Long-Term Complete Response of Unresectable Small-Cell Neuroendocrine Carcinoma of the Gallbladder following Chemotherapy and Radiotherapy: A Case Report

Abstract

Introduction

Small-cell neuroendocrine carcinoma of the gallbladder (SCNEC-GB) is an exceptionally rare and aggressive malignancy, representing fewer than 2% of gallbladder cancers. Most patients present with advanced, unresectable disease, and survival rarely exceeds 1 year despite therapy.

Case Presentation

We describe a patient in whom SCNEC-GB was discovered incidentally during routine preoperative workup for hernia repair. Imaging revealed a bulky gallbladder mass with hepatic invasion and regional lymphadenopathy; pathology confirmed SCNEC with a Ki-67 of 100%. A multidisciplinary tumor board deemed the tumor unresectable, and systemic treatment was initiated. The patient received 6 cycles of platinum-etoposide chemotherapy, which achieved marked regression, followed by hypofractionated radiotherapy to the residual primary and nodal sites. Follow-up PET/CT demonstrated a complete radiological and metabolic response. The patient has now maintained long-term disease control for more than 18 months, with no evidence of recurrence or new metastases. Such durable remission in advanced SCNEC-GB is extraordinarily uncommon.

Conclusions

This case highlights the potential of multimodal therapy to achieve long-term disease control in unresectable disease and underscores the need for collaborative efforts to define optimal strategies for this rare and lethal malignancy.

Introduction

Neuroendocrine neoplasms (NENs) account for approximately 1% of all malignancies, most frequently arising in the gastrointestinal tract (66%) and respiratory system (31%) [1]. Gallbladder neuroendocrine carcinomas (GB-NECs) are exceedingly rare, comprising approximately 0.3–0.5% of all NENs and 0.5–2% of gallbladder cancers [1–3]. The small-cell subtype (small-cell neuroendocrine carcinoma of the gallbladder [SCNEC-GB]) is the most aggressive form, typically presenting at advanced stages with early hepatic and lymphatic spread [4].

Population-based analyses, such as those from the SEER database, indicate a dismal prognosis, with a median overall survival (OS) of approximately 7 months, a 1-year OS of 36.6%, and a 5-year OS of only 7.3% [5]. Some surgical series report median OS up to 19–23 months in operable cases [6], but the majority of patients present with disease that precludes curative resection.

Unlike adenocarcinoma of the gallbladder, which has established treatment guidelines, SCNEC-GB lacks standardized recommendations because of its rarity. Radical surgery offers the best prognosis in localized cases, whereas systemic therapy remains the mainstay for advanced disease; platinum-etoposide chemotherapy is empirically adopted from small-cell lung cancer protocols [7]. Radiotherapy has historically been underutilized, but advances in image-guided and intensity-modulated techniques now allow precise delivery to complex upper-abdominal targets [8].

We present a rare case of advanced, unresectable SCNEC-GB in which the integration of systemic chemotherapy and high-precision hypofractionated image-guided radiotherapy delivered with VMAT achieved long-term disease control exceeding 18 months. In view of the exceptional nature of this outcome, we provide a comparative analysis of published cases to situate our findings within the broader clinical experience.

Case Report

A 74-year-old female patient was referred after the incidental detection of a liver lesion during preoperative workup for hernia repair. She had no history of chronic liver disease, cirrhosis, alcohol abuse, or chronic viral hepatitis and presented with no significant jaundice or constitutional symptoms. Routine laboratory testing was unremarkable. Tumor markers CEA and CA 19-9 were within normal limits.

Initial Imaging and Staging

Baseline contrast-enhanced CT demonstrated a bulky tumor replacing the gallbladder with invasion into liver segments S5-S6 and partially S4b, with lymphadenopathy in the porta hepatis, para-aortic region, and a mesenteric node. No thoracic metastases were detected. Upper endoscopy revealed external compression of the antrum and duodenal bulb without obstruction. Whole-body 18F-fluorodeoxyglucose (FDG) PET/CT demonstrated a hypermetabolic gallbladder mass with hepatic invasion and hypermetabolic nodal disease in the porta hepatis, para-aortic, and mesenteric regions, with minimal pelvic effusion (Fig. 1). Because SCNEC-GB lacks pathognomonic imaging features and remains essentially a diagnosis of exclusion, dedicated systemic evaluation including chest, abdominal, and pelvic imaging together with whole-body 18F-FDG PET/CT was performed to rule out a non-gallbladder primary; no extra-biliary primary lesion was identified.

Fig. 1.

Whole-body PET/CT with ¹⁸F-FDG shows hypermetabolic gallbladder mass with contiguous invasion into hepatic segments S5–S6 and partially S4b, measuring up to 143 mm, SUVmax 10.7 (red arrows); hypermetabolic metastatic lymph nodes: porta hepatis (SUVmax 8.3) displacing the portal vein with possible direct involvement (yellow arrows), para-aortic nodes (SUVmax 3.8), and a single mesenteric node in the transverse colon mesentery (SUVmax 4.4).

Pathological Evaluation

An ultrasound-guided percutaneous core-needle biopsy was performed targeting the hepatic component of the mass, which represented direct invasion of the liver by the gallbladder primary. Histopathological examination revealed a solid, sheet-like proliferation of small atypical cells with scant amphophilic cytoplasm, oval hyperchromatic nuclei, and a high nuclear-to-cytoplasmic (N:C) ratio. Marked nuclear molding, nuclear atypia, and hyperchromasia were observed. The tumor showed geographic areas of necrosis, frequent mitotic figures (including atypical forms), and abundant apoptotic bodies – features characteristic of SCNEC and distinguishing it from large-cell NEC (LCNEC), which typically displays rounded cells with marked nuclear pleomorphism and prominent nucleoli.

Immunohistochemistry (IHC) was performed on the Ventana BenchMark ULTRA immunostainer using the ultraView Universal DAB Detection Kit. Tumor cells showed diffuse positivity for INSM1 and cytokeratin AE1/AE3 with the characteristic perinuclear dot-like cytoplasmic staining pattern, focal strong cytoplasmic positivity for chromogranin A, and positive synaptophysin staining. Stains for p40, S100, and desmin were negative, excluding squamous, melanocytic, and myogenic differentiation. The Ki-67 proliferation index was 100%. Representative pathology images are shown in Figure 2. According to the 2019 WHO classification of digestive system tumors, the tumor was classified as a poorly differentiated, high-grade small-cell neuroendocrine carcinoma (small-cell type NEC, formerly SCNET) [9]. The IHC profile and the absence of any extra-biliary primary on systemic imaging supported a primary gallbladder origin.

Fig. 2.

Histopathology examination. Immunohistochemical staining was performed on paraffin-embedded sections using the Ventana BenchMark ULTRA immunostainer with the ultraView Universal DAB Detection Kit and antibodies against INSM1, cytokeratin AE1/AE3, chromogranin A, Ki-67, p40, S100, and desmin. a Columns of tumor tissue with solid structures formed by atypical small cells with scant amphophilic cytoplasm and oval hyperchromatic nuclei; occasional mitotic figures, including atypical forms; and numerous apoptotic bodies. b Positive reactions in tumor cells with monoclonal antibodies to INSM1, cytokeratin AE1/AE3 (diffuse strong perinuclear dot-like cytoplasmic staining), and chromogranin A (focal strong cytoplasmic staining). Negative reactions for p40, S100, and desmin. c Ki-67 proliferation index = 100%.

Treatment and Response

The decision-making process was guided by a multidisciplinary tumor board including medical oncology, radiation oncology, hepatobiliary surgery, radiology, and pathology specialists. Given the extensive hepatic involvement and nodal spread, surgical resection was deemed infeasible, as curative resection would have required extended hepatectomy with vascular reconstruction and was considered to carry unacceptable morbidity with a low likelihood of achieving negative margins. Consequently, a nonsurgical multimodal strategy was recommended, beginning with systemic chemotherapy.

The patient received 6 cycles of cisplatin (75 mg/m², day 1) plus etoposide (100 mg/m², days 1–3) every 4 weeks, supported with G-CSF. During chemotherapy, the patient experienced manageable hematologic toxicities, including grade 2 neutropenia and grade 1 anemia, which were effectively controlled with granulocyte colony-stimulating factor and supportive therapy. No treatment delays or dose reductions were required, and the patient was able to complete all 6 planned cycles. Importantly, no significant non-hematologic toxicities such as nephrotoxicity, neuropathy, or gastrointestinal complications were observed, underscoring the tolerability of this regimen in the elderly population. Posttreatment PET/CT confirmed metabolic response with no new lesions (Fig. 3).

Fig. 3.

Whole-body PET/CT with 18F-FDG after systemic treatment (6 cycles of EP chemotherapy). Interval regression of the gallbladder mass with hepatic extension (S5, S4b) and marked reduction of metabolic activity (red arrows). Complete resolution of previously hypermetabolic lymph nodes in the porta hepatis, para-aortic region, and mesenteric site (yellow arrows).

Following systemic therapy, hypofractionated radiotherapy was delivered. A 4D CT simulation was performed using a Philips Big Bore Brilliance scanner with individualized immobilization devices to account for respiratory motion and ensure reproducibility. Treatment was delivered on a Varian EDGE linear accelerator with daily image guidance (IGRT) using the RapidArc VMAT technique.

The gross tumor volume included the residual primary tumor and nodal disease, while the clinical target volume encompassed potential microscopic extension and regional lymphatic pathways. Subclinical disease received 45.0 Gy in 25 fractions (1.8 Gy per fraction), while the gross tumor volume received a simultaneous integrated boost to 50.4 Gy in 28 fractions. Dose constraints were respected for liver, duodenum, stomach, and spinal cord based on QUANTEC criteria [10]. The patient completed treatment without interruptions, experiencing only mild fatigue and transient nausea. Radiotherapy treatment planning and the cumulative dose-volume histogram are illustrated in Figures 4 and 5.

Fig. 4.

Radiotherapy treatment planning. Axial CT image showing the dose distribution with RapidArc VMAT. The CTV included the primary gallbladder tumor with hepatic extension and regional lymph nodes. The color wash illustrates dose coverage to the target volumes; yellow lines represent beam trajectories.

Fig. 5.

Cumulative dose-volume histogram for the radiotherapy plan. The curves illustrate dose distribution for the planning target volumes and organs at risk. Adequate coverage of the gross tumor and clinical target volumes was achieved, with prescribed doses of 45.0 Gy to subclinical regions and 50.4 Gy to gross disease. Dose constraints for liver, stomach, duodenum, kidneys, and spinal cord were respected.

Latest Follow-Up

At subsequent evaluations, PET/CT demonstrated a complete radiological and metabolic response, with only residual necrotic tissue in the gallbladder and adjacent hepatic segments, and no evidence of new metastases (Fig. 6). The patient has maintained long-term disease control for more than 18 months since the initial diagnosis. A detailed chronological summary of the patient’s diagnostic workup, therapeutic interventions, and radiological assessments is provided in Table 1 to illustrate the sequence of management and treatment response.

Fig. 6.

Whole-body PET/CT with 18F-FDG. Residual necrotic tissue involving the gallbladder and adjacent hepatic segments (S5, S4b) without pathological metabolic activity. Stable disease; no new metastatic lesions detected.

Table 1.

Timeline of diagnostic evaluations, treatment interventions, and corresponding radiological findings in a patient with advanced small-cell neuroendocrine carcinoma of the gallbladder

Date	Intervention	Key findings
Baseline evaluation	CT abdomen/pelvis	Bulky GB mass, hepatic invasion (S5–S6, S4b), lymphadenopathy (porta hepatis, para-aortic, mesenteric)
	EGD, colonoscopy	Gastritis, multiple epithelial lesions
	Liver biopsy	SCNEC, synaptophysin+, chromogranin A+, Ki-67 100%
​	PET/CT	Marked regression, effusion resolved
Systemic therapy	6 cycles cisplatin-etoposide	Tolerated, partial response
Interim evaluation	PET/CT	Marked regression, no new lesions
	CT, brain MRI	Slight further shrinkage, no CNS mets
Radiation therapy	hypofractionated radiotherapy (IGRT, RapidArc VMAT)	45 Gy subclinical, 50.4 Gy gross tumor volume
Follow-up	PET/CT	Complete response
	PET/CT	Residual necrotic tissue, no metabolic activity, stable

GB, gall bladder; SCNEC, small-cell neuroendocrine carcinoma.

Discussion

SCNEC-GB is an uncommon malignancy with a poor prognosis, particularly in advanced stages. SEER data show a median OS of 7 months, with 1- and 5-year survival rates of 36.6% and 7.3%, respectively [5]. Surgical series in operable cases report median OS up to 19–23 months [6], but the majority of patients are diagnosed at an inoperable stage. Importantly, a recent multicenter analysis from the Algerian GBC group comparing survival outcomes in gallbladder neuroendocrine carcinoma and gallbladder adenocarcinoma after radical R0 resection demonstrated that achieving R0 surgical margins has a marked prognostic benefit in GB-NEC and substantially narrows the survival gap relative to gallbladder adenocarcinoma [11]. This observation underscores that whenever feasible, complete surgical resection should be regarded as the cornerstone of curative-intent treatment. Our patient, however, presented with bulky hepatic invasion involving segments S5–S6 and partially S4b together with extensive nodal disease, for which extended hepatectomy with vascular reconstruction would have carried unacceptable morbidity and a low probability of negative margins; this anatomical, oncological, and physiological assessment justified the nonsurgical multimodal approach adopted in this case.

Our case demonstrates more than 18 months of disease stability without surgery – an outcome rarely documented in the literature. In the series by Liu et al. [4], only one early-stage patient achieved 25-month disease-free survival after surgery, whereas most advanced-stage cases progressed within a year. Adachi et al. [12] reported a patient with stage IVb disease who died 13 weeks postoperatively. Kepil et al. [3] described survival exceeding 3 years after surgery plus chemotherapy. Several recent case reports and small series further illustrate the heterogeneity of SCNEC-GB. Machairas et al. [13] described a mixed adenoneuroendocrine carcinoma of the gallbladder, demonstrating the particularly poor prognosis of mixed histology. Yao et al. [14] reported a case with hepatic metastasis occurring 18 months after diagnosis, highlighting that even when surgery is feasible, recurrence is common. Fujimoto et al. [15] described a rapidly growing SCNEC-GB underscoring the aggressive biology, while Garzon-Siatoya et al. [16] documented an aggressive presentation in a younger male patient, broadening the clinical spectrum. More recently, Wang et al. [17] and Akansha et al. [18] published rare cases of primary SCNEC-GB in 2025, further emphasizing both the diagnostic challenges and the dismal prognosis.

Diagnostic accuracy is crucial. Because SCNEC-GB lacks characteristic imaging features, the diagnosis remains essentially one of exclusion, and dedicated systemic imaging, including chest, abdominal, and pelvic CT together with whole-body ¹⁸F-FDG PET/CT, is required to rule out a non-gallbladder primary [19]. Histological confirmation is therefore usually obtained from cytology, fine-needle or core-needle biopsy, or surgical specimens. According to the 2019 WHO classification of digestive system tumors, poorly differentiated NECs are high-grade primary malignant epithelial neoplasms with neuroendocrine differentiation, subdivided into small-cell (SCNEC, formerly SCNET) and large-cell (LCNEC) variants [9]. Histomorphologically, both share a solid, sheet-like proliferation with geographic areas of necrosis, high mitotic activity, and abundant apoptosis. SCNEC is characterized by marked cellular pleomorphism, a high nuclear-to-cytoplasmic ratio, nuclear atypia and hyperchromasia, nuclear molding, and frequent mitoses, whereas LCNEC shows more rounded cells with marked nuclear pleomorphism and prominent nucleoli. Useful positive IHC stains include cytokeratins (CK AE1/AE3, CAM5.2, CK8/CK18), which may demonstrate a characteristic perinuclear dot-like staining pattern – synaptophysin (usually positive, occasionally weak or focal), and chromogranin A (usually positive); INSM1 is a sensitive and specific marker of neuroendocrine differentiation. These features were all observed in our patient.

The differential diagnosis includes metastatic neuroendocrine carcinoma from extra-biliary sites, particularly the gastrointestinal tract, in which CDX2 with or without SATB2 expression may help establish a gut origin, as well as a mixed neuroendocrine-non-NEN (MiNEN) component arising in conjunction with hepatocellular carcinoma or cholangiocarcinoma, and the rare clear-cell adenocarcinoma with hepatoid differentiation of the gallbladder, recently reviewed by Jagtap et al. [20]. In our case, the absence of any extra-biliary primary on systemic imaging, together with the IHC profile and the clinical-radiological context, supported a primary gallbladder origin.

For unresectable disease, platinum-etoposide remains the standard regimen, extrapolated from small-cell lung cancer. Takeda et al. [7] reported successful local control using chemoradiotherapy in locally advanced GB-NEC. Our patient’s outcome supports the benefit of combining systemic therapy with consolidative high-precision radiotherapy to residual disease. With advances such as VMAT-based image-guided radiotherapy, safe dose escalation to bulky disease while sparing critical organs has become feasible and may contribute significantly to durable control. Because of the rarity of GB-NEC, no standard chemotherapy regimen has yet been defined, and beyond platinum-etoposide, case reports describe gemcitabine-, docetaxel-, or cisplatin-based combinations, including cisplatin combined with sunitinib or with docetaxel, that may prolong survival in selected patients with neuroendocrine carcinoma of the gallbladder.

Targeted therapy and immunotherapy represent emerging dimensions of management. To date, no targeted agents are firmly established in routine clinical practice for GB-NEC. Several studies, however, have reported increased VEGF expression in GB-NEC, and the VEGF-targeting tyrosine kinase inhibitor sunitinib has been shown to prolong progression-free and OS in patients with pancreatic neuroendocrine neoplasms [21]; whether this benefit translates to GB-NEC remains to be tested in prospective studies. Li et al. [22] documented complete remission in a metastatic SCNEC-GB patient treated with tislelizumab plus EP chemotherapy, suggesting potential synergy between immunotherapy and platinum-based regimens. Given the parallels with small-cell lung cancer, where checkpoint inhibitors have improved outcomes, future cases should include PD-L1 testing and, when feasible, molecular profiling using next-generation sequencing to identify actionable targets.

The likely contributors to our patient’s favorable outcome include extreme chemosensitivity (Ki-67 = 100%), thorough systemic control with EP chemotherapy, and eradication of residual disease through hypofractionated radiotherapy. The absence of new metastases for over 18 months underscores the potential for durable control even in advanced, unresectable SCNEC-GB with an appropriate multimodal approach. Ultimately, accumulating well-documented cases with detailed imaging, pathology, and treatment data is essential to advance our understanding of SCNEC-GB and to develop consensus guidelines for its management.

Conclusion

This case highlights that platinum-etoposide chemotherapy followed by high-precision radiotherapy can achieve prolonged disease control in advanced SCNEC-GB without surgery. While such outcomes are rare, they support the integration of radiotherapy into treatment plans for selected patients in whom R0 resection is not feasible. Collaborative registries and further research, including exploration of targeted therapy and immunotherapy, are needed to refine the management of this aggressive malignancy.

Statement of Ethics

This study was conducted in accordance with the principles of the Declaration of Helsinki. According to institutional regulations, ethics committee approval was not required for this retrospective case series. Written and informed consent was obtained from each patient or their legal representatives for publication of the details of their medical cases and any accompanying images. This case adheres to the CARE 2016 guidelines; a completed CARE checklist is provided as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000553555).

Conflict of Interest Statement

The authors have no relevant financial or nonfinancial interests to disclose.

Funding Sources

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Author Contributions

All authors (N.S., J.V., K.T., D.Z., E.M., M.T., and A.Z.) contributed to the study conception and design. The first draft of the manuscript was written by K.T. and J.V.; all authors commented on previous versions of the manuscript. Images were prepared by E.M. and M.T. The final version of the manuscript was prepared by K.T. and N.S. All authors read and approved the final manuscript.

Funding Statement

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Data Availability Statement

The data that support the findings of this study are not publicly available due to patient privacy and institutional regulations but are available from the corresponding author upon reasonable request.