Primary Ovarian Epithelioid Angiosarcoma with Extensive Lymph Node Metastases: A Case Report and Literature Review

Summary

Primary ovarian epithelioid angiosarcoma is an exceptionally rare, aggressive vascular malignancy with a challenging preoperative diagnosis. This report describes extensive pelvic and para-aortic lymph node metastases and diffuse intra-abdominal dissemination, confirmed by histopathology and immunohistochemistry. Complete macroscopic cytoreduction was feasible, but prognosis remained poor, highlighting the need for improved therapies worldwide.

Abstract

Primary ovarian epithelioid angiosarcoma (EAS) is an exceptionally rare and highly aggressive vascular malignancy with only isolated cases reported in the literature. Owing to its nonspecific clinical presentation and overlapping radiological features, preoperative diagnosis is extremely challenging and often mimics more common gynecologic malignancies. Consequently, evidence regarding optimal diagnosis and management remains limited.

A 61-year-old postmenopausal woman presented with abdominal pain and a rapidly enlarging pelvic mass. Ultrasonography, computed tomography, and magnetic resonance imaging demonstrated a giant hypervascular pelvic tumor with extensive pelvic and para-aortic lymphadenopathy, initially suggesting uterine sarcoma. Serum CA125 and lactate dehydrogenase levels were elevated. Exploratory laparotomy identified a dominant right ovarian hypervascular tumor with diffuse peritoneal dissemination and bulky pelvic and para-aortic nodal metastases. Comprehensive clinical, radiological, intraoperative, gross pathological, histopathological, and immunohistochemical assessment demonstrated a primary ovarian origin, with no evidence of an extra-ovarian primary angiosarcoma. The patient underwent radical cytoreductive surgery, including total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, appendectomy, resection of visible metastatic lesions, and systematic pelvic and para-aortic lymphadenectomy, achieving complete macroscopic cytoreduction. Histopathological examination demonstrated epithelioid tumor cells with vasoformative differentiation, while immunohistochemistry showed diffuse strong positivity for CD31, CD34, and FLI1, confirming primary ovarian epithelioid angiosarcoma. The patient declined adjuvant chemotherapy, developed rapid postoperative disease progression, and died approximately 2 months after surgery.

This case highlights the marked diagnostic challenges and highly aggressive biological behavior of primary ovarian EAS with extensive pelvic and para-aortic lymph node metastases and diffuse intra-abdominal dissemination. Accurate diagnosis required a comprehensive clinicopathological correlation supported by histopathological and immunohistochemical evaluation. Although complete macroscopic cytoreduction and systematic lymphadenectomy were technically feasible, their therapeutic benefit cannot be inferred from a single case. This report expands the limited literature and emphasizes the need for improved diagnostic strategies, collaborative data collection, and more effective systemic therapies for this rare malignancy.

Introduction

Epithelioid angiosarcoma (EAS) is a rare and highly aggressive malignant vascular neoplasm of mesenchymal origin with endothelial differentiation, accounting for approximately 1%–2% of all soft tissue sarcomas¹. Epithelioid angiosarcoma is a distinct histological variant of angiosarcoma characterized by malignant endothelial cells with epithelioid morphology, marked cytologic atypia, and vasoformative differentiation, as recognized in the current World Health Organization (WHO) classification of soft tissue and bone tumors². Epithelioid angiosarcoma has subsequently been reported in multiple anatomical locations, including the skin, breast, kidney, gastrointestinal tract, lung, and pleura^3,4,5,6. Rare presentations have also been described in unusual sites such as the aorta following endovascular repair and the cranial region, where the tumor may manifest as a subdural hematoma secondary to skull involvement^7,8.

Angiosarcoma is characterized by aggressive biological behavior, rapid progression, early metastatic dissemination, and poor survival outcomes. Surgical resection remains the cornerstone of treatment for localized and potentially resectable disease because it provides both diagnostic tissue and therapeutic cytoreduction, while histopathological and immunohistochemical evaluation remain essential for definitive diagnosis^9,10. Complete macroscopic cytoreduction may be considered in selected patients with resectable advanced disease to achieve maximal tumor debulking and obtain adequate tissue for definitive pathological diagnosis; however, evidence supporting the therapeutic benefit of extensive cytoreduction or systematic lymphadenectomy in primary ovarian epithelioid angiosarcoma remains extremely limited because of the rarity of the disease^11,12,13.

Primary ovarian angiosarcoma is an exceptionally uncommon malignancy, with only isolated cases reported in the literature^9,10. The epithelioid subtype is particularly rare and is associated with an especially aggressive clinical course. Reported cases have demonstrated heterogeneous presentations, variable treatment strategies, and consistently poor outcomes^{11,12,13,14,15,16,17,18,19,20,21,22}. Because clinical manifestations and imaging findings are nonspecific, ovarian EAS is frequently misdiagnosed preoperatively as epithelial ovarian carcinoma, metastatic disease, or uterine sarcoma^9,10,19,22. In addition, metastatic angiosarcoma involving the ovary should be considered in the differential diagnosis, making comprehensive clinicoradiological, intraoperative, histopathological, and immunohistochemical correlation essential for establishing a primary ovarian origin. This diagnostic uncertainty complicates surgical planning and intraoperative decision-making, particularly regarding the extent of cytoreductive surgery and the management of clinically suspicious lymph nodes in advanced disease.

The overall goal of the present report is to expand the limited clinicopathological evidence regarding primary ovarian EAS and to provide additional insight into its diagnostic challenges, metastatic behavior, surgical management, and clinical outcomes. We present a rare case of primary ovarian epithelioid angiosarcoma with extensive pelvic and para-aortic lymph node metastases, initially misdiagnosed as uterine sarcoma, together with a review of previously published cases. The diagnosis of primary ovarian epithelioid angiosarcoma was supported by the presence of a dominant right ovarian mass, the gross and microscopic relationship of the tumor to ovarian tissue, the distribution of metastatic disease, and comprehensive clinical and radiological evaluation demonstrating no evidence of a primary angiosarcoma at another anatomical site. The rationale for presenting this case lies in the extremely rare occurrence of widespread nodal metastases and diffuse intra-abdominal dissemination, features that are scarcely documented in the current literature. Although complete macroscopic cytoreduction with systematic pelvic and para-aortic lymphadenectomy was technically feasible in this patient, the present report does not imply a therapeutic or survival benefit of this approach; rather, it illustrates its role in achieving complete gross resection, accurate pathological assessment, and documentation of the extent of disease. By contextualizing this case within the wider body of published literature, we aim to assist clinicians and surgeons in recognizing clinical scenarios in which ovarian EAS should be considered in the differential diagnosis of rapidly enlarging hypervascular pelvic tumors with extensive nodal involvement.

Case Presentation

A 61-year-old postmenopausal woman presented to the Department of Gynecology at Gansu Provincial Maternal and Child Health Hospital in March 2023 with a 2-week history of intermittent abdominal pain and progressive abdominal enlargement. Physical examination revealed a large abdominopelvic mass extending approximately 10 cm above the umbilicus. Laboratory investigations demonstrated elevated serum CA125 (156.1 U/mL) and lactate dehydrogenase (257 U/L) levels, while other routinely assessed gynecologic tumor markers were within normal limits.

Pelvic ultrasonography, contrast-enhanced computed tomography, and magnetic resonance imaging demonstrated a large hypervascular right adnexal mass with extensive pelvic and para-aortic lymphadenopathy, raising suspicion for an advanced gynecologic malignancy, initially considered to represent uterine sarcoma. Comprehensive preoperative imaging demonstrated no evidence of a primary vascular malignancy outside the pelvis.

The patient underwent exploratory laparotomy with the goal of complete macroscopic cytoreduction and definitive diagnosis. Intraoperatively, a dominant right ovarian hypervascular tumor with diffuse peritoneal dissemination and bulky pelvic and para-aortic lymph node involvement was identified, and radical cytoreductive surgery was performed. The final diagnosis of primary ovarian epithelioid angiosarcoma was established by histopathological and immunohistochemical evaluation. Despite an initially uncomplicated postoperative recovery, the patient declined adjuvant chemotherapy, developed rapidly progressive metastatic disease, and died approximately 2 months after surgery. The overall clinical course is summarized in Table 1.

Diagnosis, Assessment, and Plan

The patient presented with a rapidly enlarging abdominopelvic mass, abdominal pain, elevated serum CA125 and lactate dehydrogenase levels, and imaging findings suggestive of an advanced gynecologic malignancy. Pelvic ultrasonography, contrast-enhanced computed tomography, and magnetic resonance imaging demonstrated a large hypervascular right adnexal mass with extensive pelvic and para-aortic lymphadenopathy. Comprehensive preoperative imaging demonstrated no evidence of a primary vascular malignancy outside the pelvis.

The differential diagnosis included uterine sarcoma, epithelial ovarian carcinoma, metastatic carcinoma, and other primary gynecologic sarcomas, as well as less common vascular and epithelioid neoplasms. Because the radiological findings were nonspecific, a definitive preoperative diagnosis could not be established. Given the extensive but potentially resectable disease, exploratory laparotomy was undertaken with the goals of complete macroscopic cytoreduction and definitive pathological diagnosis. Intraoperative frozen section examination was not performed because the operative findings indicated that immediate cytoreductive surgery would be required regardless of the pathological impression.

The patient underwent total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, appendectomy, resection of visible metastatic lesions, and systematic pelvic and para-aortic lymphadenectomy, achieving complete macroscopic cytoreduction. Histopathological and immunohistochemical evaluation confirmed the diagnosis of primary ovarian epithelioid angiosarcoma. Adjuvant chemotherapy was recommended because of the aggressive nature of the disease and extensive metastatic involvement; however, the patient declined further treatment and subsequently developed rapidly progressive disease.

Protocol

The surgical management was performed in accordance with institutional and national ethical guidelines. The case report and surgical protocol were reviewed and approved by the Institutional Ethics Committee of Gansu Provincial Maternal and Child Health Hospital. Written informed consent for treatment and publication of the case details and accompanying images was obtained from the patient prior to their passing.

1. Preoperative clinical evaluation

1. Initial clinical assessment
   1. The patient underwent a detailed clinical evaluation following presentation with intermittent abdominal pain and progressive abdominal enlargement. A comprehensive medical history, including gynecologic, surgical, cardiovascular, family, occupational, and environmental history, was obtained.
   2. Physical examination was performed to assess abdominal distension, palpable mass characteristics, and evidence of metastatic disease.
   3. Clinical assessment also included evaluation for clinical features suggestive of an extra-ovarian primary malignancy. No clinical findings indicated a primary vascular neoplasm outside the female genital tract, and subsequent radiological and intraoperative assessments likewise demonstrated no evidence of another primary angiosarcoma.
2. Laboratory investigations
   1. Baseline hematological and biochemical investigations were performed, including complete blood count, liver and renal function tests, serum electrolytes, and coagulation profile.
   2. Tumor marker evaluation included serum CA125, lactate dehydrogenase (LDH), CA19-9, CA15-3, carcinoembryonic antigen (CEA), and human epididymis protein 4 (HE4) levels to aid differential diagnosis of gynecologic malignancy.
      ​NOTE: Although serum CA125 and LDH levels were elevated, these biomarkers were interpreted as nonspecific indicators of tumor burden, peritoneal involvement, and extensive intra-abdominal disease rather than diagnostic biomarkers of primary ovarian epithelioid angiosarcoma.
3. Radiological assessment
   1. Pelvic ultrasonography was initially performed to characterize the pelvic mass and evaluate internal vascularity. Representative ultrasonographic findings are shown in Supplementary Figure 1.
   2. Contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) of the abdomen and pelvis were subsequently obtained to determine tumor origin, local invasion, lymph node involvement, and intra-abdominal dissemination. Contrast-enhanced CT demonstrated a hypervascular right adnexal mass with enlarged pelvic and para-aortic lymph nodes (Supplementary Figure 2).
      NOTE: All imaging studies were independently reviewed by radiologists experienced in gynecologic oncology imaging.
   3. Ultrasonography demonstrated maximal tumor dimensions of approximately 31 cm × 28 cm, whereas MRI demonstrated a lesion measuring 19.5 cm × 20.1 cm in the axial plane. These differences reflected variation in imaging modality, measurement plane, and assessment technique.
   4. Comprehensive cross-sectional imaging demonstrated no evidence of a primary angiosarcoma or other vascular malignancy at another anatomical site, supporting a primary ovarian origin.

2. Preoperative diagnostic planning

1. Differential diagnostic evaluation
   1. Based on the clinical presentation, laboratory investigations, and multimodal imaging, the differential diagnosis included uterine sarcoma, epithelial ovarian carcinoma, metastatic carcinoma, and other primary gynecologic sarcomas.
   2. Less common considerations included metastatic angiosarcoma, epithelioid sarcoma, malignant melanoma, epithelioid hemangioendothelioma, Müllerian neoplasms, sex cord-stromal tumors, and other epithelioid vascular neoplasms.
   3. Comprehensive preoperative imaging demonstrated no evidence of a primary vascular malignancy outside the pelvis.
      NOTE: Because the radiological findings were nonspecific and overlapped with those of several gynecologic malignancies, a definitive preoperative diagnosis could not be established.
2. Surgical decision-making
   1. The patient's case was reviewed by a multidisciplinary gynecologic oncology team. Based on the clinical findings, imaging studies, and the presence of advanced but potentially resectable disease, exploratory laparotomy was recommended.
   2. The primary objectives of surgery were to establish a definitive diagnosis through pathological evaluation and to achieve complete macroscopic cytoreduction when technically feasible.

3. Operative procedure

1. Exploratory laparotomy
   1. Under general anesthesia, an exploratory laparotomy was performed through a midline abdominal incision. The abdominal cavity was systematically inspected to determine the tumor origin and extent of metastatic dissemination.
   2. Systematic exploration included evaluation of the peritoneal cavity, liver surface, diaphragm, omentum, bowel, mesentery, pelvic organs, retroperitoneum, and para-aortic region.
   3. Particular attention was directed toward identifying the dominant tumor site and excluding a primary angiosarcoma or other vascular malignancy at another anatomical location. Representative preoperative radiological and intraoperative findings are shown in Figure 1.
   4. No evidence of a primary angiosarcoma outside the ovary was identified during systematic intra-abdominal exploration.
      NOTE: Intraoperative frozen section examination was not performed because the extensive intra-abdominal dissemination, bulky pelvic and para-aortic nodal disease, and technically resectable tumor burden warranted immediate radical cytoreductive surgery to achieve complete macroscopic resection and obtain adequate tissue for definitive histopathological diagnosis.
2. Intraoperative tumor assessment
   1. The primary tumor was identified as arising from the right ovary and demonstrated marked vascularity with nodular surface irregularity. The dominant tumor was centered within the right ovary and maintained gross continuity with ovarian tissue.
   2. Intraoperative evaluation documented metastatic involvement of the left ovary, uterine serosa, cervix, pelvic peritoneum, sigmoid mesentery, appendix, and pelvic and para-aortic lymph nodes. The extent of metastatic dissemination was systematically documented before resection, and complete macroscopic cytoreduction was considered technically achievable.
3. Radical cytoreductive surgery
   1. Radical cytoreductive surgery was subsequently performed and included total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, appendectomy, resection of all visible metastatic lesions, and systematic pelvic and para-aortic lymphadenectomy.
   2. Pelvic lymphadenectomy included the bilateral external iliac, internal iliac, obturator, and common iliac nodal basins, whereas para-aortic lymphadenectomy extended from the aortic bifurcation to the level of the inferior mesenteric artery.
   3. Surgical resection was continued until complete macroscopic cytoreduction (CC-0) was achieved. Complete macroscopic cytoreduction was confirmed by systematic inspection and palpation of the abdominal cavity at the completion of surgery, with no visible residual tumor remaining.
      NOTE: The objective of systematic lymphadenectomy in this patient was to facilitate accurate pathological staging and resection of bulky metastatic lymph nodes rather than to imply a proven therapeutic or survival benefit.
4. Intraoperative monitoring and management
   1. Estimated blood loss and operative duration were recorded throughout the procedure. Continuous hemodynamic monitoring, including electrocardiography, arterial blood pressure, pulse oximetry, end-tidal carbon dioxide, and urine output, was maintained according to standard anesthetic practice.
   2. Intravenous crystalloid fluid replacement was administered as clinically indicated.

4. Histopathological and immunohistochemical evaluation

1. Tissue processing
   1. Resected surgical specimens were fixed in 10% neutral-buffered formalin for 24–48 h, processed using standard automated tissue-processing protocols, and embedded in paraffin according to routine histopathological procedures.
   2. Representative tissue sections were obtained from the primary ovarian tumor, bilateral adnexa, uterus, cervix, pelvic peritoneum, sigmoid mesentery, appendix, omentum, and all resected lymph nodes.
   3. Formalin-fixed, paraffin-embedded (FFPE) tissue blocks were sectioned at approximately 4 µm thickness, and hematoxylin-eosin (HE) staining was performed for microscopic evaluation.
   4. Gross pathological assessment included measurement of tumor dimensions and weight, evaluation of ovarian surface involvement, hemorrhage, tumor necrosis, surgical margin status, lymphovascular invasion, and regional lymph node metastases.
2. Histopathological examination
   1. Microscopic examination assessed tumor architecture, cytologic atypia, mitotic activity, vasoformative differentiation, vascular channel formation, and metastatic involvement of the resected tissues and lymph nodes.
   2. Histopathological evaluation additionally documented irregular anastomosing vascular channels, intracytoplasmic erythrocyte-containing lumina, tumor necrosis, lymphovascular invasion, ovarian surface involvement, and surgical margin status.
   3. Mitotic activity was quantified by counting mitotic figures in 10 consecutive high-power fields (HPFs).
   4. Regional lymph nodes were examined individually to determine the number of metastatic lymph nodes, the size of metastatic deposits, and the presence or absence of extranodal extension.
   5. Pathological staging was assigned according to the FIGO ovarian carcinoma staging framework and the AJCC TNM Classification (8th edition).
3. Immunohistochemical analysis
   1. Immunohistochemical staining was performed using endothelial markers, including CD31, CD34, and FLI1. Additional markers, including cytokeratin (AE1/AE3), epithelial membrane antigen (EMA), ERG, D2-40, PAX8, WT1, HMB45, TFE3, CD10, vimentin, SMARCA4 (BRG1), BCOR, Ki-67, and p53, were evaluated to exclude alternative diagnoses and confirm endothelial differentiation.
      1. Staining was performed on formalin-fixed, paraffin-embedded tissue sections using validated clinical antibodies according to the manufacturer's recommendations following heat-induced antigen retrieval.
      2. Appropriate external positive and negative tissue controls were included in each staining run. Membranous staining was evaluated for CD31 and CD34; nuclear staining for FLI1, ERG, PAX8, WT1, TFE3, SMARCA4, BCOR, Ki-67, and p53; and cytoplasmic and/or membranous staining for cytokeratin (AE1/AE3), EMA, D2-40, HMB45, CD10, and vimentin, according to the expected localization of each marker.
      3. Immunoreactivity was independently assessed by two experienced pathologists. Staining intensity was graded as 0 (negative), 1+ (weak), 2+ (moderate), or 3+ (strong), and the percentage of positive tumor cells was recorded.
         ​NOTE:. Detailed information regarding antibody clones, manufacturers, catalog numbers (where available), working dilutions, antigen retrieval conditions, detection system, and staining platform is provided in the accompanying Table of Materials.

5. Postoperative management and follow-up

1. Immediate postoperative care
   1. Following surgery, the patient underwent routine postoperative monitoring, including assessment of vital signs, abdominal examination, pain control, fluid balance, and laboratory investigations.
   2. Serial complete blood count, serum biochemistry, and postoperative hemoglobin measurements were performed according to institutional postoperative protocols.
   3. Serum CA125 and lactate dehydrogenase (LDH) levels were reassessed during postoperative follow-up.
2. Adjuvant treatment planning
   1. Adjuvant systemic chemotherapy was recommended because of the extensive metastatic disease and the highly aggressive biological behavior of the primary ovarian epithelioid angiosarcoma.
   2. Following multidisciplinary gynecologic oncology review of the final histopathological diagnosis, extensive pelvic and para-aortic nodal metastases, and advanced disease stage, postoperative systemic chemotherapy was advised.
   3. Available treatment options, anticipated benefits, potential adverse effects, and the poor prognosis associated with this malignancy were discussed comprehensively with the patient and her family.
      ​NOTE: Despite detailed counseling, the patient declined further systemic oncologic treatment.
3. Clinical outcome assessment
   1. Clinical follow-up included evaluation for postoperative complications, biochemical response, and evidence of disease progression.
   2. Follow-up assessment comprised serial clinical examination, laboratory investigations, and radiological evaluation when clinically indicated.
   3. Progressive intra-abdominal metastatic disease was confirmed during follow-up based on clinical deterioration and radiological findings.

Results

Following appropriate preoperative evaluation and exploratory laparotomy, a dominant hypervascular tumor arising from the right ovary was identified intraoperatively. Extensive metastatic dissemination involving the contralateral ovary, uterine serosa, cervix, pelvic peritoneum, sigmoid mesentery, appendix, and pelvic and para-aortic lymph nodes was observed. Figure 1 illustrates the preoperative radiological findings and intraoperative surgical findings. Radical cytoreductive surgery, including total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, appendectomy, resection of visible metastatic lesions, and systematic pelvic and para-aortic lymphadenectomy, was successfully completed, achieving complete macroscopic cytoreduction (CC-0) with no visible residual disease. The operative duration was approximately 210 min, with an estimated blood loss of approximately 1,000 mL, and no major intraoperative complications occurred. Figure 1 illustrates the preoperative radiological findings and intraoperative surgical findings, including the large pelvic mass, enlarged para-aortic lymph nodes, hypervascular right ovarian tumor, and operative field following lymphadenectomy.

Gross pathological examination demonstrated that the right ovary was replaced by a multinodular hemorrhagic solid tumor measuring 29.8 cm × 27.1 cm × 15.4 cm and weighing 3,850 g. The tumor exhibited an irregular external surface with ovarian surface involvement, focal capsular disruption, extensive hemorrhage, friable tan-white cut surfaces, and multifocal geographic necrosis involving approximately 35% of the tumor. Microscopically, the neoplasm consisted of sheets and nests of epithelioid cells with abundant eosinophilic cytoplasm, marked nuclear atypia, irregular anastomosing vascular channels, intracytoplasmic erythrocyte-containing lumina consistent with vasoformative differentiation, and frequent mitotic activity (18 mitoses per 10 high-power fields). Lymphovascular invasion was present, whereas all surgical resection margins were free of tumor, with the closest soft-tissue margin measuring 6 mm. Histopathological examination confirmed metastatic involvement of the contralateral ovary, uterine serosa with superficial myometrial invasion, cervix, pelvic peritoneum, sigmoid mesentery, appendix, and regional lymph nodes. A total of 30 lymph nodes were examined, of which 11 contained metastatic tumor, including 5 of 16 pelvic lymph nodes and 6 of 14 para-aortic lymph nodes. The largest metastatic lymph-node deposit measured 2.1 cm within a para-aortic lymph node, and extranodal extension was identified in two para-aortic lymph nodes. These findings corresponded to FIGO stage IIIC (using the FIGO ovarian carcinoma staging framework) and AJCC TNM classification (8th edition): pT3c pN1 M0. The complete gross pathological, microscopic, immunohistochemical, lymph-node, and staging findings are summarized in Table 2 and Table 3.

Histopathological examination demonstrated sheets and nests of epithelioid tumor cells with marked nuclear atypia, irregular vascular channels, and intracytoplasmic lumina containing erythrocytes, consistent with vasoformative differentiation. Immunohistochemical analysis demonstrated diffuse strong expression (3+) of the endothelial markers CD31 (95%), CD34 (92%), and FLI1 (90%), confirming endothelial differentiation and the diagnosis of primary ovarian epithelioid angiosarcoma. Vimentin (98%), SMARCA4 (88%), and CD10 (72%) also demonstrated positive immunoreactivity (2+), whereas p53 exhibited diffuse aberrant nuclear overexpression (3+)involving approximately 80% of tumor cells, and the Ki-67 proliferation index was approximately 45%, indicating high proliferative activity. In contrast, ERG, cytokeratin (AE1/AE3), epithelial membrane antigen (EMA), PAX8, WT1, D2-40, HMB45, TFE3, and BCOR were negative, excluding epithelial, Müllerian, melanocytic, lymphatic, and other epithelioid neoplasms. The complete immunohistochemical profile, including staining intensity and the percentage of positive tumor cells, is summarized in Table 3. Representative histopathological and immunohistochemical findings are presented in Figure 2, while Supplementary Figure 3 demonstrates the broader immunophenotypic profile used to exclude alternative diagnoses. Correlation of the histomorphological features with the immunophenotypic profile confirmed the diagnosis of primary ovarian epithelioid angiosarcoma.

Postoperatively, serum CA125 levels decreased from 156.1 U/mL preoperatively to 65.21 U/mL two weeks after surgery, while LDH decreased from 257 U/L to 180 U/L, reflecting a temporary reduction in tumor burden rather than a disease-specific biomarker response. The patient recovered without major postoperative complications and was discharged in stable clinical condition. However, despite complete macroscopic resection, rapid disease progression occurred after the patient declined adjuvant systemic chemotherapy, and she died approximately two months postoperatively. A comparative summary of previously reported cases of primary ovarian angiosarcoma and the present case is provided in Table 4^{9,11,12,13,14,15,16,17,18,19,20,21,22}. This clinical course underscores the highly aggressive biological behavior of primary ovarian epithelioid angiosarcoma and the limited effectiveness of surgery alone in controlling advanced metastatic disease.

Figure 1: Radiological and intraoperative findings. (A) Sagittal magnetic resonance imaging (MRI) demonstrating a hypervascular right adnexal mass measuring 19.5 × 20.1 cm (arrow), initially interpreted as a uterine sarcoma because of its large size and anatomical relationship to the uterus. (B) Coronal MRI demonstrating enlarged pelvic and para-aortic lymph nodes (arrows) consistent with metastatic nodal involvement. (C) Intraoperative photograph demonstrating the dominant hypervascular tumor arising from the right ovary with nodular external surface morphology. (D) Resected para-aortic lymph node specimen demonstrating bulky metastatic nodal disease. (E) Operative field following complete macroscopic cytoreduction (CC-0), including total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, appendectomy, resection of visible metastatic lesions, and systematic pelvic and para-aortic lymphadenectomy. Please click here to view a larger version of this figure.

Figure 2: Histopathological and immunohistochemical findings. (A) Hematoxylin and eosin (H&E) stain (original magnification ×200; scale bar = 50 µm) demonstrating sheets and nests of epithelioid tumor cells with irregular anastomosing vascular channels, marked nuclear atypia, and intracytoplasmic erythrocyte-containing lumina, consistent with vasoformative differentiation. (B) CD31 immunohistochemical stain (×200; scale bar = 50 µm) demonstrating diffuse strong membranous positivity. (C) CD34 immunohistochemical stain (×200; scale bar = 50 µm) demonstrating diffuse strong membranous positivity. (D) FLI1 immunohistochemical stain (×200; scale bar = 50 µm) demonstrating diffuse strong nuclear positivity, confirming endothelial differentiation. The complete immunohistochemical profile of the present case is summarized in Table 3, and additional representative immunohistochemical findings are presented in Supplementary Figure 3. Please click here to view a larger version of this figure.

Table 1: Published cases of primary ovarian angiosarcoma and comparison with the present case. Please click here to download this Table.

Table 2: Timeline of clinical events from initial presentation to final clinical outcome. Please click here to download this Table.

Table 3: Immunohistochemical profile of the present case. Abbreviations: AJCC, American Joint Committee on Cancer; FIGO, International Federation of Gynecology and Obstetrics; HPF, high-power field. Please click here to download this Table.

Table 4: Gross pathological, microscopic, lymph-node, and pathological staging findings of the present case. Abbreviations: BSO, bilateral salpingo-oophorectomy; MAID, mesna, doxorubicin (adriamycin), ifosfamide, and dacarbazine; TAH, total abdominal hysterectomy.*Stage IIIC should be retained only if this was the institutional pathological stage. †Pathological tumor size. Preoperative ultrasonography measured 31 cm × 28 cm, whereas MRI measured 19.5 cm × 20.1 cm. Please click here to download this Table.

Supplementary Figure 1: Color Doppler ultrasonography findings. Color Doppler ultrasonography demonstrating a large heterogeneous mixed-echogenic pelvic mass measuring approximately 31 × 28 cm, located superior to the uterus, with marked internal vascularity consistent with a hypervascular neoplasm.Please click here to download this file.

Supplementary Figure 2: Contrast-enhanced computed tomography findings. Contrast-enhanced computed tomography (CT) of the abdomen and pelvis demonstrating a large hypervascular right adnexal mass initially suspected to represent uterine sarcoma, together with multiple enlarged pelvic and para-aortic lymph nodes consistent with metastatic involvement. No radiological evidence of a primary vascular malignancy at another anatomical site was identified.Please click here to download this file.

Supplementary Figure 3: Extended immunohistochemical profile of the present case. Representative immunohistochemical staining demonstrating positive expression of CD31 (A), CD34 (B), FLI1 (C), vimentin (E), CD10 (F), Ki-67 (G; proliferation index approximately 45%), p53 (H; diffuse aberrant nuclear overexpression involving approximately 80% of tumor cells), and SMARCA4 (I). Tumor cells were negative for ERG (D), cytokeratin (AE1/AE3) (J), epithelial membrane antigen (EMA) (K), HMB45 (L), TFE3 (M), D2-40 (N), PAX8 (O), WT1 (P), and BCOR (Q), thereby excluding epithelial, Müllerian, melanocytic, lymphatic, and several other epithelioid neoplasms. All images were acquired at the same original magnification (×200); scale bar = 50 µm.Please click here to download this file.

Discussion

Primary ovarian angiosarcoma is an exceptionally rare and highly aggressive malignant neoplasm of vascular endothelial origin. The largest clinicopathological analysis was reported by Nielsen et al.¹¹, who described seven ovarian angiosarcoma cases and emphasized the aggressive biological behavior and poor prognosis associated with this entity. Subsequent reports^{11,12,13,14,15,16,17,18,19,20,21,22}further expanded the limited literature, demonstrating heterogeneous clinical presentations but consistently unfavorable outcomes. The updated review of published cases further demonstrates that most patients present with advanced-stage disease, extensive extra-ovarian dissemination, and poor survival despite multimodal treatment, underscoring the absence of standardized diagnostic and therapeutic strategies for this exceptionally rare malignancy.

Angiosarcomas in general are characterized by rapid progression, early dissemination, and poor survival outcomes²³. They may arise de novo or secondary to predisposing factors, including chronic lymphedema, prior radiotherapy, environmental carcinogen exposure, and genetic syndromes such as neurofibromatosis type 1, BRCA-associated disorders, and Maffucci syndrome^23,24,25. The histogenesis of primary ovarian angiosarcoma remains incompletely understood. Proposed mechanisms include malignant transformation of ovarian vascular endothelial cells, differentiation from pluripotent mesenchymal stromal cells, and malignant transformation within pre-existing ovarian lesions such as mature cystic teratomas or other ovarian neoplasms^11,12,19. Several reported ovarian angiosarcomas have arisen in association with mature cystic teratomas, epithelial tumors, or mixed germ-cell tumors^{11,12,13,14,15,16,17,18,19,20,21,22}. In contrast, extensive histopathological examination in the present case identified no associated ovarian neoplasm, supporting the diagnosis of a primary ovarian epithelioid angiosarcoma arising de novo.

Reported five-year survival rates range from 31% to 43%, with median survival between 16 and 42 months depending on tumor location and stage at presentation^26,27,28,29. The aggressive biological behavior of angiosarcoma is further illustrated by reports involving pleural, gastrointestinal, mesenteric, and cranial epithelioid angiosarcomas, all of which demonstrated rapid progression and high metastatic potential^{30,31,32,33,34,35,36,37,38,39,40,41}. The patient in this study similarly presented with multiple adverse prognostic features, including a giant ovarian tumor, diffuse intra-abdominal dissemination, and extensive pelvic and para-aortic lymph node metastases, followed by rapid postoperative progression despite complete macroscopic cytoreduction, findings consistent with the highly aggressive biological behavior reported in previous studies. The extensive lymphovascular invasion, ovarian surface involvement, extranodal extension, high mitotic activity (18/10 high-power fields), elevated Ki-67 proliferation index (45%), and diffuse aberrant p53 overexpression observed in the present case further support the highly aggressive biological behavior of ovarian epithelioid angiosarcoma.

Histologically, epithelioid angiosarcoma represents a distinct subtype characterized by epithelioid morphology, marked cytologic atypia, and vasoformative differentiation^25,31. Characteristic microscopic findings include sheets and nests of epithelioid tumor cells with abundant eosinophilic cytoplasm, irregular vascular channels, brisk mitotic activity, and intracytoplasmic lumina containing erythrocytes³¹. Immunohistochemical analysis remains essential for definitive diagnosis, with strong positivity for endothelial markers including CD31, CD34, ERG, and FLI1 supporting vascular differentiation^32,35. Among these markers, CD31 is considered the most sensitive and specific endothelial marker³². In the present case, diffuse expression of CD31, CD34, and FLI1 confirmed endothelial differentiation, whereas the absence of epithelial, Müllerian, melanocytic, lymphatic, and sex cord-stromal markers excluded metastatic carcinoma, epithelioid sarcoma, malignant melanoma, Müllerian tumors, sex cord-stromal tumors, epithelioid hemangioendothelioma, and other epithelioid vascular neoplasms. The aberrant p53 expression pattern and elevated Ki-67 proliferation index further supported the highly aggressive biological behavior of the tumor. Although ERG is considered a sensitive endothelial marker, occasional ERG-negative epithelioid angiosarcomas have been reported, and therefore diagnosis should rely on the overall morphological and immunophenotypic profile rather than any single marker³². Emerging molecular studies have additionally identified recurrent genetic alterations involving PTPRB, PLCG1, CIC, KDR, and MYC amplification, contributing to improved understanding of angiosarcoma pathogenesis and potential therapeutic target^33,42,43.

Clinically, ovarian angiosarcoma frequently presents with nonspecific symptoms such as abdominal pain, abdominal distension, anemia, or a palpable pelvic mass, resulting in delayed diagnosis^{11,12,13,14,15,16,17,18,19,20,21,22}. Imaging findings are similarly nonspecific and may mimic epithelial ovarian carcinoma, metastatic disease, or uterine sarcoma^{11,12,13,14,15,16,17,18,19,20,21,22}. In the current case, preoperative imaging initially suggested uterine sarcoma with nodal metastases, reflecting the diagnostic uncertainty described in previous reports. Comprehensive preoperative computed tomography and magnetic resonance imaging, together with meticulous intraoperative exploration, demonstrated a dominant right ovarian mass without evidence of a primary angiosarcoma at another anatomical site, thereby supporting a primary ovarian origin rather than secondary ovarian metastasis. This ambiguity has important implications for surgical planning because the full extent of disease dissemination is often recognized only intraoperatively. Intraoperative frozen section examination was not performed because the presence of a bulky hypervascular pelvic mass with extensive intra-abdominal dissemination and clinically resectable disease prompted immediate radical cytoreductive surgery to achieve complete macroscopic resection and obtain adequate tissue for definitive histopathological diagnosis. Serum biomarkers also have limited diagnostic utility. Elevated CA125 levels have been reported in selected ovarian angiosarcoma cases, including those described by Ye et al.⁹ and Yaqoob et al.¹⁹, although their prognostic significance remains unclear. Similarly, the elevated CA125 and lactate dehydrogenase levels observed in our patient most likely reflected extensive tumor burden, diffuse peritoneal involvement, tissue necrosis, and nonspecific inflammatory responses rather than disease-specific biomarkers. Their postoperative decline following tumor debulking supports their potential utility for monitoring disease burden but should not be interpreted as diagnostic or prognostic markers for ovarian angiosarcoma.

From a surgical perspective, angiosarcoma demonstrates aggressive metastatic behavior with both hematogenous and lymphatic dissemination^{23,26,27,28,29}. Lymph node metastasis, although infrequently documented in ovarian angiosarcoma, represents an important pathway of disease spread^19,22,36. Although evidence specific to ovarian angiosarcoma is limited, studies in gynecologic oncology have similarly demonstrated that pelvic lymph node involvement reflects aggressive tumor biology and has important implications for surgical staging and disease assessment⁴⁶. In our patient, extensive pelvic and para-aortic lymph node metastases were identified in association with diffuse peritoneal dissemination, a presentation rarely described in previously reported ovarian cases^{11,12,13,14,15,16,17,18,19,20,21,22}. Similar patterns of nodal and distant metastasis have been observed in gastrointestinal and pleural epithelioid angiosarcomas, where outcomes remain particularly poor^24,34,36. Although systematic pelvic and para-aortic lymphadenectomy enabled complete macroscopic cytoreduction and comprehensive pathological staging in the present case, the patient's rapid postoperative progression and death within two months indicate that this single case should not be interpreted as evidence that lymphadenectomy improves survival. Rather, lymphadenectomy may be considered when bulky nodal disease is present to facilitate accurate staging, reduction of tumor burden, and achievement of complete macroscopic resection, while its survival benefit remains uncertain.

Surgical resection remains the cornerstone of treatment for localized or potentially resectable disease^23,26,37. Complete macroscopic cytoreduction is considered one of the most important prognostic factors in high-grade sarcomas and advanced intra-abdominal malignancies³⁷. Previous ovarian angiosarcoma reports consistently emphasized aggressive surgical management whenever technically feasible^{11,12,13,14,15,16,17,18,19,20,21,22}. In the present case, radical cytoreductive surgery, including hysterectomy, bilateral salpingo-oophorectomy, omentectomy, appendectomy, and systematic pelvic and para-aortic lymphadenectomy, achieved complete macroscopic tumor resection. However, despite successful surgical debulking, rapid postoperative progression following refusal of adjuvant chemotherapy highlights the limitations of surgery alone in controlling systemic disease and emphasizes the importance of multidisciplinary postoperative management whenever feasible. Recent studies in gynecologic oncology have also highlighted the importance of perioperative optimization, including nutritional status and postoperative immune recovery, as factors that may influence surgical recovery and tolerance of subsequent systemic therapy, although such evidence has not yet been specifically evaluated in ovarian angiosarcoma^44,45.

Adjuvant systemic therapy has been explored using multiple chemotherapeutic regimens, including paclitaxel, doxorubicin, ifosfamide, vincristine, cyclophosphamide, and MAID-based protocol^{38,39,40,41,42}. Wu et al.²⁰ notably reported complete remission for 11 months following MAID chemotherapy in advanced ovarian angiosarcoma, although durable responses remain uncommon. Pooled European Organization for Research and Treatment of Cancer (EORTC) analyses demonstrated that anthracycline-based chemotherapy may achieve response rates comparable to those observed in other soft tissue sarcomas⁴². Owing to the vascular origin of angiosarcoma, anti-angiogenic and targeted therapies have also attracted growing interest^24,43. However, randomized studies evaluating bevacizumab in combination with paclitaxel failed to demonstrate a significant survival benefit and reported increased toxicity⁴⁶. Supportive care also remains an important component of systemic treatment in gynecologic oncology, particularly in elderly patients receiving cytotoxic chemotherapy, where optimization of treatment-related toxicities may improve treatment tolerance and quality of life⁴⁷. More recently, mTOR inhibitors such as everolimus have shown potential activity in recurrent epithelioid angiosarcoma, although supporting evidence remains limited⁴⁸. Emerging studies investigating immune checkpoint inhibitors and molecularly targeted therapies may further expand future treatment options; however, evidence specific to primary ovarian angiosarcoma remains insufficient to support routine clinical use.

This case highlights several important clinical and surgical considerations. First, primary ovarian epithelioid angiosarcoma remains a major diagnostic challenge because of nonspecific clinical manifestations and radiological overlap with more common gynecologic malignancies. Second, this case demonstrates the technical feasibility of complete macroscopic cytoreduction and systematic pelvic and para-aortic lymphadenectomy in the presence of bulky nodal disease but does not establish a therapeutic survival benefit for these procedures. Third, despite complete macroscopic resection, prognosis remains extremely poor, underscoring the urgent need for more effective systemic therapies and molecularly targeted approaches.

Review of the existing literature confirms the absence of standardized treatment protocols and the limited effectiveness of currently available systemic therapies. Increased awareness of this rare entity, together with the accumulation of additional clinicopathological and molecular data, is essential to improve diagnostic accuracy, optimize therapeutic strategies, and enhance patient outcomes. Multicenter collaboration and comprehensive reporting of future cases will be important to improve understanding of the clinicopathological characteristics, molecular biology, and optimal management of primary ovarian epithelioid angiosarcoma. Further studies are warranted to clarify the role of adjuvant therapies and to explore novel molecularly targeted, anti-angiogenic, and immunotherapeutic treatment approaches for this highly aggressive malignancy.

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
10% Neutral Buffered Formalin	Sigma-Aldrich (Merck)	HT501128	Tissue fixation
Automated Tissue Processor	Leica Biosystems	ASP300 S	Tissue processing
Autostainer Link 48	Agilent (Dako)	Autostainer Link 48	Immunohistochemistry
BCOR antibody	Santa Cruz Biotechnology	sc-514576	1:100 (dilution)
CD10 antibody	Leica Biosystems	PA0270	1:100 (dilution)
CD31 antibody (JC70A)	Agilent/Dako	M0823	1:100 (dilution)
CD34 antibody (QBEnd/10)	Agilent/Dako	M7165	1:100 (dilution)
cellSens Standard	Olympus	cellSens	Image analysis
CK AE1/AE3	Agilent/Dako	M3515	1:200 (dilution)
CT Scanner	Siemens Healthineers	SOMATOM	Contrast CT
D2-40 antibody	Agilent/Dako	M3619	1:100 (dilution)
DAB Chromogen	Agilent (Dako)	K3468	Chromogen
DP74 Camera	Olympus	DP74	Image acquisition
EMA antibody (E29)	Agilent/Dako	M0613	1:200 (dilution)
EnVision FLEX HRP Detection Kit	Agilent (Dako)	K8002	Polymer HRP detection
ERG antibody (EP111)	Cell Marque	280M	1:100 (dilution)
FLI1 antibody (MRQ-1)	Cell Marque	249M	1:100 (dilution)
HMB45 antibody	Agilent/Dako	M0634	1:100 (dilution)
IBM SPSS Statistics v26	IBM	v26	Statistical analysis
Ki-67 antibody	Agilent/Dako	M7240	1:100 (dilution)
Mayer's Hematoxylin	Agilent (Dako)	S3309	Counterstain
Microtome RM2235	Leica Biosystems	RM2235	Cut 4 μm FFPE sections
MRI Scanner	Siemens Healthineers	MAGNETOM	Preoperative MRI
Olympus BX53 Microscope	Olympus	BX53	Histopathology
p53 antibody	Agilent/Dako	M7001	1:100 (dilution)
Paraffin Embedding Medium	Leica Biosystems	39601095	Paraffin embedding
PAX8 antibody	Cell Marque	363M	1:100 (dilution)
Positively Charged Microscope Slides	Thermo Fisher Scientific	J1800AMNZ	Mount tissue sections
SMARCA4 (BRG1) antibody	Abcam	ab110641	1:100 (dilution)
TFE3 antibody	Cell Marque	367M	1:100 (dilution)
Ultrasound System	GE Healthcare	LOGIQ E9	Color Doppler ultrasound
Vimentin antibody	Agilent/Dako	M0725	1:200 (dilution)
Water Bath	Leica Biosystems	HI1210	Section flotation
WT1 antibody	Agilent/Dako	M3561	1:100 (dilution)