Desmoplastic small round cell tumor of the pleura with brain metastasis: A case report and literature review

First described in 1989 by Gerald and Rosai [1], desmoplastic small round cell tumor (DSRCT) is an uncommon and aggressive mesenchymal neoplasm of uncertain differentiation. It is typified by a chromosomal translocation that fuses the EWSR1 gene (22q12) and the WT1 gene (11p13) [2]. Desmoplastic small round cell tumor mainly affects young males and classically arises in intra-abdominal tissues, where it may involve the retroperitoneum, omentum, pelvis, or mesentery; its common sites of metastasis include the regional lymph nodes, lungs, or liver [3]. Histopathologically, the tumor displays nested aggregates of small round cells with scant cytoplasm and indistinct borders, embedded in a fibroblastic or collagenized stroma [2]. Its primitive ultrastructural appearance and variable immunohistochemical expression suggest polyphenotypic differentiation, though it typically shows EMA, desmin (cytoplasmic, “dot-like”), and cytokeratin positivity [2],[4],[5]. Only rare examples of central nervous system metastasis have been reported. This report presents an unusual case of a young female with DSRCT originating from the pleura, with local spread at diagnosis and subsequent brain metastasis. This rare tumor with an uncommon site of metastasis provides a valuable opportunity to contribute to the limited literature on the histological features and metastatic behavior of DSRCT.

A 20-year-old woman with no past medical history or tobacco use presented with dry cough and left-sided lower rib pain lasting six months. Physical examination and laboratory tests were unremarkable. However, chest X-ray revealed a 9.2 cm mass-like opacity in the left mid to lower lung zone, accompanied by a small pleural effusion.

A follow-up computed tomography (CT) scan identified a solid mass with central mineralization involving the left lower lobe and pleura; enlarged lymph nodes were found in the mediastinum (Figure 1). Positron emission tomography (PET) revealed the direct connection between the hypermetabolic mass and both the pleura and lung parenchyma. This finding caused difficulty in determining whether the pleura or the lung was the actual site of origin, which was resolved later with subsequent imaging as described below. In addition to the main mass, PET-avid metastatic foci were detected within multiple non-contiguous surfaces of the left pleura. No evidence of metastasis outside the thoracic region was found, and a magnetic resonance imaging (MRI) of the brain showed no abnormalities.

Biopsies of mediastinal lymph nodes and the left lung, performed using endobronchial ultrasound guidance, revealed densely cellular fragments of cells with round to ovoid nuclei and minimal cytoplasm. There was a proportionally smaller quantity of desmoplastic stromal tissue present (Figure 2). Ancillary study results are provided in Table 1. The biopsy was diagnosed as a poorly differentiated carcinoma with an inconclusive immunohistochemical staining pattern. Treatment was initiated for advanced-stage carcinoma presumed to be of bronchogenic origin, and the patient underwent palliative thoracic radiotherapy and chemotherapy (cisplatin, pemetrexed, pembrolizumab). The patient initially responded well to radiotherapy, with a reduction in tumor size. However, after three months of treatment, there was radiographic progression of left pleural disease and the development of new cervical lymph node metastases.

Six months after the initial diagnosis, a CT-guided biopsy of the left pleura was performed to reassess tumor morphology and explore potential new therapy options. Histologic examination demonstrated well-defined nests of small round cells embedded in desmoplastic stroma (Table 2 and Figure 3). Abundant apoptotic bodies and areas of necrosis were present. er to Table 1 for results of ancillary studies. Molecular testing using fluorescence in situ hybridization (FISH) identified an EWSR1 rearrangement. Based on the morphological characteristics observed in this biopsy, the diagnosis of desmoplastic small round cell tumor with EWSR1 rearrangement was made.

Following the biopsy, new baseline PET imaging was obtained. This revealed a notable progression of the left pleural disease, characterized by the presence of ring-like and nodular thickening of the pleura that extended into the left infrahilar region. In contrast, there was improvement observed in the characteristics of lung parenchymal involvement, including regional calcification and a reduction in size. These findings were significant as they pointed to the pleura as the likely origin site. It is important to note that definitive confirmation could not be attained due to the extensive intrathoracic disease observed during the initial presentation. Theore, these indirect pieces of evidence were utilized to establish the final diagnosis of pleural DSRCT.

In addition to the progression of pleural disease, there was increased metastatic burden in the mediastinal, left supraclavicular, and left axillary lymph nodes. New lymphadenopathy was observed in the retroperitoneal, gastrohepatic ligament, left common iliac, and left para-aortic regions. Within the limitations of the PET scan, no definite abnormalities were found in the brain.

Treatment was initiated with interval-compressed vincristine, doxorubicin, cyclophosphamide (VAC), alternating with ifosfamide and etoposide (IE), approximately seven months after the patient’s initial presentation. To improve patient tolerance, doxorubicin was later alternated with dactinomycin. Repeat imaging after 5 cycles of treatment showed a partial treatment response, but by the 11th cycle, increasing left pleural hypermetabolism on PET imaging indicated early signs of progression. At the final assessment during the 14th cycle, the disease was generally stable, but a persistent metabolic response was observed. The patient was switched to maintenance chemotherapy (vinorelbine/cyclophosphamide) with plans to repeat imaging three months later.

Unfortunately, two months into the maintenance treatment (20 months and 14 months after original presentation and DSRCT diagnosis, respectively), the patient was admitted to the hospital with decreased level of consciousness and seizure. She had been experiencing nausea and vomiting for a few days prior to admission. Upon initial assessment, the patient exhibited a fixed and dilated right pupil (6 mm) and a nonreactive left pupil (2 mm). Additionally, there were absent motor responses on the left side. A head CT scan demonstrated a 6 cm intra-axial lesion of the right frontal lobe with 1.2 cm sub-falcine herniation and entrapment of the left lateral ventricle (Figure 4). The patient underwent emergency decompressive craniectomy. Postoperatively the patient had left-sided hemiplegia, dysphagia, and aphasia, and was subsequently transferred to her local facility for ongoing care.

The histologic examination of the resected brain mass revealed large fragments of a well-demarcated, highly cellular neoplasm arranged in compact sheets. Neovascularization and scattered areas of necrosis were observed. Interestingly, there was no apparent presence of desmoplastic stroma surrounding the neoplastic cells. The adjacent brain tissue showed signs of reactive gliosis (Figure 5 and Figure 6). er to Table 1 for the results of the ancillary studies. Reverse transcription–polymerase chain reaction (RT-PCR) performed on the brain mass identified an EWSR1-WT1 fusion with breakpoints at exon 9 of EWSR1 and exon 8 of WT1.

The first documentation of pleural-origin DSRCT was published by Bian and colleagues in 1993 [9]. A literature review published in 2017 by Fois et al. [10] summarized the findings of previously reported cases of pleural DSRCT in English-language publications, totaling 15 individual cases. The most common presentations included chest pain and pleural effusion, with up to 40% of cases showing involvement of the lungs or mediastinum at the time of diagnosis. Survival beyond three years was low.

This poor survival rate is similar to non-pleural DSRCT cases. A study by Jayakrishnan et al. [11] reviewed their institutional records from 2010 to 2020 and identified seven cases of DSRCT, all males with tumors of typical intra-abdominal origin. All patients presented with gastrointestinal symptoms such as abdominal distention, pain, nausea, and vomiting. Computed tomography imaging revealed widespread peritoneal carcinomatosis in all cases, and two patients had liver metastases at the time of presentation.

The uncommon occurrence of DSRCT in the pleural region may have contributed to delays in receiving appropriate therapy in our case. Similar situations have been reported in the literature, such as the case of a 15-year-old patient with pleural DSRCT who was initially treated for tuberculous pleuritis for two months before the correct diagnosis was made [12].

Our case is not only unique in terms of its site of origin but also appears to be one of the few reported cases in the literature where DSRCT has metastasized non-contiguously to the central nervous system (CNS). This differs from a series of reports that have shown CNS spread from primary CNS DSRCT [6],[13],[14] or cases suggestive of direct extension into the CNS through involvement of spinal nerves [15],[16]. Table 3 provides a summary of DSRCT cases with indirect CNS metastasis available in the literature at the time of review [6],[17],[18],[19],[20].

Research investigating the incidence of hematogenous or indirect CNS metastasis from various types of sarcomas indicates a frequency ranging from 0.7% to 3.45%. It has been observed that in the majority of cases, metastasis to the lungs occurs prior to spread to the CNS [21]. Wiens and Hattab [7] conducted a study focusing on general solid tumor metastases in a young population (under 21 years of age) and found that approximately 2.3% of tumors demonstrated CNS metastasis. These metastases often presented as solitary lesions located in the supratentorial space. The average time from diagnosis to CNS spread was 27 months, with a subsequent average survival of 36.6 months.

The literature lacks comprehensive characterization of the morphologic features and clinical presentation of desmoplastic small round cell tumor (DSRCT) metastasis within brain tissue. The case reports listed in Table 3 do not provide details on the examination of lesional tissue, possibly due to the absence of surgical management. Theore, this case report represents the first histologic description of this uncommon scenario. Table 2 compares the three biopsies performed on this tumor. Allowing for potential therapy-related changes in the second and third specimens, histomorphologic features were largely consistent across these samples: The tumor cells displayed round to ovoid nuclei with vesicular chromatin, indistinct borders, and minimal cytoplasm. Ancillary study results were also concordant. However, the brain metastasis notably lacked desmoplastic stroma, which was evident in the other two biopsies. The absence of clinical history or previous biopsy results would complicate the diagnostic challenge posed by this morphology.

Lee et al. [22] conducted a study on five cases of primary CNS DSRCT and found that prominent desmoplastic stroma was observed in only two cases. Three out of the five cases exhibited a solid-pattern growth with peripheral entrapment of axons, leading to diagnostic overlap with other primitive CNS neoplasms such as medulloblastoma or astroblastoma. The diagnosis in all five cases was confirmed through genetic evaluation revealing EWSR1-WT1 fusion. The patients were exclusively male, with an age range of 6–25 years and a median age of 11 years. Presenting symptoms included seizures, headaches, numbness, and weakness. Four tumors were located supratentorially, while one was located in the posterior fossa. Magnetic resonance imaging findings varied from heterogeneously enhancing masses with a small cystic component to predominantly cystic masses with solid enhancing nodules. Other accounts of primary CNS DSRCT describe the stroma as varying in its presence, ranging from minimal [23] to abundant [13],[14],[24], predominantly collagenous but also described as fibromyxoid [25].

Desmoplastic small round cell tumor demonstrating a solid pattern without desmoplastic stroma has been described as a variant pattern by Ali et al. [26] in a case report of an adolescent female with intra-abdominal DSRCT. However, no subsequent tissue sampling was reported. Similarly, Al-Ibraheemi et al. [6] found the absence of desmoplasia in 6 out of 34 primary DSRCT specimens, all of which exhibited a solid pattern morphology. It is unlikely that the nature of the CNS environment was responsible for the loss of desmoplastic stroma in the CNS, as many metastatic CNS lesions of different lineages (epithelial, mesenchymal, and neuroendocrine) are associated with this feature [27] It is understandable that primary tumors lacking desmoplasia can present a diagnostic challenge as they may resemble other “small round cell” neoplasms such as Ewing sarcoma, rhabdomyosarcoma, small cell carcinoma, or lymphoma. In such cases, the use of immunohistochemical studies can help narrow down the differential diagnosis, while molecular confirmation of the EWSR1-WT1 fusion provides further identification. It should be noted that the EWSR1-WT1 fusion has been documented in neoplasms other than DSRCT [28],[29],[30] and theore must be interpreted in the context of the clinical history and histopathologic features of each case.

This case report presents a rare occurrence of DSRCT with hematogenous metastasis to the central nervous system in a young female with a pleural-origin tumor. As expected from the aggressive nature of this tumor group, our case exhibited local spread at the time of presentation. Due to delays in reaching a definitive diagnosis, the patient initially received lung cancer chemotherapeutics before transitioning to the standard VAC/IE treatment. Subsequent spread to the right frontal lobe led to significant neurological impairment and residual deficits on the left side. Recognizing the typical histomorphology of DSRCT and maintaining a high suspicion for alternative diagnoses in young non-smokers presenting with advanced thoracic disease are crucial in the initial identification of this rare entity. Conducting appropriate histological and immunohistochemical evaluations, followed by molecular confirmation of EWSR1-WT1 fusion, can help rule out mimicking conditions such as undifferentiated carcinoma, lymphoma, and other small round cell tumors.

Finally, our case represents the first detailed description of the distinctive morphological characteristics of a metastatic DSRCT within the brain, including the observed stromal heterogeneity between the primary and metastatic sites. Further literature is needed to fully define the histological spectrum of this entity.