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Background: Kaposiform haemangioendothelioma is a rare vascular tumor and may involve skin, deep soft tissue or bone. It is a locally aggressive tumor usually seen in infants. Here we report a case of kaposiform hemagioendothe- lioma in a child who responded to propranolol and steroids. Case presentation: A 3-year-old male child presented with a swelling below his right knee with characteristic violet skin lesion. There was no evidence of Kasabach–Merritt phenomenon. After no improvement with several attempts at debridement and anti-tubercular treatment; a diagnosis of Kaposiform Haemangioendothelioma was reached on the basis of overall clinical picture and histology. The child was treated with propranolol and steroids and had an excellent clinical response and a near complete resolution on imaging at 5 months. Conclusions: These cases are often misdiagnosed and despite a delay in diagnosis have good outcomes with appropriate multimodality management. This case highlights the unique and typical characteristics of kaposiform haemangioendothelioma. Keywords: Kaposiform hemangioendothelioma, Propranolol, Steroids Background term “kaposiform” relates to its resemblance to Kaposi’s Kaposiform haemangioendothelioma (KH), first sarcoma, with compact spindled tumor cells, display- described by Zuckerberg et al. in 1993, is a rare vascular ing slit like vessels and expressing CD34, usually lacking tumor and may involve skin, deep soft tissue or bone . factor VIII-AG, and surrounded by a population of fac- It is usually seen in infants and children with a median tor XIIIA-positive cells. The term “haemangioendotheli - age at diagnosis of 6.5 months (range 0.3–14.0 months) oma” implies dilemma regarding its biologic behaviour, a and an incidence of less than 1 per million [2, 3]. tumor with intermediate malignancy situated somewhere Although extremely seldom, it can also occur in older between the spectrum of haemangioma and angiosar- children and Adolescents and Young Adults (AYAs). It coma . The diagnosis is made on the basis of clinical is a locally aggressive tumor with no report of distant presentation, imaging and histopathologic examination metastasis . It may involve extremities, torso (includ- along with adequate immunohistochemistry. The main - ing retroperitoneum and intrathoracic cavity) or cer- stay of treatment remains complete surgical removal with vicofacial region in decreasing order of frequency. The wide margins. When tumor is unresectable or surgery is associated with unacceptable morbidity other treatment modalities like angiography followed by embolization, *Correspondence: email@example.com radiotherapy, vincristine chemotherapy, pharmacother- Sarcoma Medical Oncology Clinic, Department of Medical Oncology, All apy with propranolol, steroids or sirolimus have been India Institute of Medical Sciences, New Delhi, India Full list of author information is available at the end of the article used with varying rates of success [5–9]. Some patients © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Verma et al. Clin Sarcoma Res (2020) 10:12 Page 2 of 6 may develop a life-threatening complication known as He presented to our hospital in August, 2017. The child Kasabach–Merritt phenomenon (KMP). KMP is throm- had a swelling below knee over the right leg which was bocytopenia (average platelet count 25,000/mm ; range hard in consistency. The skin over the tumor was of vio - 3000–60,000/mm ) with hypofibrinogenemia resulting let color with increased temperature. The child had a from intralesional platelet activation, trapping, and con- poor nutritional status. His complete blood counts were sumption . The natural history and long-term out - suggestive of anaemia, leucocytosis and normal plate- comes after treatment are poorly understood. Here we let count. Liver and kidney function tests were normal. report a case treated with propranolol and steroids. Peripheral smear revealed microcytic and hypochromic RBCs. Bone marrow studies were normal. Workup for Case presentation primary immunodeficiency, bacterial/fungal infection A 3-year-8-month old male presented with a violet and tuberculosis was negative. A radiograph of right leg skin lesion and a swelling below his right knee which showed lytic sclerotic destructive lesion with midzone of was first noticed at an age of 7 months. The swell - transition seen involving right proximal tibia and fibula ing gradually increased in size over the next two years with soft tissue component (Fig. 1c). MRI done in 2016 and was associated with pain, low grade intermittent and 2017 (Fig. 2) revealed destruction of the right proxi- fever and decreased appetite. At this time a radiograph mal tibia and fibula with marrow oedema, oedematous was obtained which revealed lytic areas involving head changes in surrounding soft tissue, atrophy of the calf and proximal shaft of right tibia and fibula (images not muscles and a sinus tract due to prior surgical interven- shown). An exploration of lesion was done in December, tions. A bone biopsy was done which showed fibro-col - 2015 and histopathology revealed fibrofatty tissue with lagenous tissue with mild chronic inflammation. He was evidence of chronic inflammation. A provisional diagno - considered to have chronic tubercular osteomyelitis and sis of osteomyelitis was made and treatment with broad continued on ATT till August, 2018 with no response. spectrum antibiotics was initiated. However, there was A repeat biopsy of the lesion in August, 2018 showed a no symptomatic relief and the swelling progressed in size. tumor with nodular architecture. Immunohistochemistry After a repeat imaging, 2nd debridement was done in was positive for CD34, FLI-1 and CD31 (Fig. 3). It was June, 2016 (Fig. 1a) and antibiotics were continued. His- negative for EMA, desmin and myogenin. Skin biopsy topathology on this occasion showed normal bone with showed features of acanthotic epidermis with dense few areas of necrosis and no evidence of granuloma or fibrosis in the dermis and similar tumor in deep dermis. malignancy. Despite surgery, the symptoms persisted and Bone biopsy had infiltration of bone by similar tissue. Fat 3rd debridement was done in December, 2016. Results biopsy showed fibroadipose tissue with vascular prolifer - were again disappointing and he was started on empirical ation. A diagnosis of KH was made and he was referred to ATT from April, 2017 (Fig. 1b). our sarcoma clinic in September, 2018. He was started on Fig. 1 Sequential radiographs showing soft tissue and osseous changes in tibia (white arrows) and fibula (black arrows) over span of two years. Initial X-ray of 2016 a shows ill-defined sclerosis in proximal tibia and cortical erosion along the medial cortex of fibula which further progresses to circumferential cortical erosion in follow up radiograph of 2017 (b). The X-ray following three surgical debridements c demonstrates mixed lytic sclerotic changes involving proximal tibia and fibula. Gradually progressive soft tissue swelling is seen with predominant fat proliferation involving calf of right leg V erma et al. Clin Sarcoma Res (2020) 10:12 Page 3 of 6 Fig. 2 Sequential MRI of patient with Kaposiform haemangioendothelioma. Initial axial MR images a of 2016 show cortical destruction, marrow oedema involving tibia ( T ) and fibula (F) with surrounding soft tissue oedema on T1 (left) as well as STIR (right) sequences. Subsequently performed MRI in 2017 reveals increase in calf diameter and marrow oedema in both bones with visualization of plaque like hyperintensity along the muscle plane on STIR images (arrows in b). The recent MR images demonstrate trans-compartment involvement of skin (arrow in c) as thickening and hyperintense signal intensity; subcutaneous plane as fat proliferation which shows reticular pattern/lymphedema; muscles as atrophy and fat proliferation within the intermuscular plane and bones with marrow signal alteration. The similar changes are also evident on T1 weighted sagittal images of 2016 (arrow in d) and 2018 (asterisk in e) treatment with propranolol at a dose of 0.6 mg/kg twice without analgesics. His appetite improved. On follow up a day for 1 week followed by 1.1 mg/kg for 2 weeks and at 3 month he had an excellent clinical response. Imaging 1.7 mg/kg thereafter along with prednisone at 2 mg/kg. with MRI at 5 months revealed a near complete resolu- On follow-up after a month child was better; with a slight tion. He developed cushingoid features on steroids which decrease in size of swelling and pain and was able to sleep resolved on tapering of steroids. Verma et al. Clin Sarcoma Res (2020) 10:12 Page 4 of 6 Fig. 3 Histopathology of Kaposiform haemangioendothelioma. a Low power photomicrograph of the tumor showing nodular architecture with spindle cells arranged in cannon ball fashion with slit like ill formed vascular channels. (H&E 100×). b High power photomicrograph showing cells exhibiting mild pleomorphism with elongated nuclei, finely dispersed chromatin and scanty to moderate cytoplasm. Few of the vascular spaces showed RBC. There were occasional mitotic figures. (H&E 200×). c Immunostaining for CD31 showing diffuse cytoplasmic positivity in tumor cells. d Immunostaining for FLI-1 showing nuclear positivity in tumor cells The treatment plan for surgery was discussed with Due to rarity of KH, there are no prospective stud- parents. However, parents have preferred to defer any ies and only case series and case reports are available extensive surgery and decided to continue with medical to guide management. For resectable lesions, surgery is management. the mainstay of management as there is no spontane- ous regression in KH. For non-resectable lesions or for Discussion and conclusions those in which surgery will entail significant morbid - KH is set apart from other common and benign vascular ity pharmacological management is desirable to shrink lesions of childhood like juvenile haemangioma, cavern- tumor size. Such pharmacological treatment is also used ous haemangioma, angiomatosis and endovascular papil- in patients presenting with KMP to correct coagulopathy lary angio-endothelioma by its unique histopathological and decrease tumor size. Trans-arterial embolization has features and locally invasive nature . been used to treat KH of scalp and cervical region [5, 13]. The most common clinical presentation of KH is a Corticosteroids have been widely used as a first line agent characteristic violet cutaneous lesion which infiltrates the in most cases with questionable benefit as a sole agent. underlying skin on the extremities . Our patient pre- Propranolol has been used in vascular tumours like sented with typical clinical features of a cutaneous lesion angiosarcoma as part of combination metronomic chem- and a swelling in the extremity in infancy. There was no otherapy with clinically significant responses [7, 14]. Pro- evidence of KMP, profound thrombocytopenia resulting pranolol with and without steroids has shown variable from intralesional platelet trapping, in our patient. In a responses with some cases having long lasting remis- study by Croteau et al. 71% patients of KH had evidence sions in KH patients [8, 15]. Vincristine has been used as of KMP at diagnosis . Studies have indicated that trun- a sole agent and with steroids especially in patients with cal involvement and larger size may predict for more KMP with improvement in platelet counts and decrease serious involvement including KMP [11, 12]. in tumor size in some patients [6, 16]. VAT (Vincistine- Aspirin-Ticlopidine) combination therapy also showed V erma et al. Clin Sarcoma Res (2020) 10:12 Page 5 of 6 Fig. 4 Response to treatment on MRI. Follow up MRI shows resolution of reticular hyperintense pattern on T1 (a) and STIR (b) axial images with increase in bulk of the calf muscles (c) as compared to pre-treatment scan (Fig. 2) clinical response [17, 18]. In critically ill patients chem- the delay may be due to lack of expert sarcoma patholo- otherapy combinations utilising cyclophosphamide, gist and dedicated sarcoma oncologists in India . methotrexate, vincristine and actinomycin-D have been More collaboration between different specialists like utilised . Sirolimus, a mammalian target of Rapa- surgery, orthopaedics, radiology and pathology is mycin (mTOR) inhibitor, has been demonstrated to have required for streamlining and optimizing patient man- anti-angiogenic activity in pre-clinical models. In some agement. A simple way is to develop multidisciplinary patients sirolimus at a dose of (0.1 mg/kg/day) resulted in tumor board at tertiary care institutions and dedicated rapid and dramatic response [9, 20]. Platelet transfusion sarcoma clinics. is only indicated for active bleeding and/or immediately prior to surgery as it may exacerbate KMP . Abbreviations In 2013, Drolet et al. presented consensus guidelines KH: Kaposiform Haemangioendothelioma; AYAs: Adolescents and Young based on limited clinical literature . Initial diagnos- Adults; CD: Cluster of differentiation; KMP: Kasabach–Merritt phenomenon; ATT : Anti-tubercular treatment; RBCs: Red blood cells; MRI: Magnetic reso- tic workup should consist of CBC with platelet count, nance imaging; FLI1: Friend leukemia integration 1 transcription factor; EMA: coagulation studies (including PT/PTT/fibrinogen and Epithelial membrane antigen; VAT: Vincistine–Aspirin–Ticlopidine; mTOR: Mam- D-Dimer), local imaging with MRI with contrast and malian target of rapamycin; PT: Prothrombin time; PTT: Partial thromboplastin time. tissue biopsy. For cases of KH associated with KMP, first-line therapy with intravenous vincristine 0.05 mg/ Acknowledgements kg once weekly AND oral prednisolone 2 mg/kg/d OR Not applicable. intravenous methylprednisolone 1.6 mg/kg/d was rec- Authors’ contributions ommended. For cases of KH that require intervention SV contributed to patient care, literature review and drafting of the manu- because of growth or symptoms but do not have KMP, script. ED contributed to radiologic analysis and editing the manuscript. VSK contributed to direct patient care and editing of the manuscript. AB contrib- oral prednisolone 2 mg/kg/d was recommended as the uted to pathological analysis and editing of the manuscript. SR contributed first-line therapy. Treatment with aspirin at an antiplate - to direct patient care, literature review and editing of the manuscript. The let dose of 2–5 mg/kg/d could be considered as adjunc- final manuscript was reviewed and approved by all authors for submission. All authors read and approved the final manuscript. tive therapy. In our patient we started with propranolol and ster- Funding oids with a clinical response at 1 month and an excellent The authors have received no funding for this work and have no sources to declare. response on imaging at 5 months of treatment (Fig. 4). The long term adverse effects of steroid treatment, Ethics approval and consent to participate including growth retardation, a cushingoid appearance, Not applicable. and opportunistic infections have been reported . In Consent for publication the above cases steroids were gradually tapered following The patient’s mother provided consent to the writing of his case report. development of cushingoid facies. Written informed consent for publication of the clinical details and/or clinical images was obtained from the patient’s mother. A copy of the consent form There can be a delay in diagnosis of such rare is available for review by the Editors of this journal. The authors listed for tumours, as in our patient. 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