders (41%), American Indian/Alaskan Native (32%), and African Americans (26%).

In addition to the racial differences noted in tumor location, the incidence of NETs also varies by location in the GI tract. There has been an increase in the incidence of NETs, with the most remarkable increase in stomach and rectum. The most common location for carcinoid tumors in the GI tract is the appendix (38%), followed by the small intestine (29%) and large intestine (21%). However, NETs continued to comprise less than 2% of all the GI tumors in 2000–2006. NETs are extremely rare in the large intestine, accounting for 0.92% of all colonic tumors and 0.49% of all rectal tumors. There is a slight female predominance over male (52% vs. 48%), and most tumors occur the fifth and sixth decade of age. Patients diagnosed with primary appendiceal NETs tend to be younger with a median age of 47 years at diagnosis. However, patients with primary NETs of the rectum, colon, and cecum tend to be slightly older at 56, 65, and 68 years.

Classification of Neuroendocrine Tumors

Gastrointestinal NETs are classified into three major categories (WHO criteria) based on the degree of differentiation and histologic features: grade 1 (low grade, well differentiated), grade 2 (intermediate grade, well differentiated), and grade 3 (high grade, poorly differentiated). The distinction between well-differentiated and poorly differentiated NETs facilitates understanding the clinical behavior of the two categories and promotes appropriate treatment strategies. Carcinoid tumor or neuroendocrine tumor refers to low- and intermediate-grade tumors that are well differentiated, whereas neuroendocrine carcinoma is reserved for high-grade tumors that are poorly differentiated ( Table 175.2 ).

Pathology

The typical benign carcinoid tumor is a small, well-circumscribed submucosal, yellow lesion with high lipid content, often multicentric and composed of small round cells that contain dense, microscopic, neurosecretory granules. Neuroendocrine carcinomas are associated with increased cellular atypia, high mitotic activity, or necrosis. Serotonin in the neurosecretory granules reduces silver salts into metallic silver in the cytoplasm.

Argentaffin staining is pathognomonic of NETs. Argyrophilic-stained tumors are those that lack the ability to reduce silver in the absence of a reducing agent. Midgut NETs are often argentaffin positive, whereas 85% to 90% of hindgut NETs contain only 8% to 16% argentaffin-positive cells.

Immunohistochemical markers, including serum chromogranin, synaptophysin, and neuron-specific enolase, are important tools for diagnosis of NETs and surveillance following treatment. Serum chromogranin A is a useful marker to follow up patients' response to treatment with metastasis or after surgery.

Colorectal Neuroendocrine Tumors

Local growth of carcinoid tumors causes obstruction, distant metastasis, and production of bioactive substances leading to local and systemic effects. The classic carcinoid syndrome occurs in 10% to 18% of patients with carcinoid tumors. Carcinoid syndrome includes episodic flushing, wheezing, nonbloody watery diarrhea, abdominal pain, and right-sided heart failure, which are usually precipitated by serotonin-containing foods such as chocolate, caffeine, and alcohol. Serum levels of serotonin produce the symptoms of hypermotility of the intestinal tract including abdominal cramping and diarrhea. Kallikrein is associated with wheezing and flushing.

The clinical presentation of carcinoid syndrome depends on the tumor location. Midgut tumors are more likely to present with abdominal pain (40%). Hindgut tumors tend to have a more indolent course. No primary GI tumor is responsible for carcinoid syndrome because the portal venous system delivers the hormones to the liver where they are metabolized. Therefore, patients who have carcinoid syndrome must have liver metastasis or a tumor with systemic venous drainage. It is recommended that patients have a thorough work-up to evaluate for synchronous (40%) and metastatic (25%) disease at the time of diagnosis.

Imaging

Colonoscopy and biopsy are the most reliable tools for evaluating and diagnosing colorectal NETs. Endoscopic ultrasound may be useful to assess tumor size, depth of invasion, and nodal involvement. A computed tomography (CT) or magnetic resonance imaging (MRI) are often needed to evaluate for the presence of metastatic disease for lesions that are greater than 2 cm or when there is high-grade histology. Small tumors of less than 2 cm rarely metastasize. Somatostatin receptor scintigraphy may be useful in the setting of a known metastatic tumor to determine the presence of bioactive tumor and to evaluate for tumor burden.

Treatment of Primary Tumors

Surgical resection of colonic carcinoid tumors following all oncologic principles is the standard of care. In highly selected patients with small intramucosal tumors (<1 cm), endoscopic resection may be appropriate. However, endoscopic submucosal dissection is associated with higher rates of incomplete non-R0 resection and complications. For localized disease, 5-year survival rates range from 44% to 76%, whereas patients with metastatic disease experience a 5-year survival rate of 30%.

In contrast to patients with colonic tumors, patients with rectal carcinoids are often candidates for local excision because rectal NETs are usually small and follow an indolent course. They are commonly diagnosed as an incidental finding during other procedures. Tumor size (>1 cm), depth of invasion, and lymphovascular involvement are important risk factors that predict a worse outcome. Patients with high-risk lesions should be carefully counseled on the risk for recurrence associated with local excision and may be candidates for total mesorectal excision. In fact, patients with tumors larger than 2 cm are at increased risk of metastasis and may experience a 5-year survival rate of 44% with lymph node involvement and 7% if distant disease is present. Small localized rectal NETs carry a favorable prognosis with overall 5-year survival rate up to 88% and may be candidates for rectal-sparing local excision. Several local excision techniques are available. For example, endoscopic management with endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) may be appropriate for the treatment of small rectal lesions. ESD is considered superior to EMR with better R0 resection rates and similar complication and recurrence rates. In addition, transanal endoscopic microsurgery (TEM) or transanal minimally invasive surgical (TAMIS) resection may be useful tools for local excision of rectal carcinoids. These techniques may be considered for primary resection for tumors less than 2 cm, and for resection after prior incomplete colonoscopic excision.

Full oncologic resection with total mesorectal excision should be performed in patients with high-risk rectal lesions ( Table 175.3 ). Adjuvant chemotherapy or radiotherapy is generally not considered.