Radiation-Induced Angiosarcoma in a Patient With Klippel-Trenaunay Syndrome: A Case Report

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Klippel-Trenaunay syndrome (KTS) is a rare vascular disorder that typically presents in the lower limb with unilateral port-wine discoloration of the skin due to capillary malformations, varicose veins, and soft tissue and bone overgrowth.¹ The arteriovenous malformations associated with KTS pose a risk for acute events, including venous thromboembolism, as well as chronic conditions including pulmonary artery hypertension and abnormal lymphatic drainage.^2,3 Management for KTS typically follows a conservative approach consisting of compression for varicosities and laser therapy for stained skin.^1,4

Recent advancements have related KTS to non-inherited somatic mutations in the PIK3CA gene.⁵ Mutations in this gene are responsible for a group of tissue overgrowth syndromes.⁵ KTS pathogenesis has also been linked to increased angiogenesis through mutations in the angiogenic factor gene VG5Q (also known as AGGF1).⁶ Mutations in this gene have been identified that either increase transcription or highly enhance the angiogenic effects of the gene product.⁷

Radiation-induced angiosarcoma (RIAS) is a rare vascular malignancy that develops as a long-term complication secondary to radiation therapy.⁸ In the breast, RIAS manifests after a 5- to 6-year latency period.² Due to its rarity, there is no consensus on ideal RIAS treatment, but most literature emphasizes mastectomy and surgical excision with or without adjuvant chemotherapy and/or radiation.^8,9 With increasing rates of lumpectomy and adjuvant radiation as a breast-conserving alternative to traditional mastectomy, RIAS has become more prevalent over the past several decades¹⁰.

While there is no well-established direct relationship between KTS and development of angiosarcoma, there is literature that suggests a logical association between the disorders. First, there is an established link between KTS and cancer. Specifically, there are reports of skin tumors developing in KTS-affected areas due to venous ulcers related to the damaged veins.² Other reports have highlighted spontaneous angiosarcoma formation within a hemangioma/vascular malformation.¹¹ Further studies have documented the malignant transformation of vascular malformation into angiosarcoma despite surgery and radiation,¹² while other articles have shown that angiosarcoma can arise within an area of chronic lymphedema following mastectomy or radiation.¹³ This evidence, considered in the context of the pathogenesis of both KTS and RIAS, suggests a possible correlation.

The present report documents the development of a radiation-induced angiosarcoma in a 51-year-old female patient with KTS, treated by mastectomy, excision, and successful 2-stage latissimus dorsi flap with implant reconstruction and an uneventful recovery.

A 51-year-old female with a history of KTS (Figure 1) was referred to the plastic surgery clinic in January 2022 for delayed breast reconstruction following RIAS of the left breast. In 2016, she was diagnosed with invasive lobular carcinoma of the left breast by core needle biopsy for which she underwent lumpectomy followed by radiation. In 2021 she noticed a new mass with bruising over her prior incision site and was diagnosed with RIAS upon biopsy. She then underwent left mastectomy and removal of prior cosmetic breast augmentation implant followed by re-excision of mastectomy flaps for a 4.5-cm RIAS mass and adjuvant chemotherapy. The patient healed without complication from mastectomy and resection of the RIAS and presented to the plastic surgery clinic with no evidence of current disease. Prior surgical history included hernia repair (2004), subpectoral saline implant-based breast augmentation (2008), dilation and curettage (2019), and cardiac ablation (2019) in addition to the procedures described above.

Figure 1. Port-wine discoloration of the skin as a result of arteriovenous malformations secondary to Klippel-Trenaunay syndrome.

Of note, this patient experienced severe body dysmorphia after her mastectomy and RIAS excision due to the absence of her left breast juxtaposed with her large right breast augmentation. After shared decision making with the patient, it was decided that a 2-stage left latissimus dorsi musculocutaneous flap reconstruction with silicone implant would best achieve her goal of symmetry (Figure 2). 

Her reconstructive process began with a left breast latissimus dorsi musculocutaneous flap reconstruction and placement of a tissue expander (TE). Tissue expansion began 1 month post reconstruction. The TE was expanded to 200 mL over 2 months but was not expanded further due to tightness. Approximately 3 months after her first surgery, the patient was brought back to the operating room for TE to implant exchange as well as right breast mastopexy, right breast capsulorrhaphy, and right breast implant exchange (saline to silicone) for symmetry. The patient tolerated the procedure well and left the operating room in stable condition.

Postoperative course was uneventful.

Figure 2. (A) Preoperative photo, (B) One-month post-first-stage reconstruction photo, (C) Three-month post-second-stage reconstruction photo.

Due to the rarity of both KTS and RIAS, it is unsurprising that there is a paucity of literature documenting patients with both conditions. However, the abnormal angiogenesis and vasculature associated with KTS, coupled with radiation therapy, could have contributed to malignant transformation into angiosarcoma in this patient. 

Although there is no extensive documentation on the relationship between KTS and angiosarcoma, there are a handful of case reports that present the occurrence of angiosarcoma in KTS patients. In 2022, a primary pleural angiosarcoma was reported in a 17-year-old woman with KTS and PIK3CA gene mutations.¹⁴ Another report details a 49-year-old woman with KTS who presented with angiosarcoma of the breast without radiation therapy.¹⁵ A case of angiosarcoma was also reported in the leg of a 22-year-old man with KTS and associated chronic lymphedema.¹⁶ The present case report taken together with this collection of KTS and angiosarcoma occurences highlights the importance of further research into a potential connection between these 2 rare disorders.

Angiosarcoma is a very aggressive malignancy with an unfavorable patient prognosis. RIAS has a 5-year survival of only 28% to 54% with a high recurrence rate.⁸ With the high rate of local recurrence of angiosarcoma, follow-up and monitoring of the local sites is critical in managing a patient’s care. Regular computed tomography scans allow for visualization of the potential recurrence sites beneath a patient’s reconstructed breast. The patient described had a nice recovery, and the management of the RIAS was well handled by mastectomy followed by a favorable reconstructive result. Early identification, aggressive treatment, and consistent follow-up likely contributed to the patient’s positive course.

Breast reconstruction post-RIAS mastectomy presents unique challenges due to a lack of viable tissue. It is crucial that RIAS patients understand that the goal of RIAS resection is to remove as much tissue as possible due to the life-threatening nature of angiosarcoma.¹⁷ In general, the combination of implant-based and autologous reconstruction is indicated for conditions where patients lack sufficient tissue and is commonly used in patients with low BMI.^18,19 In this case, our patient lacked enough tissue to match her large right breast, and reconstruction utilizing the 2-stage tissue expander along with autologous tissue allowed for safe and modifiable enlargement of the breast in order to restore symmetry and achieve the desired cosmetic appearance.

While radiation-induced angiosarcoma and arteriovenous malformations such as KTS are distinct conditions, a link may exist between the 2. More research is needed to investigate this possible relationship. Aggressive treatment of RIAS is crucial for patient recovery, and a 2-stage latissimus dorsi flap with implant reconstruction is an optimal choice for post-RIAS mastectomy reconstruction, especially in patients hoping to achieve a large breast size.