Uterine Carcinosarcoma with Heterologous Mesenchymal Elements: A Rare Case Report

Introduction

Uterine carcinosarcomas (UCS) are rare tumours accounting <5% of uterine malignancies. The annual incidence of UCS is 0.5-3.3 cases per 100,000 females.¹

Previously categorized and managed as sarcomas, they are now viewed as high-grade epithelial tumours. These tumours are uncommon in young women and typically occur in postmenopausal women. They are known for their aggressive nature, poor prognosis and accounts for approximately 15% of deaths that are due to uterine malignancies.1-3 UCS consists of both carcinomatous and sarcomatous components and is managed similarly to endometrial carcinoma. They are treated with surgery, chemotherapy and radiotherapy. In view of their tendencies for late presentation, rapid dissemination, high recurrence rate and unfavourable prognosis, there is a pressing need for clinical trials focusing on early detection methods. The rarity of UCS with rhabdomyosarcoma and chondrosarcoma highlights the significance of further research to gain a better understanding of their clinical behaviour.

Case Report

A 58-year-old postmenopausal woman presented with complaints of postmenopausal bleeding and abdominal pain for one week. She had two previous normal vaginal deliveries and a history of hypertension. Clinical examination was unremarkable. A pelvic examination did not reveal any active vaginal bleeding. An ultrasound of the whole abdomen and pelvis revealed a uterus with a thickened endometrium measuring 8mm with both ovaries appearing grossly healthy. Additional cholelithiasis was noted. She underwent a laparoscopic cholecystectomy, hysteroscopy, dilatation and curettage under general anaesthesia.

The endometrial biopsy report revealed a poorly differentiated malignant tumour with chronic cholecystitis. Immunohistochemistry (IHC) of the endometrial curettings showed positivity for cytokeratin (CK), clusters of differentiation 10 (CD10), and S100 protein. P53 exhibited diffuse nuclear staining while cyclin D1 was negative. The findings suggested a high-grade malignant tumour with a possibility of high-grade endometrial stromal sarcoma (HG-ESS) and chondrosarcoma. Liquid-based cytology suggested the presence of atypical glandular cells.

Following this, she was referred to our unit, where a Positron Emission Tomography-Computed Tomography (PET-CT) scan was advised. The scan showed an intrauterine mass with increased fluorodeoxyglucose (FDG) uptake involving the fundus and body of the uterus, with <50% myometrial involvement at the fundus with no other focal abnormalities elsewhere in the body (Figure 1 & 2). Her serum cancer antigen (CA)125 level was measured at 40.4 U/ml.

Subsequently, she underwent surgical staging which included total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO), pelvic and retroperitoneal lymphadenectomy, infra-colic omentectomy and peritoneal biopsies. Intraoperatively, the uterus was found to be bulky approximately 12-14 weeks size, while both fallopian tubes, ovaries and omentum appear normal. Enlarged lymph nodes were observed in the bilateral pelvic region.

The histopathology report revealed a polypoidal tumour measuring 6.5x6x3cm in the uterine cavity. Microscopic examination showed that the tumour consisted of 1% carcinomatous element (high-grade endometrial glands) mixed with 40% sarcomatous elements (high-grade spindle cells) (Figure 3). The carcinomatous elements included high-grade endometrial glands with squamous metaplasia and focal clear cell morphology highlighted by CK (Figure 4). The sarcomatous component consists of high-grade spindle cells that were positive for vimentin. Heterologous elements were observed, including rhabdomyosarcoma, which was positive for desmin (Figure 5) and chondrosarcoma, which was positive for S100 (Figure 6). Diffuse staining for mutant p53 was observed (Figure 7). The tumour had invaded <50% myometrial thickness with no lymphovascular space invasion. The uterus, cervix, vagina, ovaries and fallopian tubes appeared unremarkable. The omentum, right and left paracolic peritoneum, pelvic and retroperitoneal lymph nodes were free of tumour. The stage of disease was pT1aN0, stage1A according to the 2018 International Federation of Gynecology and Obstetrics (FIGO) staging criteria.

Following a multidisciplinary discussion, she received 2 sessions of intravaginal brachytherapy (IVRT) and 25 sessions of external beam radiotherapy (EBRT) along with 6 cycles of carboplatin and paclitaxel.

A follow-up FDG PET CT scan was done after 3 months which showed no evidence of local residual/ recurrent disease in the pelvis and elsewhere in the body to suggest metastases. She is currently undergoing surveillance every 3 months.

Discussion

UCS are rare and aggressive high-grade endometrial carcinoma s comprising <5% of all uterine malignancies but accounts for 15% of all deaths caused by uterine malignancies.^1-3,5 Although these tumours are uncommon, their incidence has been on the rise over the past two decades.² They are frequently observed in postmenopausal women as seen in our case. Furthermore, UCS are associated with additional risk factors such as obesity, hypertension, and diabetes. Clinical presentations can vary but common symptoms and signs may include abnormal uterine bleeding (AUB), pelvic pain and a rapid uterus enlargement. On physical examination, a pelvic mass may be palpated or seen protruding through the cervical os.⁴ In our case, the patient exhibited only hypertension. She presented with AUB and abdominal pain with no notable positive findings upon examination.

Approximately 30%-40% will present with extrauterine disease at first presentation and over 10% will initially present with distant metastases.⁵ These factors contribute to the poor prognosis of the disease even with the best of care due to its aggressive tumour biology.

UCS are known for their distinctive biphasic morphology exhibiting a tumour comprising both epithelial and mesenchymal elements. The epithelial component typically presents as a high-grade carcinoma such as papillary serous (66%) or endometroid (42%) or other histotypes.⁴ On the other hand, the mesenchymal component can be either homologous containing cells native to the uterus including HG-ESS, fibrosarcoma, undifferentiated sarcoma or leiomyosarcoma or heterologous with mixed components including rhabdomyosarcoma (18%), chondrosarcoma (10%), osteosarcoma (5%) or liposarcoma(1%).⁴ In most cases, only one sarcomatous component is present, while 33 % of cases involve two or more sarcomatous components, with HG-ESS being the most common.³ In our case, the sarcomatous components identified were rhabdomyosarcoma and chondrosarcoma.

UCS exhibits both epithelial and stromal markers including p53, vimentin, CD-10, smooth muscle and desmin.1 The carcinomatous component of UCS may include serous or endometroid type with the latter being less common.⁴ In our case, IHC analyses showed positivity for CK emphasizing the carcinomatous element, while vimentin highlighted the sarcomatous components. Desmin highlights the rhabdomyosarcoma components. Additionally, S100 highlights the chondro-sarcomatous component with diffuse staining of p53.

Several studies have aimed to investigate the differences in protein expression between these components as potential prognostic or predictive markers. However, findings have been inconclusive due to rarity of neoplasms and limited size of case series.⁴

Diagnosis is typically determined through both, imaging and pathological examination. Sonography is commonly used as an initial diagnostic tool in suspected uterine abnormalities. CT scan is the preferred modality for staging, follow up and evaluation of distant metastases.^1,4 Though rarely reported in the literature, FDG PET scans show potential in the detection of metastases from UCS.⁴ Elevation in serum CA 125 levels is correlated with the extrauterine spread of disease and increased myometrial involvement.⁶ Endometrial sampling is frequently carried out in females with suspected uterine malignancies through endometrial biopsy or dilatation and curettage before definitive surgery. Nonetheless, it may not provide a definitive diagnosis. Complete diagnosis of this condition is typically based on pathologic evaluation.

The treatment options remain TAH and BSO along with surgical staging in patients without distant metastases.⁶ Surgical cytoreduction is reserved for patients with extrauterine disease limited to the peritoneum.⁷ However, higher rates of relapse and metastases postoperatively necessitates adjuvant therapy. For adjuvant treatment the carboplatin/ paclitaxel combination is now the recommended initial treatment.⁶

Regardless of the treatment given, the 5-year disease specific survival rates for women with stage 1 and 2, 3, and 4 were 59%, XX%,22% and 9% respectively.⁵