A Hemorrhagic nodule in a patient with chronic lymphedema

An 84-year-old woman with elephantiasis nostras verrucosa (ENV) presented with a one-year history of verrucous papules on the lower extremities and a one-month onset of a rapidly evolving tender bleeding nodule on the right leg. Her medical history included hypertension and type 2 diabetes. Her course of lymphedema was complicated by a prior Pseudomonas aeruginosa infection of the right leg that was managed with oral antibiotics and routine wound care. The patient denied fatigue, fever, chills, night sweats, and a family history of malignancy. Physical examination revealed non-pitting edema of both lower extremities with pedunculated, coalescing verrucous papules on the medial posterior legs (Figure 1a). Over the pretibial region of the right leg, there were erythematous-violaceous indurated plaques and a hemorrhagic nodule (Figure 1b). A skin biopsy of the hemorrhagic nodule was obtained and revealed ulcerated tissue with an ill-defined nodule composed of anastomosing vascular channels, erythrocyte extravasation, and high mitotic activity (Figure 2). Immunohistochemistry (IHC) was positive for ERG and CD31, with a Ki-67 index of 50%, and negative for HHV-8 and SOX-10. Your diagnosis? … Diagnosis: Stewart-Treves syndrome In this case, our patient presented with a longstanding history of chronic lymphedema secondary to ENV, which is a chronic and progressive non-filarial lymphedema that classically involves the lower extremities, and is associated with malignancy.1 The clinical presentation of ENV begins with indurated plaques with a cobblestone appearance and progresses to verrucous papules. In later stages of disease, the affected regions develop a mossy appearance with crusting and ulceration. ENV results from chronic lymphostasis, causing a diminished immune response, hyperosmotic interstitial fluid accumulation, and fibroblast proliferation, leading to fibrosis of the dermis and subcutaneous tissues. Factors such as elevated body mass index and diabetes further exacerbate pre-existing lymphedema. Persistent lymphostasis may also lead to recurrent bacterial infections and, in rare cases, malignant transformation. Currently, no guidelines exist for treating ENV, and therapy is focused on controlling lymphedema via compression therapy and mechanical elevation of the lower extremities.1, 2 The malignant transformation of endothelial cells in chronically lymphedematous tissue that results in epithelioid angiosarcoma is referred to as Stewart-Treves syndrome (STS).3 The classic presentation of STS includes women with breast cancer following mastectomy and lymph node dissection; however, Milroy's disease, ENV and filarial lymphedema may also give rise to malignancy.4 STS accounts for approximately 5% of all angiosarcomas and manifests as coalescing nodules or indurated plaques, peaking incidence between the fifth to seventh decade of life.5 The differential diagnosis for STS includes epithelioid hemangioendothelioma (EHE), Kaposi sarcoma (KS), and amelanotic melanoma. Differentiation from intermediate-grade vascular tumors relies on clinical history, physical exam, histopathology, and molecular markers. STS is rapidly progressive, with histologic assessment revealing increased mitotic activity, tissue necrosis, and ulcerations (Figure 2a).4 Histopathologic blood vessel formation displays a diverse range, from well-defined anastomosing vessels to layers of high-grade epithelioid or spindled cells lacking clear vessel formation (Figure 2b).4, 6 In contrast, EHE is an indolent vascular neoplasm with low mitotic activity, nuclear pleomorphism, and positive CAMTA1 or TFE3 IHC stain.4 KS carries risk factors including countries of endemic origins, solid-organ transplantation, or human immunodeficiency virus (HIV) infection, and the underlying etiology is driven by human herpresvirus-8 (HHV-8).7 Lastly, dermoscopy and SOX-100 IHC stain is utilized to exclude amelanotic melanoma from the differential diagnosis.8 Therapeutic approaches for STS aim to minimize spread of disease and improve survival rates. In the absence of metastatic disease, radical resection or limb amputations are recommended due to improved survival outcomes.3, 9 However, delayed diagnosis, advanced age, and rapid progression to metastatic disease limit surgical intervention, with chemotherapy and/or palliative radiotherapy reserved for metastatic disease. Despite interventions, patients have a poor prognosis, with a median survival range of four to twenty-seven months.9 In the presented case, follow-up non-contrast MRI of the right leg showed an ulcerating nodular mass extending into the adipose tissue and superficial fascia, measuring 5.6×3.6 cm. Non-contrast CT imaging of the chest and abdomen revealed three metastatic lung nodules. Given advanced malignant disease and perioperative risks of hip disarticulation, the patient elected to proceed with palliative radiotherapy. As highlighted in this report, ENV is a chronic condition that requires close monitoring. Chronic lymphostasis increases the risk of recurrent infections and malignancy, emphasizing the need for regular surveillance and timely biopsy of atypical lesions to enable timely intervention and reduce the risk of metastatic disease. We would like to thank the patient for providing informed consent for publication of this case. This study was not supported by any funding sources. None.