Introduction Ewing sarcomas primitive neuroectodermal

Introduction Ewing sarcomas/primitive neuroectodermal tumors (ES/PNETs) are relatively infrequent but the second most common sarcoma of the bone next to osteosarcoma. Nearly 80% of them occur in persons younger than 20years. Most of them arise from the bone, but 10 to 20% of them from soft tissue. ES/PNETs are pathologically characterized by small round UMI-77 which often show CD99 expression by immunohistochemistry (IHC). Approximately 85% of them are known to have a reciprocal translocation of t(11;22) (q24;q12), which makes EWSR1-FLI1 fusion gene [1]. Other fusion genes including EWSR1-ERG and EWSR1-ETV1 have also been reported in ES/PNETs [2]. In Ewing-like sarcomas, fusion genes such as BCOR-CCNB3 [3] and CIC-DUX4 [4] have been demonstrated. Thus, the fusion gene analyses are critical for the definite diagnosis of small round cell tumors including ES/PNETs and Ewing-like sarcomas. Pro-gastrin-releasing peptide (proGRP) is a precursor peptide of GRP, and elevation of serum or plasma GRP level had been reported to be a useful serological marker for patients with small cell lung cancer (SCLC) [5]. Because of instability of GRP in plasma, the improved immunoassay system to measure a precursor form of GRP, i.e. proGRP, which is stable in plasma, has been developed [6]. Now, measurement of serum/plasma proGRP is regarded as a reliable biomarker for SCLC [7]. Although serological tumor markers specific for patients with ES/PNET are not known, some reports demonstrated that serum CEA [8] or serum/plasma proGRP was elevated in several patients with ES/PNET. Elevated serum/plasma proGRP had been reported in two cases of ES/PNET [9], [10]. Moreover, Yamaguchi et al. recently reported that elevated level of plasma proGRP was detected in 5 out of 9 ES/PNETs [11]. However, it has been found that expression of GRP in ES/PNETs was not directly regulated by the EWSR1-FLI1 fusion gene [12].
Clinical Presentation A 17-year-old male presented with left chest pain at night. Chest X-ray and chest computed tomography (CT) demonstrated a 90×68mm mass arising from the left third rib. For further examinations, the patient was referred to the Department of Orthopedic Surgery, Hyogo College of Medicine. Chest X-ray and chest CT in our hospital also showed large tumor with destruction of the cortex of the left third rib (Fig. 1A and C). The laboratory data showed slightly elevated serum neuron specific enolase (NSE) (18.7ng/ml, normal range: 0–16.3ng/ml) and marked elevation of plasma proGRP (1310pg/ml, normal range; 0–81pg/ml). Serum CEA and CA19-9 were within normal range. For the definite diagnosis, bone biopsy was performed.
Materials and methods
Results
Discussion It is very rare that elevated serological tumor markers are detected in ES/PNET cases. In the case of serum CEA, only one case of 7-year-old boy with skull ES/PNET has been reported (91.09ng/ml) [8]. In the case of proGRP, on the other hand, only 7 cases with ES/PNET have been reported [9], [10], [11]. Takagi-Takahashi et al. reported a case of 69-year-old man with ES/PNET of chest wall (serum proGRP 754pg/ml, normal range: 0–46pg/ml) [9]. Yamamoto et al. reported a case of pelvic ES/PNET associated with abdominal dissemination and multiple liver metastases (plasma proGRP 3725pg/ml, normal range; 0–81pg/ml) [10]. The patient died of disease progression with the increased level of plasma proGRP (9970pg/ml). Yamaguchi et al. reported 5 cases of ES/PNET with high levels of serum proGRP (96–683pg/ml, normal range 0–46pg/ml) [11]. They consisted of2 males and 3 females between the age of 19 and 58 [11]. Two cases were arising from the bone and 3 from soft tissue of the thorax [11]. Therefore, to our knowledge, this is the 8th case of ES/PNET with serologically elevated proGRP (1310pg/ml in plasma). In the present case, normalization of plasma proGRP level was observed after chemotherapy which resulted in pathological complete response. These findings strongly suggested that ES/PNET in our case was a proGRP producing tumor. In cases of ES/PNET with elevated serum/plasma proGRP, follow-up information of proGRP level is available in only two cases; one is a case reported by Yamamoto et al. [10] and the other is the present case. Ours is the only one case showing the normalization of plasma proGRP level after chemotherapy.