Abstract
Ovarian leiomyosarcomas are extremely rare ovarian malignancies, usually associated with poor prognosis in terms of survival. Most often, ovarian leiomyosarcomas are diagnosed in postmenopausal women at an advanced stage of disease, the main symptoms consisting of abdominal pain. We present the case of a 52-year-old patient who was initially submitted to surgery for a large ruptured ovarian tumor in April 2009; at that time, total hysterectomy with bilateral adnexectomy, omentectomy, pelvic and para-aortic lymph node dissection were performed. The histopathological studies revealed the presence of an ovarian leiomyosarcoma. Five years later, the patient was diagnosed with a unique, ruptured liver metastasis and an atypical right hepatectomy was performed. The histopathological studies confirmed the metastatic origin of the lesion. At 2-year-follow-up the patient is still free from recurrent disease.
- Ovarian leiomyosarcoma
- liver metastasis
- hemoperitoneum
- atypical hepatectomy
Primary ovarian sarcomas are rare malignancies accounting for fewer than 3% of all ovarian tumors (1) and are usually seen in postmenopausal women (2). These tumors seem to have an aggressive behavior, with a poorer prognosis when compared to their uterine counterpart (2), or to epithelial ovarian adenocarcinomas diagnosed at the same stage of disease (3). The main histopathological subtypes are fibrosarcoma, rhabdomyosarcoma and endometrial stromal sarcoma (4). Data regarding ovarian leiomyosarcomas are scarce, only few cases have been reported so far in the literature (1, 2, 5). When it comes to the most appropriate therapeutic strategy, an aggressive surgical approach leading to no residual disease seems to be the golden standard. The European Society for Medical Oncology Guidelines Working Group stated in 2010 that any suspected ovarian malignancy should be submitted to surgery and total hysterectomy with bilateral adnexectomy, omentectomy and peritoneal washing are in fact minimal therapeutic requirements in these cases. The same study group stated that in certain cases pelvic, para-aortic lymph node dissection and even blind diaphragmatic peritoneal surface biopsies might be included in order to leave no residual disease (6).
We present the case of a 52-year-old patient diagnosed with an ovarian leiomyosarcoma in which the principles of resection to no residual disease were successfully applied twice, at a 5-year interval.
Case Report
A 52-year-old patient presented as an emergency case due to diffuse abdominal pain associated with abdominal distension. The clinical examination revealed the presence of a diffusely distended, painful abdomen with signs of peritoneal irritation, while computed tomography revealed the presence of a large pelvic mass measuring 10×15×12 cm, probably of ovarian origin associated with the presence of free peritoneal fluid. An emergency laparotomy was performed; intraoperatively, hemoperitoneum due to a large, ruptured ovarian tumor was found, hence total hysterectomy with bilateral adnexectomy, omentectomy, pelvic and para-aortic lymph node dissection was performed (Figures 1 and 2). In the meantime, blind peritoneal biopsies were performed. The histopathological and immunohistochemical studies revealed the presence of an ovarian leiomyosarcoma: the tumoral cells presented diffuse positive reactions for actin and were negative for inhibin, MNF 116 (cytokeratin antibody), epithelial membrane antigen (EMA) and S100. Cluster of differentiation 34 (CD34) expression was positive in vascular structures, while Ki67 was positive in up to 30% of tumoral cells.
Postoperatively, the patient was submitted to six cycles of platinum-based chemotherapy associated with an active follow-up protocol consisting of imaging studies of computed tomography (Figure 3) and magnetic resonance, associated with blood tests including carcinogenic antigen 125 (CA125) measurements every 6 months. At 5-year follow-up the patient was diagnosed with a lesion, measuring 12.8×8.2×10.7 cm in the right hepatic lobe, associated with the presence of a perilesional hematoma (Figure 4). The patient was resubmitted to surgery; intraoperatively, a ruptured liver metastasis located in segment VI according to Couinaud's classification was found and the patient was submitted to an atypical right hepatectomy (Figures 5, 6 and 7). The postoperative course was uneventful, the patient being discharged on the sixth postoperative day.
The histopathological and immunohistochemical studies confirmed the presence of a hepatic metastasis of ovarian leiomyosarcoma. Serial 3-μm sections had been cut from paraffin blocks and stained with hematoxylin and eosin (HE) (Figure 8). Immunohistochemistry was performed on 3 μm sections from 10% formalin-fixed paraffin-embedded tissues according to an indirect two-stage technique performed with a polymer-based detection system (Max Polymer Detection System, RE 7280-k; Leica, MEDIST Life Science, Bucharest, Romania). Tissue sections were spread on poly-L-lysine-coated slides, immersed in three changes of xylene and rehydrated using a graded series of alcohol. Antigen retrieval was performed in a microwave oven. For each section, endogenous peroxidase was blocked by 20-min incubation in 3% hydrogen peroxide. The sections were incubated with primary antibodies to: smooth muscle actin (1A4, 1:200; DAKO, MEDIST Life Science s.r.l., Bucharest, Romania; Figure 9a), vimentin (V9, 1:50; Figure 9b), caldesmon (h-CD,1:50; Figure 9c), CD117/cKIT (polyclonal 1:250; DAKO, MEDIST Life Science s.r.l., Bucharest, Romania), CD34 (Cell Marque, 1:100, QBend10, 1:100; Figure 9d), desmin (D33, 1:50; DAKO, MEDIST Life Science s.r.l., Bucharest, Romania; Figure 9e), estrogen receptor (6F11, 1:40; Leica, DAKO, MEDIST Life Science, Bucharest, Romania; Figure 9f), progesterone receptor (16, 1:50; Leica, MEDIST Life Science, Bucharest, Romania; Figure 9g) and Ki67 (Mib-1, 1:100; DAKO, MEDIST Life Science s.r.l., Bucharest, Romania; Figure 9h) at room temperature for 1 h. The Max Polymer Detection System was then applied for 30 min. Finally, the sections were incubated in 3′3-diaminobenzidine for 5 min, counterstained with Meyer's hematoxylin and mounted. The slides were examined and photographed on a Leica DM750 Microscope - supplied by MEDIST Life Science s.r.l., Bucharest, Romania. Negative controls were obtained by replacing the primary antibody with non-immune serum. As a positive control, a section of smooth muscle tissue was used.
Immunohistochemically, the tumor cells presented diffuse strong expression for smooth muscle actin (Figure 9a), vimentin (Figure 9b) and expression for caldesmon (Figure 9c), desmin (Figure 9e), estrogen receptor (Figure 9f), and progesterone receptor (Figure 9g), while staining for Ki67 was positive in about 65% of the tumor cells (Figure 9h). CD34 expression was positive in the vascular structures (Figure 9d), while CD117 expression was negative. The patient was readdressed to the Oncology Clinic and was submitted to six cycles of adjuvant chemotherapy. At 2-years follow-up the patient is free of any recurrent disease.
Discussion
Ovarian sarcomas are rare gynecological malignancies, the most frequently encountered histopathological subtypes being ovarian fibrosarcoma and rhabdomyosarcoma, while leiomyosarcomas are extremely rare conditions, only few cases being reported so far (4, 7). Although ovarian leiomyosarcomas are most frequently found in postmenopausal women, a few cases in pre-menopausal women have also been reported (8-11).
Pure ovarian leiomyosarcomas have an obscure origin, the main mechanisms of development consisting of malignant degeneration of ovarian smooth muscle cells, malignant transformation of uterine leiomyoma to the ovary or malignant transformation of ovarian teratomas (7). Ovarian smooth muscle cells can have various origins, such as the smooth muscle of ovarian cortical blood vessels, muscular fibers situated along the ovarian follicules, muscular fibers of the ovarian ligaments or remnants of Wolff”s duct (5, 8, 11). In Azoury and Woodruff's study conducted on 2,400 patients diagnosed with ovarian tumors, 43 primary ovarian sarcomas were reported. Among these cases, four ovarian leiomyosarcomas were found. The authors went further and classified the four cases according to their origin as tumors with teratoid origin and tumors with mesenchymal origin. While leiomyosarcomas with teratoid origin were diagnosed in younger patients and presented more frequently as unilateral lesions, leiomyosarcomas with mesenchymal origin were rather found in elderly patients and were more likely to metastasize (11).
The macroscopic aspect is characterized by the presence of solid masses which might be associated with the presence of areas of cystic degeneration (12), while the microscopic aspects are usually characterized by the presence of uniform spindle-shaped cells arranged in a whorled pattern, with areas of pleomorphism and necrosis (4).
The main histopathological characteristics supporting the diagnosis of malignancy consist of the association of any two of the following: coagulative necrosis, cellular atypia, and mitotic index greater than 10 (8).
Immunohistochemical studies supporting the diagnosis of leiomyosarcomas comprise positive staining for desmin, vimentin and smooth muscle actin (1, 5, 8); in certain cases, positivity for estrogen and progesterone receptors, p53, and B-cell lymphoma 2 might be seen (5, 8, 13).
Most often patients with ovarian leiomyosarcomas present for pelvic pain due to the compression or invasion of the surrounding viscera and are diagnosed at an advanced stage of the disease when distant metastases are already present (1, 8). This aspect explains why most cases will recur within the first years after initial treatment, the main sites of relapse being the pelvis and abdomen (8, 10, 11).
When it comes to the most appropriate staging system and therapeutic strategies, the International Federation of Gynecology and Obstetrics (FIGO) stated that the same protocols as for epithelial ovarian cancer should be applied (8), but evidence is still lacking due to the small number of cases (6). However, it has been widely demonstrated that ovarian sarcomas are associated with a poorer prognosis when compared to epithelial ovarian cancer in similar FIGO stages. The prognostic factors that influence overall survival most are tumor stage, size, grade, and mitotic index (5, 8, 14).
In Taskin et al.'s review regarding primary ovarian leiomyosarcomas, significant differences in terms of survival were reported among different FIGO stages: while 63 of patients diagnosed in stage I had no recurrent disease after a median follow-up of 42 months, only 19% of cases diagnosed in stages II-IV were still alive at 14 months' follow-up (8).
In a case control study conducted at the Dan Setlacec Center of Gatrointestinal Disease and Liver Transplantation, Fundeni Clinical Hospital, Bucharest, 11 patients diagnosed with ovarian sarcomas were matched with 11 patients diagnosed with ovarian epithelial adenocarcinomas at similar FIGO stages. The authors demonstrated that the trend for a poorer prognosis was carried throughout all FIGO stages. Among the 11 cases diagnosed with ovarian sarcoma, the histopathological studies revealed the presence of a leiomyosarcoma in a single case, a 71-year-old patient, who was intraoperatively diagnosed with a stage IIA ovarian tumor and in whom a right adnexectomy was performed. The postoperative course was uneventful, the patient being free of recurrent disease 4 years later. Regarding long-term outcomes, the overall survival of the patients diagnosed with FIGO stage II ovarian sarcomas was 90.5 months, significantly lower when compared with their counterparts diagnosed with epithelial carcinoma (with a reported overall survival of 113 months, p=0.048) (3).
When it comes to the role of surgery for relapsed disease, reported data are even scarcer. Most often, patients presenting with disseminated lesions at the time of relapse are candidates for palliative treatment and succumb to their disease within a few months (4). However, the benefits of repeated cytoreductive surgery in advanced-stage and relapsed ovarian leiomyosarcomas have also been reported; Rasmussen et al. presented the case of a premenopausal woman diagnosed with stage IIIC ovarian leiomyosarcoma who was successfully submitted to repeated cytoreductions within 7 years of the initial diagnosis (13).
The particularity of the case we reported here is the fact that the disease recurred at a single site, the patient being diagnosed with a unique ruptured liver metastasis. Literature data regarding the role of surgery for liver metastases of sarcomatous origin are also scarce, most studies conducted on this issue included cases with different origins of the sarcomatous lesion. In Goere and Elias' review regarding the role of surgery for non-colorectal non-neuroendocrine liver metastases, the authors state that liver metastases usually arise from visceral sarcomas, while lung metastases are usually associated with bone sarcomas (15). In the French cohort study conducted by Adam et al. involving 158 patients with non-colorectal non-neuroendocrine liver metastases, visceral sarcomas were diagnosed in 58% of cases. The authors reported a rate of complete R0 resection of 80%; after a median follow-up of 34 months, liver relapse was encountered in 54% of cases, leading to a second hepatectomy in 32.5%. The reported 5-year and median survival were 38,6% and 38.9 months, respectively, the most important prognostic factors associated with poor prognosis being the origin, soft tissue and visceral sarcomas versus other gastrointestinal stromal tumors, and a disease-free survival of less than 12 months (16).
Radiotherapy in association with platinum salts and ifosfamide regimens have been proposed as appropriate adjuvant treatment, with good results (8, 13, 17). However, due to the paucity of cases, a standard chemotherapeutic regimen has not yet been established, further studies on larger cohorts still being necessary.
Conclusion
Ovarian leiomyosarcomas are extremely rare gynecological malignancies, usually associated with a poor prognosis in terms of survival. However, it seems that the most important benefit in terms of survival is provided in patients diagnosed at an early stage of the disease and in whom an aggressive surgical approach consisting of complete cytoreductive surgery can be performed. The particularity of our case is the fact that although the patient was diagnosed on both occasions due to the presence of a ruptured tumor with secondary hemoperitoneum and subsequent peritoneal contamination with tumoral cells, a complete R0 resection was feasible each time. The completeness of the cytoreductive surgery performed each time seems to be the most important predictor for long-term disease-free and overall survival.
Footnotes
This article is freely accessible online.
- Received February 5, 2016.
- Revision received March 13, 2016.
- Accepted March 21, 2016.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved