Foot Pain in a 16-Year-Old Boy

A 16-year-old boy presented with an insignificant medical history of chronic pain in the right foot. The pain was described as dull and aching and increased during the past several months. Weightbearing exacerbated the discomfort but the patient also had discomfort at rest. He denied night pain, fevers, night sweats, and fatigue. There was no history of trauma. He had no other painful sites. Physical examination was remarkable only for edema on the lateral aspect of the right midfoot. There were no palpable masses in the foot or ankle. Radiographs (Fig 1) and magnetic resonance imaging (MRI) scans (Fig 2) of the area were obtained. Based on the history, physical examination, and imaging studies, what is the differential diagnosis?Fig 1A–B.: (A) An oblique radiograph of the right foot (B) a lateral radiograph of the right foot are shown.Fig 2A–B.: (A) A T-1 weighted MRI scan of the right foot (B) T-2 weighted STIR MRI scan of the right foot are shown.RADIOGRAPHIC INTERPRETATION Radiographs (Fig 1) showed surprisingly minimal bony changes. Magnetic resonance imaging scans showed diffuse bony lesions involving multiple bones, most notably the distal tibia, talus, and tarsals (Fig 2). A bone scan of the patient’s entire body showed only mild increased uptake in the involved bones but no lesions proximal to the midcalf or in other extremities. A skeletal survey showed no other osseous lesions. DIFFERENTIAL DIAGNOSIS Multicentric giant cell tumor Fibrous dysplasia Metabolic bone disease (hyperparathyroidism) Metastatic disease Vascular neoplasm (hemangioma, hemangioendothelioma, lymphangioma) Langerhans’ granulomatosis (eosinophilic granuloma) Atypical infections An incisional biopsy of the tarsal navicular was done (Fig 3). Based on the history, physical examination, imaging studies, and histologic findings, what is the diagnosis, and how should this patient be treated?Fig 3A.: (A) Low power photomicrograph of the lesion (Stain, hematoxylin and eosin; magnification, ×100).Fig 3B.: (B) Higher power photomicrograph of the lesion (Stain, hematoxylin and eosin, magnification, ×200).HISTOLOGY Diagnosis: multicentric hemangioendothelioma of bone. TREATMENT AND DISCUSSION Malignant vascular neoplasms of the bone are rare, accounting for less than 1% of all bone tumors. 2,12 Epithelioid hemangioendotheliomas comprise between 5% and 50% of malignant vascular neoplasms of bone. 11,12 Much debate exists regarding the clinical course of epithelioid hemangioendotheliomas, especially the importance of histologic grade and the significance of multicentric disease. 2,4,11,12 Epithelioid hemangioendothelioma seems to affect all age groups and seems to have a predilection for males. The male predominance has been reported in multiple studies and ranges from a slight increase in incidence to a 4:1 ratio. 2,3,5,7,9–13,15,16 Epithelioid hemangioendotheliomas have been reported in all age groups but seem to have an increased appearance in patients in the second and third decades of life. 2,5,7,9–13,15,16 Symptoms and physical examination generally add little to the diagnostic accuracy of epithelioid hemangioendotheliomas. There are no specific symptoms associated with the tumor, but pain is the most common complaint, followed by localized swelling. 1,3,6,7,9–13,16 Pain was found in association with pathologic fracture at the tumor site in some studies. 2,7,11,16 Some patients with pathologic fractures, however, reported no pain. 16 Physical examination generally is nonspecific, with local tenderness occurring in some patients. 1,12,15 A palpable mass rarely was appreciated if the tumor was in a peripheral location. 13 The anatomic distribution of the tumor may be characteristic. Epithelioid hemangioendotheliomas of bone tends to affect the bones of the pelvis and lower extremity, but may affect virtually any part of the skeleton. 2,7,9,11,15,16 Multicentric involvement has been reported in 22% to 64% of patients. 2,5,7,9,11,13,15,16 The multicentric lesions can occur in the same bone or in distant osseous sites but tend to occur in the same geographic location, most commonly one lower extremity, or the pelvis concurrently with the ipsilateral lower extremity. 2,7,15,16 The prognostic factors for epithelioid hemangioendotheliomas of the bone are the subject of debate. The clinical course of the tumor generally is agreed to be extremely variable: between that of the benign hemangioma and that of the conventional angiosarcoma. 2,4,11,12 Multicentricity has, to some, been important in predicting clinical course and prognosis. 2,3,9,11,13 Some authors think that patients with multicentric tumors have a less aggressive course and have an improved prognosis than patients with solitary tumors. 2,3,9,13 Other authors think that the opposite is true: patients with multicentric tumors fare worse than patients with solitary tumors. 7,16 This debate presents a problem to the clinician when planning treatment: to treat the multicentric lesion as a benign entity requiring observation, or at most radiation, or to consider it as a malignancy, requiring radical resection, radiation, and perhaps, chemotherapy. Many contend that histologic grade, as discussed previously, is an important determinant of outcome. 2,3,5,7,12,13,16 Parenchymal organ involvement also seems to be related to a poor prognosis. 5,7 The radiographic appearance of epithelioid hemangioendothelioma often is nonspecific. The most common appearance of the lesion is a radiolucent area with a well-defined rim of bone. 2,3,6,7,9–13,15,16 The margins of lesions seem to correlate with the histologic grade and clinical activity, with low-grade lesions displaying distinct well-defined margins. 2,3,12,13,15,16 Periosteal reaction and new bone formation are extremely rare, documented almost exclusively with a concomitant pathologic fracture. 2,9,12 Lesions identified as low grade histologically sometimes displayed intralesional trabeculae and honeycombing. 3,13 When multiple radiolucent lesions are present in the same bone or adjacent bones, the appearance is suggestive of epithelioid hemangioendothelioma. 10,12 Computed tomography (CT) scans reveal the lesion to be purely radiolucent. 11 Magnetic resonance imaging scans, although nonspecific, often show multiple areas of bone involvement with increased intensity on T2-weighted images. 2 Bone scans often reveal the multicentric nature of the lesions. 10,11 A skeletal survey is indicated to evaluate for multicentric disease because bone scans often fail to show the lesions. The gross appearance of epithelioid hemangioendothelioma is consistent with its vascular origin. The tumors generally are vascular and soft with irregular borders. 3,7,9,11–13,16 The size of the lesion is variable. The histologic appearance of epithelioid hemangioendothelioma is diagnostic (Fig 3). These lesions are characterized by the presence of epithelioid or histiocytic endothelial cells with primitive vascular differentiation. Individual cells are round or polygonal, with elongation in some portions. The cells have abundant granular eosinophilic cytoplasm, and some cells have intracytoplasmic vacuoles. A myxoid hyalinized intercellular stroma usually is observed, which is lightly basophilic, and vaguely resembles hyaline cartilage. The cells are arranged in nests and cords, typical of vascular lesions. Some cords of tumor cells resemble primitive capillaries focally, and a tiny vascular lumen containing blood sometimes is present. Rudimentary vascular spaces commonly are observed, and the intracytoplasmic vacuoles are thought to represent vascular differentiation. A mild to moderate inflammatory infiltrate was observed in most patients, with eosinophils being predominant. 1–4,6–8,11–13,16 Immunohistochemical studies are extremely useful in differentiating epithelioid hemangioendothelioma from other tumors. Factor VIII-related protein antigen stain is consistently positive in epithelioid hemangioendothelioma, and negative in surrounding tissue, consistent with a vascular origin of the cells. 1,4,7,11,12,15 Other immunohistochemical markers reported as useful in identifying tumors of vascular origin are CD31, 6,7,12 CD34, 1,7,12 vimentin, 7 and cytokeratin. 7,12 Electron microscopic examination of epithelioid hemangioendothelioma reveals clusters of oval or polygonal cells surrounded by a well-developed basal lamina, typical of cells of endothelial origin. 1,4,11,14 The intracytoplasmic vacuoles have microvilli or cytoplasmic flaps on the luminal surface, characteristic of normal endothelium. 1,4,11,14 Another frequent intracytoplasmic finding is that of Weibel-Palade bodies: small, rod-shaped bodies with arrays of internal tubules oriented parallel to the long axis. 1,4,11,14 Weibel-Palade bodies are described in the endothelium of normal arteries. 14 Epithelioid hemangioendotheliomas generally are graded according to histologic criteria. Grade 1 lesions show mild cytologic atypia, obvious tumor cell differentiation, slight nuclear variation in size and shape, rare mitotic figures, and numerous vascular channels lined with the characteristic epithelioid cells. Grade 2 lesions have more cytologic atypia, contain pleomorphic cells with prominent acidophilic nucleoli, and a show a slight increase in the number of mitotic figures. Grade 3 lesions have marked cytologic atypia, poor differentiation, marked nuclear pleomorphism, and only crude vascular formation. Most lesions show regional variability, so multiple areas of the tumor must be examined for accurate evaluation. 2,3,7,10,16 The primary treatment of patients with epithelioid hemangioendothelioma is surgical removal of the tumor. 3,9,11–13,15,16 Because of the tendency for the tumor to be multicentric, sometimes in distant sites, a full skeletal survey and investigation for synchronous lesions should be done as part of the surgical planning. 2,11,12 For patients with Grade 1 isolated lesions, surgical resection with wide surgical margins, 15,16 or curettage, 3,11 has been effective. Patients with solitary Grade 2 lesions may be treated with limb-sparing surgical resection procedures. 3,11,15,16 Patients with Grade 3 lesions should be treated similar to patients with all high-grade sarcomas, with radical or wide margins, if possible. 3,11,15,16 Careful consideration should be given before surgery, because lesions can develop elsewhere, even after an amputation. Patients with multicentric lesions, which are most likely low-grade, seem to be treated best with radiation therapy. 3,7,9,12,16 Conservative surgery (intralesional or marginal) is indicated for symptomatic lesions in patients with multicentric disease. Amputation can be considered for bulky disabling lesions. Radiation therapy has been found to be helpful in palliation of some unresectable lesions. 3,7,9,11–13,16 Significant concerns exist regarding the long-term effects and complications, particularly secondary sarcoma, in young patients. 10 Chemotherapy has been effective for some patients, 2,15 but most attempts of chemotherapy have been unsuccessful. 2,3,7,12,15,16 Because the radiographs and staging studies are equivocal, the differential diagnosis for multicentric epithelioid hemangioendothelioma is diverse, including multicentric giant cell tumor, metastatic disease, benign epithelioid hemangioma, and brown tumors of hyperparathyroidism and polyostotic fibrous dysplasia. Metastatic carcinoma, particularly in older patients, can resemble epithelioid hemangioendothelioma, but metastatic carcinomas tend to have significant fibrosis (which epithelioid hemangioendothelioma does not), and commonly has greater nuclear atypia and mitotic activity than epithelioid hemangioendothelioma. 5–7,12,14 Metastases have gland formations that may simulate lumens but they rarely anastomose. 11 Malignant melanoma may have cells of epithelioid character. 11 Immunohistochemical stains help in differentiating metastatic carcinoma from epithelioid hemangioendothelioma because carcinomas rarely stain for Factor VIII-related protein antigen, CD31, and CD34 stains that are positive in vascular tumors. 5–7,12 Benign hemangiomas can contain epithelioid cells with abundant eosinophilic cytoplasm. 7 Hemangiomas, however, have well-formed vascular channels that are more prominent than the primitive vascular differentiation of epithelioid hemangioma. Hemangiomas have a benign course, rarely show multicentricity. 6–8,12 Aneurysmal bone cysts are considered a reactive process, they have few, if any atypical cells. 13 Aneurysmal bone cysts tend to occur as isolated lesions. The presentation with multifocal lesions suggests fibrous dysplasia, multicentric giant cell tumors, Langerhans’ histiocytosis or hyperparathyroidism. Biopsy is necessary because these can be differentiated based on histologic criteria, although laboratory work can help with hyperparathyroidism. Epithelioid hemangioendothelioma of bone is a rare tumor with a broad differential diagnosis. Biopsy is necessary because the clinical and radiologic findings are nonspecific. The diagnosis is made based on routine histologic examination but confirmed with immunohistochemical stains. Its clinical course is uncertain, characterized by benign and malignant features. Epithelioid hemangioendothelioma has a propensity to be multicentric in one geographic region, but also can occur at distant sites. The prognosis of epithelioid hemangioendothelioma seems to be related to histologic grade, but has been suggested, by some, to be related to multicentricity. 2,3,9,11,13 The recommended primary treatment for patients with isolated epithelioid hemangioendothelioma is surgical removal of the tumor because the behavior can be aggressive. The treatment of patients with multicentric epithelioid hemangioendothelioma is problematic because wide resection of all lesions is not feasible. Radiation therapy may play a role in the treatment of surgically unresectable lesions and multicentric presentation, but carries the risk of overtreating a benign process. Chemotherapy has been suggested, but not uniformly recommended for the same reasons. 2,3,7,12,15,16 After a detailed discussion with the patient and outside consultation, the authors elected to treat the patient with external beam (62.5 Gy) radiation because his symptoms persisted and he had an ipsilateral proximal tibial lesion develop. There is obvious concern regarding the secondary effects of radiation therapy in a young patient. The option of a below-knee amputation was considered but the fear of other lesions developing was a concern. In retrospect, this was a wise decision because the patient had an ipsilateral proximal tibia lesion develop 6 months later that was treated with curettage and cementation. Some consideration of curetting all the lesions was entertained but deemed excessive because radiation likely would be used. The patient will be followed up closely with bone scans, bone surveys, and MRI.