“Not-So-Indolent” neuroendocrine neoplasms: two case reports of gastrointestinal small cell neuroendocrine carcinomas
Case Report

“Not-So-Indolent” neuroendocrine neoplasms: two case reports of gastrointestinal small cell neuroendocrine carcinomas

Ali Dashti1 ORCID logo, Hyun Jae Kim1, Andrew Fetz1, Jenny Chu2, David Farnell2, David F. Schaeffer2, Seng Ian Gan1, Sarvee Moosavi1

1Division of Gastroenterology, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada; 2Division of Anatomical Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada

Contributions: (I) Conception and design: A Dashti, S Moosavi, SI Gan; (II) Administrative support: S Moosavi; (III) Provision of study materials or patients: J Chu, D Farnell, DF Schaeffer; (IV) Collection and assembly of data: A Dashti, HJ Kim, A Fetz; (V) Data analysis and interpretation: A Dashti, S Moosavi, SI Gan; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Ali Dashti, MD. Division of Gastroenterology, Vancouver General Hospital, University of British Columbia, 5153-2775 Laurel Street, Vancouver, British Columbia, Canada. Email: drahdashti@gmail.com.

Background: Small cell neuroendocrine carcinomas (SCNECs) of the gastrointestinal (GI) tract are exceedingly rare and aggressive malignancies. Unlike pulmonary SCNECs, which are well-characterized, extrapulmonary GI-SCNECs lack established diagnostic pathways and treatment algorithms due to their rarity and histopathological overlap with other poorly differentiated tumors. Literature on their clinical course remains limited to isolated reports, with scarce data on site-specific presentations. These two cases contribute to the existing literature by illustrating distinct primary GI sites (gastric and rectal), underscoring the challenges in early diagnosis and the aggressive clinical progression despite intervention.

Case Description: The first patient, an 80-year-old man, presented with progressive dysphagia and dyspnea. Imaging revealed mediastinal lymphadenopathy and gastric wall thickening. Endoscopic biopsies confirmed gastric SCNEC with widespread metastases. Despite initiation of palliative care, his condition deteriorated rapidly, and he died one month after diagnosis. The second patient, a 69-year-old man, presented with significant weight loss and lower abdominal pain. Colonoscopy identified a circumferential rectal mass, and biopsies confirmed SCNEC. Staging demonstrated hepatic and nodal metastases. He received platinum-based chemotherapy and pelvic radiotherapy, achieving only transient stabilization. Following treatment cessation, his disease progressed, and despite resuming chemotherapy, he died 11 months after diagnosis.

Conclusions: These cases emphasize the necessity for heightened clinical suspicion of SCNEC in rapidly progressive GI malignancies, even in atypical presentations. Early recognition and multidisciplinary management are crucial, although current therapeutic options offer limited durability. By delineating site-specific clinical courses, this report contributes to the limited body of evidence on GI-SCNECs and underscores the urgent need for standardized diagnostic criteria and treatment protocols to improve outcomes.

Keywords: Small cell carcinoma; gastrointestinal neuroendocrine carcinoma (GI-NEC); gastric ulcer; rectal mass; case report

Received: 12 March 2025; Accepted: 03 July 2025; Published online: 28 October 2025.

doi: 10.21037/acr-2025-71

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Key findings

• Gastrointestinal small cell neuroendocrine carcinomas (GI-SCNECs) exhibit aggressive clinical behavior with rapid progression and poor response to conventional therapies, even when managed within a multidisciplinary framework.

What is known and what is new?

• GI neuroendocrine neoplasms (NENs) are typically indolent; however, small cell variants represent a rare, poorly differentiated subset with markedly aggressive biology and poor prognosis.

• These two cases—one gastric, one rectal—underscore the diverse primary sites of GI-SCNECs and illustrate their uniformly aggressive course, rapid clinical decline, and limited therapeutic durability despite early intervention. This reinforces the need to differentiate SCNECs from other NENs at initial presentation.

What is the implication, and what should change now?

• Clinicians should maintain a high index of suspicion for SCNEC in patients presenting with rapidly progressive GI malignancies. Prompt histologic differentiation is critical to guide realistic prognostication and initiate early palliative strategies, given the current lack of effective systemic treatments for this aggressive entity.

Introduction

Neuroendocrine neoplasms (NENs) encompass a diverse group of tumors arising from epithelial cells with neuroendocrine characteristics. They are rare, with an estimated incidence of approximately 0.1 cases per 100,000 population annually, and can originate in various anatomical sites, including the gastrointestinal (GI) tract (1). Most GI-NENs present as well-differentiated tumors with an indolent clinical course. However, a rare subset, known as gastrointestinal neuroendocrine carcinomas (GI-NECs), are poorly differentiated, high-grade tumors characterized by aggressive clinical behavior and poor prognosis (2).

Although survival outcomes vary by site and treatment, patients with localized GI-NECs who undergo surgery or chemoradiotherapy may achieve median survivals ranging from 11 to 49 months. In contrast, those with metastatic disease typically have significantly worse outcomes, with median overall survival ranging from 5.8 to 19 months despite systemic therapy (2).

Herein, we present two cases of the small cell variant of GI-NEC arising from the stomach and rectum, highlighting the aggressive nature of these tumors. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-71/rc).

Case presentation

All procedures performed in this study were conducted in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patients or their next-of-kin for the publication of this case report and accompanying images. Copies of the written consents are available for review by the editorial office of this journal.

Case 1

An 80-year-old previously healthy man presented to a tertiary hospital with two weeks of dyspnea, along with progressive solid food dysphagia and weight loss over one month. He had no significant medical history, family history, or psychosocial factors relevant to his current presentation. The primary concern was a rapidly worsening inability to swallow solid foods, associated with profound fatigue and a marked decrease in appetite. A computed tomography (CT) scan revealed extensive circumferential mural thickening involving a long segment of the esophagus, as well as the entire stomach and duodenum, accompanied by regional lymphadenopathy and bilateral pleural effusion (Figure 1).

Figure 1 Computed tomography scan for patient 1 showing marked gastric wall thickening (arrow).

Esophagogastroduodenoscopy (EGD) demonstrated a large gastric ulcer with a necrotic base involving most of the lesser curvature (Figure 2). There was also luminal narrowing and mucosal friability extending from the mid-esophagus to the gastroesophageal junction. Biopsies from both sites showed infiltration by poorly differentiated cells with hyperchromatic, angulated nuclei, nuclear molding, and minimal cytoplasm. Immunohistochemistry was positive for AE1/AE3, synaptophysin, and chromogranin, and negative for TTF1, CD3, and CD20, confirming neuroendocrine and epithelial differentiation. The Ki-67 proliferation index exceeded 80%, consistent with a high-grade tumor (Figure 3). These findings supported a diagnosis of pure small cell neuroendocrine carcinoma (SCNEC). Cytological analysis of pleural fluid obtained via thoracentesis revealed similar small cell morphology, confirming metastatic disease; however, no cytology image was available for publication.

Figure 2 Esophagogastroduodenoscopy for patient 1 showing a deep and massive gastric ulcer involving most of the lesser curvature of the stomach with necrotic base.
Figure 3 Histopathological and immunohistochemical analysis of the esophageal biopsy for patient 1. Hematoxylin and eosin staining shows invasion of the lamina propria by poorly differentiated hyperchromatic cells with minimal cytoplasm (top left; ×40). Tumor cells stained positive for chromogranin A (top right) and synaptophysin (bottom left). Ki-67 immunostaining demonstrated a high proliferative index exceeding 80% (bottom right; ×40).

The patient continued to experience dysphagia despite esophageal stent insertion. His case was reviewed by the oncology service; however, he was deemed unsuitable for palliative chemotherapy due to increasing frailty, likely secondary to rapidly progressive disease, reduced oral intake, and significant weight loss. He subsequently underwent a course of palliative radiotherapy targeted to the esophagus and stomach with the aim of relieving obstruction. Unfortunately, clinical benefit was minimal, and the patient’s condition deteriorated rapidly, with persistent dysphagia and respiratory failure secondary to malignant pleural effusions. Given his poor prognosis and ongoing clinical decline, he was transferred to hospice care and died approximately one month after his initial presentation.

A detailed timeline of clinical events, interventions, and outcomes is summarized in Table 1.

Table 1

Timeline of clinical events, interventions, and outcomes for case 1

Timeline Clinical events Interventions Outcomes
Week −4 Onset of progressive dysphagia and weight loss – –
Week −2 Development of dyspnea – –
Day 0 (presentation) CT scan revealed extensive gastrointestinal involvement and metastatic pleural effusions – –
Day +2 Dysphagia, luminal narrowing, necrotic gastric ulcer EGD with biopsy confirming small cell NEC Diagnosis established
Day +7 Persistent dysphagia Esophageal stent placement Partial symptomatic relief
Day +14 Ongoing dysphagia, progressive disease Initiation of palliative radiotherapy targeted to gastric lesion Minimal clinical benefit
Day +30 Respiratory failure from malignant pleural effusions, poor performance status Transferred to hospice care Death

CT, computed tomography; EGD, esophagogastroduodenoscopy; NEC, neuroendocrine carcinoma.

Patient’s family perspective

Our father had always been healthy, so when he started having trouble swallowing, we didn’t expect it to be something serious. But within a few weeks, he became very weak and lost a lot of weight. He could barely eat or move. When the doctors told us he had a very aggressive type of cancer that had already spread, it was a huge shock. The doctors were kind and explained that treatment would be difficult and might not help much. He had a stent placed and received radiotherapy to try to help him swallow, but it didn’t make a big difference. He became weaker every day and eventually struggled to breathe due to fluid in his lungs. The palliative care team helped keep him comfortable, and we were thankful for that.

Case 2

A 69-year-old man presented to a tertiary hospital with a three-month history of right upper quadrant abdominal pain and a 30-pound weight loss. Apart from hypertension, his medical history was otherwise non-contributory, and he had no relevant family history or notable psychosocial factors. A whole-body CT scan demonstrated numerous hepatic lesions along with a vertebral sclerotic lesion, raising concern for metastatic disease, with no evidence of cirrhosis (Figure 4).

Figure 4 CT imaging for patient 2 demonstrating metastatic disease. The left panel shows a coronal CT of the abdomen with multiple hypodense hepatic lesions consistent with metastases; one representative lesion is indicated by the white arrow. The right panel shows an axial CT of the chest demonstrating pulmonary nodules suspicious for metastatic disease; the black arrow highlights a nodule. CT, computed tomography.

EGD and colonoscopy were performed to evaluate for a GI primary. EGD revealed no abnormalities in the esophagus, stomach, or duodenum. Colonoscopy identified a large rectal lesion resembling a submucosal tumor with a friable surface (Figure 5).

Figure 5 Colonoscopy for patient 2 showing a submucosal lesion-like tumor with friable surface in the rectum. Biopsy confirmed rectal small cell neuroendocrine carcinoma.

Biopsy of the lesion demonstrated solid sheets of atypical, poorly differentiated cells with nuclear molding (Figure 6). Biopsy of the rectal mass revealed a poorly differentiated carcinoma composed of solid nests of atypical cells with nuclear molding and high mitotic activity (Figure 6). Immunohistochemistry was positive for CK7, CK20, synaptophysin, and chromogranin, with a Ki-67 proliferation index of 95%, consistent with a high-grade NEC. No squamous or adenocarcinoma components were identified. The sclerotic vertebral and hepatic lesions were considered metastatic deposits from the rectal NEC.

Figure 6 Histopathological and immunohistochemical analysis of the rectal tumor biopsy for patient 2. Hematoxylin and eosin staining shows infiltration of the submucosa by poorly differentiated hyperchromatic cells with scant cytoplasm (top left; ×40). Tumor cells demonstrate immunoreactivity for chromogranin A (top right) and synaptophysin (bottom left). Ki-67 immunostaining shows a high proliferative index exceeding 80% (bottom right; ×40).

After review with medical oncology, he was started on palliative carboplatin and etoposide chemotherapy. His prognosis was deemed poor with an expected survival of less than 3 months without therapy and 12 months with chemotherapy. The patient tolerated 6 cycles of carboplatin and etoposide with a repeat CT scan demonstrating stable mild reduction in liver metastasis and progression of bony metastatic disease. Unfortunately, after a brief 4-week treatment break, the patient had clinical and radiographic evidence of disease progression, and thus he was started on another 4-6 cycles of carboplatin and etoposide. He was also referred to radiation oncology for consideration of palliative radiation for disease control/symptom management of his diffuse bone disease. The patient died 11 months after diagnosis.

A detailed timeline of clinical events, interventions, and outcomes is summarized in Table 2.

Table 2

Timeline of clinical events, interventions, and outcomes for case 2

Timeline Clinical events Interventions Outcomes
Month −3 Onset of abdominal pain and significant weight loss – –
Day 0 (presentation) CT revealed hepatic and vertebral lesions; colonoscopy demonstrated rectal mass – –
Day +3 Rectal mass biopsied, confirming small cell NEC – Diagnosis established
Day +10 Poor prognosis discussed Initiation of palliative chemotherapy (carboplatin + etoposide) Partial disease control
Month +6 Stable pulmonary disease; mild hepatic improvement; progression of bony metastases Completed 6 cycles of carboplatin + etoposide Mixed treatment response
Month +7 Clinical and radiographic progression Restarted carboplatin + etoposide; referred to radiation oncology for palliative radiotherapy Disease progression despite treatment
Month +11 Clinical deterioration Supportive care only Death

CT, computed tomography; NEC, neuroendocrine carcinoma.

Patient perspective

I started having pain in my stomach that wouldn’t go away, and I was losing weight fast. When the doctors told me it was cancer that had spread to my liver and bones, it was very difficult news. The treatments did not cure it, but they helped control the pain for a time. I was frustrated that I couldn’t do the things I used to, but I appreciated that the doctors were honest with me and focused on keeping me as comfortable as possible.

Discussion

NENs are tumors arising from epithelial cells that exhibit neuroendocrine features and can occur throughout the body. GI-NENs represent a spectrum of neoplasms with significant diversity in clinical behavior, ranging from indolent, well-differentiated NETs to poorly differentiated, aggressive GI-NECs (3). According to the updated World Health Organization (WHO) classification of GI-NENs, GI-NECs can be further subdivided into small cell and large cell types, similar to the classification system used for pulmonary NECs (4-7). Although these subtypes differ histologically, they are phenotypically similar, both exhibiting highly aggressive clinical behavior.

While NENs most commonly originate in the GI tract, GI-NENs remain rare, accounting for only 0.1–2% of all GI neoplasms (8-10). GI-NECs are even rarer, comprising approximately 20% of GI-NENs, with 50–70% of cases presenting with metastatic disease at the time of diagnosis. Among GI-NECs, gastric and rectal locations represent approximately 15–20% and 20–25% of cases, respectively (11).

The clinical presentation of GI-NECs is often nonspecific, leading to delayed diagnosis and advanced disease at the time of presentation. Patients are typically asymptomatic in the early stages and frequently present with symptoms related to metastatic disease. This is partly due to the fact that GI-NECs are non-functioning neoplasms and are not associated with carcinoid syndrome or other hormonal hypersecretory states. The endoscopic appearance of GI-NECs can be variable but commonly includes submucosal tumor-like lesions or ulcerations with distinct margins, as observed in our cases (12).

Histopathological confirmation is essential to avoid misclassification. GI-NECs are characterized by positive immunohistochemical staining for neuroendocrine markers such as synaptophysin and chromogranin A. They are also defined by a high proliferation rate, with a Ki-67 index greater than 20%, which correlates with the poor oncologic prognosis associated with these malignancies (11,13).

Despite advances in the recognition and understanding of GI-NENs, the prognosis of GI-NECs remains extremely poor, with a median survival of less than 12 months (14). Gastric NEC, for example, is considered to have a worse prognosis than gastric adenocarcinoma (15,16). This poor outcome is likely multifactorial, reflecting tumor aggressiveness, delayed diagnosis, and limited responsiveness to conventional treatment. Additionally, there is no established standard oncologic treatment regimen.

Recent consensus guidelines from the North American Neuroendocrine Tumor Society (NANETS) recommend multidisciplinary evaluation and consideration of chemoradiation with or without surgical excision for localized GI-NECs (14). The role of surgery, even in localized disease, remains uncertain due to high relapse rates observed following radical resections (17). For metastatic GI-NECs, palliative systemic chemotherapy is recommended, with platinum and etoposide being the most used regimens. Although a clinical trial is currently underway to evaluate the addition of immunotherapy, there are no formal recommendations for its use currently (14).

Conclusions

GI-NECs are rare but highly aggressive tumors within the spectrum of GI-NENs. Our case reports underscore the diagnostic and therapeutic challenges associated with GI-NECs, which are defined by aggressive behavior, delayed diagnosis, and limited treatment options. Despite advances in diagnostic modalities and treatment strategies, the prognosis remains poor, with a high incidence of distant metastasis at presentation and limited response to current therapies. Further research is warranted to develop strategies for earlier detection and more effective treatments, including the potential role of immunotherapy. Clinicians should maintain a high index of suspicion for NEC in rapidly progressive GI malignancies to facilitate timely diagnosis and intervention.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-71/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-71/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-71/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were conducted in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patients or their next-of-kin for the publication of this case report and accompanying images. Copies of the written consents are available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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doi: 10.21037/acr-2025-71
Cite this article as: Dashti A, Kim HJ, Fetz A, Chu J, Farnell D, Schaeffer DF, Gan SI, Moosavi S. “Not-So-Indolent” neuroendocrine neoplasms: two case reports of gastrointestinal small cell neuroendocrine carcinomas. AME Case Rep 2025;9:154.

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