A rare case report of esophageal neuroendocrine carcinoma mimicking a submucosal tumor: Diagnosis confirmed by endoscopic ultrasound-guided fine-needle aspiration

Abstract

Esophageal neuroendocrine carcinoma is an exceedingly rare and aggressive malignancy, accounting for less than 1% of all esophageal cancers. This case report presents a unique instance of esophageal neuroendocrine carcinoma that initially manifests as a submucosal tumor-like lesion, an atypical and under-recognized presentation that can mimic benign conditions such as leiomyomas or gastrointestinal stromal tumors. Conventional endoscopic biopsy, often the first-line diagnostic tool, failed to provide a definitive diagnosis due to the tumor’s deep submucosal location and intact overlying mucosa. However, the utilization of endoscopic ultrasound-guided fine-needle aspiration proved instrumental in obtaining sufficient tissue for histopathological and immunohistochemical analyses, confirming the diagnosis of esophageal neuroendocrine carcinoma. This case underscores the critical role of endoscopic ultrasound-guided fine-needle aspiration in diagnosing rare esophageal malignancies that evade standard diagnostic approaches. Furthermore, it emphasizes the importance of considering esophageal neuroendocrine carcinoma in the differential diagnosis of unusual esophageal lesions, particularly when they exhibit unusual features or fail to respond to conventional management. Early and accurate diagnosis is essential for guiding appropriate therapeutic strategies and improving patient outcomes.

Introduction

Esophageal neuroendocrine carcinoma (NEC) is an exceedingly rare and aggressive malignancy, accounting for less than 1% of all esophageal cancers.^1,2 Despite its rarity, its recognition has increased due to advancements in diagnostic techniques and heightened clinical awareness. NEC often presents at an advanced stage, with lymph node metastasis or distant spread, leading to a poor prognosis. ³ Most cases are poorly differentiated, featuring small cell morphology, although large cell variants are also observed. Cytologically, small cell NEC (SCNEC) exhibits small cells with scant cytoplasm and molding nuclei, while large cell NEC (LCNEC) shows larger cells with vesicular nuclei and prominent nucleoli. This distinction is critical as SCNEC demonstrates higher chemosensitivity but has a poorer prognosis.

One of the challenges in diagnosing esophageal NEC is its varied endoscopic presentation. Unlike typical esophageal tumors that may exhibit ulcerations or irregular growth patterns, NECs can mimic benign submucosal tumors (SMTs), often making them difficult to differentiate during initial examinations.^4,5 This diagnostic challenge is compounded by the rarity of NEC and the failure of conventional biopsies to provide sufficient tissue for definitive diagnosis.

Recent studies have shown that esophageal NECs, particularly those presenting as SMT-like lesions, may be overlooked or misdiagnosed as benign conditions such as leiomyomas or other submucosal masses. Advanced diagnostic tools such as endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration (EUS-FNA) are crucial for accurate diagnosis as they offer detailed imaging and enable tissue acquisition, overcoming the limitations of conventional biopsies. Herein, we report a case of esophageal NEC mimicking an SMT, diagnosed at Jinhua Central Hospital in Jinhua, Zhejiang Province, China, in early 2025. This case emphasizes the importance of considering NEC in patients presenting with atypical submucosal-like lesions and underscores the utility of EUS-FNA in confirming the diagnosis.

Case report

We have deidentified all patient details to protect confidentiality, and informed consent for treatment and publication of this report was obtained from the patient. The reporting of this study conforms to the Case Report (CARE) guidelines. ⁶

A man in his early 80s, with a history of smoking and alcohol consumption, presented with progressive dysphagia that had persisted for the past 7 months. His medical history was notable for hypertension, with no prior gastrointestinal issues.

During a routine esophagogastroduodenoscopy, a smooth and firm SMT-like lesion was noted in the thoracic esophagus, approximately 28–30 cm from the incisors. The lesion exhibited the characteristic features of a typical SMT, with no ulceration or irregularities, initially suggesting a benign etiology such as a leiomyoma or gastrointestinal stromal tumor (Figure 1(a)). However, a conventional biopsy failed to provide a definitive diagnosis, revealing only nonspecific squamous epithelium and no signs of malignancy. Subsequently, contrast-enhanced computed tomography (CT) of the chest revealed esophageal wall thickening with luminal narrowing; the thickest segment measured approximately 2.1 cm, raising concern for malignancy (Figure 1(b)). Further evaluation with fluorodeoxyglucose positron emission tomography (FDG-PET) revealed a lesion measuring approximately 1.8 × 2.4 cm, with increased tracer uptake (maximum standardized uptake value: 10.3), suggesting a malignant tumor, although there was no evidence of distant metastasis or lymph node involvement (Figure 1(c)).

Figure 1.

(a) Esophagogastroduodenoscopy showed a smooth, firm, submucosal tumor-like lesion in the thoracic esophagus. (b) Computed tomography revealed thickening of the esophageal wall with luminal narrowing (red arrow). (c) Fluorodeoxyglucose positron emission tomography revealed elevated tracer uptake in the lesion, with a maximum standardized uptake value of 10.3 and (d) endoscopic ultrasound revealed a homogeneously hypoechoic mass located in the submucosal layer of the esophagus (green arrow), and a round hypoechoic lymph node adjacent to the esophagus (yellow arrow).

As the CT and FDG-PET findings suggested malignancy and a risk of deep invasion, endoscopic resection was contraindicated, and EUS-FNA was prioritized for diagnosis. EUS revealed a homogeneous hypoechoic mass within the submucosal layer of the esophagus, with well-defined boundaries, along with a round hypoechoic lymph node measuring approximately 0.5 × 0.6 cm adjacent to the esophagus (Figure 1(d)). EUS-FNA was performed, and cytological analysis revealed small cells with a high nuclear-to-cytoplasmic ratio, suggestive of a neuroendocrine malignancy (Figure 2(a)). Immunohistochemical (IHC) staining was positive for synaptophysin (Syn), insulinoma-associated protein 1 (INSM1), and CD56, while chromogranin A (CgA) and P40 were negative, confirming the diagnosis of esophageal NEC (Figure 2(b) to (e)). The Ki-67 labeling index was 70%, indicating a high proliferative potential of the tumor (Figure 2(f)). Based on the examination findings, the patient was diagnosed with SCNEC.

Figure 2.

(a) Cytological analysis revealed small cells with a high nuclear-to-cytoplasmic ratio, suggestive of a neuroendocrine malignancy. (b to e) Immunohistochemical staining showed positive staining for Syn (b), INSM1 (c), and CD56 (d), whereas CgA (e) was negative and (f) The Ki-67 labeling index was found to be 70%. CgA: chromogranin A; INSM1: insulinoma-associated protein 1; Syn: synaptophysin.

Given the patient’s advanced age and comorbidities and following discussions with his family, he declined a subtotal esophagectomy and was instead treated with radiotherapy.

Discussion

Esophageal NEC is an exceptionally rare malignancy with a poor prognosis due to its aggressive nature. Its rarity contributes to diagnostic challenges and the absence of standardized treatment protocols. Most cases are diagnosed at advanced stages, frequently with widespread metastasis. ⁷ The clinical and endoscopic presentation of esophageal NEC may lead to delays in diagnosis, particularly when the tumor mimics benign lesions such as SMT, as observed in this case.

This case is notable owing to its atypical endoscopic presentation as a smooth, firm SMT-like lesion, initially suggestive of a benign etiology. Esophageal SMTs are benign, slow-growing submucosal masses with intact mucosa, while NECs are aggressive, ulcerative malignancies with neuroendocrine markers (Syn, CD56) and high Ki-67 expression. SMTs typically exhibit spindle cells with low mitotic activity, while NECs often present with dysphagia or metastasis. EUS and biopsy can differentiate them, guiding resection (SMTs) or chemo/radiotherapy (NECs). However, the smooth, well-defined nature of the lesion, without ulceration or irregularities, complicates the diagnosis of NEC. Early diagnosis is therefore difficult, and as noted, such tumors are discovered accidentally. ⁵ In the case of larger tumors and more advanced disease, the most common initial symptoms include progressive dysphagia, anorexia, painful retrosternal swallowing, hematemesis, hoarse voice, and weight loss. ⁸ Conventional biopsy methods often fail to obtain adequate tissue for definitive diagnosis, as observed in this case. This emphasizes the limitations of standard biopsy techniques, particularly when the lesion does not exhibit typical malignant features. Given the suspicion of malignancy, advanced diagnostic tools like EUS-FNA became crucial. EUS-FNA allows for better visualization of submucosal lesions and enables precise tissue acquisition, facilitating accurate diagnosis in challenging cases like this one.

The diagnosis of esophageal NEC is typically established by histopathological evaluation, which classifies esophageal NECs into two types—SCNEC and LCNEC—each with distinct morphological features. SCNEC tumor cells are typically small to medium-sized (<3 times the diameter of a lymphocyte), with well-defined borders, a high nuclear-to-cytoplasmic (N/C) ratio, hyperchromatic round-to-oval nuclei, finely granular chromatin, and inconspicuous or absent nucleoli. In contrast, LCNEC exhibits larger tumor cells (>3 times the diameter of a lymphocyte), with poorly defined cell borders, a low N/C ratio, abundant lightly eosinophilic or clear cytoplasm, vesicular nuclei with coarse chromatin, and prominent eosinophilic nucleoli. ⁹ IHC profiling is essential for the diagnosis of digestive NECs. The recommended neuroendocrine markers include Syn and CgA. However, CgA expression may be weak or absent, particularly in SCNEC. In such cases, INSM1, a sensitive transcriptional marker (85% sensitivity in NECs), serves as a valuable diagnostic adjunct.^10–12 In our case, histopathological examination revealed a small cell carcinoma morphology, further confirmed by strong immunoreactivity for Syn and INSM1, supporting a definitive diagnosis of SCNEC. NECs are poorly differentiated, high-grade neuroendocrine neoplasms (NENs), classified as World Health Organization NEN G3 when the Ki-67 proliferation index is >20%, with most cases exceeding 50%. Elevated Ki-67 expression, demonstrated by IHC, correlates with aggressive tumor biology and rapid clinical progression. ¹³

However, as in this case, the lesion can mimic benign tumors, necessitating advanced imaging and tissue sampling techniques. IHC staining for neuroendocrine markers, along with a high Ki-67 index, plays a pivotal role in confirming the diagnosis. Furthermore, the use of EUS-FNA in this case was instrumental in obtaining tissue from a submucosal lesion that did not exhibit typical malignant features, emphasizing the value of EUS in diagnosing rare esophageal malignancies.

The treatment of esophageal NEC is complex and varies according to stage and grade. However, given its aggressive nature, early diagnosis remains the most critical determinant of improved patient outcomes. ⁴ The prognosis for esophageal NEC remains poor, underscoring the need for further research into treatment protocols to improve survival for this rare and aggressive malignancy.