Desmoplastic Small Round Cell Tumor of Parotid Gland: A Rare Entity With Diagnostic Challenge

Introduction

Desmoplastic small round cell tumor (DSRCT) is a rare aggressive mesenchymal tumor that primarily affects children and young adults with strong male predilection. ¹ The vast majority of DSRCT cases present as large intraabdominal masses involving peritoneum, omentum, mesentery, and retroperitoneum. Morphologically, DSRCT is characterized by irregular nests or sheets of tumor cells surrounded by abundant desmoplastic fibrous stroma. Immunohistochemically, DSRCT is characterized by polyphenotypic differentiation with positive staining for cytokeratin, desmin, and NSE. Molecular studies show characteristic EWSR1-WT1 gene fusion resulting from chromosome translocation t(11;22)(p13;q12) in DSRCT. ¹ Salivary gland DSRCT is exceedingly rare. To the best of our knowledge, only 6 cases have been reported in the literature. In this study, we report a case presenting as a large parotid mass. The tumor cells were positive for cytokeratin, p40, and p63, mimicking salivary gland carcinoma with squamous differentiation. We discuss the differential diagnoses and the value of molecular test, and review the literature of this rare entity.

Case Report

A 38-year-old man with past medical history of hypertension and diabetes presented with a right neck mass for 4 weeks. Magnetic resonance imaging scan identified a 5.0-cm mass with areas of necrosis involving both the superficial and deep lobes of parotid gland (Figure 1a). The mass invaded the stylomastoid foramen with possible facial nerve involvement. In addition, multiple ipsilateral neck lymph nodes were enlarged, suspicious for metastasis. Positron emission tomography scan showed a large ¹⁸F-fluorodeoxyglucose-avid right parotid mass and multiple level II and level III lymphadenopathy with maximum standardized uptake value of 4.8, the largest node measuring 2.5 cm. No other mass lesion was identified, including abdominal, pleural, or pelvic cavities.

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Figure 1.

(a) Magnetic resonance imaging showed a large necrotic mass involving the parotid gland. (b) Cross section of the resected parotid mass demonstrated a firm tan-white cut surface with areas of necrosis (arrow: necrosis).

The patient underwent total parotidectomy, facial nerve transection, and right neck lymph node dissection. Intraoperatively, the tumor was found to be adherent to the facial nerve. On gross examination, the parotid gland was almost entirely replaced by a large firm tan-white mass with areas of necrosis (Figure 1b). Multiple enlarged lymph nodes grossly positive for metastasis were identified in levels II and III.

Microscopic examination showed a multinodular tumor composed of infiltrating irregularly shaped and different-sized tumor nests embedded in abundant eosinophilic fibrotic desmoplastic stroma. Focal glandular/ductular formation was also noted. The tumor cells demonstrated epithelioid morphology with moderate amount of clear to eosinophilic cytoplasm with distinct cell borders. Focal significant nuclear pleomorphism with variation in nuclear size and shape was present (Figure 2). While mitotic activity was not brisk (up to 5/10 high power field), scattered areas of tumor necrosis were present (Figure 3). Multifocal perineural invasion and lymphovascular invasion were identified. Immunohistochemically, the tumor cells were positive for AE1/AE3, p40, p63, desmin, and weakly positive for GATA3. Tumor cells were negative for other myoepithelial markers (S100, CK5/6, calponin, and smooth muscle actin) as well as CK7, CD99, NUT (nuclear protein of the testis), synaptophysin, chromogranin, SOX10, androgen receptor, and HER2/neu (Figure 3).

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Figure 2.

(a) Lymph node with metastatic tumor (hematoxylin and eosin [H&E], 40×). (b) Large tumor cells with significant nuclear variation in size and shape. Tumor necrosis is also present (H&E, 400×).

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Figure 3.

(a) Characteristic morphology of desmoplastic small round cell tumor with different-sized nests embedded in abundant desmoplastic stroma (hematoxylin and eosin [H&E], 40×). (b) Tumor cells with moderate amount of clear to eosinophilic cytoplasm and mitotic activity (H&E, 400×; arrow: mitotic figure). (c) Focal gland/duct formation (H&E, 200×). (d) Tumor necrosis (H&E, 40×). Tumor cells are positive for (e) AE1/AE3 (200×); (f) p40 (200×); (g) p63 (200×); (h) GATA3 (200×); (i) desmin (200×); and (j) fluorescence in-situ hybridization demonstrated EWSR1 gene rearrangement.

Fluorescence in-situ hybridization (FISH) for EWSR1 gene rearrangement study was performed on paraffin-embedded tissue sections and the tumor cells were found to be positive for EWSR1 gene rearrangement (Figure 2j). The tissue was further tested for next-generation sequencing using Ewing Fusion Profile, which identified a EWSR1-WT1 gene fusion resulting from t(11;22)(p13;q12).

Based on the morphologic and characteristic EWSR1-WT1 gene fusion findings, a diagnosis of desmoplastic round cell tumor was made. The patient had an uneventful postoperative recovery, and is receiving adjuvant chemotherapy and radiation therapy. He is disease free 5 months after the surgery.

Discussion

Desmoplastic round cell tumor is an uncommon aggressive mesenchymal tumor that predominantly involves the abdominal cavity of male children and young adults. ¹ Extraabdominal DSRCT is rare, accounting for 6% of DSRCT, and can occur in varied anatomic sites, including paratesticular region, pleural cavity, sinonasal cavity, eye, facial bone, etcetera. ² Salivary gland involvement by DSRCT is exceedingly rare with only 6 cases reported in the literature.^{3 -8} Including the patient in this study, all 7 patients were male. Patients were relatively young as the age ranged from 5 years to 49 years. In 4 patients, parotid gland was involved, and the other 3 patient present with submandibular gland involvement. The diagnosis of all 7 cases was confirmed by molecular testing (PCR [polymerase chain reaction] or FISH and PCR). Three patients had lymph node metastasis at the time of surgery. Only limited follow-up data is available for patients with salivary gland DSRCT, and prognosis is dismal for patients with nodal metastasis (Table 1).

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Table 1.

Reported Cases of Salivary Gland Desmoplastic Small Round Cell Tumor.

Case	Author	Age (Years)/Sex	Anatomic Site	Size	Lymph Node Status	IHC Positive	IHC Negative	Molecular Test(s)	Outcome
1	Hill et al 3	5/Male	Parotid	Unknown	Unknown	AE1/AE3; desmin	CD99	RT-PCR	Unknown
2	Wolf et al 4	23/Male	Parotid	5 cm	Negative	AE1/AE3; desmin	CD99; S100	RT-PCR	AOD 10 months
3	Cho et al 5	26/Male	Submandibular	4 cm	Positive	AE1/AE3; desmin	S100	RT-PCR	DOD 25 month
4	Yin et al 6	24/Male	Submandibular	4 cm	Negative	CAM5.2; desmin	CD99; S100; myogenin	FISH RT-PCR	AOD 7 months
5	Pang et al 7	41/Male	Submandibular	5 cm	Positive	AE1/3; desmin; WT-1; CD56	CD99; S100; myogenin	FISH RT-PCR	DOD 5 weeks
6	Hatanaka et al 8	49/Male	Parotid	2 cm	Negative	AE1/AE3; EMA; desmin; CD56	P63; CD99; CK5/6; S100	FISH RT-PCR	AOD 3 years
7	This study	38/Male	Parotid	5 cm	Positive	AE1/AE3; P40; P63; desmin	CD99; S100; CK5/6; NUT	FISH NGS	AOD 5 month

Abbreviations: IHC, immunohistochemical stains; RT-PCR: reverse-transcriptase polymerase chain reaction; AOD, alive without disease; DOD, died of disease; FISH, fluorescence in-situ hybridization; NUT, nuclear protein of the testis; NGS, next-generation sequencing.

Diagnosis of salivary gland DSRCT can be challenging due to its rarity. It is noticeable that histomorphologically, a subset of DSRCT do not fall into the prototypic small blue tumor category. ¹ As exemplified in this study, the tumor cells are large cells and demonstrate epithelioid morphology with moderate amount of clear to eosinophilic cytoplasm. In addition, nuclear pleomorphism is present, in contract to the uniform monotonous morphology typically seen in tumors with chromosome translocation. Immunohistochemically, the tumor cells were positive for cytokeratin, p40, and p63, suggesting a squamous cell differentiation. GATA3, which is positive in many salivary gland neoplasms and considered by some people as a salivary gland origin marker, is also positive in these tumor cells. ⁹ The tumor behaved like a carcinoma with multiple lymph node metastases. Thus histomorphology, immunoprofile, and clinical behavior all point to a diagnosis of carcinoma. Indeed, in the literature one case of DSRCT was originally diagnosed as undifferentiated carcinoma. The diagnosis was questioned when the tumor followed an unusually aggressive course. And a revised diagnosis of DSRCT was made when the case was reviewed again. ³ Therefore, recognition of the histomorphologic spectrum of this entity followed by appropriate workup is the key to an accurate diagnosis.

In the salivary gland, differential diagnosis for DSRCT includes squamous cell carcinoma, myoepithelial carcinoma, hyalinizing clear cell carcinoma (HCCC), NUT carcinoma, and adamantinoma-like Ewing sarcoma. p40 has been shown to be a sensitive and specific marker for squamous cell carcinoma. ¹⁰ In this study, we found the tumor cells of DSRCT are also positive for p40. Interestingly, immunohistochemical staining for p40 had not been tested before in DSRCT in the literature, even for cases arising from head and neck region such as sinonasal cavity and facial bones. p63 was tested in one of the previously reported cases and was negative, while in the current case p63 is positive. ⁸ The morphologic features and positivity for cytokeratin, p40, and p63 of DSRCT can cause significant diagnostic confusion. The presence of abundant desmoplastic stroma, lack of keratinization, and focal gland/duct formation are morphologic clues, and a diagnosis of DSRCT should be considered especially in young patients with unusual clinical presentations. Aggressive myoepithelial carcinoma was also in the differential diagnosis for this case. Like DSRCT, myoepithelial carcinoma demonstrates polyphenotypic differentiation with expression of cytokeratin and smooth muscle markers such as calponin, smooth muscle actin, and S100. Desmin positivity is uncommon. ¹¹ More important, a subset of myoeptihelial tumors also harbor EWSR1 gene rearrangement. ¹² Partner genes that have been identified in myoepithelial carcinoma include POUSF1, PB1, ZNF44, and others.^12,13 The case in this study is positive for desmin and negative for all other myoepithelial markers. In addition, EWSR1-WT1 fusion is specific for DSRCT and has not been reported in myoepithelial tumors. The presence of abundant fibrous stroma, nested growth pattern, and clear cell morphology of DSRCT closely mimics HCCC of salivary gland, which is a rare malignant neoplasm with squamous differentiation and harbors EWSR1-ATF1 fusion. ¹⁴ HCCC is a low-grade neoplasm in which necrosis, mitotic activity, and aggressive clinical behavior are uncommon findings. ¹⁵ Rare cases of HCCC with high-grade transformation have been reported. ¹⁶ The absence of demsin positivity and/or the presence of EWSR1-ATF1 translocation support a diagnosis of HCCC. NUT carcinoma is a rare aggressive carcinoma characterized by nuclear protein in testis gene (NUTM1) rearrangement. The tumor cells are commonly positive for squamous cell markers such as p40, p63, and CK5/6. NUT carcinoma usually involves young patients (mean patient age 22 years) and follows an aggressive clinical course with median overall survival of <1 year. ¹⁷ Immunoreactivity for NUT antibody has been shown to be sensitive and specific for NUT carcinoma, and is valuable to distinguish NUT carcinoma from mimickers.^18,19 Adamantinoma-like Ewing sarcoma of the salivary gland is a recently recognized entity that is often misdiagnosed as basaloid carcinoma of salivary gland. ²⁰ The tumor cells are diffusely positive for AE1/AE3 and p40. FISH is positive for EWSR1 gene rearrangement, similar to DSRCT and HCCC. However, adamantinoma-like Ewing sarcoma is consistently positive for CD99, while DSRCT of salivary gland were negative for CD99 (Table 1). In addition, the partner gene for Ewing sarcoma is different from DSRCT.

Many soft tissue sarcomas and a few carcinomas are characterized by the presence of a translocation involving the EWSR1 gene, including myoepithelial neoplasm, clear cell sarcoma, DSRCT, Ewing sarcoma/primitive neuroectodermal tumor, extraskeletal myxoid chondrosarcoma, myxoid/round-cell liposarcoma, angiomatoid fibrous histiocytoma, HCCC, clear cell ondontogentic carcinoma, and so on. Correlation with clinical presentations, morphologic, and immunohistochemical features is necessary for making a correct diagnosis.

In summary, we report a rare presentation of DSRCT involving the parotid gland. The tumor is positive for AE1/AE3, p40, and p63. The morphologic and immunohistochemical features make the case susceptible to misclassification as salivary gland carcinoma. Molecular testing provided an essential role in establishing the diagnosis. DSRCT typically follows an unusually aggressive clinical course with local and distal metastases. Accurate diagnosis is paramount for appropriate clinical management and prognosis.