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Introduction

Primitive neuroectodermal tumors (PNETs) are a rare group of malignant tumors of neuroectodermal origin. PNETs are most commonly encountered in pediatric patients with diverse clinical manifestations, and are classified into three groups based on the tissue of origin: Central nervous system (CNS) PNETs, neuroblastoma and peripheral PNEs (pPNETs) derived from tissues outside the CNS and autonomic nervous system (1). pPNETs occur predominantly during infancy or childhood, and are located in the abdomen (2,3), thoracopulmonary region (4,5) and, rarely, in the head and neck region (6). pPNETs are extremely rare in adults, particularly in the hip muscles with bone metastasis. Metastasis is considered to be the most significant prognostic factor, and patients without metastasis may have a relatively better prognosis and longer survival time. Early correct diagnosis and accurate staging are crucial for selecting the optimal therapeutic regimens (7).

Case report

A 44-year-old woman was referred to our hospital on April 8th, 2015, with a 1-year history of progressive pain, swelling and a mass near the left hip, which had worsened over the previous month. The patient had no history of trauma, surgery, bone fracture, or accident. There was no other significant family or past medical history. Physical examination revealed a solid soft mass near the upper 1/4 of the left thigh, ~8 cm in diameter. Increased skin temperature and limited hip mobility were also observed. Tumor markers, including carcinoembryonic antigen, thyroglobulin, neuron-specific enolase, cytokeratin 19 fragment and cancer antigen 19-9 were all within the normal range. A plain CT scan of the pelvis and upper thigh was performed, which revealed a soft tissue mass lesion in the hip muscles measuring 4.3×4.3×4.4 cm (Fig. 2A). The lesion was an ill-defined, aggressive, heterogeneous, hypodense mass with multiple internal lower-density areas and mild post-contrast enhancement (Fig. 2B and C). There was a large number of bent neovessels and several branches from the left internal iliac artery and deep femoral artery on enhanced CT angiography (Fig. 2D). Three-phase dynamic imaging was performed immediately after the injection of 99mTc-3P-RGD2 via the right ulnar vein. Blood perfusion (Fig. 1A, posterior view) and blood pooling phase (Fig. 1B, posterior view) images revealed increased blood perfusion and blood pooling in the soft mass. Delayed planar (Fig. 1C, anterior and posterior view) and single-photon emission (SPECT)-CT images acquired at 1 h showed a non-uniformly increased uptake of integrin αvβ3-targeting 99mTc-3P-RGD2 with a central core of decreased uptake (Fig. 1D). The soft mass was localized at the posteromedial muscle group of the left hip. The imaging results of the SPECT-CT were the same as those on plain CT imaging. Regional accumulation of 99mTc-3P-RGD2 was observed in the ischium and ilium near the left hip joint and the suspected diagnosis was soft tissue sarcoma or pPNET with bone metastasis.

Figure 2. (A-C) Representative computed tomography images showing a mildly low-density soft tissue mass with uneven enhancement and dotted calcifications. (D) computed tomography angiography revealed a large number of bent neovessels and several branches from the left internal iliac artery and deep femoral artery. (E) Histopathological examination of a biopsy sample (hematoxylin and eosin staining) revealed a highly cellular tumor composed of a diffuse, compact sheet of tumor cells displaying monomorphic, small round, finely vesicular nuclei and occasional necrosis. The immunohistochemical staining for (F) CD99 and (G) FLI-1 yielded highly positive (+++) and moderately positive (++) results, respectively (magnification, ×20).

Figure 1. Triple-phase dynamic 99mTc-3P-RGD2 imaging immediately following intravenous injection. (A) Blood perfusion (sequential frame images acquired immediately after tracer injection; 2 sec per frame) and (B) blood pooling (acquired 5 min after tracer injection; 1 min per frame) phase images (posterior view) revealed increased blood perfusion and blood pooling in the soft mass (arrows). (C) Delayed planar imaging [(C-a) anterior and (C-b) posterior], and (D-a and D-b) computed tomography and (D-c and D-d) single-photon emission computed tomography images acquired at 1 h, showing a non-uniformly increased uptake of 99mTc-3P-RGD2 with a central decreased core (C-a and D-c, arrows). The soft mass was localized at the posteromedial muscle group of the left hip and presented as a large (5.3×2.7×3.1 cm), ill-defined, aggressive, heterogeneous, hypodense mass with multiple internal lower-density areas (D-a). Regional accumulation of 99mTc-3P-RGD2 may be seen in the ischium and ilium near the left hip joint (D-d, arrows), without significant bone density changes on computed tomography (D-b). The suspected diagnosis was soft tissue sarcoma or pPNET with bone metastasis.

Histopathological examination of the biopsy sample (hematoxylin and eosin staining) revealed a highly cellular tumor composed of a diffuse, compact sheet of tumor cells displaying monomorphic, small round, finely vesicular nuclei and occasional necrosis (Fig. 2E). The immunohistochemical (IHC) staining for CD99 and FLI-1 yielded highly positive (+++) and moderately positive (++) results, respectively (Fig. 2F). Chemoembolization and anti-angiogenic treatment were performed via the left internal iliac artery and left deep femoral artery, respectively.

Discussion

From a pathological perspective, pPNETs and Ewing sarcomas (ESs) are both composed of small round cells with identical histopathological, IHC and molecular characteristics. They are currently classified into the same tumor family with identical chromosomal translocations, and they generally represent different manifestations of the same tumor with similar genetic alterations. ES occurs predominately in the bone, while pPNETs are more common in soft tissues, such as the kidney (2,6), masseter muscle (3) and lungs (5). Furthermore, pPNETs mainly occur in children. We herein report a case of pPNET in an adult patient, originating in the hip muscles with bone metastasis. Unambiguous differentiation of pPNETs from other small round cell tumors, such as CNS PNETs, poorly differentiated carcinoma, lymphoma, desmoplastic small round cell tumor and rhabdomyosarcoma, is difficult but of vital significance. These tumors may be difficult to diagnose due to their primitive morphology. Cell membranous immunoexpression of CD99 (F) and FLI1 (G) are highly reliable markers for the definitive diagnosis of pPNET (8–10).

Tumor site, volume and the presence of metastasis, are significant prognostic factors for pPNETs. Radiology may offer important information for the diagnosis and prognosis of pPNETs. As in the present case, pPNETs commonly present as large, ill-defined, aggressive, heterogeneous, hypodense masses, exhibiting heterogeneous enhancement with varying internal lower-density regions (11,12). Due to the high incidence of metastasis at presentation, a full metastatic workup is warranted in cases with suspected pPNET. Furthermore, as pPNET is mainly diagnosed via pathological examination of biopsy samples or surgical specimens, more extensive investigations, such as nuclear medicine imaging, including whole-body technetium 99m bone scan or positron emission tomography imaging, are indicated (13). 99mTc-3P-RGD2, an integrin αvβ3-targeted radiotracer, has completed a phase III clinical study for solid tumor imaging in China; it offers a major advantage for the differential diagnosis of solid tumors and metastasis, as well as for patient selection and evaluation for anti-angiogenic therapy (14–18). The mechanism underlying this imaging technique is the high expression of integrin αvβ3 on the endothelial cells of neovessels, tumor cells, and osteoclasts. PNET, which is reported to be integrin αv-positive, has an integrin profile almost identical to that of ES, which is integrin αvβ3-positive (19). We herein present what is, to the best of our knowledge, the first report of triple-phase 99mTc-3P-RGD2 imaging (plain and SPECT-CT) for the diagnosis and staging of a patient with pPNET. The blood perfusion results of the lesion were consistent with that from enhanced CT. In addition to the CT data, 99mTc-3P-RGD2 SPECT-CT imaging also demonstrated bone metastasis, which was negative on CT in this case. The regional aggressive nature and metastatic lesions precluded complete surgical excision. Triple-phase 99mTc-3P-RGD2 imaging supported the use of transarterial chemoembolization and anti-angiogenic treatment (20). With the development of therapeutic radionuclide labeling RGD, such as 177Lu-RGD2, integrin αvβ3-targeted radiotherapy appears to be promising for the future treatment of pPNETs with bone metastasis (21).

References