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  • The management of PEComa follows the same treatment

    2019-05-09

    The management of PEComa follows the same treatment principles as other subtypes of soft tissue sarcoma. Surgical resection remains the primary treatment modality. There is no consensus on the administration of adjuvant treatment. Other treatment options, including chemotherapy and radiotherapy, have been utilized at the discretion of physicians to minimize risk of recurrence. In order to achieve complete surgical resection, neoadjuvant approaches with chemotherapy or radiotherapy have also been performed. There is still no high-level evidence to support the clinical benefit of adjuvant or neoadjuvant therapy. Close surveillance plus repeated resection remains one strategy. Long-term survival was reported in a patient with recurrent PEComa receiving multiple resections. Patients with tuberous sclerosis complex or lymphangioleiomyomatosis-related AML were shown to harbor mutations of tuberous sclerosis genes, including the harmatin gene (TSC1) and the tuberin gene (TSC2). The TSC1/TSC2 complex inhibits the downstream Rheb-GTP, which can activate the mTOR complex and lead to phosphorylation of S6 kinase, protein synthesis, and cell growth. Aberrations in TSC1 or TSC2 result in loss of function of the complex and release of inhibition of Rheb-GTP, which then aberrantly overactivates the mTOR pathway. mTOR inhibitors, such as sirolimus or temsirolimus, are thus hypothesized to possess clinical activity in neoplasms with loss of TSC1 or TSC2 expression. The pivotal study by Bissler et al. demonstrated the efficacy of sirolimus in reducing the size of AMLs and improving pulmonary function in patients with pulmonary LAM. There is also evidence of mTOR pathway overactivation in PEComa, and sirolimus was shown to be effective against malignant PEComa. PEComa mibefradil are usually immunohistochemically positive for phospho-S6 and phospho-p70S6K and negative for TSC2 and phopho-Akt. The level of phospho-S6 expression was proposed to be a predictive marker of early tumor response to mTOR inhibitors. In patients with malignant PEComa receiving sirolimus or temsirolimus, the largest case series reported a response rate of up to 50% with a median treatment duration of 128 days. Treatment toxicity is generally mild and manageable, with oral mucositis as the most commonly occurring adverse effect. The reported 1-year survival rate was 78.8% with a median overall survival of 2.4 years. Primary or secondary resistance to mTOR inhibitors was reported, but the exact mechanism is largely unknown. Possible resistance mechanisms, as seen in other tumors treated with mTOR inhibitors, include mutations in mTOR, feedback loop activation of the PI3K/Akt pathway, increased activation of the alternative ERK/MAPK pathway, decreased expression of 4E-BP1, or overexpression of downstream eIF4E. Conventional chemotherapy has little efficacy in malignant PEComa, despite reports of cases showing clinical response. Interestingly, expression of estrogen and progesterone receptors has also been noted in PEComas with predominant spindle morphology. Letrozole, an aromatase inhibitor, has been reported to have a favorable and sustained effect in PEComa. In addition to systemic treatments, aggressive local treatments, such as radiotherapy and surgical resection, may still play some roles in managing metastatic PEComa. Long-term disease control achieved by repeated metastasectomy was also reported. TFE3 gene fusion has been demonstrated in several types of neoplasia, including alveolar soft part sarcoma (ASPS) and pediatric renal cell carcinoma. Recently, a subset of PEComa has also been shown to harbor TFE3 gene rearrangement. This subset of rearranged PEComa is distinctive from their non-rearranged counterpart in several aspects. They typically comprise pure epithelioid cells arranged in an alveolar pattern and stain strongly for TFE3 and HMB-45 while expressing minimal muscle markers. Their morphology bears a similarity to ASPS under light microscopy, and the differential diagnosis can be made on the basis that ASPS is negative for HMB-45 and Melan-A and harbors a unique ASPSCR1-TFE3 translocation. TSC2 is not inactivated in this subset of PEComa, which theoretically implies that treatment with an mTOR inhibitor will not be effective. The presence of this subset of rearranged PEComa may serve to partly explain the primary resistance to mTOR inhibitors. However, the primary resistance seen in our case is unlikely to be explained by TFE3 gene rearrangement considering the tumor\'s positivity for muscle markers and the predominant spindle pattern.