Primary Malignant Peripheral Nerve Sheath Tumor of the Stomach: A Rare Case Report and Review of Literature

Introduction

Malignant peripheral nerve sheath tumor (MPNST) is a relatively rare type of spindle cell sarcoma, accounting for approximately 5–10% of all soft tissue sarcoma cases.^1,2 MPNST originates from the peripheral nerve or has varying degrees of nerve sheath differentiation. Most MPNSTs are high-grade sarcomas with frequent local recurrence and distant metastasis. They are most common in patients ages 20 to 50 years. ³ Most MPNSTs occur in association with nerve trunks, with the most common anatomic sites being the proximal portions of the upper and lower extremities and the trunk. However, MPNST rarely occurs in the stomach. Only six cases of MPNST originating in the stomach have been reported in the previous literature since 1979.^4–8 There is little knowledge about its clinicopathological features and management options. We present a case of primary MPNST of the stomach. Spindle cell tumors in the stomach should be evaluated carefully. When S-100 is completely negative, H3K27 trimethylation (H3K27me3) immunohistochemical staining can help make a successful differential diagnosis.

Case Report

A 58-year-old Chinese man experienced epigastric paroxysmal discomfort for one month with no obvious causative factors. He had a 20-year history of dilated cardiomyopathy. A general physical examination revealed no pigmentation and tumor on the body surface. Abdominal computed tomography revealed abnormal thickening of the gastric wall on the lesser curvature side. The chest and head computed tomography findings were within normal limits. Gastroscopy revealed a giant mass with central ulceration. The biopsy revealed a spindle cell tumor-infiltrating the lamina propria. The tumor cells showed significant dysplasia with nuclear hyperchromasia, a high nuclear to cytoplasmic ratio, and frequent mitosis. Keratin (AE1/AE3), CD34, KIT, DOG1 (ANO1), S-100, smooth muscle actin, and desmin were all immunohistochemically negative. The biopsy diagnosed a malignant spindle cell tumor. The patient underwent a radical subtotal gastrectomy of the proximal stomach.

An ulcerated mass was found on the side of the gastric body's lesser curvature (Figure 1). The tumor, which measured 5.0 cm × 4.5 cm × 1.5cm, had infiltrated the serous membrane. There was a total of 20 lymph nodes detected. Histologically, the tumor showed push-infiltrating invasion pattern with mucosal ulceration (Figure 2A). The tumor was composed of cellular spindle cell proliferations resembling fibrosarcoma, arranged in long fascicles with a woven or storiform pattern (Figure 2B). The presence of irregular map-like necrosis was significant (Figure 2C). The tumor cells infiltrated the lamina propria surrounding the tumor ulcer. The tumor cells had enlarged and hyperchromatic nuclei, scant cytoplasm, and frequent mitosis(15/10 high-power fields) (Figure 2D). Immunohistochemical staining for keratin (AE1/AE3), epithelial membrane antigen (EMA), CD34, KIT, DOG1, S-100, SOX10, smooth muscle actin, desmin, myogenin, MDM2, CDK4, P16 (CDKN2A),SS18-SSX (SS18::SSX), Pan-Trk (NTRK) and NUT (NUTM1) were negative (Figure 3A-C). With positive control staining of normal background cells, complete loss of H3K27me3 expression was observed (Figure 3D). There were no lymph node metastases observed.

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Figure 1.

Gross finding of the tumor. The tumor has an ulcerative appearance.

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Figure 2.

Microscopic features of the tumor. At low magnification, the tumor is ulcerative with pushing infiltration at the bottom (A). The tumor is composed of closely spaced spindle cells arranged in a woven pattern (B). Irregular map-like necrosis was significant (C). At high power, enlarged and hyperchromatic nuclei, scant cytoplasm and frequent mitosis can be seen (D).

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Figure 3.

Immunohistochemical findings of the tumor. Spindle tumor cells were negative for keratin (A), KIT (B) and S-100 (C). Tumor cells have a complete loss of H3K27 trimethylation expression (D), and note endothelial cells as internal positive controls.

The patient received no postoperative adjuvant therapy. There was no evidence of local recurrence or metastases during the two years and six months follow-up after the surgery.

Discussion

MPNST is a spindle cell sarcoma originating from peripheral nerves or showing differentiation of nerve sheath components. ¹ MPNST is a sporadic soft tissue tumor that accounts for 5–10% of all soft tissue tumors. ² MPNSTs are more common in women between the ages of 20 and 50. ³ MPNSTs most commonly occur in the buttocks, thighs, upper arms, and side of the spine. A few tumors occur in the head and neck, and extremely rare stomach tumors. There are only seven patients in the world with MPNST in the stomach, including our patient (Table 1). Six of them, including our patient, had symptoms of upper abdominal discomfort, and another patient had symptoms of upper gastrointestinal bleeding.^4–8 Among the reported patients, five chose subtotal gastrectomy, and one patient was unable to perform a subtotal gastrectomy due to chest wall invasion and died three weeks after exploratory laparotomy.

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Table 1.

The Summary of Clinicopathological Features for Reported Cases of MPNST.

Author	Age(Yrs)/Sex	Size (cm)	Histopathological results	Immunohistochemical results	Symptom	Therapy	Prognosis
Croker et al	72/female	10 × 7	Spindle cells; mitoses visible	NA	Epigastric discomfort; fatigue	Supportive care	Died 3 weeks later
Bees et al	10/female	3(diameter)	Spindle cells; neuronal differentiation	Vimentin( + ); neuron specific enolase( + ); EMA(-); PAS(-); S-100(-)	Abdominal pain; pallor; fainting; mlena	Billroth 1 gastrectomy	No recurrence
Loffeld et al	41/female	4(diameter)	Oval round shaped cells;mitoses were rare	Vimentin( + ); lack epithelial markers, SMA and S-100 protein	Mlena	Total gastric resection	No recurrence
Takemura et al	70/male	6 × 5	Spindle cells	S-100( + ); KIT(-); CD34(-); SMA(-)	Abdominal pain; melena	Distal gastrectomy	Multiple liver metastases 3 months later; died 5 months later
Eun Young Kim et al	48/male	9 × 9	Spindle cells; mitoses visible; pleomorphic nucleis	S-100( + ); KIT(-); desmin(-); ANO1(-); EMA(-);keratin (-); CD34(-); CD68(-); CD99(-); actin(-); BCL-2(-)	Epigastric discomfort; melena	Subtotal gastrectomy	No recurrence
Our patient	58/male	5 × 4.5	Spindle cells; mitoses visible; necrosis	H3K27me3(-);S-100(-); SOX10(-); KIT(-); DOG1(-); keratin (-);EMA(-); myogenin(-); SS18-SSX(-); SMA(-); desmin(-); MDM2(-); CDK4(-); CD31(-); NUT(-); Pan-Trk(-)	Epigastric discomfort	Subtotal gastrectomy	No recurrence
Rădulescu et al	27/female	NA	NA	NA	Epigastricpains; melena	Symptomatic treatment	NA

Yrs: years; NA: not available; EMA, epithelial membrane antigen; SMA, smooth muscle antigen.

Among the reported gastric MPNSTs, four tumors had an ulcer shape, and two had a multi-nodular shape. The ulcerated mass has the chest wall appearance of gastric adenocarcinoma. As a result, MPNST is easily misdiagnosed as a common gastric adenocarcinoma in clinical practice, and the exact diagnosis depends on pathological examination. The histology of primary gastric MPNSTs is consistent with that of soft tissues. The tumor is composed of dense spindle cells that grow in long fascicles with occasional storiform or sweeping arrangements similar to fibrosarcoma. The tumor cells have hyperchromatic nuclei and a small amount of cytoplasm. The nuclei are wavy or comma-shaped. Rapid mitotic activity ranging from just a few mitotic figures to more than 50/10 high-power fields is easily recognized.

The role of immunohistochemistry in the diagnosis of MPNST is limited. There are currently no specific positive immunohistochemical markers. The staining of S-100 protein is frequently preferred. S-100 may display focal positivity. S-100 can also be completely negative in around one-half of tumors. SOX10 is also a sensitive melanocytic and schwannian cell's marker. Nonaka et al observed that SOX10 has higher sensitivity and specificity than S-100 for the diagnosis of MPNST, but completely negative SOX10 staining also occurs in some tumors. ⁹ S-100 and SOX10 staining were completely negative in our tumors. Studies have suggested that H3K27me3 expression is completely or partially missing in MPNST, except for epithelioid MPNST. Mito et al evaluated H3K27me3 immunohistochemistry staining results in 180 cases of spindle cell neoplasms. ¹⁰ About 54% of MPNSTs showed complete loss of H3K27me3, whereas just 2 of 156 histologic mimics had complete loss of H3K27m3. Prieto-Granada et al reported that more than 90% of sporadic MPNSTs havea complete deletion of H3K27me3. ¹¹ The above studies suggest that the complete deletion of H3K27me3 is significant in diagnosing MPNST. The decrease in expression of H3K27me3 MPNSTs is caused by the inactivation of polycomb repressive complex 2 (PRC2) components EED and SUZ12.The above changes further led to the loss of H3K27me3.^11–14 Although S-100 and SOX10 stains were negative in our tumor, the complete loss of H3K27me3 confirmed the diagnosis of MPNST.

Sarcomatoid carcinoma, gastrointestinal stromal tumor, leiomyosarcoma, rhabdomyosarcoma, melanoma, clear cell sarcoma, synovial sarcoma, dedifferentiated liposarcoma, NTRK- rearranged spindle cell tumors and sarcomas with NUT alterations are the prominent morphological differential diagnosis. Keratin and EMA staining are common in sarcomatoid carcinoma, but they were negative in this tumor.The most common soft tissue tumor in the stomach is the gastrointestinal stromal tumor, while no expression of CD34, KIT, and DOG1 could preclude this diagnosis. Negative expression of S-100, smooth muscle actin, desmin, and myogenin protein can distinguish melanoma and clear cell sarcoma, leiomyosarcoma, and rhabdomyosarcoma. MDM2, CDK4, and P16 staining were negative in the tumor, ruling out dedifferentiated liposarcoma. SS18-SSX is a novel SS18::SSX fusion-specific antibody for the diagnosis of synovial sarcoma. ¹⁵ The negative staining of SS18-SSX could rule out synovial sarcoma. The negative staining of Pan-Trk, CD34, S-100 and NUT could exclude the diagnosis of NTRK-rearranged spindle cell tumors and sarcomas with NUTM1 alterations.

Numerous studies have proven that complete surgical resection is the most effective treatment for limited MPNST.^1,16–18 Negative surgical margins are critical to the prognosis of MPNST. The disease fatality rate in patients with positive margins is 1.8 times that of patients with negative margins. ² During surgical resection, a wider negative margin is the prerequisite for a good prognosis. ¹⁶ Furthermore, current treatment methods also include neoadjuvant and postoperative radiotherapy.^17,19 Kahn and colleagues found that the patients who received radiotherapy had a longer median overall survival(33.1 months) than patients who did not receive radiotherapy (17.4 months). ¹⁹ There are other studies supporting the effects of radiotherapy participation.^3,20 Chemotherapy is also used in patients with distant metastases and no chance of surgery.^16,21 However, radiotherapy or chemotherapy for malignant peripheral nerve sheath tumors originating in the stomach has not been reported. More case reports are needed to assess the efficiency of neoadjuvant therapy for malignant peripheral nerve sheath tumors of the stomach. Primary MPNST of the stomach may have a poor prognosis. Two out of seven patients die or have liver metastases. During the 2.5-year follow-up after the surgery without adjuvant therapy, our patient had neither recurrence nor distant metastasis. This patient requires close and long-term monitoring.

In summary, we reported an extremely rare MPNST of the stomach, with cellular spindle cell proliferation and complete loss of H3K27me3. The tumor should be distinguished from a series of spindle cell tumors, and sufficient immunohistochemical staining is critical for the differential diagnosis. The complete loss of H3K27me3 confirms the diagnosis of MPNST. The current treatment method for MPNST of the stomach is primarily surgical resection.