Primary epithelioid angiosarcoma of the vulva: A rare tumor at an unusual site

Abstract

Epithelioid angiosarcoma of the vulva is an exceptionally rare and highly aggressive malignancy originating from endothelial cells. Its etiology remains unclear, though risk factors such as prior radiotherapy and chronic lymphedema have been identified. We report a case of a 44-year-old woman with no significant medical history who presented with a rapidly enlarging, foul-smelling mass on the right labia majora. The tumor measured 30 cm and exhibited central necrosis, ulceration, and bleeding. Radical tumor resection and right inguinal lymphadenectomy were performed, followed by reconstruction using a keystone design perforator island flap and a V-Y advancement flap. Histopathology confirmed a high-grade epithelioid angiosarcoma, positive for ERG, CD31, CD34, podoplanin, EMA, and a Ki-67 proliferation index of 60%. Further treatment consisted of adjuvant radiotherapy (61 Gy) and doxorubicin-based chemotherapy. At one-year follow-up, the patient remained free of recurrence or metastasis. Primary epithelioid angiosarcoma of the vulva is extremely rare, particularly in patients without known risk factors. Management involves radical surgical resection with adjuvant radiotherapy and chemotherapy as indicated. Reporting such cases is essential to enhance understanding and guide evidence-based management of these challenging neoplasms.

Introduction

Angiosarcomas are uncommon, aggressive malignant neoplasms that arise from endothelial cells of blood and lymphatic vessels. They represent about 2% of all soft tissue sarcomas, have locally aggressive behavior, and frequently metastasize. These tumors commonly occur in the head and neck—scalp in particular—the chest, extremities, trunk, liver, heart, bone, and spleen.^1–4

It is a sporadic tumor in the female genital tract with a reported incidence of less than 1%. Among this subset of patients, primary vulvar angiosarcomas are very uncommon entities, having been described in only a handful of patients.^5,6

The symptoms are generally nonspecific and mimic benign or other malignant vulvar disorders, making clinical diagnosis difficult to establish.^6,7 Histopathological assessment with immunohistochemical staining, such as CD31, CD34, and ERG, is required for tumor diagnosis.^8–10

Because of its rarity at this location, there is no evidence-based treatment, and available recommendations for treatment are usually derived from angiosarcomas occurring at other sites.^2,5

Presentation

Patient history

Case: A 44-year-old woman, with a parity of 2, and with no significant past medical history, presented with an enlarging vulvar mass. She initially presented with a lesion on her right labia majora that she had noticed approximately 1 year ago, which did not increase in size until 2 months before presentation, when it began to grow rapidly and provoked discomfort when walking (Figure 1). The patient was referred to computed tomography (CT), magnetic resonance imaging (MRI), fine-needle aspiration (FNA), and core biopsies as a standard tumor work-up. Three months following her initial appointment, she came back for a follow-up visit, and the tumor was ten times bigger (Figure 2).

Figure 1.

Initial presentation of the tumor.

Figure 2.

Follow-up examination after 3 months.

Clinical examination

During the clinical examination, a large, exophytic vulvar mass approximately 30 cm in its greatest diameter was observed on the vulva, involving the right labia majora and minora, vaginal introitus, and mons pubis to the left labia majora. The lesion showed central ulceration with extensive necrosis and was actively bleeding. There was a significant foul-smelling discharge containing blood and necrotic tissue. The size and location of the mass impaired the patient’s mobility, affecting her ability to walk and perform daily activities. On palpation, the mass was firm, non-tender, and fixed to its base. Ipsilateral inguinal lymphadenopathy was noted, while no palpable contralateral inguinal lymph nodes were detected. On vaginal examination, the mass displaced the right vaginal wall but did not invade it. There was no involvement of the urethra or rectum.

Work-up

Preoperative MR imaging revealed invasion of the vagina, the rectus abdominis aponeurosis, and surrounding soft tissues (Figure 3). Cytological examination of the FNA was classified as group 5, strongly suggestive of malignant anaplastic sarcoma, although the tissue of origin could not be definitively determined. Core biopsies failed to provide definitive results despite two attempts due to large areas of necrosis. Because of the rapidly growing lesion and tumor’s large size, active bleeding, and foul smell, we chose not to delay treatment for further diagnostic procedures and proceeded directly with surgery, based on a working diagnosis of sarcoma.

Figure 3.

Preoperative contrast MRI of the pelvis. (a) Sagittal plane and (b) axial plane.

Surgical management

Radical tumor resection and a right inguinal lymphadenectomy were planned using a multidisciplinary surgical approach (a gynecologist and a plastic surgeon). A keystone design perforator island flap (KDPIF) with omega modification for pubic region reconstruction and a pedicled anterolateral thigh (ALT) flap for perineal, vulvar, and vaginal reconstruction were part of the reconstructive plan (Figure 4, photo a).

Figure 4.

(a) Preoperative planning; (b) anterior view; (c) frog leg view (tumor excision and right inguinal lymphadenectomy).

Surgical treatment included wide local excision of the tumor (3 cm margins), which included resection of the right labia majora and minora, partial resection of the left labia majora, mons pubis, aponeurosis of the rectus abdominis, periosteum of the pubic symphysis, and right lateral wall of the vagina (Figure 4 photos b and c). Intraoperatively, gross pathological vascularity was noted, which contributed to both preoperative and intraoperative bleeding issues. Right inguinal lymph node dissection was performed in view of the presence of clinically enlarged lymph nodes and the absence of a definitive diagnosis preoperatively. Intraoperatively, the plan for soft tissue reconstruction was modified after the tumor excision. The vaginal wall was reconstructed with direct suture, obviating the need for a pedicled ALT flap. The soft tissue defect measured 550 cm² and was reconstructed using 2 perforator-based fasciocutaneous flaps: vulvar reconstruction was performed using a V-Y advancement flap from the right medial inner thigh. A large keystone flap was advanced to cover the defect in the pubic area (Figure 5).

Figure 5.

Reconstruction of the defect with KDPIF omega modification and V-Y advancement flap. (a) Anterior view; (b) frog leg view.

Histopathological findings

The specimen weighed 3580 grams, the tumor measured 24.5 x 23.5 x 21 cm, and the surface showed skin ulceration measuring 9 x 6.5 cm. The surgical margins on fixed material were: 1.1 cm-1.4 cm on lateral, upper, and lower resection margins, 0.5 cm from the nearest medial resection margin (vaginal wall), and the deep resection margin was 1 mm (periosteum of pubic bones), signifying extensive local invasion.

Microscopy revealed a malignant mesenchymal neoplasm, partially ulcerated and covered by stratified squamous epithelium, infiltrating the papillary and reticular dermis with dilated, congested vessels. The non-encapsulated, hypercellular lesion comprised polygonal to spindle-shaped cells with eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli. Rare, atypical cells with hyperchromatic nuclei and areas of solid, diffuse growth with focal vascular channel formation were identified.

Immunohistochemical staining was positive for ERG, CD31, CD34, Podoplanin, and EMA, and negative for SMA, Desmin, S-100, CD68, AE1/AE3, and HHV-8. The Ki-67 proliferation index was 60% in hotspots, and the mitotic index was 6-7 mitoses per 10 high-power fields.

The specimen from the lymphadenectomy revealed 4 lymph nodes with diameters of 1.1 cm to 1.9 cm, and microscopic analysis of the nodes showed reactive changes without a neoplastic substrate.

Adjuvant treatment

Post-operatively, the patient’s recovery was satisfactory, and good healing of the reconstructed site was observed. Two months after surgery, adjuvant treatment with chemo and radiotherapy was conducted: the patient received 61 Gy of radiotherapy and doxorubicin monotherapy (6 cycles 70mg/m² q 21 days). The patient had excellent compliance with oncological treatment with no adverse side effects reported.

Follow-up

The flaps used for reconstruction are durable and structurally intact after radiotherapy (Figure 6). No local recurrence or metastasis observed clinically and radiographically at 1-year follow-up: magnetic resonance imaging of the pelvis at 1 year after surgery showed no radiological signs of local recurrence, and PET-CT showed no evidence of distant metastasis (Figure 7). Regular follow-up of the patient is continued every 3 months.

Figure 6.

One year follow-up. (a) Anterior view; (b) frog leg view.

Figure 7.

Pelvic MRI with contrast one year post-operatively. (a) Sagittal plane; (b) axial plane.

Discussion

Wagner et al. evaluated the incidence of angiosarcoma, demographics, and extent of disease at presentation in all reported patients with a new diagnosis of angiosarcoma in the USA from 2001 to 2020 (n = 19,289). Visceral angiosarcomas were reported in 24.4% (n = 4,701), of which 2.2% (n = 102) were found in the female reproductive system. ¹¹ An evidence-based historical review by Sheinis et al. and Stolnicu et al. found that the publication on cases of vulvar angiosarcoma was so scant that it is likely to be one of the rarest types of cancer at this location.^7,12 While exact risk factors remain incompletely described, several associations have been reported, including chronic lymphedema, a history of radiotherapy to the area, exposure to foreign material or substances, prior trauma or surgery and specific hereditary cancer syndromes.^3,13,14 Of particular interest, our case had no obvious risk factors.

Most published case reports of vulvar angiosarcoma are associated with previous radiotherapy or other risk factors (Table 1). To date, two documented cases of primary vulvar angiosarcoma in healthy patients have been reported, and the epithelioid subtype has been histologically and immunohistochemically confirmed in only one of these cases.^7,15 Sheinis et al. described a case of primary multifocal angiosarcoma of the vulva without reporting the relevant medical history, and in the report of Lafever et al. previous surgical interventions were noted (incision and drainage, and hysterectomy, and bilateral salpingo-oophorectomy) that may represent a potential risk factor.^12,14,16

Table 1.

Reported cases of vulvar angiosarcoma (2003-2021).

Author, year	Age (yrs)	Risk factors	Location on the vulva	Tumor size (cm)	Histologic type	Immunohistochemistry	Treatment	Recurence/metastasis	Follow up	Outcome
Our case	44	None	Right labia majora extending to mons pubis	24.5 x 23.5 x 21 cm	Epithelioid angiosarcoma	ERG+, CD31+, CD34+, Podoplanin+, EMA+; Ki-67 60%, SMA−, Desmin−, S-100−, CD68−, AE1/AE3−, HHV-8−	Radical excision; Adjuvant doxorubicin and radiotherapy	None	12	NED
Stolnicu et al. 2021 7	43	Primarly misdiagnosed as angiofibroma	Left labia majora	Primary lesion: fragments 1.5–4.2 cm; recurrence lesion: 6 cm	Poorly differentiated angiosarcoma	CD31+, Vimentin+, EMA+; Desmin−, S100−, Myogenin−, SMA−	Surgical excision; referred to oncology; adjuvant details NR	Local recurrence after 3 years	36	AWD
Sheinis et al. 2016 12	64	NR	Vulva (not specified)	2.2 cm	Multifocal angiosarcoma	CD31+, D2-40+, ERG+; HHV-8−, TFE-3−	Vulvectomy + bilateral inguinal lymphadenectomy; paclitaxel, nab-paclitaxel,radiation, gemcitabine	1st recurrence: 3 weeks (vulva + left obturator LN); 2nd recurrence: 4 months; metastasis to bone; 1 of 5 inguinal LN positive	24	AWD
Das & Sonowal 2021 15	40	None	Mons pubis to left labia majora	10 × 10 × 4 cm	Epithelioid angiosarcoma	CD31+, Vimentin+, EMA+; Desmin−, S100−, Myogenin−, SMA−	Surgical excision	NR	NR	NR
Lafever et al. 2014 16	67	Prior melanoma; two incision and drainage procedures on vulvar lesions prior to diagnosis; total abdominal hysterectomy with bilateral salpingo-oophorectomy	Multifocal: mons, bilateral labia majora	Multiple: 0.5, 1.8, 2.5 cm	High-grade angiosarcoma	CD31+, CD34+	Paclitaxel adriamycin, bevacizumab, valproic acid, radiation	Disseminated at diagnosis (liver, pancreas, kidney)	<12	DOD
Yost et al. 2017 4	90	Post-radiation + lymphedema	Labia majora extending to mons pubis	20 × 10cm	Grade 2 epithelioid angiosarcoma	CD31+, ERG+, Vimentin+; CD34−	Declined (hospice)	No treatment given	NR	AWD
Mayer et al. 2021 17	65	Post-radiation	Labia majora, left mid-lateral predominant	2 cm nodules, bilateral involvement	High-grade angiosarcoma	CD31+, C-MYC+, Ki67 elevated; Pancytokeratin−	Radical bilateral vulvectomy	NR	13	NED
Guirguis et al. 2007 18	74	Post-radiation	Mons pubis	NR	Epithelioid angiosarcoma	NR	Surgical resection	Recurrence at 6 months; metastatic disease	>6	AWD
Kondi-Pafiti et al. 2003 19	76	Post-radiation	Mons pubis, with extension to labia majora	14 × 12 cm	High-grade angiosarcoma	Vimentin +; Factor VIII +	Extensive surgical excision	None at 1 year	12	NED

Abbreviations: yrs = years; cm = centimeters; NR = Not reported; DOD = Died of disease; AWD = Alive with disease; NED = No evidence of disease.

Epithelioid angiosarcomas characteristically express endothelial markers including CD31, ERG, CD34 (often variable), Factor VIII, and Podoplanin (D2-40 in subsets), with high proliferative indices such as elevated Ki-67 (>50% hotspots) and increased mitoses (typically >5/10 HPF). They lack melanocytic (S-100, HMB-45, Melan-A), epithelial (AE1/AE3, usually EMA), smooth muscle (SMA, Desmin), histiocytic (CD68), and HHV-8 markers, distinguishing them from melanoma, carcinoma, leiomyosarcoma, histiocytic tumors, and Kaposi sarcoma. This immunoprofile, combined with epithelioid morphology, confirms the diagnosis of high-grade epithelioid angiosarcoma.^9,20

Gessi et al. detected HHV-8 in angiosarcoma tissue via in situ hybridization and PCR, suggesting an association with angiosarcoma. ²¹ However, Schmid and Zietz’s subsequent study of 40 independent angiosarcomas, including vulvar cases, demonstrated that HHV-8 was not detectable in the tumor tissue. ²²

The rapid progression observed in aggressive epithelioid angiosarcoma is driven by abnormal endothelial proliferation, dysregulated angiogenesis, activation of oncogenic pathways, and a highly infiltrative phenotype, all of which were evident histologically and morphologically in our case. Together, these findings define a highly aggressive neoplasm with strong potential for recurrence or metastasis and a poor prognosis. ²³

Radical surgical excision is the most appropriate approach for the complete removal of these aggressive and infiltrative tumors, allowing for local disease control and prevention of recurrence. Achieving R0 resection significantly reduces the risk of tumor regrowth and improves survival. ²⁴

Sarcoma resection creates large soft tissue defects due to wide oncologic margins. Reconstruction prioritizes stable coverage, protection of vital structures, preservation of function, aesthetics, low donor morbidity, and support for adjuvant therapy. In pelvic cases, it focuses on urinary/sexual function and quality of life using versatile, low-morbidity perforator flaps (single or multiple) for challenging defects while retaining pliability.^25,26

The keystone perforator island flap is increasingly used in sarcoma reconstruction for its reliable vascularity, simplicity, and versatility, while the V-Y island flap from the thigh is a well-established technique for vulvar reconstruction following oncologic resection or extensive defects, offering reliable vascularity based on perforator vessels, minimal donor site morbidity, and good aesthetic and functional outcomes.^27–31

Sarcomas most often metastasize through hematogenous routes; however, certain histological subtypes, including rhabdomyosarcoma, epithelioid sarcoma, clear cell sarcoma, and angiosarcoma, tend to spread via the lymphatic system. ²⁴ Involvement of regional lymph nodes has been reported in 10% to 40% of angiosarcoma cases. Chan et al. documented lymph node metastases in approximately 23% of 150 patients with analyzed angiosarcoma. ³²

In our case, a right-sided lymphadenectomy was performed because of palpable lymph nodes and their proximity to the primary tumor. The decision to proceed with lymphadenectomy was influenced by the tumor’s large size, necrotic and bleeding characteristics, and closeness to regional lymphatic pathways. This approach aligns with the current understanding that, in high-risk, large, or necrotic tumors, lymphadenectomy enhances local control and provides valuable staging information to guide adjuvant therapy decisions. ²⁴

Adjuvant chemotherapy combined with radiotherapy is used to target microscopic tumor foci that cannot be eliminated by surgical resection alone.^4,12,23 Most commonly used drugs include taxanes and anthracyclines such as paclitaxel and doxorubicin. Paclitaxel is the standard first-line chemotherapy for epithelioid angiosarcoma, including vulvar forms, in both localized and metastatic disease. Doxorubicin may be used as an alternative or in combination regimens. ³³ Combination regimens include carboplatin-paclitaxel-pembrolizumab for advanced disease, doxorubicin-cyclophosphamide-paclitaxel for aggressive cases, and gemcitabine-docetaxel when paclitaxel is contraindicated.^2,34–38

Adjuvant radiation therapy for angiosarcoma typically involves delivering a total dose of 60-70 Gy in daily fractions of 2.0-2.5 Gy over 6 to 7 weeks, using modern techniques such as intensity-modulated radiation therapy (IMRT) to maximize local control while reducing toxicity. This method is especially recommended for high-grade tumors, positive or close margins, and large or deeply invasive lesions, often combined with chemotherapy to improve outcomes. ³⁹

There are no published formal clinical practice guidelines from major organizations (NCCN, ESMO, ASCO) specifically addressing neoadjuvant therapy for angiosarcoma. Heinhuis et al.’s systematic review shows neoadjuvant chemotherapy downsizes tumors, enables negative margins, and reduces surgical morbidity across sites. ⁴⁰ Though unreported for vulvar angiosarcoma, neoadjuvant radiotherapy is reasonable in advanced cases for sarcoma and vulvar carcinoma guidelines to downstage the disease and improve outcomes. ⁴¹

For patients who are not candidates for surgical resection, multimodal systemic therapy comprising chemotherapy, radiotherapy, and/or immunotherapy may be used as a palliative measure. Nevertheless, the evidence supporting these non-surgical approaches is limited, particularly for vulvar angiosarcoma, and such treatment decisions should be individualized based on patient performance status and disease characteristics.^41–43

The optimal management of angiosarcomas currently involves radical surgical resection with wide margins, complex reconstruction, and adjuvant chemoradiotherapy.^33,39

The survival statistics for epithelioid angiosarcoma of the vulva are poor, with over 50% of patients being deceased within 12 months of diagnosis, and the estimated 5-year overall survival is less than 30%. High mitotic rate and grade, as well as positive surgical margins, are associated with increased recurrence and mortality. These underscore the aggressive nature of this malignancy and the importance of early diagnosis and intensive multimodal therapy.^5,17 In our case, on a one-year follow-up, the patient showed no evidence of locoregional recurrence or distant metastasis.

Conclusion

This case report presents the successful treatment of an uncommon and aggressive vulvar epithelioid angiosarcoma using radical surgery, complex reconstruction, and adjuvant chemoradiotherapy. The report highlights key aspects of managing rare and aggressive tumors, including the importance of early detection despite diagnostic challenges, the necessity of aggressive surgical procedures with appropriate reconstruction, the need for multimodal treatment, and the value of a collaborative approach to enhance patient outcomes. Further research and reporting of similar cases are essential for developing evidence-based guidelines for managing these tumors.