Introduction

Inflammatory myofibrobrastic tumor (IMT) is a rare neoplasm composed of myofibroblastic spindle cells with inflammatory cell infiltrate, predominantly occurring in the lung or abdominal cavity of children and young adults. Recently, a variant of IMT with malignant characteristics and consisting mainly of round-to-epithelioid cells has been proposed to be a subclass of epithelioid inflammatory myofibroblastic sarcoma (EIMS) [1].

Herein, we report the first case of an EIMS arising in the pleural cavity, confirmed by immunohistochemistry and fluorescence in situ hybridization (FISH), in an older adult patient.

Case report

A 57-year-old Japanese man with a complaint of dyspnea on exertion was found to have massive right pleural effusion on an annual routine chest radiograph. As an automobile repair worker, he had been exposed to asbestos over a 3-year period. He was referred to our hospital, and chest drainage was carried out to reduce his dyspnea. Chest computed tomography (CT) after pleural effusion drainage revealed a huge intrathoracic tumor with heterogeneous density (Fig. 1a) and without other intrapulmonary nodules. F18-fluorodeoxyglucose (FDG) positron emission tomography revealed abnormally increased FDG uptake in the mass (standardized uptake value, max 10.7), but no other abnormally increased FDG uptake was detected, including in the abdomen (Fig. 1b). Based on these findings, the tumor was thought to have arisen in the pleura or chest wall. Pleural effusion cytology revealed only inflammatory cells with no evidence of malignancy. Serum tumor marker levels, including carcinoembryonic antigen and cytokeratin fragment 19–9, were all within normal limits.

Fig. 1
figure 1

a Chest computed tomography (CT) after pleural effusion drainage revealing a huge intrathoracic tumor of heterogeneous density. b F18-fluorodeoxyglucose (FDG) positron emission tomography revealing abnormally increased FDG uptake (standardized uptake value, max 10.7) in the mass (arrow). No other abnormally increased FDG uptake was detected, including in the abdomen. c A follow-up chest CT revealing that the tumor had enlarged rapidly over 2 months, coming to occupy much of the right pleural cavity

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We performed thoracoscopic tumor biopsy and talc poudrage for an accurate diagnosis and management of pleural effusion, because curative resection was not expected due to an insufficient pulmonary reserve. When examined during the operation, the tumor appeared cystic and glossy, and protruded extensively into the pleural cavity. A tumor tissue biopsy was obtained for pathological examination. Follow-up chest CT showed that the tumor enlarged rapidly during the following 2 months, coming to occupy much of the right pleural cavity (Fig. 1c). Based on the pathological and genetic findings, thoracic oncology group at our institution has just started administering anaplastic lymphoma kinase (ALK) inhibitor as an alternative treatment to surgery for this aggressive tumor.

Pathological and genetic findings

Microscopically, the tumor consisted of two different histological types, one of which was of high cell density (Fig. 2a) and the other with low cell density and myxoid stroma (Fig. 2b). Both of these areas contained inflammatory cells, mainly lymphocytes and histiocytes, and were rich in capillaries. Tumor cells were rounded and epithelioid in shape, not spindle, with round nuclei with small nucleoli. Immunohistochemical analysis revealed that the tumor cells were positive for vimentin, desmin, CAM 5.2 (focal), and AE 1/AE 3 (focal), and were negative for Calretinin, CD30, CD31, CD33, alpha-smooth muscle actin, HHF35, myogenin, S100, HMB45, CD20, CD79a, CD3, CD5, leukocyte common antigen, and CD68KP-1. In addition, the tumor cells were positive for ALK, exhibiting a cytoplasmic pattern with perinuclear accentuation (Fig. 2c). FISH analysis was carried out on the formalin-fixed paraffin-embedded tissue slice (4 μm in thick) in this tumor, using bacterial artificial chromosomes, RP11-348G16 for Ran-binding protein 2 (RANBP2), and RP11-984I21 and RP11-62B19 for ALK. It produced a merged signal in the tumor cells, indicating that the partner of the gene rearrangement of ALK was RANBP2 (RANBP2-ALK fusion, Fig. 2d). Based on these pathological and molecular findings, the tumor was diagnosed as EIMS.

Fig. 2
figure 2

a Microscopic findings of the dense cellular region of the tumor. Tumor cells were epithelioid in shape, not spindle, with round nuclei with small nucleoli. The tumor contained inflammatory cells, mainly lymphocytes and histiocytes, and was rich in capillaries. b Microscopic findings of the sparse cellular region of the tumor. The tumors contained abundant myxoid stroma and inflammatory cells. c The tumor was positive for anaplastic lymphoma kinase (ALK), exhibiting a cytoplasmic pattern with perinuclear accentuation. d Fluorescence in situ hybridization analysis. Spectrum Green–labeled ALK locus-spanning and Spectrum Red–labeled ran-binding protein 2 (RANBP2) locus-spannig probes resulted in merged signals (arrows), indicative of RANBP2-ALK fusion

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Discussion

The designation of EIMS has recently been proposed as a variant of IMT, reflecting its malignant clinical behavior [1]. This report described the morphological, immunohistochemical, and molecular genetic characterization of EIMS. The common features shared by EIMS are as follows: (1) round-to-epithelioid tumor cells, (2) abundant myxoid stroma with inflammatory infiltrate, (3) immunopositivity for ALK, and (4) RANBP2-ALK fusion gene. All of these features were identified in the present case and, therefore, we gave the diagnosis of EIMS. The only immunohistochemical difference between our case and those previously reported was a lack of CD30 expression [1].

The expression of RANBP2-ALK fusion, which is considered specific to EIMS, has only been reported in 8 previous IMTs (Table 1) [1–5]. It was noteworthy that there were only male patients and all tumors arose in the abdominal organs (e.g., the peritoneum, mesentery, and omentum). Although it is unclear whether the present case originated from the pleura or chest wall, this is the first case report of an intrathoracic IMT with a RANBP2-ALK fusion gene diagnosed as an EIMS. A conclusive explanation for this anatomical site predilection has yet to be found. There were two patterns of immunohistochemical staining for ALK: a nuclear membrane staining pattern in seven cases and a cytoplasmic pattern in the remaining one, as seen in the present case. Although surgical resection was performed as an initial treatment in all cases, the tumors exhibited an aggressive clinical course.

Table 1 Comparison of 9 IMTs with RANBP2-ALK fusion
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As the treatment of choice for IMT/EIMS, surgical resection is recommended when possible [1, 6, 7]. In the present case, curative resection was unrealistic, because the tumor grew very rapidly over a 2-month period (based on chest CT) and the patient had insufficient pulmonary reserve. The effectiveness of alternative treatment modalities such as radiotherapy, chemotherapy, and steroids is uncertain [6, 7]. Recently, it was reported that administration of the ALK inhibitor crizotinib in a case of IMT with a RANBP2-ALK fusion resulted in a sustained partial response [5]. Thoracic oncology group at our institution has just started administering ALK inhibitor, which may provide therapeutic effect for this aggressive tumor.

Conclusion

We report the first case of an EIMS arising in the pleural cavity. ALK inhibitor may be the best alternative treatment to surgery for this aggressive tumor.