Pathohistological Diagnosis, Immunohistochemical Analysis and Optimal Complex Treatment in Primary Ovarian Leiomyosarcoma

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The immunohistochemical (IHC) analysis is required to clarify the pathogenesis of sarcoma cells [8,9]. Due to the rare incidence of primary ovarian leiomyosarcoma, the optimal complex treatment has not yet been determined.

ARTICLE INFO Summary
Primary ovarian leiomyosarcoma (OLMS) is an extremely rare and aggressive neoplasm. By 2018, only 73 clinical cases of ovarian leiomyosarcoma have been published in the English medical literature. We present a right-sided OLMS in a 77-year-old woman. A total abdominal hysterectomy with bilateral adnexectomy and partial omentectomy was performed. Moderately differentiated (G2) leiomyosarcoma of the right ovary is diagnosed on the basis of morphological and immunohistochemical (IHC) examination. According to the FIGO classification, it refers to an early IA clinical stage corresponding to pT1aN0M0. Despite the early clinical stage, after 6 months of diagnosis, a local recurrence with paravertebral soft tissue metastases were diagnosed, and after 6 months-disease progression with distant bone, lung and liver metastases werе observed. The article emphasizes the importance of immunohistochemical analysis for the diagnosis of soft tissue sarcomas with organ localization, unfavorable prognosis and the need for complex oncological treatment, despite the early clinical stage. In principle, the main treatment is radical surgery, but an individual assessment of adjuvant chemo-radiotherapy (Ch-RT), depending on the sarcoma volume and adverse pathohistological tumor characteristics, is required.

Discussion
Primary OLMS is a rare neoplasm of teratoma or non-teratoma origin [10]. Non-teratoma OLMS is very rarely diagnosed and is defined as "true" leiomyosarcoma [11]. Leiomyosarcomas of teratoma origin are unilateral and occur at a young age, and nonteratomas are diagnosed mainly in adults [3]. The pathogenesis of OLMS is unclear, but theories include malignant degeneration of smooth muscle cells in the mesonephrotic elements surrounding the ovary and in the walls of blood vessels, or migration with malignant transformation of uterine leiomyoma in the ovary [1,2,3]. However, malignant transformation of leiomyoma is rarely seen [3]. Migration of subserous uterine leimiosarcomas with secondary ovarian involvement is possible [12]. Macroscopically, tumors are unilateral ovarian solid masses with or without cystic degeneration, depending on the size of the formation [5,8,9].
These cells are arranged corolla-like ( Figure 1C) with nests of polymorphism, nuclear mitosis, and necrosis [7]. Often, sarcoma cells are organized into tangled or intertwined bundles with areas of pleomorphism [3]. IHC markers for the diagnosis of ovarian leiomyosarcoma include desmin, vimentin, smooth muscle actin (SMA), and S-100 [13,14]. We report the strongly positive IHC expression of sarcoma cells to desmin and SMA, as well as focal positive to S-100 ( Figure 2). In OLMS, some authors reported positive expression of estrogen receptors, progesterone receptors, p53 and bcl-2 [1,13,15]. In the presented clinical case, estrogen and progesterone receptors are negative ( Figure 3A & 3B).

Differential Diagnosis (DD)
Pathomorphological and IHC analysis of OLMS to differentiate undifferentiated sarcomas, mixed Mueller tumors, sarcomoid form of sex-cord stromal tumors and Krukenberg tumors is required.
Leiomyosarcomas are distinguished from benign tumors by hypercellularity and increased mitotic activity / above 10 on a field with magnification x10 [16]. DD for other rare ovarian sarcomas such as chondrosarcoma, malignant schwannoma, angiosarcoma, and rhabdomyosarcoma is required [5]. In the presented case we

Prognosis
Primary OLMS were associated with an unfavorable prognosis [9,17]. In a large number of cases the disease has a poor prognosis with a fatal outcome one year after diagnosis [3]. In the presented clinical case we take into account the following prognostic adverse pathohistological characteristics: tumor formation with a diameter above 5cm, high mitotic activity (Ki67-17,4%), extensive areas with tumor necrosis, tumor capsule with growth from tumor cells.

Treatment
Due to the rare OLMS diagnosis, the standard treatment approach has not yet been specified [6,9]. The most commonly used treatments include total abdominal hysterectomy, bilateral salpingo-oophorectomy, excision of a residual tumor, and possibly total tumor resection [1]. The main treatment method is surgery, which varies from surgery to preserve fertility to total abdominal hysterectomy, bilateral salpingo-oophorectomy and removal of the sarcoma mass [8]. OLMS requires total tumor surgical resection, which significantly improves the prognosis [1,3,13,15,[17][18][19].
In large tumor formations, Dixit et al recommend postoperative chemotherapy to improve local tumor control and to suppress distant metastasis, although their adjuvant effect has not been sufficiently demonstrated [8,13,19,20]. Shakfeh and Woodruff present 2 clinical cases of OLMS, of which one patient exited after 12 months without specific treatment, and the other has a 4-year survival after total hysterectomy with bilateral salpingooophorectomy followed by postoperative radiotherapy alone [21]. To increase survival in patients with advanced OLMS, maximally radical surgery, followed by combined chemo-radiotherapy as well as immunotherapy to prevent distant metastasis is required [3,6].

Conclusion
Primary ovarian leiomyosarcoma is an extremely rare aggressive systemic neoplasm. For diagnosis, strict pathomorphological and immunohistochemical analysis is required. In general, the prognosis is unfavorable. The main treatment is radical surgery.
To assess the need for postoperative adjuvant chemo-radiotherapy, it is necessary to clarify a number of malignant pathohistological features. Improving survival in patients with early clinical stage requires complex treatment, including radical surgery followed by combined chemo-radiotherapy, as well as immunotherapy to prevent distant metastases.