Kaposiform hemangioendothelioma (KHE) is a vascular tumour of intermediate malignancy [1]. The prevalence of KHE is approximately 0.91 per 100,000 children, with a slight male predominance. KHE manifests in infancy in 93% of cases, and in 60% of patients, onset occurs during neonatal period [2]. The most common locations are the extremities, followed by the trunk and the head-face-neck regions [2–4]. Visceral involvement- such as the thymus, mediastinum, and spleen - has been reported less frequently [5]. The clinical presentation of KHE is heterogenous and depends mainly on tumour location, size, and associated complications. Laboratory evaluation, including coagulation tests and a complete blood count, is essential in all suspected cases. Between 50% and 70% of patients develop

Kasabach-Merritt phenomenon (KMP) - a potentially life-threatening consumptive coagulopathy with thrombocytopenia and hypofibrinogenemia - with a reported mortality of up to 30%. Thus, early identification and initiation of treatment are critical [2]. KHE is often misdiagnosed as other vascular tumours or malformations, including tufted angioma, infantile, congenital, verrucous malformations/haemangioma, spindle cell haemangioma, or Kaposi sarcoma which also occurs in children [5].

While surgical resection was considered the definitive treatment, it is often not feasible due to the tumour’s infiltration across tissue planes and the associated risk of bleeding. Other treatment options have included vincristine, corticosteroids, propranolol, interferon, and radiotherapy. Since 2010, numerous reports have documented successful treatment with sirolimus. Most recently, Chinese experts published diagnostic and therapeutic guidelines for KHE [6]. However, it should be noted that these guidelines have not been extended to other countries [7].

We present a case of infantile KHE with complete remission following oral sirolimus therapy. This case underscores the efficacy of sirolimus and highlights the importance of a multidisciplinary approach in managing this complex and potentially life-threatening condition.

A 7-month-old male presented with expanding mass in left popliteal fossa was admitted to the Department of Oncology, Paediatric Haematology, Clinical Transplantology and Paediatrics of the Children’s Clinical Hospital of the University Clinical Centre of the Medical University of Warsaw, due to suspected neoplastic disease.

An infant with trisomy 21, from the gravida 4, para 3, was born via spontaneous vaginal delivery, at 40 weeks of gestational age, with a birth weight of 2900 grams. Apgar scores were 9-9-9-10. Shortly after birth, the infant experienced episodes of oxygen desaturation and respiratory distress. Echocardiography identified a peri membranous ventricular septal defect. A surgical repair of the cardiac defect was performed at 4 months of age. During the postoperative period, the patient developed pulmonary hypertension treated with inhaled nitric oxide. Follow-up echocardiograms revealed normal chamber dimensions and preserved biventricular systolic function.

At 8 months of age, the patient was admitted to our department. On physical examination, he presented with characteristic phenotypic features of trisomy 21, a midline thoracic scar consistent with previous cardiac surgery and a firm, immobile mass (about 40mm x 35 mm) was noted under the left popliteal fossa, with overlying skin cyanosis. Additionally, a flexion contracture of the left knee exceeding 15 degrees was observed. Laboratory testing showed no haematological features suggestive of KMP. Ultrasound imaging identified an intratissue lesion of increased echogenicity and moderate internal vascularization on colour Doppler. Magnetic resonance imaging (MRI) demonstrated a poorly defined lesion (33.9mm x 31.2 mm) involving the skin of the popliteal fossa, with infiltration into the semitendinosus and semimembranosus muscles. No evidence of bone involvement was noted [Figure 1, 2]. Histopathological analysis of a biopsy of the lesion confirmed the diagnosis of KHE, characterized by nodular vascular formations resembling capillary haemangiomas. Immunohistochemical staining demonstrated positivity for CD34, CD31, FL-1, ERG, and focal positivity for D2-40, while staining for Glut-1 was negative. The Ki-67 proliferation index was estimated at 1–2%. Overall, the findings were consistent with KHE involving the soft tissues of the left popliteal region, with infiltration of adjacent muscle structures, in the absence of bone involvement and without evidence of KMP at the time of diagnosis.

Sirolimus therapy was initiated at a dose of 0.8 mg/m²/dose twice a day to maintain trough levels 5–15 ng/ml [Figure 3]. Simultaneously, the patient has been receiving ongoing physiotherapy as part of a multidisciplinary approach to care. Within two months of initiating therapy, ultrasound imaging revealed a marked reduction in lesion size (13 mm × 4 mm × 28 mm), accompanied by marked improvement in joint contracture. The child experienced no severe toxicity related to sirolimus. The therapy was well tolerated, with no severe adverse events. The only noted toxicity was transient grade 1 hypertriglyceridemia, classified according to Common Terminology Criteria for Adverse Events (CTCAE v5.0).

MRI performed after four months of therapy confirmed complete remission, and sirolimus therapy was successfully discontinued. Full mobility in the left knee joint was restored. The patient has been followed clinically at three-month intervals for the past nine months, with no evidence of disease recurrence and sustained clinical well-being.

The International Society for the Study of Vascular Anomalies (ISSVA) provides an internationally accepted classification system for VAs, most recently updated in 2025. These are broadly divided into two categories: vascular tumours, which include proliferative changes of endothelial cells, and vascular malformations, which are structural vascular abnormalities lacking proliferative features [1].

KHE, initially introduced by Zukerberg et al in 1993, is locally aggressive/borderline vascular neoplasm [8]. The term reflects its morphological resemblance to Kaposi sarcoma (“kaposiform”) and its borderline malignant behaviour (“haemangioendothelioma”) [5]. KHE often infiltrates across tissue planes, involving the dermis, subcutaneous tissue, fascia, muscle, and occasionally bone.

In our patient, the diagnosis of KHE was confirmed through histopathological examination. Definitive diagnosis requires identification of infiltrative nodules composed of fascicles of spindle-shaped endothelial cells and slit-like vascular channels with irregular tumour margins. Immunohistochemical staining is also supportive, with positive markers including D2-40, CD31, CD34, VEGFR-3, hyaluronan-1, and Prox-1, and negative staining for Glut-1 [9].

Early diagnosis and prompt treatment are crucial for improving outcomes of patients with KHE. Due to the broad clinical spectrum and lack of standardized treatment regimens, management of VAs is complex, necessitating a multidisciplinary team approach. This often includes paediatricians, haematologist-oncologists, radiologists, surgeons, pathologists, anaesthesiologists, and physiotherapists.

While surgical resection was considered the gold standard for definitive treatment, it is often not feasible due to the infiltrative nature of the lesion and risk of profuse bleeding. Moreover, treatment of KHE has included high-dose steroids, chemotherapy (e.g., cyclophosphamide), antiplatelet therapy (e.g., aspirin), propranolol, embolization, radiotherapy, and sclerotherapy. In 2013, consensus treatment statements by Drolet et al. proposed a combination regimen of vincristine and corticosteroids for complicated KHE with KMP, and oral corticosteroids alone for KHE without KMP [10]. However, due to relevant side effects of corticosteroids and vincristine with prolonged or recurrent hospitalizations for treatment in neonates, inconsistent rates of complete remission, there was need to look for new, more target-specific therapeutic agents.

In recent years, sirolimus, used “off-label” in patients with VAs, has shown increasing promise.

Sirolimus is a macrolide antibiotic originally isolated from Streptomyces hygroscopicus found in soil samples from Easter Island (Rapa Nui, hence the name "rapamycin”). It inhibits the mammalian target of rapamycin (mTOR), a serine-threonine kinase, suppressing cellular proliferation and lymphocyte activation by blocking the G1 phase of the cell cycle. Initially developed as an immunosuppressant for solid organ transplantation, sirolimus has since found application in oncology and VAs. A systematic review by Schmid et al. involving 215 KHE patients concluded that sirolimus should be considered a first-line therapy for patients with KHE in treatment of KMP and reducing tumour size [4, 11]. At present, according to the KHE expert consensus panel in China, the preferred treatment of unresectable KHE is monotherapy with sirolimus. For patients with KHE who do not respond to sirolimus in combination or without corticosteroids, the use of vincristine in combination with or without corticosteroids may be considered as potential treatment option [7]. Further support comes from Wang et al., who claimed that sirolimus is efficacious and well tolerated in KHE patients [3]. On the other hand, results of multicentre cohort study in the USA suggested that individualized treatment decision depends on clinical scenario and patient/physician preferences. They observed no significant difference in therapy response or durability of disease comparing sirolimus and vincristine regimens [12]. Prospective trials are still needed to directly compare sirolimus monotherapy with other combined therapies.

Sirolimus oral formulation and favourable benefit-risk profile make it an attractive therapeutic option. Moreover, serum trough levels can be monitored, which allows for well-controlled therapy. Reported trough ranges typically fall between 5–15 ng/mL, with 10–15 ng/mL being the most targeted [3, 11]. However, lower trough levels (4–6 ng/mL) may be adequate for infants to improve safety [13]. In our patient, as reported by Wang et al. [3], the initial sirolimus plasma level was elevated but stabilized within the first month of therapy [Figure 3].

When surgical biopsy is performed, according to Chinese consensus statement sirolimus initiation should be postponed until the wound has healed to avoid any interference with tissue regeneration [7]. However, Mehl et al., in a retrospective cohort study, reported that sirolimus administration at lower concentrations (mean 6.5 ng/mL) may not significantly increase perioperative complication rates in paediatric patients undergoing resection of vascular anomalies [14]. This suggests that sirolimus concentration may be a potential variable influencing wound healing.

The overall safety profile of sirolimus is favourable [3]. In a study by Roessler et al., the most frequently observed severe adverse event (SAE) was viral pneumonia. The authors noted that some SAEs may be related to preexisting immunodeficiency, for example, due to low immunoglobulin levels [15]. Similarly, Qiu et al. reported that the most common SAE leading to temporary treatment interruption was pneumonia, followed by upper respiratory tract infections, mucositis, and elevated liver transaminase levels. Interestingly, prophylactic use of trimethoprim-sulfamethoxazole did not reduce infection incidence [16]. On the other hand, there are isolated reports in the literature of Pneumocystis jirovecii infection, primarily among patients receiving concurrent corticosteroid therapy [15]. More commonly, sirolimus is associated with transient dyslipidaemia, including hypertriglyceridemia and hypercholesterolemia, although these do not reach severe levels [16]. Our patient developed mild, transient hypertriglyceridemia without requiring treatment interruption.

Importantly, our patient showed a rapid response to sirolimus in terms of both tumour size reduction and restoration of motor function. Sirolimus was discontinued nine months ago, and no rebound tumour growth has been observed. Complete remission was achieved after a relatively short four-month course of therapy, with parallel progress in psychomotor development.

Due to the heterogeneous nature of KHE clinical presentation, no clear treatment guidelines currently exist, although rapid therapeutic intervention is often required to mitigate associated complications. Current evidence supports sirolimus as an effective, well-tolerated, and easy-to-administer drug that may be considered a first-line treatment option. However, the role of sirolimus in terms of dosage and therapy duration is yet to be defined. Clinicians and families should be aware of potential infectious and metabolic side effects, and therapy should ideally be managed in specialized centres with multidisciplinary expertise.