Developments in Systemic Therapy for Soft Tissue and Bone Sarcomas

The past year has led to significant changes in systemic therapies used to treat soft tissue sarcomas, mainly dominated by the removal of the recently approved drug olaratumab as part of combination therapy with doxorubicin from the NCCN Guidelines for Soft Tissue Sarcoma, according to Dr. Suzanne George. Several histology-specific drugs have entered the space, including pazopanib and pembrolizumab, the latter of which was approved as a category 2B recommendation for alveolar soft part sarcoma, highlighting the rather limited role of immunotherapy in sarcomas. Dr. George also discussed updated data for sorafenib in the treatment of desmoid tumors, as well as the importance of larotrectinib in TRK fusion-positive tumors.

We present a 13-year-old girl who had been operated for the intraspinal mass in upper thoracic spine and paraparesis with thoracic limited laminectomy and excision of the tumor mass elsewhere. The histopathological examination was reported to be aggressive fibromatosis. After 2 years, she presented again with 1-year duration of progressive deformity in the upper thoracic spine and weakness of both lower limbs. Focal kyphosis at T4-T5 was measuring 68°. Magnetic resonance imaging (MRI) showed recurrent tumor involvement of posterior elements of T2-T5 and paravertebral soft tissues with signal changes in the cord at T2-T5 vertebral levels with focal kyphosis and internal gibbus. She underwent posterior spinal revision decompression with internal gibbectomy and instrumented fusion. The histopathology showed features suggestive of aggressive fibromatosis. After wound healing at 2 weeks, she underwent 3-D conformal radiotherapy, based on the preoperative tumor extent on MRI (dose of 45 Gy in 25 fractions over 5 weeks). She had normal neurology at 2-year follow-up and was tumor free on MRI. Hence, aggressive fibromatosis can recur following successful surgical wide excision. Multilevel thoracic laminectomy in growing children can cause progressive spinal deformity and neurological deficits. Operative treatment of recurrent tumor involves en bloc excision with instrumented fusion followed by local radiotherapy. This is the first pediatric recurrent spinal fibromatosis reported with successful treatment as per author’s knowledge.

Desmoid-type fibromatosis (DTF) is a lesion characterized by clonal proliferation of myofibroblasts, which exhibits an infiltrative growth pattern. It is necessary for them to be distinguished from other fibroblastic and myofibroblastic lesions as well as spindle cell tumors. Altered Wnt signaling can act as a defining characteristic of DTF, with nuclear beta-catenin serving as a diagnostic marker for. Transcription factor E3 (TFE3) has been linked to Wnt pathway activation and regulation, and may add value to the diagnosis of DTF. The present study, therefore, sought to assess whether TFE3 is a specific diagnostic marker for DTF. Nuclear TFE3 and beta-catenin staining was performed on a wide range of tumor types such as DTF (n = 46), nodular fasciitis (n = 14), neurofibroma (n = 5), dermatofibrosarcoma protuberans (n = 5), gastrointestinal stromal tumor (n = 10), sclerosing epithelioid fibrosarcoma (n = 2), synovial sarcoma (n = 5), leiomyoma (n = 3) and cutaneous scar tissue (n = 4) using an immunohistochemical approach. FISH assay was carried out to examine Xp11.2 translocations/TFE3 gene fusions. Statistical difference between immunohistochemical expression of TFE3 and beta-catenin was analyzed. The expression of nuclear TFE3 protein was found in 43 (93.5%) DTF tissue samples, ranging from moderate to intense expression levels. The distribution rates of TFE3 positivity in nodular fasciitis, gastrointestinal stromal tumor, leiomyoma and scar tissue samples were 42.9, 40, 25 and 33%, respectively. All studied samples of neurofibroma, synovial sarcoma, sclerosing epithelioid fibrosarcoma and dermatofibrosarcoma protuberans were negative for TFE3. This study reveal that TFE3 has a potential to serve as a diagnostic marker capable of assisting in the differential diagnosis of DTF and other spindle cell lesions.

We have conducted a phase II study to evaluate the efficacy and safety of tamoxifen and sulindac in treatment of primary unresectable and recurrent desmoid tumors. Eligible patients were ≥18 years of age who had measurable histologically confirmed recurrent or newly diagnosed tumors not amenable to R0 resection, or those who underwent tumor excision with gross residual desmoid tumor. The primary objective was to estimate progression-free survival. Patients received 20 mg tamoxifen and 300 mg sulindac daily for up to 12 months according to absence of disease progression or unacceptable drug toxicity. 25 patients, 12 males and 13 females, whose ages ranged from 18-60 years. Most (88%) had a good performance status (ECOG 1). A total of 6 of 15 patients with recurrent desmoid tumors had histories of prior local radiotherapy for their primary tumors. There were 10 newly diagnosed patients, 15 (60%) had recurrent disease and only one patient had a diagnosis of familial adenomatous polyposis. Only 22 patients completed the treatment protocol and were evaluated for clinical response and time to progression. All patients were evaluated for safety profile. The overall response rate was 60%, with complete response observed in 8% and partial response in 52%. At two years, the estimated progression-free survival rate was 55% with a median progression free survival of 25 months. According to the results of this study, systemic treatment with tamoxifen and nonsteroidal anti-inflammatory drugs is safe and effective in patients with desmoid tumors.

The aim of this report is to analyze a rare clinical case of an aggressive intra-abdominal DT successfully treated with sorafenib. A 36-year-old man presented with increasing colicky abdominal pain and a self-palpable mass in his left abdomen. Fourteen years earlier he was diagnosed with a large intra-abdominal tumor, which adhered to the left colonic flexure, part of the major gastric curvature and the spleen. Subsequent exploratory laparotomy revealed a voluminous mass in the epigastrium, arising from the posterior surface of the stomach and invading the superior mesenteric vessels, transverse mesocolon and the small bowel mesentery. As the tumor was unresectable, a jejunojejunal bypass was performed. Traditional therapeutic interventions proved insufficient, and the patient was started on sorafenib with a subsequent full-disease response. DT’s pathogenesis has been associated with mutations in the adenomatous polyposis coli (APC) gene or beta-catenin gene CTNNB1, sex steroids or previous surgical trauma. Local treatment modalities, such as surgery or radiotherapy, are implemented in aggressively progressing or symptomatic patients. Sorafenib is a hopeful therapeutic option against DTs, while several pharmacological agents have been successfully used.

Intra-abdominal desmoid tumors (DTs) can mimic recurrence or progression of gastrointestinal stromal tumors (GISTs). Differential diagnosis is important to avoid unnecessary or inappropriate treatment. All 8 patients experienced surgical resection of GIST, and median time to diagnosis of DT was 1.8 years after surgical resection. All sites of DT were in the peritoneum around the surgical sites of GIST. The following clinical suspicion coupled with radiological findings contributed to the suspicion of intra-abdominal DTs: (1) Occurrence of a new single lesion in the peritoneum around the surgical sites of GIST; (2) uncontrolled lesion with imatinib while other lesions being controlled with imatinib; (3) well-defined ovoid shaped lesion with delayed or mild enhancement and absence of necrosis, hemorrhage, and cystic change on computed tomography; and (4) a lesion showing mild or no hypermetabolic activity on 18fluorodeoxyglucose-positron emission tomography, contrary to initially hyperactive lesion of GIST. All DTs were surgically removed except for one unresectable DT and only one DT recurred at another site of peritoneum, which was also surgically removed. Intra-abdominal DT should be a differential diagnosis for a new single lesion in patients with GIST.