The authors are indebted to Flo Witte for medical editing.
Hemangiopericytoma (HPC) is a soft-tissue neoplasm most commonly seen in adults; only 5–10% of cases occur in children. Childhood HPC comprises two distinct clinical entities. In children older than 1 year, it behaves in a manner similar to adult HPC. Infantile HPC, however, although histologically identical to adult HPC, has a more benign clinical course. The reasons for these differences in the natural history of HPC are not well understood.
The authors reviewed the clinicopathologic features of HPC as well as the treatment and outcomes of the 12 children (9 males and 3 females) treated for this disease at St. Jude Children's Research Hospital over a 35-year period.
At diagnosis, 9 patients were older than 1 year and 3 were younger than 1 year. Among the 9 older patients, tumors were most commonly found in the lower extremities (n = 5). One patient had been treated for acute lymphoblastic leukemia 15 years earlier. One patient had metastatic disease at diagnosis, and three had unresectable tumors. Two patients experienced objective responses to chemotherapy. Three patients died of disease progression. Among the three infants, two had unresectable disease at diagnosis, and both experienced excellent responses to neoadjuvant chemotherapy. In one case, the response of the tumor to chemotherapy correlated with maturation to hemangioma. All three infants are alive without evidence of disease.
Hemangiopericytoma (HPC) is a soft-tissue neoplasm of pericytic origin that most commonly affects adults in the fifth or sixth decade of life.1, 2 This tumor usually arises in the lower extremities or pelvis, and 10–20% of patients have metastatic disease at the time of diagnosis.2–4 In adults, the clinical features, treatment, and outcome of HPC are similar to those of other soft-tissue sarcomas. The clinical behavior of HPC is difficult to predict based on histology, although histologic signs, such as the mitotic index and the degree of cellularity, hemorrhage, and necrosis, seem to correlate with prognosis.2
Only 5–10% of all cases of HPC occur in children.2, 5 However, some cases of childhood HPC may have unique features: As many as 40% occur during the first year of life,5 and most of them are considered to be congenital.2, 5, 6 Indeed, 4 of the 9 patients in the original report by Stout and Murray were infants.1
It has become apparent that infantile HPC merits distinction as a specific entity.2, 5 Although its clinical and histologic features are indistinguishable from those of adult HPC, infantile HPC is less aggressive, and excellent responses to chemotherapy and even spontaneous regressions have been documented.2, 5, 7–13 The biologic basis for these differences is not well understood. In this report, we discuss the natural history of childhood HPC and describe the treatment and outcome of 12 children, including 3 infants, who were treated for the disease at our institution over a 35-year period. We also report one case of infantile HPC in which the patient's response to chemotherapy was associated with histologic evidence of maturation to hemangioma.
MATERIALS AND METHODS
A review of the records of all patients treated at St. Jude Children's Research Hospital between March 1962 and December 1997 identified 12 patients with a diagnosis of HPC. One of the authors (J.J.J.) reviewed and confirmed all diagnoses. Tumors were diagnosed by standard histopathologic techniques. Histologic grade was determined by the Pediatric Oncology Group (POG) grading system,14 which is based on tumor histology, mitotic index, and extent of necrosis (Table 1). The information gathered from patients' charts included the clinical features and radiologic characteristics of the tumors, the treatment provided, and the patients' outcomes. Data were current to September 1998.
Table 1. Pediatric Oncology Group Nonrhabdomyosarcoma Soft Tissue Sarcoma Grading Systema
Necrosis and mitotic count are the most important parameters by far in making this assessment. The remainder are of borderline significance and may be helpful in a case that is difficult to place using necrosis and mitotic count alone. Specific diagnoses included in Grades 1 and 3 are excluded from Grade 2.
Myxoid and well-differentiated liposarcoma
Well-differentiated or infantile (age ≤ 4 years) fibrosarcoma
Well-differentiated or infantile (age ≤4 years) hemangiopericytoma
Any other sarcoma not in Grade 1 with >15% necrosis and/or ≥5 mitoses/10 high-power fields using a ×40 objective
Tumor size, lymph node involvement, and degree of tumor invasiveness were categorized according to the tumor, lymph node, metastasis (TNM) system of the International Union Against Cancer (UICC).15 According to this system, T1 lesions are confined to the organ of origin, and T2 lesions have invaded contiguous organs. Both categories are classified further by tumor maximum dimension as a (<5 cm) or b (≥5 cm). Lymph node involvement is designated as N1, absence of lymph node involvement is designated as N0, absence of metastases is designated as M0, and distant metastases at the time of diagnosis is designated as M1.
The disease stage of our patients was determined by using the Intergroup Rhabdomyosarcoma Study grouping system.16 According to this system, patients with tumors that are completely resected are placed in Clinical Group I. Clinical Group II includes those patients whose tumors are grossly resected with either microscopic evidence of residual disease at the primary site (Group IIa), regional lymph node involvement that is completely resected (Group IIb), or regional lymph node involvement that is grossly removed with evidence of microscopic residual tumor (Group IIc). Patients with gross residual disease are placed in Clinical Group III, and patients with metastatic disease are placed in Clinical Group IV.
Individualized treatment plans are shown in Tables 2 and 3. Briefly, children in Clinical Groups I and II were treated with primary surgical resection of the tumor. Two patients also received adjuvant radiation therapy. Children in Clinical Groups III and IV were treated with neoadjuvant chemotherapy; two of them also received radiation therapy.
Table 2. Clinical Characteristics, Treatment, and Outcome of Children Older than 1 Year with Hemangiopericytoma
Patient characteristics, therapy, and outcomes are shown in Tables 2 and 3. Nine patients were older than 1 year and three were younger than 1 year when the diagnosis of HPC was made. Data from these two groups of patients were analyzed separately.
HPC in Children Older than 1 Year
This group of nine patients included seven males and two females (Table 2). The median age of the patients at diagnosis was 16 years (range, 4–20 years). The median follow-up was 3.6 years (range, 1.1–21.1 years). Five tumors were located in the lower extremities, and four were located on or in the head. All lesions were categorized as POG Grade 3. At diagnosis, two tumors had involved local lymph nodes, and one had metastasized to the lung. One patient age 17 years with HPC of the sphenoid sinus (Patient 6) had been diagnosed with acute lymphoblastic leukemia when he was age 2 years and had been treated with multiagent chemotherapy and 24 grays (Gy) of cranial irradiation.
Six patients underwent resection of the tumor at diagnosis. Three of these patients had negative margins of resection (Group I), and three were considered retrospectively to have microscopic residual disease (Group IIa). One of the Group I patients received adjuvant radiotherapy. Of the three Group II patients, only one received adjuvant radiotherapy. The two patients with unresectable disease (Group III) and the patient with metastatic disease at diagnosis (Group IV) were treated initially with neoadjuvant chemotherapy. Neoadjuvant radiotherapy also was used in the treatment of the two Group III patients.
Six patients experienced tumor recurrence at a median of 11.5 months after diagnosis (range, 1–33 months). Two recurrences were local, two were distant (lung, bone, or both), and two were both local and distant (lung, bone).
All three patients with Group I lesions had local control of the disease. One patient had a distant recurrence (lung), which was treated with surgery alone. All three patients are alive and without evidence of disease.
Of the five patients with Group II or III disease, the three who received either no radiotherapy or a radiation dose < 50 Gy developed either local recurrences (n = 2 patients) or local and distant recurrences (n = 1 patient), whereas the two patients who received doses > 50 Gy had local control of the disease, although one of them sustained a distant recurrence. The two patients with Group III disease had partial responses to neoadjuvant chemotherapy. Two patients died of disease progression, one patient is alive with disease, and two patients are alive without evidence of disease.
The patient with Group IV disease had an HPC unresponsive to chemotherapy and died of disease progression shortly after diagnosis. The estimated 5-year survival rate for these patients was 53% ± 21%.
HPC in Infants
This group of three patients included two boys and one girl (Table 3). All were found to have HPC either at birth or during the first 2 months of life. Histologically, the tumors did not differ from those in older children and were considered to be POG Grade 1 lesions despite the increased cellularity and the high mitotic index and degree of necrosis. Two patients (Patients 11 and 12) with unresectable lesions at diagnosis were treated with neoadjuvant chemotherapy with very good clinical responses, as shown in Figure 1. Histologically, these responses correlated with a marked reduction in cellularity, leaving a few delicate capillaries embedded in variably dense, collagenous connective tissue (Fig. 2A). Patient 11 underwent a complete tumor resection after neoadjuvant chemotherapy. Patient 12 had unresectable HPC of the thigh with involvement of the femur; en bloc resection of the soft tissue mass with curettage of the bone lesion was performed after a good response to neoadjuvant chemotherapy had been achieved (Fig. 1). This patient continued to receive chemotherapy after surgery and, although there was microscopic evidence of residual tumor after surgery, remains alive without evidence of disease.
Patient 10 was found to have HPC of the lung at birth. The tumor was resected, and a local recurrence was treated with chemotherapy. In this case, treatment with chemotherapy resulted in “maturation” of the HPC to a lesion that was indistinguishable from a capillary hemangioma (Fig. 2B). All three patients are alive without evidence of disease at 1.0 year, 1.3 years, and 4.8 years from diagnosis.
This report describes the clinical features, treatment, and outcomes of a group of children with HPC and confirms the distinct characteristics of infantile HPC. HPC is considered a heterogeneous clinicopathologic entity that comprises two distinct clinical syndromes: adult HPC and infantile HPC. This series shows that childhood HPC includes both syndromes, and the distinction between the two is of paramount importance for proper clinical management.
The behavior of HPC in children older than 1 year does not appear to differ from adult HPC. The 9 cases in the current study illustrate that outcome is related directly to the presence of metastatic disease and the adequacy of local control. For both adults2, 4 and children,5, 6, 11 surgical treatment with curative intent is the most important predictor of survival. Adjuvant radiotherapy has a definite role in the treatment of HPC in both the primary setting and the recurrent setting.17–19 Radiation doses > 50 Gy are required for local control of disease, as shown by our cases.17, 18 The role of chemotherapy is more debatable. Some reports have documented objective responses to a variety of chemotherapeutic agents in both adults20–23 and children,6, 24 although the role of chemotherapy in the treatment of HPC is not well established.17 Two of our three patients older than 1 year who received neoadjuvant chemotherapy experienced objective responses.
Our three cases show clearly that infantile HPC is a distinct entity. Like adult HPC, infantile HPC most commonly appears in the soft tissues of the lower extremities.5–7, 11 However, it is more likely than adult HPC to appear as intraoral lesions9, 25 and to be multicentric.1, 5, 12 Its presentation may be very dramatic, with rapid growth and, occasionally, life-threatening bleeding.6, 7, 11, 26 Since the early descriptions of HPC, it has become apparent that, despite the presence of histologic features of aggressiveness, such as increased mitotic rate and focal necrosis, infantile HPC is more responsive to treatment than adult HPC:2, 5 Reports describe both excellent responses to chemotherapy7–11 and spontaneous regressions.8, 11–13 Nevertheless, true malignant HPC also may occur in infants.5, 7 The early recognition of these features may help in the differential diagnosis from other neoplasms, thus avoiding inappropriately aggressive therapy.27 Local control of unresectable tumors may be achieved without radiation therapy or mutilating surgery, as shown by one of our cases.
The reasons for the rather benign characteristics of infantile HPC are not well understood. Infantile HPC shares some clinical and histologic features with other infantile neoplasms that differ in clinical characteristics from the same types of tumors in adults, such as infantile fibrosarcoma and infantile myofibromatosis. Infantile fibrosarcoma, which usually is congenital, differs from adult fibrosarcoma in its chemoresponsiveness and in its ability to regress spontaneously.28, 29 Infantile myofibromatosis usually is diagnosed in patients younger than 1 year, and 60% of cases are congenital.30 One-third of cases are multicentric, and spontaneous regressions also are common.30 An HPC-like pattern, with high mitotic grade and necrosis, can be found often in the centers of the nodules.30 Several authors have confirmed the overlapping histologic features of infantile HPC, infantile fibrosarcoma, and infantile myofibromatosis.31–34 The term composite myofibromatosis has been proposed as a unifying category for these infantile neoplasms, in which areas with histologic features of each of these entities coexist.34
Ultrastructural studies of HPC in adults have shown differentiation of pericytes into smooth muscle and also into cells with myofibroblastic features.35–37 In adults, HPC also may show a spectrum of perivascular myoid differentiation.38 Some authors have suggested that HPC may arise from a pluripotent cell that is capable of differentiating along smooth muscle, pericytic, and glomic cell lines.38 It is possible that infantile HPC retains its ability to differentiate into more mature cells, thus accounting for its similarities with infantile myofibromatosis and its ability to regress spontaneously.
In this report, we provide further evidence that the distinctive characteristics of infantile HPC may be related to its ability to differentiate into more mature tissue. In one of our cases, histologic evidence showed that infantile HPC matured to hemangioma after treatment with chemotherapy. To our knowledge, such maturation has not been reported previously and may explain in part the spontaneous regression observed in some cases. Infantile HPC has been reported to have proliferation of endothelial cells into the lumina of the vascular spaces, suggesting a type of tumor that may be a transitional form between HPC and hemangioendothelioma.2 Moreover, ultrastructural studies have shown forms of transition between pericytes and endothelial cells.39
In summary, our series confirms that childhood HPC may comprise two different clinical entities. In children older than 1 year, HPC does not differ significantly from adult HPC, and surgical therapy is the mainstay of treatment. Infantile HPC, however, seems to be characterized by chemoresponsiveness and spontaneous regression; it also may mature into a more benign vascular neoplasm. These unique features of infantile HPC should be considered in the differential diagnosis of soft-tissue neoplasms in infants, so that inappropriately aggressive therapy can be avoided.27