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Neuroendocrine Tumors of the Colon and Rectum

Oncology
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Introduction

Neuroendocrine tumors (NETs) of the colon and rectum are a rare malignancy. NETs represent about 1% of colonic malignancies and about 2% of rectal malignancies [1, 2]. In the United States, the estimated incidence of colon NETs is approximately 0.3 per 100,000 and the estimated incidence of rectal NETs is approximately 1 per 100,000 [3].
The mean age of diagnosis of colonic NETs is 63 years and the majority of patients are white [4, 3]. Conversely, the mean age of diagnosis for rectal NETs is 56 years and the incidence is higher among Asian and Black patients [5-6].

Pathology

The World Health Organization (WHO) classifies colon and rectal NETs based on grade and differentiation. Well-differentiated NETs are divided into three grades, which are determined by 1) mitoses/ mm2 and 2) Ki-67 proliferation index.
G1 (low grade tumors) have <2 mitoses/mm2 and Ki-67 <3%. G2 (intermediate grade tumors) have 2-20 mitoses/mm2 and Ki-67 from 3-20%. G3 (high grade tumors) have >20 mitoses/mm2 and Ki-67 >20%.
Poorly-differentiated tumors, or neuroendocrine carcinomas (NECs), are divided into small cell type or large cell type [7]. It is critical to delineate between well-differentiated and poorly-differentiated colon and rectal NETs because their tumor behavior is inherently different.

Presentation

The majority of colon and rectal NETs are non-functioning and often found incidentally on surveillance endoscopy [8-9]. Symptoms of colon and rectal NETs include abdominal/pelvic pain, blood per rectum, changes in bowel patterns, or weight loss, though most are asymptomatic [10-13].
In rare cases, patients can present with the typical carcinoid syndrome (i.e., flushing, diarrhea, bronchoconstriction) [10,14].

Staging and Diagnosis

The staging for colon and rectal NETs follows the T, N, M staging system developed by the National Comprehensive Cancer Network (NCCN). The definitions for TNM staging for colonic and rectal NETs are detailed in Table 1 [14].
Table 1. American Joint Cancer Commission TNM staging classification of colorectal NETs
TxPrimary tumor cannot be assessed
T0No evidence of primary tumor
T1Tumor invades lamina propria or submucosa and size ≤ 2 cm
T1aTumor size <1 cm in greatest dimension
T1bTumor size 1-2 cm in greatest dimension
T2Tumor invades muscularis propria or size >2 cm with invasion of lamina propria or submucosa
T3Tumor invades through muscularis propria into subserosa or into nonperitonealized pericolic or perirectal tissue
T4Tumor invades peritoneum or other organs
  
NxRegional lymph nodes cannot be assessed
N0No regional lymph node metastases
N1Regional lymph node metastases
  
M0No distant metastases
M1Distant metastases
  
Stage IT1, N0, M0
Stage IIaT2, N0, M0
Stage IIbT3, N0, M0
Stage IIIaT4, N0, M0
Stage IIIBAny T, N1, M0
Stage IVAny T, Any N, M1
T stage is defined by tumor size and depth of invasion. Nodal status and tumor metastasis are dichotomous definitions for NETs. In terms of work-up, abdominopelvic imaging with CT or MRI are typically initially obtained and colonoscopy is utilized to evaluate the entire bowel for synchronous lesions [14]. Endoscopic ultrasound or pelvic MRI can be used to further characterize rectal NETs [15-16].
Somatostatin receptor imaging can also be used to better localize NETs. Biochemical testing is not routinely recommended [3] although serum chromogranin A can be used as a tumor marker to monitor treatment response or long-term surveillance [17].

Management

For colon NETs, the utility of systemic medical treatment depends on the histology of the tumor. Low-grade well-differentiated tumors are typically refractory to traditional chemotherapy medications [18-19], however, patients with metastatic disease may benefit from octreotide treatment [14,20]. For colon NECs, cytotoxic chemotherapy has been associated with improved survival in various studies [21-22]. Surgical resection of primary colon NETs with regional lymphadenectomy is the recommended surgical treatment [14].
For NECs, the European Neuroendocrine Tumor Society recommends surgery for localized or locoregional disease but no debulking for metastatic disease [23]. For patients with advanced high-grade disease, studies have shown that surgical resection does not improve survival [18,24].
Endoscopic resection is not currently recommended for colonic NETs. For rectal NETs, the NCCN recommends local excision for those less than 1 cm and radical resection for those larger than 2 cm and for tumors that have metastasized to lymph nodes [25]. Endoscopic resection can be used for small (<1 cm) tumors that do not invade beyond the submucosa when there is no locoregional lymph node metastasis [16]. Other endoscopic techniques including band snares and submucosal dissection have been described in the literature [26-28].
A transanal excision can be used for rectal NETs that are located distally in the rectum, intermediate in size (1-2 cm), and confined to the submucosa/muscularis propria [29]. Rectal NETs in the middle and upper portions of the rectum can be resected with transanal endoscopic microsurgery [30]. Radical resection (low anterior resection or abdominoperineal resection with total mesorectal excision, depending on the tumor location) should take place for larger rectal NETs (> 2cm), tumors invading the muscularis propria, or tumors with locoregional lymph node involvement [31].
For poorly-differentiated rectal NETs, a combination of oncologic resection and systemic chemotherapy is often utilized [21, 32-33]. Systemic therapy alone for rectal NETs is typically reserved for metastatic disease and regimens include somatostatin formulations, interferon alpha, and various chemotherapy regimens [34-36].

Survival

The survival for colon versus rectal NETs differs. For patients diagnosed with grade 1 or 2 colonic tumors, the median survival is 261 months for localized disease, 36 months for regionally invasive disease, and 5 months for disease with distant metastases [37].  Patients with high grade colonic NECs have a median survival of 7.1-9.0 months [21,38].
The survival for patients with well-differentiated rectal NETs is >85% [1,5,39]. If the rectal NET has metastasized to lymph nodes, five-year survival decreases to 54-70%, and if there is distant metastasis, five-year survival drops considerably to 15-32% [1,5,40]. For patients with poorly-differentiated rectal NECs, five-year survival is approximately 13-33% [21,41].

Surveillance

The NCCN has put forth surveillance guidelines for patients with colonic NETs and includes physical exam every 3-4 months after resection, biochemical marker testing, and abdominal/pelvic imaging [14]. For rectal NETs, surveillance depends on the size of the tumor. For patients with tumors <1 cm, long term surveillance with endoscopy or imaging is not recommended [11,25].
For patients with tumors between 1-2 cm or who undergo local excision, EUS or MRI is recommended at 6 and 12 months [25]. Patients with tumors > 2 cm or who have formal resections should be followed closely with annual EUS or MRI for up to ten years [11,25].

Conclusions

NETs arising from the colon and rectum are rare. The tumors can range from indolent to aggressive, and treatment options and prognosis vary depending on tumor characteristics, size, and location of the tumor.

References

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