Kaposiform hemangioendothelioma is a rare pediatric neoplasm that presents most commonly in the soft tissues. We report the case of a 1-month-old infant who presented with stridor and was found to have a diffusely infiltrating tumor in the thymus that extended into the pericardium and up the carotid sheaths. Histologic examination revealed a vascular tumor infiltrating among the lobules of the lymphocyte-depleted thymus. The lesion had features of both a capillary hemangioma and Kaposi sarcoma. Immunoperoxidase studies on formalin-fixed, paraffin-embedded tissue demonstrated the neoplastic endothelial cells to be positive for vascular markers CD31 and CD34. Antibody to factor VIII-related antigen labeled feeding vessels, but failed to stain the lobules of tumor. Although these tumors have been treated in a fashion similar to capillary hemangiomas in the past, it may be important to differentiate Kaposiform hemangioendotheliomas because of their association with Kasabach-Merritt syndrome and recent success with more aggressive chemotherapy regimens.
Kaposiform hemangioendothelioma is an uncommon vascular neoplasm initially described in 1979 as a congenital retroperitoneal hemangioendothelioma.1 A complete description of the clinical features, identification of the sites of prevalence, and coinage of the phrase “Kaposiform hemangioendothelioma” were introduced in 1993 by Zukerberg et al.2 The tumor occurs almost exclusively in childhood, with the ages at presentation ranging from 1 month to 19 years. The lesions occur most commonly in the retroperitoneum and deep soft tissue of the extremities, although some have also been reported in superficial soft tissues, chest wall, scalp, neck, and mediastinum. These tumors tend to be locally invasive, but are not known to produce distant metastases.
The tumors often are associated with Kasabach-Merritt syndrome, a consumptive coagulopathy associated with vascular lesions.3–7 Several retrospective studies on patients who presented with Kasabach-Merritt syndrome have revealed that what was originally diagnosed as a capillary hemangioma may often be better described as a Kaposiform hemangioendothelioma.8–10 Other presenting symptomatology includes nonspecific symptoms of tumor burden (eg, weight loss and malaise) and obstructive symptoms (eg, vomiting due to gastrointestinal obstruction or stridor due to tracheal compression). We describe the case of a 1-month-old infant who presented with stridor and was found to have an extensive tumor involving the thymus.
REPORT OF A CASE
An infant was brought to medical attention owing to the development of stridor at 1 month of age. After a course of treatment for bronchiolitis failed to relieve symptoms, computed tomographic and magnetic resonance imaging scans showed a diffuse process in the mediastinum, with extension up the carotid sheaths. Echocardiogram showed a pericardial effusion, which when tapped consisted of blood. The patient was referred to a cardiothoracic surgeon for biopsy of the lesion. Intraoperatively, thymus appeared replaced by a tumor that was densely adherent to the pericardium and wrapped around the innominate veins. Intraoperatively, the patient demonstrated a diffuse coagulopathy and was transfused with fresh blood. At surgery, the tumor was friable and vascular. The excised lesion consisted of firm, tan-pink tissue measuring 4.5 × 2 × 0.5 cm. Postoperatively, the patient developed several episodes of thrombocytopenia and anemia, although coagulation parameters such as partial thromboplastin time and prothrombin time remained normal. Six months after surgery, the infant remains dependent on a tracheostomy with continuous positive airway pressure, because of airway compression by tumor. Platelet infusions were found to exacerbate the patient's symptoms, and once stopped the patient's condition stabilized.
MATERIALS AND METHODS
The tissues were fixed in neutral buffered formalin and embedded in paraffin. Sections 4 μm thick were routinely stained with hematoxylin-eosin. Immunohistochemical studies were performed on formalin-fixed, paraffin-embedded tissue, using the avidin-biotin-peroxidase complex method (Dako Corporation, Carpinteria, Calif). Slides were pretreated by the steam method of heat-induced epitope retrieval. The following antibodies were used: CAM 5.2 (1:3 dilution; Becton-Dickinson, San Jose, Calif), CD31 (1:2 dilution; Dako), CD34 (1:10 dilution; Becton-Dickinson), factor VIII (1:500 dilution; Dako), CD3 (1:20 dilution; Dako), CD20 (1:5 dilution; Dako), and CD1a (1:2 dilution; Immunotech, Marseille, France).
Histopathology of the tumor consisted of residual thymic structures enveloped by a proliferation of spindled cells (Figure 1). The lobular thymic architecture was intact, but spindled cells surrounded the lobules. Hassall corpuscles of the thymic medulla were evident centrally within lobules. The thymus was depleted of lymphocytes. Although a portion of the tumor appeared to contain a fibrous capsule, much of the tumor infiltrated surrounding fat. At the periphery of the lesion, vascular spaces appeared dilated and had a thin endothelial lining. Other areas were densely cellular with a lobular infiltrate of plump endothelial cells surrounding small capillaries. A mitotic rate as high as 3 mitoses per 10 high-power fields was noted. Adjacent to areas resembling juvenile capillary hemangioma were epithelioid endothelial cells in glomeruloid configurations (Figure 2). These cells had hyaline inclusions and hemosiderin pigment. Occasional spindled cells surrounding slitlike vascular spaces were noted.
Immunohistochemically, the spindled tumor cells were positive for CD31 and CD34. Antibody to factor VIII-related antigen highlighted the endothelium of feeding vessels, but failed to stain the small endothelial cells of the tumor. Residual thymic epithelial cells stained positively for cytokeratin using the CAM 5.2 antibody (Figure 3). Scattered lymphocytes within and around the tumor were primarily mature T cells (positive for CD3 and negative for CD1a). Occasional B cells were demonstrated with CD20 antibody.
According to our review of the literature, the histopathology of Kaposiform hemangioendothelioma in the thymus has not been described previously. Although there are many histologic similarities to cellular hemangioma of infancy, it may be important to distinguish these 2 entities for a couple of reasons. Kaposiform hemangioendotheliomas often are associated with Kasabach-Merritt syndrome, a consumptive coagulopathy in patients with large vascular tumors. In addition, several recent studies have demonstrated some efficacy with fairly aggressive chemotherapeutic regimens in the treatment of Kaposiform hemangioendothelioma.11,12
Mediastinal hemangiomas account for less than 1% of mediastinal masses and are usually of the cavernous type. They have a benign course. Rare cases of mediastinal hemangioendothelioma have been reported.13–15
The pathogenesis of Kaposiform hemangioendothelioma is unknown. Although Kaposi sarcoma has been associated with human herpesvirus 8, this virus has not been found in association with Kaposiform hemangioendothelioma.16
Several features differentiate cellular hemangioma from Kaposiform hemangioendothelioma. First, the Kaposiform hemangioendothelioma tends to be diffusely infiltrative, whereas the hemangioma tends to be circumscribed. In the present case, the spindled cells appeared to infiltrate within thymic lobules. The latter are recognizable by the presence of Hassall corpuscles and lymphocytes.
The hemangioendothelioma may have areas resembling the juvenile form of capillary hemangioma. However, there are also glomeruloid proliferations of epithelioid endothelial cells. Some cells have intracytoplasmic lumina with hyaline globules, and there may be hemosiderin deposition. In addition, there are areas of spindled cells with slitlike vascular spaces resembling Kaposi sarcoma. As in the present case, the endothelial cells are typically positive for vascular markers, such as CD31 and CD34, but usually fail to stain with antibody to factor VIII. This pattern is similar to the antigen-expression profile of Kaposi sarcoma. Typically, high mitotic rate and nuclear atypia are not features of Kaposiform hemangioendothelioma.17 In this case, the highest mitotic rate was in areas closely resembling juvenile capillary hemangioma. Mitoses are a feature of the immature form of this benign lesion. However, the aggressive clinical course and the histopathologic features (eg, infiltrative pattern, epithelioid cells, and spindled cells) in our case favor the diagnosis of Kaposiform hemangioendothelioma.
Differentiation from Kaposi sarcoma is straightforward. Aside from the lymphadenopathic form seen in Africa, Kaposi sarcoma is rarely seen in children. Although both entities (Kaposiform hemangioendothelioma and Kaposi sarcoma) have spindled cells with slitlike lumina, hyaline globules, hemosiderin deposition, and endothelial antigen expression, the Kaposiform hemangioendothelioma also has areas of epithelioid endothelium, often in glomeruloid nests.
In summary, the thymus is an unusual site of presentation for a Kaposiform hemangioendothelioma. This neoplasm should be considered in the differential diagnosis of anterior mediastinal masses, particularly in pediatric patients presenting with a coagulopathy. Further recognition of this entity may lead to improved therapy and to a better understanding of the associated consumptive coagulopathy.
The authors acknowledge the expert technical assistance of Teresa Gainey, Tracy Lamb, Yvonne Veloso, and Renee Workman.