Challenges in the Management of Stage IV Clear Cell Sarcoma of Soft Tissue in Young Adults: Case Report and Review of the Literature

Clear cell sarcoma (CCS) of soft tissue is a rare and aggressive form of malignant mesenchymal tumor, commonly presenting in the distal lower extremities of young adults. Also known as “malignant melanoma of soft parts” because of its melanocytic line of differentiation, CCS separates from malignant melanoma at a genetic level with the presence of an oncogenic fusion driver gene EWSR1-ATF1. In general, for diagnosis and treatment, sarcomas should be addressed to specialized reference centers for multidisciplinary management. In the effort of providing the best care for patients with rare cancers, detailed published case reports bring valuable insight for physicians facing these entities. Clinical trials have not succeeded in offering active therapy in this setting so far. Hence, we present a case of stage soft tissue CCS in a young woman with its diagnostic and treatment challenges.

A 27-year-old Caucasian female, without known family history for cancer, presented 2 years ago with a right pigmented plantar lesion with progressive growth over 3 months. Medical history and physical examination revealed Eastern Cooperative Oncology Group (ECOG) performance status of 2, skin type II, antalgic standing position due to a right plantar firm, immobile and painful mass of 4/2 cm. The patient had normal blood work and a negative human chorionic gonadotropin (for pregnancy screening).

Diagnostic imaging was performed as presented in Figure 1a and b. The patient had undergone a right foot contrast MRI, which showed a plantar soft tissue tumoral growth involving the flexor tendons of fingers II, III, and IV. Additional PET-CT revealed an FDG avid tumor with a SUV of 7.9, two FDG-positive right inguinal adenopathies and one subcutaneous nodule in the superomedial portion of the right hip. No other pathological findings were described.

An incisional biopsy was performed in a general surgery department. The pathology report showed with hematoxylin and eosin staining a mesenchymal proliferation consisting of polygonal cells with round to oval hyperchromatic nuclei and clear cytoplasm. Cells were disposed in clusters separated by fibrous septa. The tumor invaded aponeurosis tissue in the studied material. The mitotic count was 1 mitosis per 10 HPF. The immunohistochemistry profile was positive for the melanocyte-specific marker HBM-45 and for S-100, SOX-10, EMA, CD 99, and FL-1 and negative for melan-A, desmin, CKAE1/AE3, CD 34, and calretinin. Morphologic and immunohistochemistry results concluded the final diagnosis of CCS FNCLCC (French Federation of Cancer Centers) grade 2 (differentiation 3, necrosis 0, mitotic activity 1, total 5). Further molecular FISH testing revealed EWSR1 gene rearrangement and genetic testing negative for BRAF mutation. Clinical, imaging, histological, and molecular studies led to the final diagnosis of plantar CCS FNCLCC grade 2, stage IV.

The case was discussed in the multidisciplinary team in our tertiary academic center with the decision of local therapy, specifically upfront surgery: amputation of the right foot and local excision of the in-transit nodule and right inguinal +/− pelvic lymph nodes. The patient refused surgery at first. At that time, there were no available clinical trials for inclusion of this case. Despite the recommendation of having surgery, the patient started treatment in a secondary center with definitive/neoadjuvant radiotherapy, with volumetric modulated arc therapy technique, 66 Gy/33 fr/45 days, delivered to the right plantar region and 60 Gy/30 fr/40 days to the subcutaneous nodule and right inguinal pathologic lymph nodes.

The first evaluation scan was performed 10 days after the completion of the radiotherapy and showed early progression of inguinal macroscopic nodes. The patient was directed to surgery where amputation of right foot and ankle with right inguinal lymphadenectomy was performed. The pathology report revealed R0 resection, the same histology, but FNCLCC grade 3 (differentiation 3, necrosis 1, mitotic activity 2) and 5 out of 5 lymph nodes evaluated were positive for metastasis with capsular effraction.

The postoperative CT scan showed a new pathological right obturator node (14 mm) and suspected subcutaneous nodules at the level of the right hip. First-line chemotherapy was started with an anthracycline-based regimen (doxorubicin 20 mg/m², ifosfamide 3,000 mg/m², plus MESNA) administered on a port-a-cath. Ovarian inhibition with goserelin 3.8 mg was associated.

After 2 cycles of chemotherapy, the patient presented with a right inguinal abscess and evolution of subcutaneous lesions of the right hip. Abscess drainage was performed with subsequent microbiology tests positive for Acinetobacter baumannii MDR (multidrug resistant) and Enterococcus faecalis. Antibiotics were started with the persistence of the local infection with Acinetobacter baumannii MDR for which she continued the treatment with colistin and Tigecycline, but sterilization was never achieved. Due to progressive disease, second-line therapy with pazopanib 800 mg daily was started with a very good response at 3 weeks, clinical partial response, with necrosis. Figure 2a and b represent the progressive disease at the right hip. Palliative radiotherapy was performed 8 Gy/1 fr, with a 3-dimensional technique, targeting the subcutaneous metastases located at the right hip. The patient received antalgic therapy with fentanyl 50 μg every 72 h and morphine sulfate 20 mg as a quick relief.

Three weeks after the initiation of the targeted therapy, the patient was admitted with signs of localized right inguinal. During hospitalization, the patient developed neurologic symptoms with blurry vision, miosis, and grand mal seizures associated with elevated blood pressure of 200/120 mm Hg. The CT scan of the brain ruled out brain metastases and raised the suspicion of posterior reversible encephalopathy syndrome (PRES) which was confirmed by the subsequent brain MRI (Fig. 3). An acute ischemic lesion was also observed in the parieto-occipital area. On brain scans, vessels showed permeability without signs of thrombosis. It was not possible to identify the exact cause of PRES. The syndrome could have developed in the context of patient’s comorbidities such as septic state and malignancy, but it could also be caused by any of the medication received (anthracyclines, tyrosine kinase inhibitors [TKIs], corticosteroids, antibiotics). All the treatment with potential implications in PRES and not critically needed was discontinued. Under antihypertensive, vasodilator, and anticonvulsant drugs, the neurological symptoms improved.

After a few days of improvement, the patient suddenly became comatose and was transferred to the intensive care unit. The evolution was rapidly unfavorable, resulting in the death of the patient. Survival of the patient was 15 months.

CCS of soft tissue has a very low incidence representing less than one percent of all sarcomas [1]. As a particularity, CCS shares ultrastructural features with malignant melanoma, showing a melanocytic line differentiation with melanin synthesis and S-100 and HMB-45 protein expression, hence the alternative name of “malignant melanoma of soft parts.” Occasionally, these similarities can lead to diagnosis challenges [2]. Differential diagnosis is now possible using genetic testing which can reveal the genetic signature of CCS represented by chromosomal rearrangements as t(12; 22)(q13; q12) or t(2; 22)(q33; q12) with the affected genes of EWSR1-ATF1 or EWSR1-CREB1.

Synchronous metastatic disease (any T, N1, M0, any G or any T, any N, M1, any G) is an even more challenging entity since the guidelines are nonspecific about optimal management. For limited stage IV disease, options of treatment include local therapy (resection/amputation, radiotherapy, regional limb therapy) to control the primary tumor or systemic therapy consisting of chemotherapy [3]. However, the tumor becomes resistant to chemotherapy in the metastatic setting [4]. The overall survival is poor, around 14.5 months [5].

Physicians treating rare tumors should include their patients in clinical trials. Recent advances in understanding CCS biology pointed out new potential therapeutic targets.

A study of a retrospective international series from the World Sarcoma Network included 55 patients with advanced CCS receiving different types of systemic therapy. Pazopanib, a TKI, was the most used drug in this setting after common sarcoma chemotherapy regimens. However, the benefit of targeted therapy was limited, with a poor response rate [6]. Other TKIs (sunitinib, sorafenib) showed objective tumor response after progression on conventional chemotherapy, a treatment used off-label and described only in case reports [7, 8]. In our case, the prescription of pazopanib in second line was possible. It was administered considering the experience with the drug in other types of sarcomas and as a last resource, given the poor tolerance and inefficacy of the chemotherapy and infectious complications associated in this patient. The PRES was unexpected but correctly and rapidly diagnosed in this patient.

PRES is characterized by diverse clinical symptoms, including visual disturbances, headaches, seizures, and altered consciousness. MRI scans typically reveal edema in the posterior subcortical regions. Common triggers include hypertension, preeclampsia/eclampsia, renal failure, cytotoxic agents, and autoimmune conditions. Although most patients recover, PRES can lead to significant morbidity and mortality. Treatment involves addressing the underlying cause and managing associated complications, such as seizures [9].

Recently, in the literature, there have been an increased number of case reports regarding PRES as an adverse event to angiogenesis inhibitors [10]. In our case, PRES occurred during the first month of treatment with hypertension and neurological symptoms, as described in other case reports from the literature [11]. With this case report, we want to raise awareness about the occurrence of this rare adverse event for proper diagnosis and management.

Advances in the treatment of CCS were made by Mae H. et al. [12] who studied ex vivo and on mice the efficacy of histone deacetylase inhibitor vorinostat to target the oncogenic driver fusion gene EWSR1-ATF1. Vorinostat, a drug used in treatment of cutaneous T-cell lymphoma, also proved to be an active agent in CCS in this research.

The oncogenic MET receptor has been associated with the oncogenic pathway in CCS. In the phase II trial “CREATE” studying the activity of crizotinib (MET TKI) in six different types of cancers, the treatment did not met its primary endpoint (objective response rate) in patients with CCS showing variable responses in MET-positive cancers [13]. This result suggests the presence of other factors involved in CCS pathogenesis.

CCS seems to have a high-grade intrinsic resistance to chemotherapy and radiotherapy. Immunotherapy produced rare responses in patients with CCS as showed in the series of 11 cases from MD Anderson treated with checkpoint inhibitors [14]. Combining immunotherapy with targeted therapy might be a potential milestone in developing an effective treatment.

CCS of soft tissue/melanoma of soft parts is a rare form of sarcoma occurring in young adults. For this orphan tumor, especially for stage IV disease, there are no data supporting the optimal treatment, conventional therapy having poor efficacy. These cases should be referred to specialized expert centers to benefit from clinical trials, especially phase I trials. Past trials did not achieve to establish new active therapies for CCS; thus, further research is mandatory.

Ethical approval is not required for a case report in accordance with local and national guidelines. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images. To protect the patient’s right to privacy, all identifying data were removed.

The authors have no conflicts of interest to declare.

No funding was received for conducting this study.

Diana Iordache was the first author who contributed to this article, gathered the data, and wrote the draft. Anita-Andrea Kövendi contributed to the drafting of the manuscript. Raluca Popița, Iunia Patricia Cebotaru, and Annamaria Patka contributed with their expertise to review of the article. Zsolt Fekete, Ioana Năstase, and Cristina Ligia Cebotaru were the supervisors who coordinated the structure of the article and were responsible for the final manuscript review.

Data supporting this study are included within the article and supporting materials. Supplementary data are available from the corresponding author, Zsolt Fekete, fekete.zsolt@umfcluj.ro. The CARE Checklist has been completed by the authors for this case report and attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000540084).