Primary uterine osteosarcoma arising in a leiomyoma with rapid local recurrence: A case report

Highlights • Primary uterine osteosarcoma is an extremely rare and aggressive neoplasm.• There is no clear consensus about the optimal systemic treatment.• Chemotherapy treatment options can be deduced from previous studies of bone and soft tissue sarcomas.


Introduction
Extraskeletal osteosarcoma (ESOS) is a malignant mesenchymal neoplasm that produces osteoid, bone, or chondroid material without demonstrable attachments to bone or periosteum (Choi et al., 2014). This rare tumor can be diagnosed in the trunk, thigh, upper extremities, and retroperitoneum. ESOS represents approximately 2 % to 5 % of osteosarcomas and less than 1 % of all soft-tissue sarcomas . (Allan and Solle, 1971). Uterine sarcomas are uncommon, accounting for 1-2 % of all uterine neoplasms. Pure heterologous osteosarcomas are a rare type of uterine sarcoma with documentation of disease limited to less than 20 case reports (Lin et al., 2002).
In the published literature composed of small number of case reports, the mean age of diagnosis of primary uterine osteosarcoma was 64 years of age (range 41 to 82) (Hardisson et al., 2001). Table 1 depicts a summary of prior published case reports. The main presenting symptoms included abnormal vaginal bleeding; abdominal pain/fullness caused by a large abdominal mass (Tsukasaki et al., 2016). Prognosis was noted to be poor for patients diagnosed with ESOS with five-year survival rate reported as low as 28 %. There is a high risk for recurrence and a dismal survival rate (Jensen et al., 1998 May;Nystrom et al., 2013). There is limited data regarding adjuvant therapy after surgical management. In this case report,we present a 57-year-old female who presented with primary uterine osteosarcoma arising in a leiomyoma with rapid locoregional recurrence 1 year after initial diagnosis.

Case
A 57-year-old female with a history of uterine fibroids presented to the emergency department with abdominal pain. Her past medical history was unremarkable. The patient reported intense infraumbilical abdominal pain, abdominal distention, urinary frequency, and incomplete bladder emptying. Her physical exam was notable for large uterus measuring approximately 18 weeks with fullness palpated in the posterior cul-de-sac. Upon admission, she was found to have acute kidney injury with creatinine of 2.04 mg/dL (normal value 0.7 to 1.3 mg/dL). Other laboratory findings including serum electrolytes and hepatic functions were within normal limits. CT of the abdomen and pelvis noted a 15 cm heterogeneous pelvic mass with peripheral coarse calcification, inseparable from the posterior uterine wall and bilateral mild hydroureteronephrosis secondary to mass effect on the distal ureters. A pelvic magnetic resonance imaging (MRI) was notable for an enlarged uterus measuring approximately 19 × 12 × 14 cm with a complex proteinaceous and calcified lesion measuring 15 × 10 × 12 cm extending between the posterior uterine fundus to the lower uterine segment (Fig. 1). No malignant cells were seen on cervical cytology obtained during hospitalization. An attempt was made to perform an endometrial biopsy, however given the position of the cervix, this was not feasible and safe. After discussing the alternatives, the patient agreed to proceed with a total abdominal hysterectomy and bilateral salpingo-oophorectomy. Intraoperative findings included an enlarged fibroid uterus measuring approximately 24 weeks with a large calcified mass measuring 10 × 10 cm, adherent to posterior uterine wall and anterior to the rectosigmoid colon. The remainder of the abdominal survey did not yield any significant findings suggestive of malignancy. An intraoperative frozen specimen pathological evaluation revealed acute inflammation. The patient had an uncomplicated post-operative course and was discharged home on postoperative day 3. Her acute kidney injury was resolved after the surgery, once the compression on distal ureters was relieved with removal of the hysterectomy specimen.
Final pathological evaluation of the hysterectomy specimen yielded a weight of 701 g and intermediate-grade primary uterine osteosarcoma, measuring 7 × 4 cm arising in a leiomyoma with degenerative changes. The specimen was noted to have dusty red brown, edematous tissue. Microscopically, low magnification showed mesenchymal proliferation with osteoid formation, with tumor cells having densely eosinophilic cytoplasm resembling osteoblasts. There was significant cytological atypia and the associated leiomyoma consisted of proliferated smooth muscle cells without cytological atypia. There was a moderately pleomorphic sarcomatous component, forming thin trabeculae of bone (Fig. 2). A post-operative PET/CT was without evidence of FDG avid distant metastasis. The patient's case was reviewed at the gynecologic oncology and sarcoma tumor boards with a consensus to proceed with observation. This conclusion was made given the early stage of disease and extrapolation of data from early-stage uterine sarcomas which demonstrated no improvement in oncological outcomes with addition of adjuvant therapy. The patient underwent surveillance with CT chest/ abdomen/pelvis and physical exams every 3 months. Approximately 1 year after her diagnosis, she presented to the emergency room with nausea, vomiting, and abdominal pain. A CT of the abdomen and pelvis noted a large 12 cm metastatic peritoneal mass in the right lower abdomen demonstrating invasion of the distal ileal loops and cecum, with resultant proximal small bowel obstruction. After extensive discussion of limited management options, she opted for surgical management and underwent a secondary tumor debulking, which entailed a right hemicolectomy. Intraoperative findings were notable for a 15 × 15 cm mass in the right pericolic gutter involving the ascending colon from cecum to the hepatic flexure (Fig. 3). This large mass was deemed to be the cause of her small bowel obstruction. The patient had an uneventful post-operative course. She has been dispositioned to systemic chemotherapy in the form of doxorubicin and ifosfamide, after recovering from the surgery. The patient has completed two cycles of chemotherapy and she remains alive with cancer.

Discussion
Extraskeletal osteosarcoma, also known as soft tissue osteosarcoma, is a rare malignant neoplasm that produces osteoid, bone, or chondroid material but lacks bone or periosteum involvement. It is an extremely aggressive tumor with a poor prognosis. The exact etiology of ESOS is still unknown but several associated prognostic factors have been proposed, such as the history of trauma, local radiation therapy, and changes in soft tissue lesions and malignant fibrous tissue disease (Liao Table 1 Previous primary uterine osteosarcoma cases.  et al., 2019). This case report presents a patient with initially confined uterine osteosarcoma and rapid recurrence of disease one year after diagnosis. In this particular case, histological evaluation yielded an absence of an epithelial component, no evidence of osteosarcoma origin in bone, and had presence of neoplastic osteoid. Immunohistochemical staining for smooth muscle cell markers was negative, indicating the absence of leiomyosarcoma components. Given all of these elements, the neoplasm reported fulfills the diagnosis of primary uterine osteosarcoma. As our patient's osteosarcoma was uterine-confined after primary surgical resection, management was extrapolated from studies of leiomyosarcoma where observation is the standard of care (Byar et al., 2022). A systemic review addressing the effect of adjuvant chemotherapy or radiation on localized ESOS also found no difference in 5-year disease free survival rate between surgery and adjuvant chemotherapy versus surgery alone groups (Tsukamoto et al., 2022). After the patient's locoregional recurrence was managed surgically, she was initiated on  systemic chemotherapy. There is no clear consensus about the optimal chemotherapy regimen for patients with ESOS. For advanced or metastatic leiomyosarcoma cases, the use of gemcitabine plus docetaxel, doxorubicin (with or without ifosfamide), single-agent gemcitabine, ifosfamide, trabectedin, pazopanib, and dacarbazine are recommended (NCCN, 2020). The standard of care for high grade bone sarcomas includes a multi-agent regimen with a combination of doxorubicin, cisplatin +/− methotrexate or ifosfamide (Ferrari et al., 2018). There are some case reports suggesting the use of gemcitabine-docetaxol as a potential regimen for long term progression free survival (Strippoli et al., 2015). For our current case report, treatment options were deduced from previous studies of bone and soft tissue sarcomas. The patient is currently on her second cycle of chemotherapy and tolerating treatment well. In summary, we present a 57-year-old female with a rare diagnosis of primary uterine osteosarcoma. Most notably in this case was the rapid and aggressive locoregional recurrence, approximately 1 year after initial diagnosis. This case adds to the growing but still sparce literature surrounding this rare tumor. There are limited data regarding systemic treatment options. Therefore, until more effective systemic treatment options are developed, surgical resection remains the primary treatment in the up-front and recurrence settings.
Written informed consent and IRB review was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.  Fig. 3. Operative specimen of recurrent mass. Specimen included 15 cm mass in the right pericolic gutter involving the ascending colon from cecum to the hepatic flexure. Mass is encircled.