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Introduction

Angiosarcoma (AS) is a rare soft tissue sarcoma, accounting for 2–5% of all soft tissue sarcomas (1). Since the tumor originates from vascular endothelial cells, it can occur at any anatomical site, although it frequently occurs in the skin of the head and neck in elderly men.

The etiology of primary AS is unknown, but secondary AS is associated with radiation exposure, and chronic lymphoedema (Stewart-Treves syndrome), exogenous toxins, and familial syndromes such as neurofibromatosis are hypothesized to be risk factors as well (1,2).

Primary uterine AS is an extremely rare type of tumor, and only 30 cases have been reported in the English literature to date (3). The 5-year survival rate is <35%, which is equivalent to that of other sites of AS (2,4). In addition, the median overall survival time for patients with metastatic AS is <11 months (5). Standard systemic chemotherapy for patients with unresectable disease has not yet been established.

Here, the patient presented with intra-abdominal recurrence very early on after complete surgical removal for uterine AS, but achieved remission with paclitaxel and carboplatin combination therapy. Further research, including more case reports, is required to improve our understanding of this rare histological type. In the present report, the case of a 57-year-old woman is documented in detail and a literature review on AS is provided.

Case report

The patient was a 57-year-old woman, gravida 1, para 1, with no complications. She had a history of an open abdominal myomectomy at age 31. There were no significant findings in her family history.

She presented to the outpatient department of Ishikiriseiki Hospital (Higashiosaka, Osaka, Japan) in August 2022 with complaints of abdominal distention, loss of appetite, and dyspnea. Transvaginal ultrasound (Xario 100G; Canon Inc.) revealed a large uterine tumor. No abnormal vaginal bleeding was observed on internal examination. A blood test showed hemoglobin (Hb) 4.5 g/dl (normal range: 12.0–15.2 g/dl), serum lactate dehydrogenase (LDH) 409 IU/l (normal range: 106–211 IU/l), and D-dimer 9.4 µg/ml (normal range: <1.0 µg/ml), and carbohydrate antigen (CA) 125 66.6 U/ml (normal value: <35.0 U/ml). CA125 was measured using CA125 II Abbott Alinity G06330R04 (Abbott Molecular Inc.). Magnetic resonance imaging (MRI) (Ingenia 3T; Philips) showed a heterogeneous 27×20 cm mass in the uterus with high and low signal areas in the T2-weighted imaging. The solid part of the tumor showed a high signal in the diffusion-weighted imaging and a low signal in the apparent diffusion coefficient map (b value=0 sec/mm2), suggesting the presence of a malignant tumor (Fig. 1A-C). There were no abnormal findings in the cervix, suggesting that there was no cervical invasion or malignant tumor originating from the cervix (Fig. 1D). Computed tomography (CT) (Aquilion PRIME; Canon Inc.) (Fig. 2A) showed a heterogeneous, septate, mixed density mass with calcified areas on the left medial side in transverse section. Using 18-fluorodeoxyglucose-positron emission tomography CT [(18F) FDG-PET/CT; Discovery ST; GE Yokogawa Medical Systems Inc.] showed no lymph node swelling and no evidence of metastatic lesions. Hypermetabolism was observed at the margins of the uterine tumor, where MRI images suggested the presence of a malignant tumor (Fig. 2B). An ultrasound examination of the lower limbs did not reveal deep vein thrombosis. Cytological examinations of the cervix and endometrium were all negative.

Figure 1. Magnetic resonance imaging. (A) T2-weighted image. A 27×20 cm mass (white arrowhead) with heterogeneous high and low signal areas in the uterus. (B) Diffusion-weighted image. The solid part of the tumor showed a high signal (white arrowhead). (C) Apparent diffusion coefficient map. The solid part of the tumor showed a low signal (white arrowhead). (D) Sagittal section. There was no invasion into the cervix or malignant tumor of cervical origin (white arrowhead).

Figure 2. Radiological findings. (A) Computed tomography scan. A heterogeneous, septate, mixed-density mass was seen in the transverse section. (B) Positron emission tomography-computed tomography. Hypermetabolism was seen in the area where the presence of a malignant tumor was suggested by magnetic resonance imaging (white arrowhead).

Despite a total of 20 units of red blood cell (RBC) transfusion (140 ml/unit), the Hb levels remained low, and the patient developed heart and respiratory failure, requiring intensive care, including ventilator management. The patient underwent surgery with strict anesthetic management to improve their condition. Intraoperative findings showed massive hemorrhagic ascites and a smooth, enlarged uterus with numerous dilated blood vessels (Fig. 3A). There were no disseminated lesions in the abdominal cavity, and there were firm adhesions between the uterus and the sigmoid colon. Intraoperative frozen section analysis suggested leiomyosarcoma. Finally, total abdominal hysterectomy, bilateral salpingo-oophorectomy, partial sigmoid colectomy: Functional end-to-end anastomosis were performed. The total blood loss and weight of the excised specimen were 3,140 ml and 7,100 g, respectively. A total of 8 units of RBC transfusion was required during the operation. The macroscopic appearance of the resected uterine tumor was a spongy hemorrhagic tumor with necrotic tissue (Fig. 3B). Cytological examination of the hemorrhagic ascites was negative.

Figure 3. Macroscopic image. (A) Intraoperative findings showed a smooth, enlarged uterus with numerous dilated blood vessels, and strong adhesion (white arrowhead) between the uterus and sigmoid colon. (B) A spongy, hemorrhagic tumor with necrotic tissue.

Pathological examination revealed that the atypical cells with enlarged nuclei and distinct nucleoli formed a reticular structure like a vascular cavity and proliferated (Fig. 4A). Immunohistochemical staining of paraffin-embedded tissue showed strong positivity for CD31 (Fig. 4B) and partial positivity for CD34 (Fig. 4C). Based on the above, the patient was diagnosed with primary epithelioid angiosarcoma. Hematoxylin and eosin staining was performed using Carrazi's hematoxylin (Muto Pure Chemicals Co., Ltd) and Pure Eosin Solution (Muto Pure Chemicals Co., Ltd) on an automated staining device (Tissue-Tek® Prisma™ Plus; Sakura Finetek Japan Co., Ltd). For immunohistochemical staining, CD31 antibody (cat. no. IR61061-2; Ready-to-Use) and CD34 antibody (cat. no. IR63261-2; Ready-to-Use) were used as primary antibodies, and EnVision FLEX/HRP (cat. no. K800021-2J; Ready-to-Use) was used as the secondary antibody (all from Agilent Technologies Japan, Ltd), all tests were performed in the department of pathology according to the standard protocol, following the manufacturer's instructions. The tumor was confined to the uterus, and it was diagnosed as primary uterine angiosarcoma (T1NXM0; 8th edition of the American Joint Committee on Cancer).

Figure 4. Pathological findings. (A) Hematoxylin and eosin stain. The atypical cells with enlarged nuclei and distinct nucleoli formed a reticular structure like a vascular cavity and exhibited signs of proliferation. Magnification, ×100. (B) CD31 staining showed a strong positive signal in the malignant cells. Magnification, ×100. (C) CD34 staining showed a partially positive signal in the malignant cells. Magnification, ×200.

Adjuvant chemotherapy was not performed at the patient's request. Even though a complete surgical resection was achieved, a CT scan performed 1 month after surgery revealed the presence of three new solid tumors (maximum diameter of 7 cm) in the abdominal cavity (Fig. 5). The patient was diagnosed with intra-abdominal recurrence of uterine AS and received 21 cycles of intravenous paclitaxel (175 mg/m2) and carboplatin (area under the curve=6 mg/ml/min) once every 3–4 weeks. Tumor response was evaluated every 3 cycles. Tumors gradually decreased in size, therefore, the patient requested long-term chemotherapy. In addition, CA125 and LDH levels normalized after 3 cycles of chemotherapy and have remained normal. D-dimer levels gradually decreased from the start of chemotherapy and normalized 10 months after the last cycle, where they remained normal. No serious adverse events were observed during chemotherapy, but according to the Common Terminology Criteria for Adverse Events version 5.0, grade 1 neutropenia and peripheral neuropathy were observed. At the time of writing this report, she was still alive with no disease 31 months after the primary surgery.

Figure 5. Computed tomography scan performed 1 month after surgery. The largest of the three new solid tumors that had recurred in the abdominal cavity (maximum diameter 7 cm) (white arrowhead).

Discussion

AS is a very rare disease, with the skin being the most common primary site of origin. A small number of cases have also been reported in gynecological organs such as the uterus, ovaries, vagina, and vulva (1,2,4). AS is classified into primary and secondary forms. In this case, no risk factors for secondary AS were identified. Therefore, it was diagnosed as primary uterine AS (1,2). To the best of our knowledge, as summarized previously (3), only 30 cases have been reported to date.

The majority of patients with uterine AS are postmenopausal, with a median age of 61 years (age range: 17–81 years). The most common symptom is postmenopausal vaginal bleeding, and patients may present with weight loss and anemia (3). Our patient was postmenopausal but, notably, did not present with vaginal bleeding; instead, she exhibited an enlarged uterus and ascites. A distinctive clinical feature in this case was the patient's poor response to massive blood transfusions, coupled with the observation of extensive hemorrhagic ascites intraoperatively. The anemia improved rapidly following hysterectomy. We hypothesize that the persistent anemia, despite no visible vaginal bleeding, likely resulted from internal hemorrhage due to the tumor's friable and abnormally proliferative vasculature. This internal bleeding may have contributed to both intratumoral hemorrhage and the accumulation of hemorrhagic ascites, which were confirmed during surgery.

Radiologically, the most distinctive characteristic of uterine AS is the heterogeneous tumor with a mixture of different signal intensities, described ‘cauliflower-like’ on T2-weighted imaging (6). Although the MRI in our case was affected by motion artifacts due to the patient's inability to remain still, the characteristic findings were evident, supporting the diagnosis. Radiomics analysis, which has been increasingly utilized to enhance diagnostic accuracy in uterine malignancies (7), has not yet been specifically applied to uterine angiosarcoma due to its rarity. Future development of radiomics-based approaches could potentially contribute to the non-invasive assessment of such rare tumors.

Macroscopically, consistent with previous case reports, the tumor presented as a spongy, hemorrhagic mass with necrotic tissue (6,8). Histopathologically, anastomotic vascular lumens lined by highly atypical endothelial cells were observed, accompanied by extensive hemorrhage and necrosis-features characteristic of AS. Tumor cells in AS exhibit varying degrees of nuclear atypia and may present with epithelial or spindle cell morphology, sometimes making differentiation from benign vascular proliferations challenging. Conversely, highly atypical cells may form solid sheets with minimal vascular formation, necessitating differentiation from carcinosarcoma, leiomyosarcoma, adenosarcoma, metastatic carcinoma, and malignant melanoma. Immunohistochemical staining is therefore crucial for definitive diagnosis of AS. These tumors typically express endothelial cell markers such as CD31, CD34, and von Willebrand factor (2). In our case, positive staining for CD31 and CD34 enabled an accurate diagnosis at an early stage.

To date, evidence-based treatment regimens for AS remain limited, with most published reports consisting of retrospective case series. Uterine AS typically progresses rapidly and carries poor prognosis, with a 5-year survival rate of <35% (4). Furthermore, the median overall survival for patients with metastatic AS is <11 months (5). Despite these discouraging statistics, our patient achieved complete remission following recurrence of uterine AS through systemic chemotherapy. The patient is still alive with no evidence of disease 31 months after the initial treatment.

Radical surgery remains the first-line treatment for resectable AS. For most cases of uterine AS over the past 50 years, surgical treatment (simple hysterectomy and bilateral salpingo-oophorectomy) has been the primary treatment approach (3). Generally, lymphadenectomy is not recommended for visceral AS unless there is clear involvement of regional lymph nodes (9). Neoadjuvant/adjuvant chemotherapy for localized resectable AS is not a standard treatment. Despite the limited number of cases, adjuvant chemotherapy for stage III or IV ovarian AS has been reported to potentially improve overall survival (4). A European retrospective study of primary AS involving 33 sarcoma centers demonstrated that adjuvant chemotherapy may improve outcomes in patients with large tumors (>5 cm) and/or high predicted 10-year mortality risk (>60%), although the optimal regimen remains undetermined (10). In our case, surgery was performed as the primary treatment, achieving complete resection with negative margins (R0). Intraoperative frozen section analysis suggested leiomyosarcoma, a subtype for which lymph node assessment is generally not indicated. Therefore, nodal sampling was not performed. The diagnosis of primary AS confined to the uterus (T1NXM0) was clinically appropriate, though it should be noted that standardized prognostic staging of visceral AS has not yet been established. Previous reports have indicated that tumors >5 cm portend a poor prognosis in uterine AS (3). While adjuvant therapy was recommended, our patient declined this treatment option. Despite an initially favorable postoperative course, early imaging was performed due to the high risk of recurrence and metastasis. This revealed three distinct solid tumors in the abdominal cavity. We postulate that microscopic hematogenous metastases were likely present at the time of surgery despite complete macroscopic resection, leading to early recurrence. This reflects the aggressive biological behavior of uterine AS.

Chemotherapy is generally considered the first-line treatment for metastatic and locally advanced AS (2). In our case, given the presence of atypical tumors in the vascular cavity of the primary uterine AS and the development multiple abdominal tumors hypothesized to be hematogenous metastases, chemotherapy was selected rather than radiotherapy. Anthracycline (5,11,12), paclitaxel (13,14), or gemcitabine (15) based regimens are currently considered first-line treatments, although there is no consensus regarding the optimal chemotherapy regimen for these patients. At the time of treatment decision, evidence-based chemotherapy options were limited; however, paclitaxel-based chemotherapy had shown efficacy in a small number of AS cases. Notably, the ANGIOTAX study investigating cutaneous angiosarcoma demonstrated complete responses with paclitaxel-containing chemotherapy (14). Three previous cases of uterine AS treated with paclitaxel and carboplatin have been reported in the literature (3,6,16). In all these cases, surgery was performed as the primary treatment, with paclitaxel and carboplatin combination therapy administered as adjuvant chemotherapy. Overall survival in these cases ranged from 2–14 months: one patient died from lung metastasis, while the other two patients remained alive with no evidence of disease. Based on these observations, paclitaxel and carboplatin combination therapy appears potentially effective for uterine AS when chemotherapy is indicated. However, this conclusion is limited by the absence of robust retrospective or prospective studies and the small number of documented cases.

In our patient, elevated levels of CA125, LDH, and D-dimer were observed after surgery and at the time of recurrence. These values gradually decreased during chemotherapy and eventually normalized. While previous reports have suggested associations between CA125, LDH, and AS, the literature lacks data regarding their changes following treatment. Konishi et al (6) and Strickland et al (17) reported elevated pre-treatment CA125 levels in cases of uterine AS. Wang et al (18) identified pretreatment LDH levels as an independent prognostic factor for AS through multivariate analysis. These markers, being readily measurable in general clinical practice, may potentially serve as valuable biomarkers for monitoring treatment response and disease status in uterine AS.

In general, the response to chemotherapy for metastatic and locally advanced AS is not sustained. As in this case, the options after remission with taxane-based chemotherapy are limited. Immune checkpoint inhibitors (ICI) have revolutionized treatment in multiple cancer types, but development has been slow due to the heterogeneity of sarcoma types. Recent trials have evaluated various ICI strategies in AS, including ICI monotherapy, combinations with tyrosine kinase inhibitors (TKI), and chemotherapy combinations, with results varying by subtype. The combination of ipilimumab and nivolumab (SWOG S1609, objective response rate, 25%) suggests potential value, but this was limited to cutaneous AS (19). Combination therapies such as cabozantinib and nivolumab (Alliance A091902, objective response rate, 59%) have shown similar responses in cutaneous and non-cutaneous angiosarcoma, suggesting that TKIs may improve responses in tumors that have been resistant to ICIs to date (20). These findings may serve as a reference treatment strategy for future relapses in our patient.

In conclusion, we report a rare case of recurrent uterine AS that achieved complete remission with long-term systemic chemotherapy using paclitaxel and carboplatin. Early detection of recurrence through vigilant follow-up was critical, given the aggressive nature of angiosarcoma. While this case showed a favorable response to chemotherapy, the findings should be interpreted cautiously and may not be generalizable, considering the limitations inherent to a single case report. Despite the lack of standardized treatment protocols for recurrent or advanced uterine AS, our report suggests that paclitaxel and carboplatin combination therapy may represent a viable therapeutic option. Further accumulation of cases and studies is warranted to enhance our understanding and optimize management for this rare and aggressive malignancy.

Acknowledgements

Not applicable.

Funding

Funding: No funding was received.

Availability of data and materials

The data generated in the present study may be requested from the corresponding author.

Authors' contributions

YI, YH and KT conceived and designed the study. YI, YH, AY, MK, KY and KT acquired, analyzed and interpreted the data. YI, YH and KT drafted and revised the manuscript. YK reviewed the pathological specimens. All authors have read and approved the final manuscript. YH and KT confirm the authenticity of all the raw data.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Written informed consent was obtained from the patient for the publication of the case details and associated images.

Competing interests

The authors declare that they have no competing interests.

References