Esophageal nerve sheath tumor: A rare benign tumor with diagnostic challenges—A case report

Abstract

Esophageal nerve sheath tumors are the least common type of esophageal submucosal tumors, with fewer than 60 cases reported in the literature.¹ These tumors typically occur as a solitary lesion in individuals aged 40–70, with a slight female predominance² and possible links to genetic syndromes such as neurofibromatosis type 2.³ Due to their rarity, they are often poorly recognized clinically and misdiagnosed prior to surgery. We present a rare case of esophageal nerve sheath tumor, diagnosed on esophagogastroduodenoscopy in a 46-year-old male who presented with chronic iron deficiency anemia. The patient was successfully treated with endoscopic submucosal dissection. This case highlights diagnostic and therapeutic considerations of this uncommon entity.

Introduction

Benign nerve sheath tumors account for <2% of esophageal tumors. ¹ Originating from Schwann cells of the peripheral nervous system, these tumors are histologically characterized by bland spindle cells with strong S-100 protein expression and an absence of markers—CD117, CD34, smooth muscle actin, and desmin. Most lesions are asymptomatic and discovered incidentally; larger lesions may cause dysphagia, and more rarely, chest pain, dyspnea, and bleeding. ⁴

These tumors typically occur in individuals aged 40–70, with a slight female predominance and possible links to genetic syndromes such as neurofibromatosis type 2 (NF2). ³ Uncommon and with overlapping features of other submucosal lesions, they are frequently misdiagnosed. Misidentification may lead to overtreatment or unnecessary surgical intervention. For example, while gastrointestinal stromal tumors (GISTs) may carry malignant potential and require oncologic management, benign nerve sheath tumors may be treated more conservatively with endoscopic resection. We present a rare case of esophageal nerve sheath tumor to add to the limited existing data and support a better understanding of this entity.

Case description/methods

A 46-year-old African American male with a medical history of obesity, obstructive sleep apnea, and chronic obstructive pulmonary disease underwent upper endoscopy and colonoscopy for workup of chronic microcytic anemia unresponsive to oral iron therapy. He denied any relevant symptoms, smoking, or family history of cancer. The physical exam was unremarkable. The endoscopy revealed a 10 mm nonobstructing, polypoid submucosal nodule located at 37 cm from the incisors, in the lower third of the esophagus, with normal overlying mucosa (Figures 1 and 2). Gastric biopsies showed the presence of Helicobacter pylori gastritis.

Figure 1.

Endoscopic image of the mid-esophagus demonstrates a submucosal mass outlined with a solid blue line.

Figure 2.

Endoscopic image of the mid-esophagus using NBI, showing the same submucosal mass outlined with a solid green line. NBI reveals no pit patterning.

The patient was referred for endoscopic ultrasound (EUS), which demonstrated a hypoechoic, well-demarcated lesion arising from the submucosa, measuring 9 × 7 × 5 and 4.6 mm in thickness. Fine needle biopsies obtained with a 22-gauge needle showed reactive squamous mucosa with subepithelial spindle cell proliferation. Due to concern for malignant potential, endoscopic submucosal dissection (ESD) was performed with complete resection without complication. A 3-month follow-up endoscopy confirmed full resection with appropriate mucosal healing. He had no dysphagia or reflux at that time. Cross-sectional imaging showed no evidence of metastases.

Histopathological evaluation of the resected specimen revealed a localized subepithelial spindle cell proliferation composed of Schwann cells, set against a background of a mixed inflammatory infiltrate (Figure 3). To further characterize the lesion, a panel of immunohistochemical stains was performed. The spindle cells were positive for S-100, SOX10, and Bcl-2, supporting a Schwannian lineage (Figure 4). CD34 was positive in vascular structures and focal in stromal cells at the lesion base. Smooth muscle actin and desmin highlighted the muscularis mucosa extending toward the squamous epithelium. Scattered histiocytes were identified using CD68 and CD163, and CD117 highlighted a prominent mast cell population. The spindle cells were negative for ALK1, STAT6, HMB45, Melan-A, DOG1, CD1a, calretinin, and EMA. Neurofilament staining revealed occasional axons, suggesting a more benign end of the spectrum, such as a Schwannoma, rather than a neurofibroma, which displays greater architectural disorganization and cellular atypia. The overall features are suggestive of a benign nerve sheath lesion.

Figure 3.

Histopathologic examination of the mass using H&E stain, shown with a scale bar of 1 mm.

Figure 4.

S-100 immunostain with red chromogen highlights a population of elongated-to-spindled cells, some of which appear to be arranged in short fascicles. The findings are most consistent with a nerve sheath (Schwannian) proliferation. A zoomed-in inset (scale bar: 0.1 mm) is shown in the upper-right corner. The yellow arrow highlights areas of S100 protein positivity, supporting the diagnosis of a nerve sheath tumor.

Ultimately, he underwent an otherwise negative dermatologic workup, in which multiple fleshy pedunculated papules were noted on the posterior neck; a shave biopsy was performed, and three papules were removed without definitive findings. He continues to have chronic microcytic anemia.

Discussion

Benign esophageal nerve sheath tumors are exceedingly rare and often misdiagnosed as other submucosal lesions, such as leiomyomas, GISTs, and granular cell tumors. ⁵ Their clinical and endoscopic presentation can be nonspecific, particularly when the lesion is small and asymptomatic. Their morphological complexity contributes to diagnostic difficulty, as a variety of terms have historically been used to describe similar lesions. In this case, preliminary biopsies revealed an erratic spindle cell population, suggesting an invasive desmoid tumor. However, unlike the more commonly observed presentations involving large, bulky, intraluminal polypoid masses, this lesion’s small size and endoscopic features were more consistent with a benign process.

Peripheral nerve sheath tumors, comprised of schwannoma, neurofibroma, and granular cell tumor, are rare, benign neural lesions. Their localization to the gastrointestinal (GI) tract is very rare. Epidemiologically, esophageal schwannomas account for <2% of all esophageal tumors, with a predilection for middle-aged to older adults and a higher incidence in women, particularly in Asian populations.^1,6 Molecular data analysis has revealed that 40% of GI nerve sheath tumors have a sporadic deletion of one NF1 tumor suppressor gene at 17q11.2, rather than the biallelic loss characteristic of familial NF, which is responsible for 14% of esophageal neurofibroma.^7,8 Most esophageal schwannomas present as solitary, sporadic lesions arising in the upper or mid-esophagus, and they lack a clear association with neurofibromatosis, particularly NF2.^{4 –9} While the presence of a schwannoma in any location may warrant brief consideration of NF2-related syndromic features, NF1 is more typically associated with neurofibromas rather than schwannomas.^9,10

The endoscopic appearance is typically that of a submucosal, well-circumscribed, smooth, elevated lesion covered by normal-appearing mucosa. Occasionally, the surface may show mild erythema or erosion if the lesion is large or ulcerated. On EUS, these lesions arise from the muscularis propria or submucosa and appear as homogeneous or inhomogeneous hypoechoic masses with smooth margins, exhibiting minimal vascularity and no significant cystic changes.^11,12

When comparing EUS–guided fine needle aspiration (FNA) and EUS–FNB, a systematic review of tissue-acquisition methods demonstrated a clear advantage for FNB, with diagnostic yields increasing from 74.6% with FNA to 84.2% with FNB. This improvement is particularly relevant for smaller lesions, where securing sufficient core tissue is more difficult, and FNA is more often nondiagnostic. ¹³

Definitive diagnosis requires histopathological evaluation and immunohistochemistry, with hallmark S-100 protein-positive spindle cells and negative staining for CD117, CD34, desmin, and smooth muscle actin.^6,11,12 The aggressive spindle cell carcinoma, common to smokers, is similarly described as biphasic spindle cells amidst reactive squamous dysplasia of the middle esophagus. ¹⁴ Careful pathological analysis remains critical in distinguishing these entities.

Table 1 summarizes the Immunohistochemistry profile for nerve sheath tumors.

Table 1.

Differential immunohistochemical profile of nerve sheath tumors. ¹⁵

Tumor type	Positive markers	Negative markers
Benign schwannoma	S-100 protein, SOX10, GFAP, ± BCl-2 protein a	CD117, CD34, desmin, smooth muscle actin, CD68
Granular cell tumor	S-100 protein, SOX10, CD68	CD117, keratin, desmin, smooth muscle actin, BCL-2 protein
GIST	CD117, DOG1, CD34	Desmin (<5%), S-100 protein (rarely positive)
Leiomyoma	Desmin, smooth muscle actin	CD117, CD34, S-100 protein

GIST: gastrointestinal stromal tumor.

a

BCL-2 is not a characteristic marker for either schwannoma or granular cell tumor; schwannomas typically lack consistent BCL-2 expression, and granular cell tumors are generally BCL-2 negative. ¹⁵

Treatment strategies

Given the malignant potential associated with spindle cell carcinoma, our patient underwent curative resection with ESD. Surgical esophagectomy with gastric pull-up has traditionally been used for larger or suspected malignant tumors.^12,16 Reports comparing endoscopic and surgical approaches for early esophageal disease show a broad range of outcomes. Overall, ESD tends to carry a lower immediate risk, with a 30-day mortality of 1.0% versus 4.6% after surgery, and postoperative infections reported in only 0.3% of cases compared with 7.7% following surgical resection. ¹⁷ Thoracoscopic or open esophagectomy was associated with a significantly higher complication burden, with overall complications reaching 44%–45%, reoperations in about 10%, and an in-hospital mortality of around 1%. ¹⁸ Despite this difference in perioperative morbidity, long-term outcomes were similar between the two approaches, with comparable local recurrence rates (4.7% for ESD vs 6.8% for surgery) and no meaningful differences in bleeding or stricture formation. ¹⁷ Collectively, these findings highlight ESD as a less invasive option that offers lower short-term risk while still providing durable oncologic control in appropriately selected patients.

Conclusion

Nerve sheath tumors of the esophagus are rare and often pose significant diagnostic challenges due to their nonspecific endoscopic and histological features. These lesions are typically benign and can be effectively treated with ESD. This case adds to the limited literature highlighting the diagnostic complexity of such tumors.