Successful Management of Kaposiform Hemangioendothelioma with Long-Term Sirolimus Treatment: a Case Report and Review of the Literature

Matteo Chinello¹, Daniela Di Carlo², Francesca Olivieri², Rita Balter¹, Massimiliano De Bortoli¹, Virginia Vitale¹, Ada Zaccaron¹, Elisa Bonetti¹, Alice Parisi³ and Simone Cesaro¹.

1 Pediatric Hematology Oncology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
² Mother and Child Department, University of Verona.
³ Department of Pathological Anatomy, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.

Corresponding author: Matteo Chinello, M.D. Pediatric Hematology Oncology, Azienda Ospedaliera Universitaria Integrata, Piazzale A. Stefani 1, 37126, Verona, Italy. Fax: +390458127887, Tel: +390458127816. E-mail:

Published: July 1, 2018
Received: April 25, 2018
Accepted: June 15, 2018
Mediterr J Hematol Infect Dis 2018, 10(1): e2018043 DOI 10.4084/MJHID.2018.043
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Background: Kaposiform Hemangioendothelioma (KHE) is a rare vascular tumour of the infancy and the first decade of life. It is locally aggressive and potentially life threatening when associated with consumptive coagulopathy, known as Kasabach-Merritt syndrome (KMS). No consensus or guideline for the therapy has been reached because of the lack of prospective trials, and the different standard care suggestions are based on retrospective case series.
Case report: We report the case of a 9-month-old male with KHE and KMS in which the initial response, obtained with prednisone and vincristine, was subsequently consolidated and strengthened by long-term treatment with sirolimus, a mTOR inhibitor. A summary of the published data is presented as well.
Conclusions: The inhibition of mTOR pathway represents the most important therapeutic innovation introduced in the last few years for KHE. Our case shows the effectiveness and good tolerance of long-term therapy with sirolimus.


Kaposiform Hemangioendothelioma (KHE) is a rare vascular tumour of the infancy and the first decade of life. KHE shows no sex predilection, is locally aggressive and potentially life threatening when associated with consumptive coagulopathy known as Kasabach-Merritt syndrome (KMS). KHE has an incidence of 0.7/100.000/year,[1] and it can appear anywhere over the body with a wide range of clinical presentations. Macroscopically KHE is characterised by the presence of abundant vascular structures that infiltrate the surrounding soft tissues, and it is structured as a tender mass that causes pain when platelets congest within the vessels, and coagulation cascade is activated. Tumour nodules have irregular borders and they are composed of fascicles of spindle endothelial cells which are positive for vascular markers like CD31 and CD34, and negative for Glut1, with a low Ki67 proliferative index, rare mitosis, no nuclear atypia, no necrosis. KHE shows no tendency to metastasize.[2] KMS is usually associated with a reduction of platelets count and haemoglobin, a lengthening of prothrombin time (PT), partial thromboplastin time (PTT), and to a reduction of fibrinogen. No consensus or guideline for the therapy has been reached because of the lack of prospective trials, and the different standard care suggestions are based on retrospective case series. We report a severe case of KHE with KMS successfully treated with prednisone and vincristine, used to induce the initial response and subsequently consolidated and strengthened by long-term treatment with sirolimus. The inhibition of mTOR pathway by sirolimus is an important therapeutic innovation introduced in the last few years, and a review of the published data is discussed.

Case Report

A 9-month-old male was admitted to the emergency department several times in three months for respiratory and urinary tract infections, constipation, recurrent abdominal pain with globose abdomen, and failure to thrive. The blood exams showed a recurrent thrombocytopenia interpreted as resulting from infections. Screening for celiac disease was negative. In the last access to the emergency department blood exams showed thrombocytopenia (110 x109/L) and anaemia (Hb 8,9 g/dl) with white blood cell 8.3 x109/L, PT 1.26 (n.v 0.80-1.17), PTT 1.17 (v.n 0.80-1.20), fibrinogen 0.83 g/L (n.v 2-4), D-dimer >10.000 mcg/L (n.v < 0,25), antithrombin III 100% (n.v 70-130). In the following weeks, he manifested a progressive decrease in the number of platelets, with a minimum value of 9 x 109/L.
An ultrasound of the abdomen revealed a solid mass of about 6 x 2,3 cm in the retroperitoneal space, without clear margin, locally spread around the mesenteric vessels’ origins. The lesion was confirmed by magnetic resonance imaging (MRI) (Figure 1). A biopsy was performed: the histological features (Figure 2) and the immunophenotype with CD 31 (JC/70A) +, CD 34 (QBEND/10)+, GLUT1 -/+, PODOPLANIN (D2-40) +, PROTEIN S100 -, Herpes virus 8 (13B10) - were diagnostic for KHE and the clinical and laboratory features were indicative of KMS. The child started a 6-week therapy with prednisone at the dose of 2 mg/kg/d (with a slow tapering), an 8-week course of vincristine (0,05 mg/kg/week) associated with sirolimus (3 mg/m2), modulated to maintain a blood concentration within the therapeutic range of 7,5-10 ng/ml. During the following months, there was a progressive clinical improvement with a 4 kg weight increase in 5 months. Platelet count increased to > 50 x10
9/L after 15 days of therapy and normalized (> 150 x109/L) after 4 months. As of 31st January 2018, the patient was being treated with sirolimus for 20 months without any clinical or biochemical side effects or infection complication. The MRI performed at 1, 9, 16 months showed a progressive reduction of the mass (Figure 1).

Figure 1 Figure 1.  Abdominal MRI performed at 1, 9, 16 months.

Figure 2 Figure 2. Biopsy histological features.


We report a case of  KHE with KMS that continues to respond to long-term treatment with sirolimus without side effects. We performed a review of the literature of all cases of KHE in patients under the age of 18 with the aim of defining typical characteristics of the disease. We analysed 42 papers [1-3,8,9,11,12,15-49] including case reports, brief reports, case series, consensus, clinical letters, short communications, letters to the editor, retrospective studies, reviews and research letters. Data are summarised in table 1. The number of patients with KHE is 89 even if in 55% of cases the diagnosis is not supported by the histology. The most frequent sites are the extremities (43%). KMS is described in 59% of patients and it always occurs in the abdominal sites (100%). In nearly all cases it is already present at the diagnosis; when KMS is not present at the onset the risk to develop it over time is low. Moreover, KMS occurs in 87% of the masses > 5 cm and 100% of those > 10 cm, suggesting that dimensions are related to the risk of developing KMS (Table 1). No guideline has been defined, and different therapeutic medical and surgical treatments have been used for KHE with and without KMS. Radical surgery is one of possible treatment, and in cases of KMS it can resolve the coagulopathy, but unfortunately, most of the lesions are not surgically attackable, or they are only partially resectable. Embolization and sclerotherapy are other techniques rarely used due to the difficulty to cannulate small vessels and because of the risk of complications.[3] Radiotherapy has proven to be effective, but it is limited by important side effects.[4,5] Steroid therapy, even at high doses, is widely used for this type of pathology and the literature data showed that 65% of the patients took a steroid (table 1). The most commonly used steroid is methylprednisolone (dose of 2 mg/kg/day) followed by prednisone and dexamethasone. This therapy often gives good results, but it is burdened by significant side effects especially when used for long time.[21,24,31,49] Vincristine is an effective chemotherapeutic drug, administered once a week at a dosage of 0.05 mg/kg/dose. Vincristine has been used in 34% of patients especially in association with steroid therapy in patients with KMS. Vincristine resulted effective although the complete remission was rare and the duration of therapy is limited by side effects.[6,7,8] Propranolol has been shown to be effective in the treatment of KHE,[9] but the use in monotherapy is not able to control the disease.[3] Interferon, antiangiogenic drugs such as bevacizumab[10] and aspirin[11] have been tested. Sirolimus is a mTOR inhibitor that is a serine/threonine kinase regulated by phosphoinositide-3-kinase. It is an important therapeutic option that has been increasingly used in the last few years. It affects cell growth and angiogenesis; it is also a powerful immunosuppressor and an antitumoral drug.[1,12] In multiple studies the effectiveness of the use of Sirolimus and other mTOR inhibitor has been described,[3,12,13,14] proving to be particularly active in vascular and lymphoproliferative disorders. Moreover, the mTOR inhibitors can be used in monotherapy even for long periods, being able to control cases of the non-completely regressed disease, and in spite of the necessity of constant control of blood levels, they resulted manageable and with little side effect. Literature data reported in table 1 show that 17% of patients received mTOR inhibitors, especially as second-line therapy after the use of steroids, vincristine, and others.[8,19,20,21] It has been administered for months every day, in some cases twice a day, modulating the dose according to blood concentration (range 7-10 ng / ml).[1,3,8,12,16,19,20,21,25,28,32,34,49] According to the data summarised in table 1, the most used therapeutic schemes are: steroid + other (33%) and steroid + vincristine + other (18%). In our case, the initial therapy of vincristine and prednisone was combined with sirolimus to obtain a regression of the KMS. Long-term therapy with sirolimus has shown to be effective in controlling the disease without side effects.

Table 1 Table 1. Features of patients. 


KHE is a locally aggressive tumor, and it is potentially life threatening when associated with consumptive coagulopathy known as KMS. Although there is no univocal consensus on the therapy, our case shows that in cases of KHE with KMS a multidrug therapy (steroid + vincristine + mTOR inhibitor) followed by maintenance with the mTOR inhibitor monotherapy is a valuable option, with effective disease control and no relevant side effects. Future studies are needed to validate this approach and define the best duration of treatment.


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