Clinicopathological analysis of epithelioid inflammatory myofibroblastic sarcoma

  • Authors:
    • Xuemei Du
    • Ying Gao
    • Hongyu Zhao
    • Bin Li
    • Weimin Xue
    • Daye Wang
  • View Affiliations

  • Published online on: April 18, 2018     https://doi.org/10.3892/ol.2018.8530
  • Pages: 9317-9326
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Abstract

Inflammatory myofibroblastic tumor (IMT) is a distinctive neoplasm composed of myofibroblastic and fibroblastic spindle cells, accompanied by the inflammatory infiltration of plasma cells, lymphocytes and/or eosinophils. Epithelioid inflammatory myofibroblastic sarcoma (EIMS), which primarily consists of cells with a round or epithelioid morphology, is associated with a poor prognosis and rapid development of local recurrence, and has been recognized to be a variant of IMT. Diagnosis of EIMS is difficult owing to its close resemblance to malignant mesothelioma, anaplastic large cell lymphoma, gastrointestinal stromal tumor and other malignant diseases. In the present study, a case of this rare tumor was evaluated in a 26‑year‑old male who was admitted to hospital after experiencing abdominal pain for ~18 days and abdominal distention for 1 week. The patient's tumor was examined by imaging, gross examination, histology, immunohistochemistry and fluorescence in situ hybridization (FISH). The magnetic resonance imaging enhanced‑scanning image revealed that the morphology of the tumor was irregular, and signal was medley consisting of high and low hybrid reinforcement. Tumors were located in the bladder and rectal pit, in the lower part of the lower abdomen, indicating the presence of malignancy and involvement of the small intestine and rectum. Enhanced‑scanning imaging revealed notable inhomogeneous enhancement. Gross examination revealed that the tumor was solid and had a variegated appearance with alternating fleshy and mucoid areas in the cut surface. Microscopically, the tumors were dominated by sheets of epithelioid‑to‑round cells with a prominent inflammatory infiltrate. The majority of the stroma was myxoid. Immunohistochemically, the tumor cells exhibited diffuse strong staining for ALK receptor tyrosine kinase (hereafter ALK), vimentin, tumor protein P53, desmin, Wilms' tumor 1 and programmed death‑ligand 1. FISH analysis also revealed the existence of ALK rearrangement. The expression of PD‑L1 in EIMS indicates that the immune checkpoint blockade could represent a novel therapy for the treatment of EIMS.

Introduction

Inflammatory myofibroblastic tumor (IMT) is a mesenchymal neoplasm composed of myofibroblastic spindle cells in a myxoid to collagenous stroma with an inflammatory infiltrate chiefly comprised of plasma cells and lymphocytes, occasionally admixed with eosinophils and neutrophils (1). IMT usually affects children and adolescents, although a broad age range has been documented. The most common anatomical locations are the abdominopelvic region, lung, mediastinum and retroperitoneum (1).

In a mesenteric inflammatory myofibroblastic tumor, T1 weighted sequence four minutes after Gadolinium injection demonstrated intense enhancement of the peripheral inflammatory component, whilst the central fibrotic component is hypovascular (2). IMT is considered to be a soft tissue tumor with an intermediate biological behavior. However, a small percentage of cases behave aggressively (3).

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is considered to be a variant of inflammatory myofibroblastic tumor (IMT), as it has similar malignant characteristics and mainly consists of round-to-epithelioid cells (4) with a pattern of nuclear membrane or perinuclear immunostaining for ALK receptor tyrosine kinase (hereafter ALK). ALK is a receptor tyrosine kinase gene located on chromosome 2p23. Rearrangements involving this gene generally result in hyperactivity of ALK protein and correlate well with ALK protein expression by immunohistochemistry (5). Subsequent studies further demonstrated that this distinctive nuclear membrane staining pattern of ALK corresponded to ALK-RANBP2 fusion (68). The nuclear membrane staining pattern of ALK seems to be suggestive of RANBP2-ALK fusion in IMT because it has not been observed in other ALK rearrangements to date. The RANBP2 gene, located on chromosome 2q12, encodes a 358-kd nuclear pore protein and, therefore, has been attributed to the nuclear membranous localization of ALK expression by immunostaining (6,7). Clinically, EIMS is more clinically aggressive than IMT and patients exhibit reduced disease-free survival rates (4). Recognizing EIMS as a distinct variant of IMT is very important as patients with ALK-rearrangement EIMS may benefit from targeted therapy. EIMS closely resembles malignant mesothelioma (MM), anaplastic large cell lymphoma (ALCL), gastrointestinal stromal tumor (GIST) and other cancer types, meaning it is difficult to diagnose. Magnetic resonance imaging (MRI) enhanced scanning is a MRI scan following an intravenous injection of a contrast agent. This is a useful clinical technique for evaluating the severity, location and extent of the tumor (9). As EIMS has not been widely recognized, we analyzed its imaging, clinicopathological, immunohistochemical, molecular cytogenetics and treatment. The aim of the present study was to improve understanding of the disease.

Materials and methods

Patient information and selection

A 26-year-old male patient diagnosed with EIMS, who had been in abdominal pain for eighteen days and abdominal distention for 1 week, presented to the Capital Medical University Affiliated Beijing Shijitan Hospital (Beijing, China) in November 2015. This patient was selected for the present study as they presented with inflammatory myofibroblastic tumor cells with a round or epithelial morphology. The present study was approved by ethics committee of the Capital Medical University Affiliated Beijing Shijitan Hospital (Beijing, China) and the patient provided written informed consent for inclusion.

Imaging examination

The lesion was observed with magnetic resonance imaging enhanced scanning at the Capital Medical University Affiliated Beijing Shijitan Hospital (Beijing, China). A MRI scan was carried out following intravenous injection of some kind of contrast agent Gd-DTPA (0.2 ml/kg, Consun Pharmaceutical Group Limited, Guangzhou, China). Dynamic contrast-enhanced MRI has become an important component of the multiparametric strategy and is emerging as a useful clinical technique for evaluating the severity, location and extent of the tumor (9).

Histopathological analysis

Removed surgical specimens were fixed in 10% phosphate-buffered, neutral formaldehyde solution at room temperature for 24 h and dehydrated in an ascending series of ethanol. Samples were routinely embedded in paraffin, washed with xylene, then rehydrated in a descending series of alcohol, washed with distilled water, and stained with hematoxylin and eosin for 30 min at room temperature. Sections (4-µm thick) were observed under a light microscope with the magnifications of ×40, ×100, ×200 and ×400.

Immunohistochemical study

Removed surgical specimens were fixed in 10% phosphate-buffered, neutral formaldehyde solution at room temperature for 24 h. Tissue sections (4-µm thick) were deparaffinized, rehydrated and antigen retrieval with working solution of EnVision, FLEX Target Retrieval solution High Ph (50×) according to the manufacturer's protocol [EnVision FLEX+, Mouse, high Ph (Link) HRP; cat. no. K8002; Dako; Agilent Technologies, Inc., Santa Clara, CA, USA] in PT Link (cat. no. PT100; Dako; Agilent Technologies, Inc.) at 95°C for 20 min, and washed in distilled water (10). Endogenous peroxidase was blocked by DAKO Envision flex peroxidase-blocking reagent for 10 min, then washed again three times in the EnVision™ FLEX Wash buffer (Dako; Agilent Technologies, Inc.). The slides were incubated for 20–30 mins at room temperature in humidity chamber with appropriate dilutions of primary antibodies (primary antibodies are detailed in Table I) along with their positive and negative controls. Immunohistochemistry was done manually according to DAKO EnVision method (10), The sections (4-µm thick) were then incubated with secondary antibody (EnVision FLEX/HRP, cat. no. K8002; Dako; Agilent Technologies, Inc., Santa Clara, CA, USA) for coupling reaction for 20–30 min at room temperature. The substrate (EnVision FLEX DAB+ Chromogen) was used to produce crisp brown color at the site of target antigen. The hematoxylin (1–2 dips) was used as a counter stain. Sections were observed under a light microscope with the magnifications of 40, 100, 200 and ×400.

Table I.

Primary antibodies used for immunohistochemistry.

Table I.

Primary antibodies used for immunohistochemistry.

TargetSupplierCatalog numberDilutionStaining
ALKOrigene Technologies, Inc., Beijing, ChinaTA801287Ready to use+
PD-L1Origene Technologies, Inc.TA507087Ready to use+
PD-1Origene Technologies, Inc.TA314461Ready to useLymphocyte +
Ki-67Origene Technologies, Inc.UM8700331:100Index 40%
P53Gene Tech Co., Ltd., Shanghai, ChinaGM700101Ready to use+
DESOrigene Technologies, Inc.TA5023281:60Focally +
CKOrigene Technologies, Inc.ZM-00691:80Focal +
EMAGene Tech Co., Ltd.GM0613291:200
CAM5.2Origene Technologies, Inc.ZM-0316Ready to useFocal +
MyoglobinOrigene Technologies, Inc.ZA-0192Ready to use
CALDESGene Tech Co., Ltd.GM355701Ready to use
VimentinGene Tech Co., Ltd.GM0725291:120+
CD30Gene Tech Co., Ltd.GM0751291:35
CD3Origene Technologies, Inc.ZM-04171:120Lymphocyte +
CD20Gene Tech Co., Ltd.GM0755291:200Little lymphocyte +
CD4Origene Technologies, Inc.ZM-0418Ready to useLymphocyte +
CD8Gene Tech Co., Ltd.GT211202Ready to useLymphocyte +
MCGene Tech Co., Ltd.ZM-0386Ready to use
CalretininOrigene Technologies, Inc.TA3536301:60Focal +
WT-1Gene Tech Co., Ltd.GM356102Ready to use+
D2-40Gene Tech Co., Ltd.GM3619291:60
HMB45Origene Technologies, Inc.ZM-0187Ready to use
CD117Origene Technologies, Inc.ZA-0523Ready to use
DOG1Origene Technologies, Inc.ZM-0371Ready to use
SMAOrigene Technologies, Inc.ZM-0003Ready to use

[i] CALDES, caldesmon; CK, cytokeratins; DES, desmin; EMA, epithelial membrane antigen; MYF4, myogenin; PD, programmed death; PD-L1, programmed death-ligand 1; CD, cluster of differentiation; MC, mesothelial cells; WT-1, Wilms' tumor 1; DOG1, anoctamin-1; SMA, smooth muscle actin.

Fluorescence in situ hybridization (FISH)

FISH was performed on 4µm-thick paraffin sections with Vysis ALK Break Apart FISH Probe kit, according to the manufacturer's protocol (Abbott Laboratories, Chicago, IL, USA). The probe of ALK dual color separation of Abbott Company are composed of 3 ′one ALK orange fluorescent probe ~300 KB and 5 ′one ALK green fluorescent probe ~442 KB. The hybridization results were viewed by an epi-illumination fluorescence microscope (maginification, ×1,000). For no ALK rearrangement, these specimens contain fused orange and green signals or a single green signal without a corresponding orange signal; whilst for ALK rearrangement, these nuclei contained rearranged or ‘broken apart’ signals, 2 or more signal diameters apart.

Reverse transcription-polymerase chain reaction (RT-PCR)

RT-PCR analysis was performed to investigate the fusion location of the RAN binding protein 2 (RANBP2) and ALK gene. Total RNA was extracted from 20 µm-thick paraffin sections (AmoyDx® FFPE DNA and RNA Extraction kits; Amoy Diagnostics Co., Ltd., Xiamen, China), and reverse transcription (cat. no. ADx-AE01; Amoy Diagnostics Co., Ltd.) was conducted by random hexamer primers method to cDNA. The primer sequences of RANBP2-ALK were as follows: Forward, 5′-CAGACTCAGTGCCTGATGGATA-3′ and reverse, 5′-CGGAGCTTGCTCAGCTTGTA-3′. The PCR (2X Taq Master mix, Takara Bio, Inc., Otsu, Japan) reaction ran for 35 cycles under the following conditions: 95°C for 30 sec, 50°C for 30 sec and 72°C for 60 sec. An expected 139-bp amplified product was detected in the present case. β-actin was included as a reference gene, the primer sequences of β-actin were as follows: Forward, 5′-CACAGTAGGTCTGAACAGACTC-3′, and reverse, 5′-AGTGATCTCCTTCTGCATCCTG-3′. RANBP2-ALK fusion point was confirmed by direct sequencing (YMFX Biotech Co., Ltd.) of the chimeric cDNA product. The 2−∆∆Cq method (11) was used to determine the relative quantification of miR expression in the tissue samples.

Results

Magnetic resonance imaging examination

Images from magnetic resonance imaging enhanced scanning demonstrated that the morphology of the tumor was irregular, and signal was medley consisting of high and low hybrid reinforcement. Tumors located in the bladder and rectal pit in the lower part of the lower abdomen indicated the malignancy and involvement of the small intestine and rectum (Fig. 1A). Inhomogeneity was observed following enhanced scanning imaging (Fig. 1B).

Gross examination

Gross examination revealed that the tumor was located in the right abdominal wall (5.0×3.2×0.5 cm), left iliac fossa (2.5×2.0×1.0 cm), the greater omentum (17×12×4.5cm), part of the right hemi-colon (1.8×1.5×1.5–0.3×0.3×0.2 cm), the rectum (5.6×3.5×4.0 cm) and the abdominal cavity (25×19×10 cm). The tumor was solid and had a variegated appearance, with alternating fleshy and mucoid areas at the cut surface (Fig. 2).

Histopathological examination

Microscopically, tumor cells were not densely arranged. (Fig. 3A), and stroma is myxoid (Fig. 3B). Lymphocytes infiltrated into the stroma (Fig. 3C). The tumor cells were epithelioid, with eccentric nuclei, prominent nucleoli and abundant eosinophilic cytoplasm (Fig. 3D).

Immunohistochemical examination

Immunohistochemical staining results are depicted in Table I. The tumor cells exhibited diffuse strong staining for ALK (Fig. 4A), DES (Fig. 4B), PDL1 (Fig. 4C) and vimentin. Similarly, there was positive staining for Wilms' tumor 1 and tumor protein P53. The Ki-67 index was ~40%. The tumor cells also exhibited positive staining for the cytokeratins (CK) CAM5.2 and calretinin, although this staining was weaker. There was no reactivity to epithelial membrane antigen (EMA), smooth muscle actin (SMA), anoctamin-1 (DOG1), CD117, antibody HMB-45, antibody D2-40, mesothelial cells (MC), CD30, caldesmon or myoglobin. Infiltrated lymphocytes were mainly T cells, with a small number of B cells also present.

FISH analysis

FISH analysis revealed the presence of ALK rearrangements through the identification of a set of separate green and orange signals, a fused signal in tumor cell nuclei or through only one orange signal and a fused signal (Fig. 4D).

Genetic features

An expected 139-bp amplified product was detected in the sample (Fig. 5A). Positively amplified results (268-bp) of β-actin as a house-holding gene were also present (Fig. 5B). The RANBP2-ALK fusion point was at exon 18 of RANBP2 and exon 20 of ALK (Fig. 5C), which was confirmed by direct sequencing of the chimeric cDNA product.

Discussion

Clinically, EIMS occurs mainly in children and adolescents, although the overall range in age varies widely, with previous studies reporting on patients aged between 7 months and 65 years, with a median age of 33.4 years (Table II) (4,1220).

Table II.

Literature review of published EIMS cases.

Table II.

Literature review of published EIMS cases.

Author, yearCaseAge/SexAnatomic siteTreatmentFollow up, months(Ref.)
Marino-Enriquez et al, 2011  159 years/MMesentery of the small bowelSE+CT12 (STD)(4)
  241 years/MOmentumSE+CT+ALKi40 (ANED)
  36 years/MOmentumSE+CT13 (AWD)
  428 years/MMesentery of the small bowelNANA
  563 years/MMesentery of the small bowelSE+CT3 (DOD)
  642 years/M Intra-abdominalSE+CT13 (AWD)
  77 months/MPeritoneumSE+CT+RT36 (STD)
  840 years/MPeritoneumSE+CT+RT28 (STD)
  931 years/FMesentery of the small bowelSE+CT11 (STD)
106 years/MOmentum and mesenterySENO
1139 years/MMesentery of the small bowelSENO
Li et al, 20131219 years/FPelvic cavitySE3 (STD)(12)
1339 years/MPelvic cavitySE+CTRecurrent
Liu et al, 20151422 years/MPelvic cavitySE+ALKiNo recurrence(13)
Kimbara et al, 20141522 years/MPelvic cavitySE+CT+ALKiTS(14)
Kurihara-Hosokawa et al, 20141622 years/MPelvic cavitySE+CT+ALKiTS(15)
Zhou et al, 2015178 years/MPelvic cavitySE8 (STD)(16)
Wu et al, 20151847 years/FPelvic cavitySE+CT+RT8 (STD)(17)
Bai et al, 20151965 years/MColonResection SE+ Chinese medicineMetastases(18)
Yu et al, 20162037 years/FRectumSE8 (ANED)(19)
2155 years/MMesentery of ileumSE+CT10 (ANED)
2222 years/MMesentery of colonSE+ALKi14 (AWD)
2358 years/FOmentumSE+CT8 (STD)
2415 years/FTransverse colonSE7 (ANED)
Jiang et al, 20172545 years/MAbdominal cavitySE+crizotinib2 (DOD)(20)
Kozu et al, 20142657 years/MPleural cavityALKiNO(21)
Fu et al, 20152721 years/MLung with multiple bone metastasesSE+ALKi4 (STD)(22)
Current case2826 years/MPelvic cavitySE+CT8 (STD)

[i] ALKi, ALK inhibitor; ANED, alive, no evidence of disease; AWD, alive with disease; CT, chemotherapy; STD, succumbed to disease; NA, data not available; RT, radiotherapy; SE, surgical excision; TS, tumor shrinkage, NO, no follow-up.

The majority of patients with EIMS are male. In Table II, the male:female ratio is 21:7. EIMS is mainly located in abdominal cavity (4). In Table II, 26 cases occurred in the abdominopelvic area (4,1220), with two cases located in the pleural cavity (21,22). The most common symptom of EIMS is abdominal pain prior to surgery (19).

In soft tissue sarcomas, the tumors are often heterogeneous in composition, including areas of fibrosis, mucous degeneration, necrosis, and hemorrhage (23). Magnetic resonance imaging (MRI) enhanced scanning shows that high signal is a rich blood supply area (usually a tumor area), no enhancement area is a blood free region (equivalent to a liquefied necrotic area). From high signal to no signal, there also are different levels of reinforcement, which are related to tumor tissue structure, tumor angiogenesis and so on. A tumor can also appear high and low hybrid reinforcement. In the present case, the tumor comprises mucous degeneration and necrosis. The signal was medley consisting of high and low hybrid reinforcement.

Common characteristics of EIMS include: i) Round-to-epithelioid tumor cells; ii) abundant myxoid stroma with inflammatory infiltrates; iii) immunopositivity for ALK with a nuclear membrane or perinuclear staining pattern; iv) Desmin ES positive in the cytoplasm of tumor cells; and v) the frequent presence of the RANBP2-ALK fusion gene. All of these features were identified in the present case, meaning a diagnosis of EIMS was reached.

Immunohistochemically, EIMS exhibited nuclear membrane or perinuclear accentuation staining pattern of ALK, which was observed in 100% (25/25) of cases from a selection of previous studies (Table III) (4,1322). Another diagnostic immunophenotype is the diffuse strong expression of DES in almost all cases (92%; 23/25). In addition, the tumors displayed variable expression of SMA (45.5%, 10/22), CD30 (57.9%, 11/19) and cytokeratin (20%, 4/20) (Table III) (4,1322).

Table III.

Immunohistochemical, cytogenetic and molecular features of 28 cases of epithelioid inflammatory myofibroblastic sarcoma.

Table III.

Immunohistochemical, cytogenetic and molecular features of 28 cases of epithelioid inflammatory myofibroblastic sarcoma.

CaseIHCALK



Author, year DESSMACALDESCD30CKEMAMYF4S100IHCFISHRT-PCR(Refs.)
Marino-Enriquez et al, 20111+ + ++NANANA+NM+NA(4)
2+ + ++ + ++NM+RANBP2-ALK
3+ + +NANANA+NM+NA
4+ + ++ +NA+ +NA+NMNANA
5+ + ++ + ++PN+NA
6+ + +NANANANANANANA+NMNANA
7+ + +MA+ + +NANANA+PN+NA
8+ ++ ++NM+NA
9+ + ++ +NA+NM+NA
10+ + +NA+ + +NANANANA+NM+RANBP2-ALK
11+ + ++ ++ + +NA+NM+RANBP2-ALK
Liu et al, 201512+ +NA+ +NANA+PN+RANBP2-ALK(13)
Kimbara et al, 201413+ ++ +NANANANA+NMNARANBP2-ALK(14)
Kurihara-Hosokawa et al, 201414NANANANANANANANA+NMNARANBP2-ALK(15)
Zhou et al, 201515+ + ++ + +NA+ + ++NM+NA(16)
Wu et al, 201516+ + +NA+ + +NA+PN+RANBP2-ALK(17)
Bai et al, 201517+ + ++ + +NANA+ +NANANANANA(18)
Yu et al, 201618+ + +NA+NM+NA(19)
19+ + +NA+NM+NA
20+ + ++PN+NA
21+ + ++ ++ +NA+NM+NA
22+ + +NA+NM+NA
Jiang et al, 201723+ + ++ + +NANANANANANA+NM+RANBP2-ALK(20)
Kozu et al, 201424+ + ++ ++NM and +PN+RANBP2-ALK(21)
Fu et al, 201525+ + ++NM+NA(22)
Current case26+ + ++ ++NM+RANBP2-ALK
Total 92%45.5%0%57.9%20%0%0%0%100%100%100%
(23/25)(10/22)(0/13)(11/19)(4/20)(0/12)(0/18)(0/21)(25/25)(21/21)(10/10)

[i] +, rare positive cells; + +, focal positive staining; + + +, diffuse positive staining; -, negative staining; +NM, nuclear membrane staining; +PN, cytoplasmic staining with perinuclear accentuation; CALDES, caldesmon; CK, cytokeratins; DES, desmin; EMA, epithelial membrane antigen; FISH, fluorescence in situ hybridization; MYF4, myogenin; NA, data not available; RT-PCR, reverse transcription-polymerase chain reaction; SMA, smooth muscle actin; RANBP2, RAN binding protein 2; IHC, immunohistochemistry; ALK, ALK receptor tyrosine kinase.

Of the patients with IMT examined by Gleason and Hornick (3), ~50% aberrantly expressed the ALK protein, triggered by clonal rearrangements of the ALK gene located on chromosome 2p23. EIMS tumors harbor a specific RANBP2-ALK fusion gene resulting from t(2;2)(2q12; 2p23). All 21 cases tested by FISH exhibited an ALK translocation signal. Notably, all 10 cases in which the cDNA fusions were examined by RT-PCR exhibited identical fusion points, between exon 18 of RANBP2 and exon 20 of ALK (Table III). RANBP2 encodes a nuclear pore protein, which is likely to lead to the nuclear membrane or perinuclear staining pattern in EIMS.

Diagnosing EMIS can be challenging owing to the unusual epithelioid-to-round cell morphology and atypical nuclear features. EMIS should be differentially diagnosed with diseases as follows: i) Distinguishing EIMS from ALCL can be difficult, as the rare sarcomatoid variant of ALCL can exhibit spindle cell morphology and an overlapping immunophenotype, including reactivity for CD30, ALK and SMA and non-reactivity for EMA. Strong expression of DES and the distinctive nuclear membrane pattern of ALK staining are not observed in ALCL. The RANBP2-ALK has never been reported in ALCL either. ii) Malignant mesothelioma (MM), MC, CK5 and calretinin are present in MM, but ALK is absent. iii) Epithelioid GIST is positive for CD117, DOG1 and CD34. Mutations to c-Kit and platelet derived growth factor-α are also present in GIST. GIST exhibits negative ALK staining. iv) The solid variant of alveolar rhabdomyosarcoma is frequently ALK-positive, lacks fibrovascular stroma and forms sheets of round cells with variable rhabdomyoblastic differentiation. Antibodies against MyoD and myogenin are highly specific and sensitive for its diagnosis; and v) epithelioid leiomyosarcoma (ELS) ELS commonly displays greater cellular atypia and pleomorphism, and higher cellular density. ELS generally lacks an extensive myxoid background and inflammatory infiltrates (12) and lacks ALK nuclear membrane expression (Table IV).

Table IV.

Differential diagnosis of EMIS.

Table IV.

Differential diagnosis of EMIS.

DiseaseIHCMolecular pathology
EMISCD30 (+), ALK (+), SMA (+), EMA (+) and DES (+)RANBP2-ALK
ALCLCD30 (+), ALK (+), SMA (+), EMA (+) and DES (−)T cell gene rearrangement
MMMC (+), CK5 (+), Calretinin (+) and DES (−)P16/CDKN2A
GISTCD117 (+), DOG1 (+) and CD34 (+)c-Kit and PDGFα
Alveolar RhabdomyosarcomaMyogenin (+)PAX3-FOXO1 and PAX7-FOXO1 fusion gene
Epithelioid leiomyosarcomaALK (−)HMGA and MED12

[i] ALCL, anaplastic large cell lymphoma; MM, malignant mesothelioma; GIST, gastrointestinal stromal tumor; IHC, immunohistochemistry; EMIS, epithelioid inflammatory myofibroblastic sarcoma; RANBP2, RAN binding protein 2; PDGF, platelet growth factor receptor; CK, cytokeratins; CDKN, cyclin-dependent kinase inhibitor; DES, desmin; EMA, epithelial membrane antigen; SMA, smooth muscle actin; PAX, paired box; FOXO1, forkhead box O1; HMGA, high mobility group AT-hook; MED12, mediator complex subunit 12 gene; MC, mesothelial cells.

Currently, the majority of cases of EMIS are treated by surgical resection combined with chemotherapy (4,12). Several reports indicated that patients with an ALK gene rearrangement had a notable response to ALK targeted therapy (1315); however, disease recurrence is common following resection (24). In the present case, the patient was treated with chemotherapy prior to and following surgical resection, but succumbed as a result of cachexia due to tumor metastasis to the thoracic cavity.

Staining for programmed death-ligand 1 (PD-L1) was diffusely positive in the present case. The expression of PD-L1 in this patient was comparable to that in other genitourinary cancer types, such as bladder cancer (20%) (25), and non-genitourinary cancer types, such as breast cancer (23.4%) (26), colorectal cancer (36%) (27), testicular seminomas (73%) (28) and cancer of the oral cavity (73%) (29). The PD-1/PD-L1 axis has a notable role in the immune antitumor response (30,31). PD-L1 expression in tumor cells is considered to be predictive of the tumor response to immunomodulatory therapies targeting the PD-1/PD-L1 pathway (32). Unlike chemotherapy and molecularly targeted therapy, the checkpoint blockade immunotherapies result in durable clinical responses through the induction, activation, and expansion of tumor-specific cytotoxic T cells. Immune checkpoints serve an essential role in maintaining self-tolerance and regulating the amplitude and duration of T cell responses (33). Immunotherapies with checkpoint blockade antibodies that block PD-1 (or its ligand PD-L1) can restore and augment cytotoxic T cell responses against chemotherapy-refractory tumors, leading to durable responses and prolonged overall survival with tolerable toxicity (33).

In conclusion, EIMS is a highly aggressive IMT variant with epithelioid-to-round cell morphology, myxoid stroma and nuclear membrane or perinuclear ALK staining. Detection of ALK rearrangement in the present study provides further evidence for the diagnosis of the tumor and a reliable reference for ALK-targeted therapy. The expression of PD-L1 in EIMS indicated the immune checkpoint blockade, which could represent a novel anti-EIMS therapy.

Acknowledgements

The authors would like to thank to Mr. Yongqi Chen (Department of Pathology, Beijing Aerospace General Hospital, Beijing, China) for editing the language of this paper.

Acknowledgements

Not applicable.

Funding

The present study was supported by grants from the 2016 Basic clinical cooperation project of China Capital Medical University (grant no. 3500-11722913).

Availability of data and materials

The datasets generated in the present study are available on reasonable request from the corresponding author.

Authors' contributions

XD was responsible for consulting literature, reviewing slices and drafting the manuscript. YG conducted the molecular genetic studies and immunohistochemistry experiments. HZ made was responsible for the paraffin sections. BL obtained and analyzed the MRI report. WX conducted the FISH experiment. DW took part in analysis and interpretation of data, edited the language of this paper and provided funding support.

Ethics approval and consent to participate

The study protocol was approved by the Medical Ethics Committee of Beijing Shijitan Hospital, Capital Medical University (Beijing, China).

Consent for publication

Written informed consent was obtained from patient's father.

Competing interests

The authors declare that they have no competing interests.

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June-2018
Volume 15 Issue 6

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Online ISSN:1792-1082

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Copy and paste a formatted citation
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Spandidos Publications style
Du X, Gao Y, Zhao H, Li B, Xue W and Wang D: Clinicopathological analysis of epithelioid inflammatory myofibroblastic sarcoma. Oncol Lett 15: 9317-9326, 2018
APA
Du, X., Gao, Y., Zhao, H., Li, B., Xue, W., & Wang, D. (2018). Clinicopathological analysis of epithelioid inflammatory myofibroblastic sarcoma. Oncology Letters, 15, 9317-9326. https://doi.org/10.3892/ol.2018.8530
MLA
Du, X., Gao, Y., Zhao, H., Li, B., Xue, W., Wang, D."Clinicopathological analysis of epithelioid inflammatory myofibroblastic sarcoma". Oncology Letters 15.6 (2018): 9317-9326.
Chicago
Du, X., Gao, Y., Zhao, H., Li, B., Xue, W., Wang, D."Clinicopathological analysis of epithelioid inflammatory myofibroblastic sarcoma". Oncology Letters 15, no. 6 (2018): 9317-9326. https://doi.org/10.3892/ol.2018.8530