Gastrointestinal Neuroendocrine Tumors—Case Series from a Tertiary Care Center with Review of Literature

Abstract

Neuroendocrine tumors account for 0.5% of all malignancies, and their incidence is around 2/100,000 with a female predilection within the age range of 50 years at the time of presentation. NETs in India have a different clinicopathological profile compared to those in Western countries. Very few limited studies are available in Indian literature with regard to the epidemiology, presentations, histopathological characteristics, and treatment outcomes in patients with gastrointestinal neuroendocrine tumors. This warrants the need for documentation of these tumors, and we hereby present a case series of four patients diagnosed with NETs who presented within a period of 9 months at our rural tertiary care center.

Introduction

Neuroendocrine tumors account for 0.5% of all malignancies, and their incidence is around 2/100,000 with a female predilection within the age range of 50 years at the time of presentation. The primary sites include the gastrointestinal tract (62–67%), the lung (22–27%), and metastatic disease in 12–22% of the cases [1]. The name neuroendocrine tumors refers to the neural and endocrine differentiation arising due to the dense core granules and synthesis/secretion of monoamines from the diffuse endocrine system located in the gastrointestinal (GI) tract and in the pancreas. They are most commonly seen in the GIT (55%), and in the bronchopulmonary system (25%). They can develop at any GI site (GI-NETs) which can include the small intestine (45%), rectum (20%), appendix (16%), colon (11%), and stomach (7%) [2]. In the last decade, the incidence of these tumors has been steadily increasing, as a result of advancements made in various diagnostic modalities like CT, magnetic resonance imaging, scintigraphy, positron emission tomography, ultrasound-guided fine needle biopsy, pre- and postoperative histopathological evaluation with adjunct techniques like immunohistochemistry and serum tumor markers. The clinicopathological profile of NETs in the Indian population differs from Western countries as most of them present with metastatic disease at the initial presentation itself [3]. Very few limited studies are available in Indian literature with regard to the epidemiology, presentations, histopathological characteristics, and treatment outcomes in patients with gastrointestinal neuroendocrine tumors. Therefore, we have compiled a case series of four patients diagnosed with NETs presenting with varied symptoms, their pre-operative evaluation, and surgical outcome over a period of 9 months at our rural tertiary care center.

Case Reports

This case series describes four cases of gastrointestinal NETs diagnosed over a period of 9 months between June 2023 and Feb 2024 as shown in Table 1 at Sri Madhusudan Sai Institute of Medical Sciences and Research, Muddenahalli, Chikkaballapura. There were three male patients and one female patient with age range between 37 and 76 years. All male patients presented with tumor in the small intestine and the female patient presented with tumor in descending colon which is very rare.

Table 1.

Summary of cases

	Age, sex	Initial presentation	Site, size	Diagnostic workup	Grade	Lymphnode	IHC	Modality of treatment	Outcome
Case 1	58 yrs, male	Subacute intestinal obstruction	Ileum, 2 × 1 cm	CECT showed focal segmental (12 mm length and 9 mm thickness), circumferential mural thickening of proximal ileum	Grade 2, well differentiated	Positive for metastasis	Synaptophysin + , chromogranin + , Ki-67 index > 3%	Resection and anastomosis of ileal stricture	Alive and on chemotherapy
Case 2	37 yrs, male	Pain in epigastric region	Duodenum D2, 2.3 × 2 cm	CT scan shows mass lesion in the D2 segment	Grade 2, well differentiated	Positive for metastasis	Synaptophysin + , chromogranin + , Ki-67 index > 3%	Whipple’s procedure	Alive and on chemotherapy
Case 3	76 yrs, male	Frank blood in stool	Duodenum D1, 3 × 2 cm	PET CT shows mass in the duodenum likely NET with hepatic metastasis	Grade 2, well differentiated	Positive for metastasis	Synaptophysin + , chromogranin + , Ki-67 index > 3%	Segmental duodenal resection with metastatectomy of liver segment	Alive
Case 4	75 yrs, female	Pain abdomen associated with loss of weight and appetite associated with melena	Descending colon, 5.5 × 5 cm	PET-CT shows mass lesion in descending colon with proximal dilation of colon	Grade 2, well differentiated	Positive for metastasis	Synaptophysin + , chromogranin + , Ki-67 index > 3%	Palliative hemicolectomy	Alive

Case 1

A 58-year male patient presented with pain abdomen of 3–4-month duration, aggravating with food intake and associated with altered bowel habits. CECT abdomen revealed focal segmental circumferential mural thickening of the proximal ileum with pre-stenotic dilation of the bowel loop. The patient was diagnosed with subacute intestinal obstruction secondary to stricture and posted for surgery. Intra-operatively an ileal stricture with mass measuring 3 × 3 cm was noted and resection with end-to-end anastomosis was performed. Postoperative period was uneventful, and histopathology revealed well differentiated neuroendocrine carcinoma with lymph-nodal metastasis.

Case 2

A 37-year male patient presented with on-and-off episodes of epigastric region pain associated with vomiting and loose stools of 8-month duration. On evaluation with CT, a heterogeneously enhancing mass was noted in the peri-ampullary region. The patient underwent a classical Whipples procedure, and postoperative period was uneventful. Histopathology revealed well differentiated neuroendocrine carcinoma of the duodenum (D2) with lymph-nodal metastasis (Figs. 1, 2 and 4A, B.

Fig. 1.

A Well differentiated neuroendocrine carcinoma in the duodenum-D2 (arrow). Hematoxylin and eosin stain 4 × . B NET arising in the submucosa of the small intestine (arrow). H&E stain 4 × . C Solid nests of tumor cells with stippled chromatin. H&E stain 10 × 

Fig. 2.

Case 2: Gross specimen images of Whipples resection – NET Duodenum D2

Fig. 4.

NET-Duodenum—A Diffuse cytoplasmic positivity for chromogranin in tumor cells. B Diffuse cytoplasmic positivity for synaptophysin in tumor cells. Case 3: NET-Duodenum—C Diffuse cytoplasmic positivity for chromogranin in tumor cells. D Diffuse cytoplasmic positivity for synaptophysin in tumor cells

Case 3

A 76-year male patient presented with complaints of blood in stool (frank blood) with on-and-off episodes, not associated with any other symptoms like pain abdomen and altered bowel habits. A PET CT revealed a primary neuroendocrine tumor of the duodenum with hepatic metastasis. DOTANOC PET/CT scan confirmed the same (Fig. 3). The patient underwent segmental duodenal resection with cholecystectomy and liver metastatectomy as a palliative procedure. Histopathological examination revealed well differentiated neuroendocrine carcinoma with lymph node metastasis and liver metastasis (Fig. 4C, D).

Fig. 3.

A CT image of tumor in the duodenum (arrow) with hepatic metastasis (yellow arrow). B DOTONAC scan image showing neuroendocrine carcinoma metastasis in the liver (arrow)

Case 4

A 75-year female patient presented with complaints of pain abdomen of 3-month duration associated with melena and abdominal distension. Colonoscopy revealed a mass lesion in descending colon. Further, PET CT revealed a mass lesion in the descending colon with pericolic lymph nodes and liver metastasis. DOTANOC PET/CT scan confirmed the same. Pre-operative colonoscopic biopsy revealed poorly differentiated adenocarcinoma. The patient underwent left hemi-colectomy, and postoperative period was uneventful. Histopathology revealed well differentiated neuroendocrine carcinoma with lymph node metastasis.

Discussion

Neuroendocrine tumors (NETs) comprise a heterogeneous group of neoplasms arising from the amine-producing neuroendocrine cells which are ubiquitous in the body. They are classified as functional and nonfunctional based on the peptides being secreted. Majority of these arise sporadically but can be seen in association with multiple endocrine neoplasia (MEN) syndrome type 1 with familial clustering [1]. NETs are also known to be present with synchronous (occurring at the same time) second primary malignancies or as metachronous (occurring at different times) malignancy, without any genetic predisposition [4]. These tumors can be slow-growing benign indolent or malignant lesions with widespread metastasis. Presenting symptoms can be vague and nonspecific, most often related to the mass effects of the tumor [4]. They include vague abdominal colic (68–78%), abdominal distention, weight loss (32–50%), bleeding, biliary obstruction or metastasis (21–50%), and vomiting (36%) [1, 5]. In our case series, patients presented with symptoms like epigastric pain, pain abdomen associated with melena, and frank blood in stool. There was one patient (Case 1) who presented with pain abdomen and on radiological evaluation was diagnosed as subacute intestinal obstruction which intra-operatively appeared as a stricture and turned out to be neuroendocrine carcinoma postoperatively which was similar to a case reported by Selvi et al. [5]. Small intestinal NETs are the most common small bowel malignancies accounting for 25% of all GI-NETs surpassing primary adenocarcinomas [1]. They are often multifocal and indolent but can metastasize in advanced disease. They originate from the enterochromaffin cells of the submucosa, at the base of the intestinal crypts. Duodenal NETs account for 2% to 3% of all GI-NETs and are increasingly becoming more prevalent with male predilection and with a mean age of 60 years at the time of diagnosis. We had two cases of duodenal NET in the D1 and D2 segments, which were incidentally discovered while evaluating for melena. 10% of these tumors would have been metastasized to the liver and 40 to 60% to local lymph nodes at the time of initial presentation itself as seen in Case 3. Colonic NETs arise from Kulchitsky cells located within the crypts of Lieburkuhn of the colon and are more commonly seen in the right colon with cecal predominance. Pre-operative evaluation of these tumors include ultrasonography, CT scan, or a PET CT. Currently, DOTANOC PET-CT is been regarded as a promising tool for detecting metastasis in NETs with high sensitivity and specificity in visual and semiquantitative assessment and is considered better than 18F-FDG PET-CT [6]. Thus two of our patients (Cases 3 and 4) were diagnosed with metastatic lesions in the liver confirming neuroendocrine origin pre-operatively itself. Patients with suspected NETs on radiology are usually advised to undergo tumor marker evaluation in plasma, serum, or urine, for 5-hydroxy indole acetic acid (5-HIAA), chromogranin A (CgA), serotonin, neuron-specific enolase (NSE), neurokinin A, E-cadherin, or neuropeptide K which have been recognized and studied significantly over a period of time. Also, many literature studies have shown neuron-specific enolase associated with high specificity (100%) with varying sensitivity (32%) as a serum marker for NETs [7]. There has been a variety of site-specific terminologies and criteria used in the pathologic classifications of neuroendocrine tumors across different organ systems. The European Neuroendocrine Tumor Society had proposed tumor–node–metastasis grading systems to classify these tumors from Grade 1 to Grade 3 considering proliferative indices Ki-67 in the years 2005 and 2006 [8]. WHO has classified gastroenteropancreatic (GEP) NETs into two categories based on Ki-67 proliferation indices: well differentiated (Grade 1 and 2) and poorly differentiated (Grade 3) in 2010 [9, 10]. The most commonly used histologic classification schemes include both the European Neuroendocrine Tumor Society and WHO systems which incorporate mitotic rate and Ki-67 index (Table 2) [10].Tumor differentiation and tumor grade often correlate with mitotic count and Ki-67 proliferation index. The treatment options are outlined based on tumor characterization (primary site, histopathological diagnosis, and staging) considering patient’s clinical picture, prior treatments, and comorbidities. They include surgical resection of locally invasive tumors, targeted chemotherapy, peptide receptor radionuclide therapy (PRRT), immunotherapy, liver-directed treatment like radiofrequency ablation (RFA) for small metastatic tumors, and hepatic artery embolization, which when combined with chemotherapy is called chemoembolization. Our case series emphasizes the increasing prevalence of these tumors especially in rural population of Southern India within a short span of 9 months with lymph nodal and hepatic metastasis at the time of initial presentation itself. This also indicates that these tumors can be silent nonfunctional until advanced stages of the disease.

Table 2.

WHO classification of NET (2019) [11]

Differentiation	Grade	GI-NET (excluding pancreas)
Well differentiated	Low grade (G1)	< 2 mitoses/10 Hpfs and/or < 3% Ki-67 index
	Intermediate grade (G2)	2–20 mitoses/10 Hpfs and/or 3–20% Ki-67 index
	High grade (G3)	> 20 mitoses/10 Hpfs and/or > 20% Ki-67 index
Poorly differentiated	High grade (G3)	> 20 mitoses/10 Hpfs and/or > 20% Ki-67 index

Conclusion

NETs in India have a different clinicopathological profile compared to those in Western countries. Majority of the patients have metastatic disease at initial presentation, highlighting the importance of raising awareness among patients and the medical community. More multi-institutional research studies are needed for better understanding of the epidemiological, clinical features, and to develop recommendations for optimal treatment of this previously “rare” yet “not so rare” disease. With the increasing prevalence of these tumors over the last decade early screening and diagnosis with early intervention plays a pivotal role in modifying the due course of the disease.

Data Availability

The authors confirm that the data supporting the findings of this study are available within the article.

Declarations

Consent to Participate

The authors certify that they have obtained all appropriate patient consent forms.

Conflict of Interest

The authors declare no competing interests.