Colorectal neuroendocrine tumors (NETs) originate from neuroendocrine cells in the intestinal tract, and represent a small area within oncology, but one which has provided increasing new data during the past years. Although the World Health Organization has determined clinical and histological features to predict prognosis for such tumors, they may not be valid on an individual basis. We aim to give an overview of the recent findings with regard to pathology, molecular genetics and diagnosis of NETs.

Neuroendocrine (NE) cells are distributed throughout the human body, including the gastrointestinal (GI) tract, pancreas, lung, thyroid, adrenal gland and many other organs[1-4]. The GI tract has the largest population of NE cells[5]. However, neuroendocrine tumors (NETs) of the colon and rectum are rare. Results from analyses of the Surveillance, Epidemiology and End Results database demonstrated that the age-adjusted incidence of carcinoids of the small intestine and digestive system has increased by 460% and 720%, respectively, in the past 30 years due to, at least in part, the improvements in diagnostic technology such as endoscopy, as well as doctors’ increased awareness[6]. In 2003, Modlin et al[7] reported that the incidence of NETs in the GI tract was 2.5-5 cases per 100 000 population annually. Males are more often affected than females, with a proportion of 1.8:1[8]. In the large intestine, NETs are more commonly found in the rectum (54%), then in the cecum (20%), sigmoid colon (7.5%), rectosigmoid colon (5.5%) and ascending colon (5%)[9].

Colon NETs usually appear as large tumors and often already have regional lymph nodes or liver metastasis at the time of diagnosis, therefore the prognosis is poor. On the other hand, NETs occurring in the rectum are often diagnosed incidentally during colonoscopy, therefore they are typically small, localized, non-functioning tumors with rare metastasis, probably as a result of early detection[6,8,10,11].

Colorectal NETs are traditionally classified as typical carcinoid, atypical carcinoid and undifferentiated cancer according to the differentiation of the disease[12,13]. The term carcinoid can no longer characterize the entire morphologic and biologic spectrum of neoplasms of the disseminated NE cell system. The updated World Health Organization (WHO) classification of 2000 adopted the neutral and inclusive terms, tumor and carcinoma. In this classification, it is clearly explained how to characterize well-differentiated NETs (benign behavior or uncertain malignant potential), well-differentiated NE carcinoma (low-grade malignancy), and poorly-differentiated NE carcinoma of high-grade malignancy [small cell carcinomas (SCCs)][14,15]. The morphologic/biologic criteria including tumor size, angioinvasion, proliferative activity, histological differentiation, metastasis, invasion, and hormonal activity (association with clinical syndromes or diseases) have also been added (Table 1).

Well-differentiated NE tumor was referred to as typical carcinoid historically, and well-differentiated NE carcinomas were termed atypical carcinoid. Although this framework is helpful, lesions of uncertain behavior are poorly defined. In the WHO classification, SCC is synonymous with the term “poorly-differentiated NE carcinoma”, but there is no clear differentiation between large cell NE carcinomas (LCNECs) and mixed endocrine-glandular neoplasms. No coincident repeat diagnosis could be made by different pathologists or by different institutions, although the WHO classification of colorectal NETs has been used for several years. The main reason is that the WHO classification has not been closely adhered to[1]. Pathological recognition of these tumors is critical, as the treatment strategy, particularly chemotherapy for a particular subtype, largely depends on the underlying pathology[16,17].

The molecular mechanisms of NET tumorigenesis are unclear; however, these aspects have been focused on in many recent reports[51]. Increased knowledge of the molecular background for the development of NETs may improve the management of these tumors in the future. A number of genetic syndromes including multiple endocrine neoplasia syndrome-type 1 (MEN1), vov Hippel-Lindau syndrome, and neurofibromatosis-type 1 may be associated with intestinal NETs[8,52]. Some studies have demonstrated neither classic oncogenes (scr, ras, myc, fos, jun) nor suppressor genes (P53, RB) present in NETs[52,53]. However, there are reports of other gene site deletions. For example, PDCD4 was found to be absent in NETs; this is a gene which is interrelated with cell proliferation, located at 11q13 close to MEN1[54].

The microsatellite instability (MSI) caused by mismatch repair (MMR) damage is an important cause of tumorigenesis in hereditary nonpolyposis colorectal cancer (HNPCC)[55-58]. Stelow et al[59] discovered the loss of MMR genes in colorectal SCCs, but not along with HNPCC. The chromosome instability caused by the loss of MMR genes possibly follows a different pathway from MSI in SCC tumorigenesis. Arnold et al[60] studied 34 poorly-differentiated colorectal NETs, 38 well-differentiated benign or malignant fore-/midgut NETs, and 150 sporadic colorectal cancers with known MSI status and found that 20/34 (59%) colorectal NETs vs 11/38 (29%) fore-/midgut NETs were CpG island methylator phenotype (CIMP) positive. The Ki-67 index was significantly higher in poorly-differentiated colorectal NETs compared with the less malignant fore-/mid-gut NETs. However the CIMP status did not correlate with survival.

Research in NET molecular genetics should target early detection, prognosis predicting, or treatment selection. Currently, new technologies should be used to find new sensitive and specific biochemical and tissue markers for colorectal NETs.

NETs are a challenging group of diseases, and the lack of a widely accepted staging system limits the clinician’s ability to provide meaningful prognostic information to the patients. In October 2009, the 7th edition of the AJCC for the first time gave a detailed TNM description for NETs, classifying primary tumor (T), regional lymph nodes (N), and distant metastasis (M), respectively. However, no clarified TNM staging has been established for colon and rectal NETs[61].

In 2008, Landry et al[62,63] proposed a different staging system from that of conventional colorectal adenocarcinomas in the study of 4710 rectal NETs and 2459 colon NETs (Table 2). In their report [62], it was revealed that rectal NETs were the only primary malignancy in 82% of patients, 17% patients had one additional malignancy and 1% had two or more additional malignancies. The mean and median sizes of primary tumor were 1 and 0.6 cm, respectively. About 4.1% had regional lymph node metastases, and 2.4% presented with distant metastases at the time of diagnosis. The 5-year survival rates for patients with stages I and II disease were 97% and 84%, respectively. The 5-year survival rate for stage III patients was 27% with a median survival time of 45 mo. The 5-year survival rate for stage IV patients was 20% with a median survival time of 31 mo. The 10-year survival rates of the disease for stages I through IV were 91%, 56%, 14%, and 2.5%, respectively.

In another study[63] of colon NETs, the researchers demonstrated that there were regional lymph node metastases in 48% of patients, and distant metastases in 24% of patients at the time of diagnosis. The 5-year survival rates for stages I and II were 97% and 69%, respectively. Similarly, the 5-year survival rate for stage III disease was 21%, with a median survival time of 27 mo. The 5-year survival rate for stage IV disease was 17%, with a median survival time of 20 mo. The 10-year survival rates for stages I through IV were 92%, 47%, 15%, and 5.4%, respectively.

Some studies have suggested some risk factors of colorectal NETs related to poor outcome, such as tumor size, depth of wall penetration, presence of lymphatic or venous invasion, and mitotic rate of metastasis in colorectal NETs[64-69]. The tumor size is related to prognosis. Most rectal NETs are less than 1 cm at the time of diagnosis[70,71]. The malignancy rate increases when the tumor grows larger than 1 cm. However, for small-sized tumors less than 1 cm at detection with predominant submucosal invasion there is usually a relatively high incidence of distant metastasis, about 1.7%-3.4%[71,72]. Some reports have shown that cancer-specific survival of patients with colorectal NETs without metastasis was better than that of those with adenocarcinomas. However, the survival rate is similar between carcinoid and adenocarcinoma if the tumors have lymph node or distant metastases[65]. On the other hand, colorectal NE carcinomas behave aggressively and are associated with a worse prognosis than that of conventional colorectal adenocarcinomas of the same stage[16,39].

The complexity, heterogeneity and scarcity of NETs, rare colorectal neoplasia, account for almost no improvement of survival rates in the past 30 years. The diagnosis for colorectal NETs mostly depends on pathology with the aid of immunohistochemistry. As we have summarized here, the 2000 WHO classification of colorectal NETs provides a solid basis for localization, biology and prognosis of individual NETs, but there are still some types of tumors not properly described. More studies will be needed with regard to diagnosis, treatment and prognosis.