Neuroendocrine tumors (NETs) are rare neoplasms arising from peptide-producing neuroendocrine cells and account for less than 1% of all malignancies.1 Within the gastrointestinal tract, carcinoid tumors are most frequently located in the appendix, followed by the ileum, rectum, and stomach.2 Duodenal NETs (D-NETs) constitute only 0.4%–1.8% of gastrointestinal malignancies, making them particularly uncommon, with an estimated incidence of 0.7 per 100,000 population.3 D- NETs are rare neoplasms of gastrointestinal tract often detected incidentally during endoscopy. Their clinical pattern, endoscopic appearance and histopathological spectrum are variable.3 D- NETs represent 1%–3% of all gastrointestinal NETs.2 They show a slight male predominance and usually occur in older individuals, with the average age at diagnosis between 50 and 60 years .4 The detection of duodenal carcinoids has increased in recent years due to widespread use of upper gastrointestinal endoscopy, improved accessibility to endoscopic procedures and advances in imaging techniques, especially computed tomography (CT), facilitating early diagnosis even in asymptomatic individuals.5 We report a case series of D-NETs identified in symptomatic patients during routine diagnostic upper gastrointestinal (GI) endoscopy. The diagnosis was further confirmed by histopathological evaluation supported by immunohistochemical staining.

CASE PRESENTATION We report six cases of D-NETs encountered in our institute. The patients included were four females and two males, with ages ranging from 40 to 75 years. The most common presenting complaints were pain abdomen and melena. Endoscopic evaluation revealed mucosal erosion in four cases, correlating clinically with symptoms of melena. In one patient two nodular lesions with overlying mucosal ulceration was identified. Central umbilication was observed in one lesion (Fig-1), representing a characteristic endoscopic feature of neuroendocrine tumors. In one case, a polypoidal lesion was identified in the second part of the duodenum (D2), extending into the duodenal bulb Histopathological examination revealed well-differentiated NET in six cases, while one case exhibited moderately differentiated NET. Tumor cells were arranged in nests, trabeculae, insular patterns, and rosettes (Fig 2, 4, 5). The cells displayed uniform round nuclei with finely granular “salt and pepper” chromatin and moderate amount of cytoplasm (Fig 3–7). The grading was assigned according to WHO classification criteria based on proliferative activity. Immunohistochemistry analysis demonstrated diffuse cytoplasmic positivity for synaptophysin and chromogranin in all cases, confirming neuroendocrine differentiation (Fig 8–11). The Ki-67 labeling index ranged from 0.2% to 4%. Five tumors had a Ki-67 index <3%, consistent with WHO Grade I NETs (Fig 12). One tumor showed a Ki-67 index of 4%, corresponding to a Grade II NET (Fig 13). None of the tumors in this series were clinically functional. CASE SERIES Case 1: A 61-year-old female presented with epigastric pain of two weeks duration and recurrent episodes of non bilious vomiting. No history of hematemesis or melena. No prior history of peptic ulcer disease. Past medical history was significant for diabetes. On examination her vitals were stable. No palpable mass. Lab investigations revealed normal counts. Serum amylase and lipase were normal. Ultrasound abdomen was normal. No organomegaly. Upper GI endoscopy revealed a single nodular lesion in the first part of the duodenum with mucosal erosion. Surrounding mucosa appeared unremarkable. Histopathological examination showed a well-differentiated neuroendocrine tumor. Immunohistochemistry demonstrated diffuse positivity for Chromogranin and Synaptophysin, and Ki-67 proliferation index was 2%, consistent with a WHO grade 1 neuroendocrine tumor. Considering the small lesional size, low proliferative index, and absence of invasive or metastatic disease, the lesion was managed with endoscopic resection followed by proton pump inhibitor therapy and regular endoscopic follow-up. Her post op was uneventful. Case 2: A 40-year-old female presented with epigastric pain and nausea. No history of flushing or diarrhoea. Routine blood work up showed normal profile. On examination, her vitals were stable, no organomegaly. Upper gastrointestinal endoscopy revealed a polypoidal lesion measuring 1.0 × 1.1 cm in the second part of the duodenum extending into the duodenal bulb, with surface erosion. The lesion was amenable for endoscopic biopsy. Biopsy revealed a moderately differentiated neuroendocrine tumor without lymphovascular invasion, with immunopositivity for Chromogranin A and Synaptophysin. The Ki-67 index was 4%, corresponding to a WHO grade 2 tumor. In view of the lesion size, intermediate proliferative activity, and absence of metastatic disease, endoscopic resection was performed, and the patient was advised close clinical monitoring with periodic endoscopic and radiological assessment. Case 3: A 48-year-old male presented to gastroenterology OPD with complaints of epigastric pain and intermittent episodes of melena for approximately 4 weeks. Patient denied any significant weight loss or altered bowel habits. He was not on any NSAIDs. Past medical and surgical history was unremarkable. On examination mild pallor was noted. Per abdomen examination demonstrated mild epigastric tenderness. No organomegaly. Hemoglobin was 8 gm/dl. LFT, RFT and serum electrolytes were within normal limits. Upper gastrointestinal endoscopy demonstrated a single sessile polypoidal lesion measuring 0.5 cm in the first part of the duodenum with mucosal erosion with active bleed. Histopathology revealed a well-differentiated submucosal neuroendocrine tumor with rare mitosis. Overlying mucosa showed erosion. Strong Chromogranin A and Synaptophysin positivity and a Ki-67 index of 0.4% was noted in IHC stains. Given the small lesion size and very low proliferative activity, complete endoscopic excision was undertaken, and the patient was advised routine endoscopic follow-up. Case 4: A 48-year-old female presented with blackish discolouration of stools and associated generalised weakness. There was no history of diarrhoea, pain abdomen or vomiting. Had no significant past history. No history of liver disease or peptic ulcer. Her menstrual history was unremarkable. She was not on any medications. Mild pallor was noted. Digital rectal examination confirmed melena. Lab findings showed Hb 7.9 gm/dl, other counts are WNL. Coagulation profile was normal. Endoscopic evaluation revealed two nodular lesions in D1 measuring 0.6 and 0.8 cm. Both lesions demonstrated underlying mucosal ulceration. Contrast enhanced CT showed no evidence of local invasion. No regional lymph nodes. The patient was managed with endoscopic treatment of both lesions. Histopathological examination confirmed a well-differentiated NET with diffuse neuroendocrine marker positivity and a Ki-67 index of 0.2%, consistent with WHO grade 1. In this case absence of endocrine symptoms and lack of family history favoured sporadic etiology. Patient was managed with close clinical follow up every 6 months and periodic endoscopic surveillance in view of the multifocal nature of the disease. Case 5: A 52-year-old male presented to the emergency department with epigastric pain and melena. There was no history of diarrhoea, hematemesis or vomiting. His past medical history was unremarkable and was not on any medications. On examination he was hemodynamically stable with mild pallor and abdomen was soft with mild epigastric tenderness. Lab investigation revealed microcytic hypochromic anemia (Hb 9 gm/dl). Coagulation profile was normal. Organ function tests were normal. Upper gastrointestinal endoscopy was performed to evaluate potential bleeding source and it showed a single nodular lesion in the first part of the duodenum. Histological examination demonstrated a well-differentiated neuroendocrine tumor with immunopositivity for chromogranin and synaptophysin and a Ki-67 index of 0.8%. Owing to the localized nature of the tumor and low proliferative index, a complete endoscopic resection was performed, followed by periodic endoscopic evaluation. Case 6: A 75-year-old female presented with generalised weakness and easy fatiguability since 3 months. On further enquiry she gave a history of passing intermittent dark coloured stools over past few weeks which she had considered insignificant. She had well controlled hypertension past 10 years. No history of liver disease. Family history was not contributory. She was hemodynamically stable. Vitals were WNL. No icterus, cyanosis or lymphadenopathy. Her stool tested positive for occult blood. Hb was 8 gm/dl and smear showed microcytic hypochromic anemia. Serum ferritin was reduced. Counts were within normal limits. Upper gastrointestinal endoscopy revealed a nodular lesion measuring approximately 1 cm in the first part of the duodenum with central umbilication. Histopathological examination showed a well-differentiated neuroendocrine tumor with diffuse Chromogranin and Synaptophysin positivity and Ki-67 index of 0.4%. Considering the patient’s age, lesion characteristics, and absence of metastatic disease, endoscopic resection was carried out along with correction of anemia, and the patient was advised regular clinical and endoscopic assessment.

D-NETs account for nearly 1–3% of all gastroenteropancreatic (GEP) neuroendocrine neoplasms, most of which are sporadic and non-functional. Notably, more than 90% of D-NETs do not produce a functional clinical syndrome, and less than 30% are associated with hormone-related symptoms.³˒⁶ Most D-NETs arise in the first or second part of the duodenum.³˒⁶ These tumors are primarily non-functional and may remain asymptomatic in the early stages. Symptoms typically appear only when the tumor grows or invades surrounding tissues. Early symptoms are often non-specific, making the diagnosis of NETs challenging. These tumors most commonly present in the 4th decade of life and show a higher incidence in males.⁶ The majority of GEP-NETs that are non-functional present with non-specific clinical features, including abdominal pain, nausea, vomiting, upper GI bleeding, anorexia, melena or jaundice.⁷ In our study, there were six cases: four females and two males, aged 40–75 years. All patients presented with non-specific symptoms such as abdominal pain, nausea, generalised weakness and melena. None of the patients showed features related to hormone secretion, such as carcinoid syndrome, Cushing’s syndrome, Zollinger–Ellison syndrome, or acromegaly.⁸˒¹¹ D-NETs are typically small, solitary lesions, with the majority measuring less than 2 cm in diameter.⁹ They are commonly described as submucosal nodules exhibiting a hemispherical shape or presenting as flat elevated lesions. Their surface usually appears yellowish in colour, resembling the adjacent mucosa.⁹˒¹⁰ As these tumors enlarge, they may become depressed at the center with central umbilication or ulceration due to cystic change.⁹ Most tumors are confined to the mucosa or submucosa.¹⁰ The incidence of lymph node and liver metastasis is low.⁸˒¹²˒¹³ The 5-year survival rate among patients with well-differentiated D-NETs is 80–85%, compared to 72% in those with well-differentiated neuroendocrine carcinoma (NEC).¹¹˒¹⁴ According to the European Neuroendocrine Tumor Society (ENETS)¹⁵ consensus guidelines, D-NETs are divided into five subtypes, which include: 1. Gastrinomas (50–60%) 2. Somatostatin-producing tumors (15%) 3. Non-functional serotonin-containing tumors (13–27%) 4. Poorly differentiated neuroendocrine carcinomas (<3%) 5. Gangliocytic paragangliomas (2%) Some of the differential diagnoses for D-NETs include: gastrointestinal stromal tumors (GISTs), adenomas, adenocarcinomas, Brunner gland hyperplasia and heterotopic gastric mucosa.¹⁶ The diagnosis of D-NETs is established through histological and immunohistochemical examinations. Chromogranin A, synaptophysin, PGP 9.5, and non-specific enolase are the most sensitive and specific markers in the detection of neuroendocrine tumors.¹⁷ Studies show that 45–100% of duodenal carcinoids test positive for Chromogranin A, 80–100% for non-specific enolase and 91% for synaptophysin.¹⁸˒¹¹ In general, the most sensitive methods for locating NETs include computed tomography, magnetic resonance imaging (MRI), and somatostatin receptor scintigraphy (SRS). In the case of duodenal tumors, SRS is useful as a specific imaging modality, considering that >75% of these tumors measure under 1 cm.¹⁹ Studies indicate that conventional imaging techniques detect <15% of tumors smaller than 1 cm, whereas SRS identifies approximately 50%.²⁰˒²¹ To identify primary tumors, upper gastrointestinal endoscopy remains the most sensitive method. It may be complemented with endoscopic ultrasound (EUS) when possible, particularly for assessing local extension. For complete staging, spiral CT/MRI and SRS are recommended.¹⁹ The pathological diagnosis of NETs involves several essential components. First, confirmation of the neuroendocrine nature of the tumor is achieved by demonstrating positivity for NET markers such as synaptophysin and chromogranin A on immunohistochemistry. Next, assessment of the proliferative activity of the tumor is a key factor in grading. The proliferative activity is evaluated by: i) Mitotic count (number of mitotic figures per 10 high-power fields), and ii) Ki-67 index (percentage of tumor cells showing nuclear labelling). According to the WHO classification, NETs are divided into three grades based on mitotic rate and Ki-67 index (Table 2).²³ G1 and G2 tumors are classified as well-differentiated NETs, whereas G3 tumors are categorized as neuroendocrine carcinomas (NECs).²² For accurate grading of NETs, it is essential to count at least 50 high-power fields in the most mitotically active regions.²³ The optimal management for these tumors is surgical excision, performed either endoscopically or surgically, depending on the size and characteristics of the lesion. For small polypoid tumors (<4 cm) located in the duodenal bulb, endoscopic polypectomy can serve as an effective therapeutic approach. Before undertaking therapeutic intervention, it is essential to exclude local lymph-node metastasis, preferably through endoscopic ultrasonography (EUS). Following treatment, careful endoscopic surveillance is required to rule out local recurrence of the tumor.²³

This case series highlights the predominance of well-differentiated, low-grade D-NETs. The patients ranged widely in age with female predominance and commonly presented with non specific symptoms like epigastric pain, nausea and features of upper GI bleeding. Notably none of the cases demonstrated classical clinical carcinoid syndrome and most lesions were detected incidentally during endoscopic evaluation. Endoscopic evaluation typically revealed small nodular or polypoidal lesions, some with erosive changes. Histopathological examination, along with confirmation by neuroendocrine immunohistochemical markers, remained crucial for accurate diagnosis. Small tumor size and low proliferative activity allowed successful management with endoscopic resection in all cases and patients were advised periodic endoscopic surveillance. Overall this case series highlights importance of early endoscopic evaluation in patients presenting with anemia or upper gastrointestinal symptoms.

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