A case report of primary Kaposiform hemangioendothelioma of the humerus

Abstract

To examine the clinicopathological and immunohistochemical features of Kaposiform hemangioendothelioma (KHE) and discuss its differential diagnosis and prognosis. A patient with KHE was examined; the patient’s clinical and histopathological features were observed, and the expression levels of CD31, CD34, ERG, D2-40, SMA, GLUT-1, and LANA-1 were assessed. The patient was a four-year-old child with primary KHE of the humerus. She was admitted to the hospital because of pain in the right elbow joint and limited movement for more than 2 years. Imaging revealed Langerhans cell histiocytosis. The child was not diagnosed with Kasabach-Merritt phenomenon (KMP). The tumor consists of multiple hemangiomatous nodules with infiltrative growth separated by fibrous connective tissue. The proliferating hemangiomatoid nodules consisted of crisscrossing short spindle-shaped cell bundles and erythrocyte-containing lacunar or crescentic vessels. Immunohistochemical staining showed that the tumor cells diffusely expressed CD31, CD34, ERG, and other vascular endothelium-derived markers; further, the tumor cells expressed neither GLUT-1 nor LANA-1. The patient’s general condition improved after surgical resection. There was no tumor recurrence after more than 8 months of follow-up. Primary KHE of the humerus is a rare vasculogenic tumor. It presents with morphological features that require an accurate differential diagnosis.

Introduction

Kaposiform hemangioendothelioma (KHE) is a rare borderline tumor which has locally invasive features, and is a rare vascular tumor typically first seen in infancy as a distinctive cutaneous lesion with ill-defined borders. ¹ Clinical manifestations are more involved in the skin of the purplish red hard mass. KHE is an infiltrative tumor that may cross tissue planes from dermis into subcutis, fascia, muscle, and bone. ² Very few KHE patients showed deep lesions without skin involvement, while primary bone lesions were rarer, and most cases were single lesions. Here, we report a unique case of KHE in the humerus. We aimed to alert clinicians to diagnose KHE at specific sites, which helps for clinic therapy.

Case description

Clinical data

A female 4-year-old child was admitted to the hospital with pain in the right elbow joint and limited movement for more than 2 years. Two years prior, the child gradually began to experience pain in the right elbow joint, accompanied by limited movement and mild swelling. Consequently, she had difficulty flexing her elbow joints to dress. During these activities, she experienced pain and was reluctant to participate. She also occasionally complained of numbness in her fingertips. Subsequently, the child started refusing to use her right hand for eating or performing other actions. Recently, family members observed that the middle and lower sections of her right upper arm had atrophied, compared to the unaffected side, with no apparent abnormalities in her fingertips. Due to persistent weakness and discomfort, she sought treatment at another hospital. Radiographic and computed tomography (CT) examinations showed that the patient’s right elbow joint (right distal humerus, right proximal ulna) exhibited uneven bone quality (Figure 1(a)), which led to a tumor diagnosis. A specialist examination in our hospital showed that the child was conscious and slightly uncooperative during the physical examination and questioning. The right elbow joint was markedly swollen, and the muscles in the right upper arm exhibited atrophy compared to those of the left side. There was no apparent atrophy in the right deltoid or forearm muscles. The local skin temperature over the right elbow was slightly elevated, with normal skin color, soft texture, no ulcerations, and an intact subcutaneous layer. Pressing on the proximal end of the right humerus and distal ulna elicited induration and pain. The child resisted the application of pressure. The bone was not palpable. Blood supply and sensation in the fingertips were satisfactory. The patient denied any history of trauma. Since the disease’s onset, the child has maintained a good mental and physical state, with normal appetite, food intake, and sleep. The family noted a gradual increase in the child’s weight, from approximately 10 kg at disease onset to 12 kg.

Figure 1.

Radiographic image shows the tumor in the humeral metaphysis (a); MRI plain scan showing that the tumor is located in the humeral metaphysis (b); MRI fat-suppression sequence and enhanced scan, showing significant enhancement of the tumor (c).

CT results

Partial bone resorption and destruction were observed at the distal end of the right humerus, and soft tissue density shadow filling was observed inside, with an area of approximately 30 mm × 22 mm. There was an absence of periosteal reaction surrounding the lesion. Given the potential for eosinophilic granuloma, further examination using magnetic resonance imaging (MRI) with enhancement was deemed necessary. MRI results: The right distal humerus exhibited irregularly shaped abnormal signals. These were characterized by low to slightly low signal intensity on T1 weighted images (T1WI) and uneven high signal intensity on T2 weighted images (T2WI) and Proton Density Weighted Imaging (PDWI) with fat suppression. The maximum area of a slice measured approximately 22 mm × 22 mm. The lesion exhibited expansive growth, and there was evidence of local bone involvement; the cortex was compromised, with no apparent periosteal reaction (Figure 1(b)). The lesions demonstrated uneven and marked enhancement. Adjacent soft tissue swelling was noted. On T2WI and PDWI with fat suppression, an uneven high signal was observed. Post-contrast enhancement suggested a high probability of significant pathology (Figure 1(c)).

Laboratory tests

The activated partial thromboplastin time (APTT) was 42.00s, while platelet count, fibrinogen content, prothrombin time, red blood cell count, hemoglobin content, and D-2 polymer test results were all normal. The patient underwent humeral lesion resection on September 13, 2022. Intraoperative findings: occupying lesion of the right distal humerus, about 2.0 cm × 2.0 cm in size, with bright red granuloma-like appearance, localized osteocortical defect of the distal humerus, and localized granulomatous hyperplasia of the elbow joint capsule.

Pathological examination

A pile of gray-white and gray-brown tissue with a total volume of 2.5 cm × 2.0 cm × 0.5 cm and soft texture was identified. Microscopic observation revealed that the tumor consisted of multiple angiomatous nodules with infiltrative growth. Angiomatous nodules are composed of short, spindle-shaped, or round-like cells. Furthermore, the spindle cells were noted to be organized in bundles, and some areas of spindle cells are interspersed with each other, forming slit-like structures of various sizes and irregular shapes. These structures occasionally contained leaked red blood cells and hyaline globules. Between the nodules, fibrous connective tissue intervals were present. Additionally, focal lesions demonstrated myxoid degeneration, along with the proliferation and accumulation of histiocytes that phagocytosed hemosiderin particles. Notably, more mature and differentiated capillaries were observed at the periphery of certain nodules. In some nodules, cystic dilation of lymphatic vessel-like structures and scattered lymphocytes within the nodules were evident. The cells, along with a small number of eosinophils, were not obviously allotypic or mildly allotypic, and nuclear mitosis was rare, lacking significant atypia. Some cells have irregular and distorting nuclei, similar to epithelioid cells, with fine nuclear chromatin and small nucleoli, and nuclear mitosis is not easy to see. (Figure 2(a)–(d)). Importantly, the examination revealed no evidence of tumor necrosis or peripheral nerve invasion, although multinucleated giant cells were dispersed within the tumor. Immunohistochemically, the tumor cells diffusely expressed CD31 (Figure 2(e)), CD34 (Figure 2(f)), and ERG. Areas of cystic expansion around the nodules expressed D2-40 (Figure 2(g)). The tumors exhibited focal SMA expression (Figure 2(h)) and weak expression of F8 factor. Tumor cells were negative for GLUT-1 and LANA-1. The Ki-67 proliferation index was approximately 5% (Figure 2(i)).

Figure 2.

Low magnification shows that the tumor is distributed in a lobular shape (a, b); Under low to medium magnification, the nodule is mainly composed of spindle cells with mild morphology, and an open lumen and well-differentiated capillaries can be seen at the edge (c, d); Spindle cells express vascular endothelial markers CD31 and CD34, respectively, observed with the EnVision method at medium magnification (e, f); Tumor cells express lymphatic endothelial marker D2-40, observed with the EnVision method at medium magnification (g). Tumor cells express lymphatic endothelial marker SMA, observed with the EnVision method at medium magnification (h); The Ki-67 proliferation index was approximately 5% (+) (i).

Pathological diagnosis

Kaposiform hemangioendothelioma (KHE).

Treatment and follow-up

The child was followed up for 8 months and was in good physical condition. Considering the young age, no other treatment was administered postoperatively.

Discussion

KHE is predominantly observed in infants and young children, bearing similarities to both capillary hemangioma and Kaposi sarcoma. Initially reported by Niedt in 1989, this entity was first referred to as a hemangioma with Kaposi-like features. Later, Tsang and Chan proposed the term “Kaposi-like infantile hemangioendothelioma.” In 1993, Zukerger further refined its nomenclature to “Kaposi-type hemangioendothelioma,” a designation later endorsed by the World Health Organization (WHO) in 2002. This terminology has been retained to the present. The latest (fifth) edition of the WHO classification of soft tissue and bone tumors categorizes KHE as a locally aggressive vasogenic tumor, exhibiting characteristics of both capillary hemangioma and Kaposi sarcoma, with the specific International Classification of Diseases for Oncology (ICD-O) code being 9130/1.

KHE occurs predominantly in children and is infrequent in adults. ³ Approximately 60%–70% of cases manifest in the limbs and trunk, with subsequent occurrences noted in the retroperitoneum, groin, head, neck, and, less commonly, in the mediastinum, thymus, digestive tract, female reproductive system, and bones. ⁴ KHE is rarely found in the bones. Our case is therefore an exceptional one. Notably, this disease often presents alongside Kasabach-Merritt phenomenon (KMP), characterized by a decrease in platelets and coagulation factors, leading to a consumptive coagulation disorder in patients with KHE or tufted angioma. The occurrence of KMP is significantly correlated with tumor size, age of onset, and depth of infiltration of the lesion.^2,5 Importantly, the majority of patients with deep KHE also experience KMP. ⁶ In KHE, abnormally proliferating vascular endothelial cells tend to sequester more platelets. Due to the robust proliferation of these cells and hemodynamic alterations, the risk of vascular endothelial damage significantly escalates, thereby stimulating the consumption of coagulation factors and fibrosis. Consequently, increased dissolution may result in bleeding within the tumor area and, in severe cases, disseminated intravascular coagulation, ⁷ which predominantly accounts for mortality in most patients. In the present case, the APTT was only marginally elevated, and KMP was absent. The skin overlying the tumor appeared normal in color but exhibited an elevated temperature, likely attributable to localized tumor growth in the bone surrounding the humerus, leading to a relatively smaller tumor size. ⁸ Under microscopic examination, KHE, presenting in various body regions, consistently exhibits a similar morphology. These formations manifest as vascular globules, which differ in size and are arranged in a nodular distribution. The nodules, separated by fibrous connective tissue, present as vascular globules of varying sizes when viewed at low magnification.

Diagnosis and differential diagnosis

Lobular distribution characteristics ⁹ : Cells in the nodule are abundant and densely arranged and are mainly composed of morphologically benign spindle and/or oval cells. The cells are interlaced to form fissures of various sizes and shapes. A large number of leaked red blood cells, proliferation, and aggregation of macrophages that phagocytose hemosiderin-containing granules, and occasionally fibrin microthrombi, can be seen. ¹⁰ In typical cases, round, epithelioid cells and/or spindle cells can often be seen locally distributed in nests, with fissures or dilated vascular spaces on one side of the nests forming a structure similar to Bowman’s cyst ¹¹ ; the structure resembling Bowman’s cyst is observable in this particular case. The more mature, differentiated capillary lumina typically appear round, oval, or irregular, and they frequently contain 1-2 spindle-shaped vascular endothelial cells. These cells are predominantly located around the tumor area. ¹² In this instance, the peritumoral region exhibits expanded lymphatic vessel-like structures, which can be delineated through D2-40 immunohistochemical staining. It is generally posited that KHE originates from anomalies in angiogenesis and lymphangiogenesis. Some researchers hypothesize that this might be linked to the tumor tissue secreting lymphatic endothelial growth factor, thereby inducing local tumor differentiation into lymphatic vessels. Lymphocyte infiltration is a common feature in such tumors. In this specific case, alongside lymphocytes and plasma cells, a limited quantity of eosinophils was detected within the tumor. Moreover, the irregular and distorting nuclei of some tumor cells, as well as the presence of a small number of multinucleated giant cells scattered throughout the tumor, may lead to misidentification as Langerhans cell histiocytosis (LCH). ¹³ The tumor cells, in this case, diffusely express CD31, CD34, and ERG. The cystic expansion area surrounding the nodule demonstrates D2-40 expression, indicative of local lymphatic differentiation. Additionally, focal SMA expression suggests the presence of vascular pericytic cell differentiation within the tumor. Notably, the cells do not express CD1α, S-100, Langerin (CD207), GLUT-1, and LANA-1. ¹⁴ The differential diagnosis of Kaposi-type hemangioendothelioma of the primary bone mainly includes the following: (i) Kaposi sarcoma predominantly affects adults and is characterized as a low-grade malignant tumor with vasculogenic origins. In certain instances, it has been complicated by human immunodeficiency virus (HIV) infection. Clinically, the condition is categorized into three stages—patch, plaque, and nodule—based on distinct morphologies of skin lesions. However, the histological morphology is not identical in different periods, and the tumor tissue consists of interlocking spindle-shaped cells, with slit-like structures of varying sizes between the spindle cells. Additionally, extravasated red blood cells and hyaline globules are present, although glomerular structures are absent in the tumor. The tumor cells exhibit vascular markers and positive for HHV-8. ¹⁵ In the case of this child, who did not have HIV infection, histological morphology revealed glomerular-like structures, and LANA-1 was not detected through immunohistochemical staining. (ii) Spindle cell hemangioma predominantly occurs in adolescents and affects the superficial soft tissues of distal limbs. Microscopically, these lesions exhibit features akin to cavernous hemangiomas, encompassing solid spindle cell areas and polygonal epithelioid cells in varying proportions. In cavernous hemangioma-like areas, phenomena such as mixed distribution, thrombosis, organized recanalization, and calcification are frequently observed. The area comprising epithelioid cells may undergo differentiation, resembling the vascular lumen structure characteristic of epithelioid hemangioendothelioma. Although the spindle cell area exhibits morphological similarities to KHE, it is distinguished by its expression of Vimentin, SMA, and D2-40, while lacking expression of vascular endothelial markers. ¹⁶ At present, there are still differences in the identification of the nature of this tumor, and some scholars believe that it is a benign form of vascular proliferation. Furthermore, some believe that the disease occurs due to lymphatic malformation; notably, this tumor overlaps with KHE and tufted angioma in terms of tissue morphology and immunophenotype. Molecular testing can be performed when the identification is difficult. Importantly, spindle cell hemangioma frequently harbors IDH1/2 exon mutations. (iii) Infantile hemangioma, the most prevalent vasculogenic tumor in children, comprises proliferating vascular endothelium and perivascular cells. Predominantly occurring in women and on the head and face, it is typically inconspicuous at birth but may rapidly grow in the ensuing months. While some cases spontaneously regress, the tumor cells express GLUT-1 and vascular endothelial markers but not lymphatic markers. Conversely, some cases of KHE are present at birth, show no spontaneous regression, and the tumor cells lack GLUT-1 expression. These cells do express vascular endothelial markers and some lymphatic vessel markers. ¹⁷ (iv) Tufted angioma: a relatively rare benign vascular proliferative disease (ICD-O code: 9161/0), typically presents at birth or develops within the first year, predominantly in the trunk and limbs. Clinical manifestations are varied and non-specific, with some cases possibly associated with KMP; spontaneous resolution has been observed in certain cases. ¹⁸ Histopathologically, it resembles KHE, characterized by small nodules of vascular endothelial cells, vascular pericytes, and capillaries, with proliferating cells in the nodules arranged in concentric circles. Some vascular endothelial cells protrude into the lumen, and surrounding cells may form crescent-shaped fissures. The tumor cells express vascular endothelial cell markers, vascular pericytes express SMA, and tumor cells focally express D2-40 but not GLUT-1. Given the tissue morphology and immunophenotype’s similarity to KHE, the WHO classification of soft tissue and bone tumors (5th edition) suggests these may represent different manifestations or stages of the same tumor. When superficial, the tumor is often diagnosed as Tufted angioma; however, if it occurs deeper, particularly in viscera and retroperitoneum, with indistinct boundaries and surrounding adipose tissue infiltration, it is more likely diagnosed as KHE. ¹⁹

Conclusion

The prevalence of KHE is low and varies widely. Currently, there is no international scoring system to assess the severity of KHE, nor are there standardized guidelines for treatment. The primary approach to managing KHE is through extensive tumor resection. The prognosis of patients is influenced by factors such as the tumor’s location, the degree of involvement, and the presence of KMP. Surgical resection was previously considered the optimal treatment for this condition. However, the advent of sirolimus and the specific characteristics of the KHE have made complete resection challenging. Currently, pharmacologic treatment is the most effective treatment option.^20,21 Recently, sirolimus has gained recognition for treating complex vascular anomalies and tumors in pediatric patients. In this case, the child exhibited a stable condition post-surgery, and considering the child’s tender age, the parents opted against additional treatments. The patient has been under observation for over 8 months, during which no recurrence of the tumor has been observed.