Current advances in neuroendocrine neoplasms of the colon and rectum

Abstract

Compared with colorectal adenocarcinoma, neuroendocrine neoplasms (NENs), which affect the colon and rectum, are uncommon tumor conditions that have received relatively limited attention in basic research. Furthermore, the scarcity of these NENs has hindered extensive clinical investigations, thereby leading to a dearth of robust evidence for guiding clinical practice and impeding the establishment of standardized approaches for diagnosis and treatment. However, with the increasing awareness of population screening, as well as the increasing popularity of colonoscopy screening programs, the incidence of colorectal NENs has gradually increased. Moreover, some high-grade NENs are highly malignant and invasive, thereby leading to poor treatment outcomes and prognoses. These challenges have elicited increased attention from clinical physicians, thus prompting researchers to explore relevant studies using limited specimens and clinical data. This scenario has resulted in preliminary findings that provide evidence for addressing diagnostic and therapeutic challenges associated with NENs of the colon and rectum. In this article, we review recent literature reports and summarize the advances regarding the diagnosis and treatment of colorectal NENs.

Key Words: Neuroendocrine neoplasm; Colon; Rectum; Research progress; Diagnosis; Treatment

Core Tip: Colorectal neuroendocrine neoplasms represent a rare and highly heterogeneous group of tumors that are demonstrating increased detection rates. Due to their low incidence, difficulties in case collection and sample acquisition have led to slow progress in both clinical and basic research, thus resulting in a lack of standardized international guidelines and consensus on their treatment. We have reviewed and summarized recent research developments in this field, with an aim of providing readers with a comprehensive understanding of the current state of research and inspiring future studies.

INTRODUCTION

Although colorectal cancer is the third most common cause of cancer-related death worldwide, its incidence and mortality have decreased in the United States over the past three decades[1]. In contrast, the incidence of colorectal neuroendocrine neoplasms (NENs), which represent a rare type of colorectal cancer, has increased in recent decades[2]. For a long period of time, physicians have developed treatment options for colorectal NENs based on previous experiences in managing small cell lung carcinoma and colorectal adenocarcinoma, mainly due to the lack of research that has specifically focused on colorectal NENs. In recent years, there has been a surge in attention devoted to colorectal NENs because of their increased incidence. As a result, some clinical and basic research studies have been conducted utilizing limited clinical data and specimens. This has led to the development and updating of consensuses and guidelines by various organizations, with an aim of standardizing the management of colorectal NENs[3-6].

EPIDEMIOLOGY

Based on the patient registration data sourced from the Surveillance, Epidemiology, and End Results (SEER) program in the United States, it is evident that the incidence of NENs (despite their rarity) has consistently increased on an annual basis. The age-adjusted incidence rates of NENs were 1.09 per 100000 in 1973, 5.25 per 100000 in 2004, and 6.98 per 100000 in 2012, representing a 6.4-fold increase over the past 40 years[7,8]. Recent data obtained from KY, United States, indicated that the incidence rate further increased to 10.3 per 100000 in 2015[9]. Colorectal NENs account for approximately 10.9% to 25.2% of all NENs diagnosed in the human body; moreover, the incidence and growth rates of rectal NENs are much higher than those of colon NENs. In 1973, 2004, and 2012, the incidence rates of colon NENs were 0.02 per 100000, 0.2 per 100000, and 0.2 per 100000, respectively, whereas the incidence rates of rectal NENs were 0.2 per 100000, 0.86 per 100000, and 1.04 per 100000, respectively[8,10]. Data obtained from the Netherlands suggest that the incidence rate of colorectal NENs increased from 0.36 per 100000 in 2006 to 0.75 per 100000 in 2011, with the incidence rate of rectal NENs being 3.15 times higher than that of colon NENs[11]. Additionally, data from the United Kingdom indicate that the incidence rate of colorectal NENs increased from 0.2 per 100000 in 1995 to 0.7 per 100000 in 2018[12]. Currently, there is a lack of reliable data on the incidence rate of colorectal NENs in the Asian population because of the absence of large-scale multicenter studies. Limited data suggest that the incidence rate of rectal NENs in the Asian population is much higher than that of colon NENs. A retrospective study from Korea indicated that colorectal NENs accounted for 82.2% of gastroenteropancreatic NENs, and the incidence rate of rectal NENs was observed to be 33 times higher than that of colon NENs[13]. Moreover, the colorectal neuroendocrine tumor (NET) study from Japan suggested that the incidence rate of rectal NENs was 34.7 times higher than that of colon NENs[14]. Furthermore, a retrospective study from China indicated that the incidence rate of rectal NENs was 11.3-12.4 times higher than that of colon NENs[15,16].

Neuroendocrine carcinomas (NECs) are a relatively rare malignant tumor subtype of colorectal NENs, accounting for approximately 25.9% of all NENs[17]. Despite its small proportion within colorectal NENs, NEC exhibits a highly malignant nature, with strong invasiveness and a very poor prognosis. Epidemiological studies have indicated an incidence rate of 0.2 per 100000 for NEC, with an annual growth rate of 2.2%, thereby highlighting the need for researchers to focus attention on this disease[2].

The increasing incidence of colorectal NENs in recent years remains perplexing. Current evidence suggests that a family history of cancer is the most significant risk factor for NEN development, followed by obesity and diabetes mellitus[18]. Additionally, a younger age, previous history of malignancy, elevated fasting plasma glucose levels, and hypertriglyceridemia have been identified as potential risk factors[19].

PATHOLOGICAL CLASSIFICATION

In the 4^th edition of the World Health Organization (WHO) classification of digestive system tumors in 2010, colorectal NEN were further classified into G1 NENs, G2 NENs, G3 NENs, and mixed adeno NEC (MANEC) based on tumor proliferation activity and components. All G3 NENs were initially classified as poorly differentiated NECs[20,21]. Subsequent studies revealed significant heterogeneity in the pathological features, treatment responses, and prognoses of G3 NENs. Some patients in this group exhibit different histological morphologies, clinical behaviors, and biological characteristics compared to patients with typical NECs. Moreover, these patients demonstrate better pathological differentiation and longer survival times after treatment[22,23]. In 2017, this tumor subgroup was first identified in pancreatic NENs and termed high-grade NET[22,24]. In the 5^th edition of the WHO classification of digestive system tumors published in 2019, the G3 classification was introduced for colorectal NENs[21]. Furthermore, colorectal G3 NENs are divided into G3 NETs and G3 NECs. G3 NETs are well differentiated, whereas G3 NECs are poorly differentiated; moreover, these NENs exhibit significantly distinct pathological and molecular changes. Despite both G3 NECs and NETs being classified as NENs, they are independent cancer types that are not significantly correlated with each other. Additionally, clinical observations have demonstrated that the non NEN component in some mixed tumors is not limited to solely adenocarcinoma; rather, it can also include squamous cell carcinoma and other components. Similarly, the NEN component is not limited to NEC; instead, it can be a NET. Therefore, the previous term known as MANEC has been changed to mixed neuroendocrine-non NENs. The 2019 WHO classification and grading criteria for colorectal NENs are shown in Table 1.

Table 1 2019 World Health Organization Classification and grading criteria for colorectal neuroendocrine neoplasms.

Category	Subtype	Differentiation	Grade	Ki67, %	Mitotic rate (/10HPF)
NET	NET G1	Well	G1	< 3	< 2
	NET G2	Well	G2	3-20	2-20
	NET G3	Well	G3	> 20	> 20
NEC	Small cell	Poor	G3	> 20	> 20
	Large cell	Poor	G3	> 20	> 20
MiNEN		Well/poor	G1–G3	Any	Any

NET: Neuroendocrine tumor; NEC: Neuroendocrine carcinoma; MiNEN: Mixed neuroendocrinenonneuroendocrine neoplasm; HPF: High-power field.

The introduction of the G3 NET classification has allowed for a more personalized approach to the diagnosis and treatment of high-grade colorectal NENs. G3 NET tumors do not respond well to platinum-based chemotherapy regimens and can be effectively treated with somatostatin analogs and temozolomide-based chemotherapy regimens, thereby resulting in longer survival. Conversely, NECs are more sensitive to platinum-based chemotherapy regimens but are associated with shorter survival times[25]. Most G3 NET tumors exhibit typical histopathological features, and the progression from G1/G2 tumors to G3 tumors can occur in NETs. G3 NET tumors often coexist with classical NET G1/G2 regions, thus allowing for differentiation from NECs[26,27]. However, challenges in differentiating G3 NETs from NECs can arise due to limited sample sizes, excessive necrosis, and poor specimen fixation in laboratory settings. Therefore, a comprehensive assessment incorporating the Ki67 proliferation index, genetic characteristics, and clinical manifestations is often necessary for accurate diagnosis. NET G3 tumors typically demonstrate a Ki67 proliferation index less than 55%, thus indicating slower tumor progression. In contrast, NECs usually demonstrate a Ki67 proliferation index above 55% and are frequently associated with mutations in the KRAS, BRAF, P53, and RB1 genes, thus indicating increased malignancy, increased invasiveness, and rapid progression[25,28,29].

RECENT ADVANCES IN BASIC RESEARCH

The investigation of colorectal NENs has been hindered by their low occurrence and the absence of preclinical models. Currently, the published literature on colorectal NENs primarily consists of retrospective clinical studies, with only a few studies focusing on basic research. The understanding of the pathogenesis and molecular mechanisms of colorectal NENs remains incomplete, which considerably hinders the development of effective clinical treatment strategies. The current literature involving basic research in colorectal NENs mainly comprises bioinformatics studies utilizing sequencing data and molecular biology studies based on limited clinical models[30].

Several studies have conducted whole-exome sequencing on a limited number of collected colorectal NET samples, which revealed the presence of common driver gene mutations, such as those in PAPR4, BRWD1, MYCBP2, NIN, ZNF292, APC, TP53, and FBXW7. Additionally, aberrant signaling pathways, including the P53 pathway, PI3K-AKT pathway, DNA damage repair pathway, WNT pathway, and mTOR signaling pathway, have been identified. Moreover, these tumors demonstrate a low tumor mutation burden (TMB), with a median TMB of 1.15 being reported. Potential targeted therapy targets in colorectal NETs include the FGFR1 gene amplification, the BRAD1 gene mutation, and the BRCA2 gene mutation[30-32]. In contrast, sequencing and immunohistochemistry studies of colorectal NECs have revealed distinct genetic characteristics that significantly differ from those of colorectal NETs; instead, the colorectal NEC characteristics closely resemble those of colorectal adenocarcinoma[33,34]. Notably, high-frequency gene mutations observed in colorectal NECs include TP53, APC, KRS, BRAF, and RB1; moreover, the TMB is notably elevated compared with that of colorectal NETs, with a median TMB of 5.18 being reported. The presence of a BRAF mutation presents a promising target for potential targeted therapy in colorectal NEC, whereas the upregulation of CCL5 gene expression may serve as a potential predictive biomarker for immunotherapy[35,36].

Due to the low proliferative activity and lengthy cell cycle of colorectal NETs, reliable preclinical models for cellular and animal experiments are lacking. Previous attempts to establish organoid models using colorectal NETs have been unsuccessful[37]. However, in 2022, researchers achieved success in cultivating an organoid model from a liver metastasis specimen obtained from a patient with a rectal NET[38]. This model was subsequently utilized to investigate the effectiveness of a novel gold nanoparticle targeting SSTR2 in inhibiting tumor growth. Preclinical models for colorectal NECs are also limited and primarily consist of cell lines, patient-derived xenografts (PDXs) and organoids. Currently, there are no commercially available cell lines for colorectal NECs, and the reported cell lines in the literature have mainly been established by researchers themselves, such as SS-2, HROC57 (with the BRAF gene mutation), NEC-DUE1 (without the BRAF gene mutation), NEC-DUE2 (with the BRAF gene mutation), and JC053 (with the BRAF gene mutation). Experimental studies on the SS-2 cell line have demonstrated that the upregulation of integrin α2 expression increases the invasiveness of colorectal NEC cells and that anti-integrin α2 antibodies can inhibit their invasive properties. Integrin α2 may be a novel potential therapeutic target for patients with metastatic colorectal NECs[39,40]. Experiments on the HROC57 cell line have demonstrated that colorectal NEC cells are sensitive to platinum-based chemotherapy drugs[41]. Cell and animal experiments on these cell lines and PDX models have demonstrated that drugs targeting BRAF and MEK (such as dabrafenib, trametinib, and cobimetinib) can inhibit tumor cell proliferation, thereby suggesting the potential efficacy of this treatment strategy in colorectal NEC patients with BRAF mutations[42]. However, some colorectal NEC patients with BRAF mutations are inherently resistant to BRAF inhibitors or can develop resistance during treatment. In 2020, researchers reported that methylation of the EGFR gene inhibits its expression, which indicates sensitivity to BRAF inhibitors in colorectal NEC patients, whereas high expression of the EGFR gene suggests resistance. Therefore, the combination of BRAF inhibitors and anti-EGFR antibodies (such as cetuximab) may be a potential therapeutic approach to prevent the development of resistance to BRAF inhibitors[43]. Additionally, in 2022, other researchers reported that BRAF splice variants can confer resistance to BRAF inhibitors in NEC cells; however, this resistance could be overcome by MEK/ERK inhibitors[44]. Compared with two-dimensional cell lines, organoid models offer a three-dimensional culture system that more accurately mimics the in vivo environment. Despite the challenges encountered while establishing colorectal NEC organoid models, researchers have successfully established seven colon NEC organoid models using four surgical specimens and three endoscopic biopsy specimens and have investigated their genetic characteristics. These findings provide more reliable preclinical models for the future development of novel therapeutic strategies[37,45].

RECENT ADVANCES IN CLINICAL RESEARCH

The high heterogeneity and low incidence rate of colorectal NENs pose challenges for conducting prospective clinical research. Currently published clinical studies on colorectal NENs are predominantly retrospective, encompassing small sample studies from single or multiple centers, as well as large sample studies based on public clinical databases such as the SEER database and the National Cancer Database (NCDB). Researchers have explored various aspects of colorectal NENs, including clinical manifestations, treatment strategies, treatment efficacy, patient prognoses, and the development of predictive models via the analysis of clinical data. However, many unresolved clinical uncertainties remain, particularly regarding treatment options for metastatic patients and colorectal NECs. The performance of high-quality clinical research to address these important issues is imperative for improving the prognoses of these patients.

The accurate assessment of lymph node metastasis is crucial in determining the appropriate treatment approach for well-differentiated colorectal NETs. However, studies have demonstrated significant variations in the sizes of metastatic lymph nodes in colorectal NETs, with an average maximum diameter of only 4.31 mm and a minimum diameter of 2-3 mm being observed. More than 50% of metastatic lymph nodes demonstrate a maximum diameter smaller than 5 mm, thereby rendering their detection unreliable via conventional imaging techniques[46,47]. Somatostatin receptor scintigraphy has demonstrated high sensitivity and specificity in detecting lymph node metastasis; however, it is a costly procedure[47]. Several clinical studies have identified tumor size, depth of invasion, tumor grade, lymphovascular invasion, and other factors as risk factors for regional lymph node metastasis in patients with colorectal NETs[48-51]. Some researchers have developed clinical prediction models incorporating these risk factors, which have demonstrated promising predictive value. Nevertheless, the preoperative collection of some of the variables included in these models can be challenging, thereby impeding their practical clinical utility[52-54].

Although local excision (including endoscopic resection and transanal excision) has demonstrated favorable efficacy for early, small colorectal NENs, controversy remains regarding the appropriate indications for selecting local excision as a treatment. Surgeons often encounter challenges in deciding between local excision and radical surgery in clinical practice. The 2010 North American NET Society guidelines and the 2012 European NET Society (ENETS) guidelines recommended local excision for colorectal NENs smaller than 2 cm in size[20,55]. However, several studies have indicated that a significant number of patients with lesions smaller than 2 cm still exhibit lymph node metastasis or distant metastasis[56,57]. The updated version of the ENETS guidelines in 2016 made modifications to the 2012 version; however, these updated guidelines did not provide clear recommendations for determining the threshold size of colorectal NENs suitable for local excision[58]. Current research suggests that local excision is safe and effective for rectal NENs smaller than 1 cm in size after ruling out invasion of the muscularis propria and lymph node metastasis. However, for NENs measuring 1-2 cm in size (particularly in the colon), there is currently no consensus, and clinical physicians need to make comprehensive decisions based on individual cases[59].

For patients with locally advanced colorectal NENs, the choice of treatment should be tailored according to the degree of tumor differentiation. In the case of well-differentiated colorectal NETs, radical surgical resection is considered the most effective treatment option, thereby resulting in favorable postoperative outcomes. However, there remains a debate regarding the optimal treatment approach for poorly differentiated colorectal NECs, particularly regarding whether the approach should involve surgical intervention or nonsurgical methods[60]. Due to the rarity of colorectal NECs, the current treatment strategies are primarily based on those strategies used for small cell lung cancer. In small cell lung cancer, distant metastasis often occurs at early stages, thus making a nonsurgical treatment strategy preferable for patients with locally advanced disease. Limited research data currently exist regarding the determination of whether radical surgical treatment should be chosen for locally advanced colorectal NECs. A small sample cohort study conducted in France in 2015 suggested that radical surgery did not provide survival benefits compared with chemoradiotherapy[61]. However, a 2019 study based on the NCDB database revealed a 5-year overall survival rate of 31.7% in the radical surgery group, 15.9% in the chemotherapy group, and 0% in the no treatment group, thus indicating a survival benefit due to radical surgery[62]. Some studies also suggest that the treatment of colorectal small cell carcinoma should be differentiated from that of non-small cell carcinoma. A 2015 study based on the SEER database revealed that radical surgery did not improve the overall survival of patients with locally advanced small cell carcinoma of the rectum, whereas another SEER study conducted in the same year reported a survival benefit from radical surgery for patients with locally advanced non-small cell carcinoma, with a median survival of 21 months being reported in the surgery group compared with 6 months in the nonsurgical group. However, radical surgery does not improve survival in small cell carcinoma patients[2,63]. Notably, the available evidence is limited and conflicting, thereby highlighting the need for further research in this area. Nevertheless, despite the lack of clear evidence from evidence-based medicine supporting the survival benefits of radical surgery, most gastrointestinal surgeons currently prioritize radical surgical resection as the main treatment strategy for patients with locally advanced colorectal NECs.

For patients with distant metastasis of colorectal NENs, chemotherapy and biological therapy are the main treatment options. Palliative primary tumor resection may not offer survival benefits for patients with unresectable metastatic colorectal NENs[64]. Surgical resection may be suitable only for patients with bleeding, intestinal perforation, or obstruction complications. The performance of surgery on asymptomatic patients may demonstrate risks of surgical complications and delayed administration of chemotherapy. However, the available drugs and regimens for these patients are quite limited. Currently, only a few somatostatin analogs and lutetium-octreotate have received FDA approval for the treatment of metastatic colorectal NEN patients. Consequently, internists frequently encounter the challenge of determining the most appropriate subsequent treatment after failure of first-line therapy[30]. For patients with well-differentiated colorectal NETs, biological therapy is the primary treatment approach. Specifically, if tumor cells express somatostatin receptors, satisfactory therapeutic effects can be achieved via the administration of somatostatin analog injections or peptide receptor radionuclide therapy. Moreover, chemotherapy options for well-differentiated colorectal NETs are quite limited. The main utilized regimen involves the combination of temozolomide and capecitabine. For patients with poorly differentiated colorectal NECs, the standard first-line treatment typically involves a combination of platinum-based chemotherapy (using cisplatin or carboplatin) and etoposide. This chemotherapy regimen has demonstrated an average response rate of approximately 45% in these patients[59]. When considering the similar genetic features between colorectal NECs and adenocarcinomas, some studies have attempted to apply first-line chemotherapy regimens traditionally used for colorectal adenocarcinomas to treat colorectal NECs. However, the response rate to chemotherapy has only been observed to be 16.7%[65]. In recent reports, tumor regression has been observed in colorectal NEC patients with BRAF mutations following treatment with BRAF inhibitors. These findings suggest the potential value of targeted BRAF therapy in this subset of patients. However, further high-quality clinical research is needed to explore and validate the efficacy of this treatment strategy[66-68].

CONCLUSION

In summary, colorectal NENs are a rare type of tumor exhibiting an increasing incidence rate. These tumors exhibit significant heterogeneity, thereby resulting in variations in clinical manifestations, treatment strategies, therapeutic efficacy, and prognosis. These variations are influenced by factors such as the primary tumor site, tumor grade, differentiation, and stage of the tumor. Currently, the diagnosis and treatment of early-stage and well-differentiated colorectal NENs have been well established, with a consensus being reached on treatment approaches and favorable prognoses. However, there is a lack of extensive research and consensus regarding the management of poorly differentiated and advanced NENs. As a result, treatment options for these patients are not well defined, and the prognosis tends to be poorer. The main focus of future research should involve the development of reliable preclinical models, the performance of comprehensive basic and drug research, and the implementation of prospective, multicenter, large-sample clinical studies. These efforts are crucial in addressing existing controversies and providing high-level references for clinical decision-making.