Primary adrenal leiomyosarcomas are non‑functional mesenchymal malignant tumors of the adrenal gland, and are thought to arise from the smooth muscle wall of the central adrenal vein or its branches [2].

These tumors are very rare and represent only 0.1% to 0.2% of all retroperitoneal soft

tissue sarcomas in adults [7]. To the best of our knowledge, only approximately 45 cases have been reported in the English literature [5].

PAL can be asymptomatic and discovered incidentally during imaging performed for reasons unrelated to the PAL itself. The most common symptom at presentation is abdominal [5, 8-17] as was the case of our patient or flank pain [2,5,7,18,19]. Other symptoms include weight loss [17, 20-24] and lower extremity edema due to tumor growth into the inferior vena cava [5, 25].

They are typically found in image studies as large heteroge­neous masses with no specific characteristics, which makes them undistinguishable from other adrenal tumors [10]. The etiology of adrenal leiomyosarcoma remains unknown, but HIV and EBV infections are suggested to be factors related to its occurrence [7].

There are no distinct biochemical tests that are useful to identify and confirm PAL preoperatively.

PAL do not produce any adrenal hormonal derangement and dosing adrenal hormones are consistently normal, and no specific tumor markers have been identified. Elevated concentration of neuronspecific enolase (NSE), which normalized postoperatively, was noted in one patient with PAL [26]. The level of serum NSE was significantly high preoperatively and NSE protein was highly expressed in the resect­ed tumor. After surgery, serum NSE level became normal. It is suggested that serum NSE level could be a useful biomarker for the early detection for PAL.

Currently, the diagnosis of PAL is based on histopathological and immunohistochemical findings, showing a neoplasm consisting of spindle cells that stain positively for one or more of the following smooth muscle cell markers; SMA , desmin  and vimentin  [5] In addition to SMA and desmin, the tumor of our patient demonstrated positive immunoreactivity for H-caldesmon, also a marker of smooth muscle cells, in accordance with previous reports in patients with leiomyosarcomas of other origins [27]. The proliferation index Ki-67 was high (≥ 20 %) in our patient, which is in agreement with reported cases showing an index between 20% and 75%. [1,8,14,15,28]

The only and the best treatment modality of PAL is surgical resection with negative margins, after the evaluation of the tumor secretion to exclude the diagnosis of a functional tumor [29].

The histologic grade has been correlated with its biological behavior and prognosis (3), and these tumors rarely metastasize to regional lymph nodes, with metastases most frequently occured in the liver and lungs as our case report. Several cases have been reported where the tumor has invaded the inferior vena cava and caused a thrombosis [10, 25,30]

Postoperative adjuvant radiotherapy is suggested for locally advanced malignancies of soft tissue sarcomas [31]. However, the benefit of chemotherapy is very limited and can be used in cases of inoperable tumors, incomplete resections, and metastatic disease.

In metastatic disease, the longest survival of patients reported is three years after surgery [29].

Few single-agent chemotherapies have shown a reasonable response rate with acceptable toxicity to justify their use in the treatment of metastatic STS. Two of the most commonly used single agents are doxorubicin and ifosfamide [32].

Considering polychemotherapy, gemcitabine plus docetaxel can be considered in patients who cannot tolerate doxorubicin because of their cardiac history. The authors of the phase III study concluded that doxorubicin should remain the standard first-line treatment of metastatic soft tissue sarcomas, but gemcitabine/docetaxel can be considered an acceptable alternative in patients with cardiac dysfunction in whom doxorubicin is contraindicated. [33]

Trabectedin (Yondelis) is antineoplastic agent recently approved in the United States to treat advanced liposarcoma and leiomyosarcoma in patients who have already been treated with an anthracycline-based regimen.40 Trabectedin is a marine-derived tetrahydroisoquinolone alkaloid that binds to the minor groove of DNA, which disrupts the function of DNA binding proteins and leads to cell-cycle perturbation and apoptosis [34]. It is currently approved for administration via a central venous line at a dose of 1,5 mg/m2 IV over 24 hours on day 1 of a 21-day cycle. A multicenter, randomized, open-label, phase III trial compared trabectedin with dacarbazine in patients with advanced leimoyosarcoma or liposarcoma who had been treated previously with standard chemotherapy, including previous anthracycline-based chemotherapy [35]. Patients were randomized   to receive either trabectedin 1,5 mg/m2 IV over 24 hours or dacarbazine 1000 mg/m2. The two drugs were administered on day 1 of a 21-day cycle. The primary endpoint was OS, with PFS as a secondary endpoint. Results of the trial showed significantly higher median PFS (4,2 months versus 1,5 months) with trabectedin compared with dacarbazine, without difference of median OS.

Pazopanib (Votrient) is a multitargeted tyrosine kinase inhibitor that targets and inhibits vascular endothelial growth factor receptors (VEGFR), PDGFR, fibroblast growth factor receptors, and c-Kit. It is indicated for the treatment of patients with advanced STS who have received prior chemotherapy, except for patients with liposarcoma [36] A randomized, double-blind, phase III study by the European Organization for Research and Treatment of Cancer compared pazopanib 800 mg orally daily until disease progression or intolerable toxicity with placebo in patients with various histological STS subtypes, patients with liposarcoma were excluded [37]. The primary endpoint was PFS, with OS as a secondary endpoint. Patients receiving pazopanib exhibited significantly better median PFS compared with placebo (4.6 months versus 1.6 months). However, no significant difference in OS was observed.

Regorafenib (Stivarga) is another multitargeted TKI that exerts its antineoplastic activity by targeting and inhibiting VEGFR, RET, c-Kit, BRAF, and PDGFR [38]. While regorafenib is not yet approved by the FDA for the treatment of non-GIST STS, its safety and efficacy have been evaluated in a randomized, placebo-controlled, phase II trial in patients with leimyosarcoma, liposarcoma, synovial sarcoma, or other types of STS that had been treated previously with a variety of agents [39]. Patients were randomized to receive regorafenib 160 mg orally daily for 21 days followed by seven days off or matching placebo. A total of 181 patients were randomized to treatment. The primary endpoint was PFS and OS was a secondary endpoint. Compared with placebo, regorafenib demonstrated a significant benefit in PFS among patients with leiomyosarcoma (3.7 months versus 1.8 months) and synovialo sarcoma (5.6 months versus 1.0 months). Patients with liposarcoma did not experience a benefit in PFS compared with placebo (1.1 months versus 1.7 months).