High-Grade Angiosarcoma Transformation in Schwannoma and SMARCB1 Mutation: A Case Report

Introduction

Angiosarcomas are malignant tumors of vascular endothelial cell origin. Angiosarcomas can occur anywhere in the body, but the most common sites are skin and soft tissues [1–3]. Angiosarcomas are rare malignancies and account for less than 4% of soft tissue tumors [4]. Epithelioid angiosarcomas are highly aggressive subtypes of angiosarcomas in which the morphologic appearance of malignant cells is predominantly epithelioid, exhibiting polygonal shapes with abundant eosinophilic cytoplasm, round-to-oval nuclei, and distinct cell borders [1,3,5]. The epithelioid subtype of angiosarcomas is mostly found in deep soft tissues, but other sites can be found in the skin, thyroid, and adrenal glands, and bone [1,3]. These tumors occur mostly in adults and are rare among children [4].

Schwannomas are the most common primary benign tumors of the peripheral nervous system arising from Schwan cells. Schwannomas become malignant in approximately 5% of cases [6,7]. Most frequently, schwannomas present as asymptomatic or painless masses, especially in the regions of the head and neck, as well as the flexor surfaces of the upper and lower limbs. Four histological types of schwannomas have been described: glandular, epithelioid, cellular, and ancient schwannomas [4,8].

An epithelioid angiosarcoma arising in a schwannoma is very rare. Fewer than Unithiol 25 cases have been reported in clinical literature [9–23]. Due to the non-specific symptoms of this extremely rare malignancy at the time of presentation, clinicians face a diagnostic challenge that may affect treatment decisions and outcomes. This is the first reported case with SMARCB1 frameshift loss-of-function (LOF) mutation in this rare subtype of sarcoma. SMARCBI is a tumor-suppressor gene located on chromosome 22q11.23 and prevents cell proliferation. SMARCB1 frameshift LOF mutations impair this normal gene function, leading to aggressive cancers like rhabdoid tumors, significantly affecting diagnosis, treatment options, and patient outcomes [24]. We present a rare case of high-grade metastatic epithelioid angiosarcoma arising in a schwannoma with SMARCB1 frameshift LOF mutations in a 58-year-old man who presented with slow-growing masses on the right back, right upper limb, and neck. We further highlight the diagnostic and treatment approach.

Case Report

FOLLOW-UP:

The pathology report indicated the left lateral upper back mass tissue had benign mature fibroadipose tissue, consistent with lipoma. Surprisingly, the left medial upper back mass showed high-grade epithelioid angiosarcoma arising in a schwannoma and extending to the peripheral resection margins (Figures 3–5). These were microscopically described as SOX10-positive, S100-positive CD31 positive, and excisional margins-positive.

Following this rare diagnosis, the medical oncology team was involved, and a positron emission tomography-computed tomography (PET/CT) scan suggested PET avid lesions concerning for metastatic disease to the regional nodes, including the left supraclavicular nodes, right paratracheal nodes, bilateral hilar and subcarinal region, and to the left pedicles of thoracic spine at the level of the fifth and sixth ribs and tonsillar region (Figure 6). The left neck lymph node percutaneous biopsy confirmed metastatic disease. Tempus molecular profiling showed SMARCB1 frameshift LOF. The patient’s pain and discomfort in the back persisted after removal of the masses. The patient was started on weekly paclitaxel as a single agent for angiosarcoma, started at 80 mg/m2 weekly for 6 cycles. He tolerated the first cycle of chemotherapy without serious concerns. His back pain also started to gradually improve. After the second chemotherapy cycle, another PET scan was done to assess the prognosis of the disease while on treatment, which showed that while there were some areas of improvement in nodal activity, there was marked progression of left posterior chest wall soft tissue with extensive involvement of adjacent ribs. The PET scan also showed several new skeletal metastases to the sternum, mid-thoracic area, right pelvis, and vertebrae. At this point, the patient was counseled on more treatment options, and he agreed to start immunotherapy with pembrolizumab every 3 weeks based on molecular profiling and the high mutation burden rate. He was also started on palliative radiation. Despite these treatments, he continued to have worsening cancer-related body pain without any improvement in symptoms. After the third cycle of pembrolizumab, he was started on tazemetostat, an enhancer of zeste homolog 2 (EZH2) inhibitor approved by the FDA for treatment of SMARCB1 frameshift LOF mutation. Even with this treatment combined with radiation therapy and aggressive pain control with opioids, the patient continued to experience worsening general body aches and was in great pain. After the fourth fraction of radiation treatment, he decided to stop all forms of treatment and enter hospice care. He was very grateful and thankful for the care the team had provided him. During his transition to hospice, pain management was continued with morphine. At 8 months follow-up, which was 2 months after beginning hospice care, a follow-up phone call revealed that the patient had died.

It is important to note that a multi-year follow-up with periodic imaging and clinical assessments is crucial for understanding prognosis and treatment effectiveness. However, in this specific case, due to the highly aggressive nature of the high-grade epithelioid angiosarcoma and the rapid progression of disease, we were unfortunately unable to obtain long-term follow-up data, as the patient died within 8 months after the first visit. After the first cycle of chemotherapy, a follow-up assessment revealed he had tolerated treatment with mild improvement in pain. Symptoms eventually worsened, with increasing concerns for bone pain and general body weakness. A PET scan after the second chemotherapy cycle revealed marked disease progression with new skeletal metastases. The patient continued to have interim follow-ups for symptom management and the introduction of new treatments, including immunotherapy, radiation therapy, and targeted therapy with tazemetostat. Despite these interventions, his symptoms further worsened, which is typical of malignancies with poor prognosis like high-grade epithelioid angiosarcoma. At this point, circulating tumor DNA (ctDNA) was positive, a biomarker correlated with radiological disease progression. While the plan was to continue periodic clinical and imaging assessments, the patient’s condition deteriorated rapidly, and he decided to switch to hospice care. Typically, while the prognosis is poor, some patients with this malignancy live several months, depending on the presence or absence of metastatic disease at the time of diagnosis, as well as treatment tolerability.

Discussion

PROGNOSIS AND LONG-TERM FOLLOW-UP:

Despite aggressive treatment, the prognosis of high-grade epithelioid angiosarcoma remains guarded due to its high metastatic potential. Long-term follow-up is very important, involving periodic imaging and clinical assessments to detect early recurrence. As seen with our patient, despite chemotherapy and radiation therapy, circulating tumor DNA (ctDNA) was positive, which is a biomarker that correlates with the progression of radiological disease. By 6–7 months into treatment, the patient’s disease had symptomatically progressed, and the patient died soon after stopping all chemotherapy and starting hospice care. Prognosis, however, depends on invasion of local tissues and or presence of metastatic disease. Xiang et al’s review showed that of the 21 patients reported with a similar condition, at least 7 of those who eventually died after 1–27 months of follow-up either had metastatic disease or had tumor invasion of local tissues. The patients had also been treated with either complete resection or complete resection plus chemotherapy either. The 8 who had no evidence of disease at last follow-up mostly had local disease [10].

Conclusions

Clinicians should recognize that high-grade angiosarcoma arising in a schwannoma is a rare but aggressive malignancy. The presentation may be non-specific, so diagnosis requires thorough histopathological and immunohistochemical evaluation to differentiate it from other neoplasms. Treatment involves surgical resection with clear margins, supplemented by radiation therapy and potentially chemotherapy due to the high metastatic risk. Molecular profiling may also be necessary to identify any mutations for targeted therapies. Prognosis is generally poor, necessitating vigilant long-term follow-up for recurrence or metastasis. Multidisciplinary management is essential for optimal patient outcomes.