An extra-glossal ectomesenchymal chondromyxoid tumor with RREB1::MRTFB fusion-positive: A case report of a rare tumor at a rare site

doi:10.21203/rs.3.rs-5283364/v1

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Case Report

An extra-glossal ectomesenchymal chondromyxoid tumor with RREB1::MRTFB fusion-positive: A case report of a rare tumor at a rare site

https://doi.org/10.21203/rs.3.rs-5283364/v1

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Background: Ectomesenchymal chondromyxoid tumor (ECT) is a rare benign intraoral tumor which almost exclusively presents as a small mass of the anterior dorsal tongue. Recently, the RREB1–MRTFB (previously known as MKL2) fusion gene has been identified in 90% of ECTs, all located in the tongue, emphasizing its genetic distinctiveness. Herein we report one mesenchymal tumor involving the bottom of the left foot of young women with RREB1–MRTFB fusions.

Case presentation: The tumor presented as well-circumscribed masse. After complete excision recurrence was not observed at 6 months. Although tumor were originally unclassifiable, targeted RNA sequencing revealed RREB1 (exon 8)–MRTFB (exon 11) fusion transcripts. The tumor cells showed mild nuclear atypical with very low mitotic activity. Immunohistochemistry staining show S100, glial fibrillary acidic protein, CD56 diffuse positive, variable expression of SMA, and negative for SOX10、P63. Overall, these findings suggest that they may represent previously undescribed extra-glossal ECT involving the plantar fascia. However, it has brought many obstacles to our diagnosis because of its unclassical morphology and uncommon site.

Conclusions: We report for the first time a mesenchymal chondromyxoid tumor with RREB1-MTRFB gene fusion occurring in the foot. This case furthers awareness of the extra-glossal distribution of ECT. By carefully observing morphology and combining immunohistochemistry and molecular techniques, we can effectively avoid misdiagnosis and missed diagnosis of the diseases.

extra-glossal ectomesenchymal chondromyxoid tumor

ECT

RREB1

MRTFB

MKL2

Ectomesenchymal chondromyxoid tumor (ECT) is a very rare lesion almost exclusively occurring in the tongue, which was first described by Smith et al. in 1995[1]. The recently review article show that the average age of patient is 40 years range from 2.3 to 78 years. The tumor shows no significant sex predilection[2]. Most of these tumors have been identified on the anterior aspect of the dorsal surface of the tongue[2, 3]. Rare examples of lesions involving the lateral part of the tongue, gingiva[4], hard palate [5, 6], tonsillar bed [7] and the right body of the mandible[8] have also been reported. These tumors are reported as a slow-growing, painless, well-circumscribed, firm submucosal nodule without ulceration. The size generally ranged from 0.3 to 4.0 cm in diameter, with very rare exceptions more than 4.0 cm. Microscopically, the tumour was composed of small round-to-fusiform cells arranged in sheets, with a myxoid or hyalinized strom. Occasionally, hemorrhage, and cyst formation can be seen.

The term “ectomesenchymal chondromyxoid tumor,” given in the first relevant publication, is descriptive, based on the presumption of tumor origin from migrated ectomesenchymal cells of the neural crest. The reason is that the anterior tongue is derived from the neural crest mesenchyme of the first branchial arch, explaining the distinct predilection of this tumor for that location. The neural crest theory is also reinforced by immunohistochemical expressivity related to neural tissue such as GFAP, S-100, and CD56. Furthermore, Dickson et al.[9] recently discovered a novel RREB1–MRTFB (previously known as MKL2) fusion gene in 90% of 21 ECTs, all located in the tongue, which emphasizes their genetic distinctiveness.

Herein, we report one mesenchymal tumor involving the bottom of the left foot with RREB1– MRTFB fusions. Although the tumors was originally unclassifiable, histological review and additional immunohistochemical work-up in the light of genetic information revealed a phenotypical resemblance to ECT of the tongue, suggesting that they may represent its extra-glossal counterpart.

A 20-year-old young girl with left plantar swelling and pain for 4 years. Outpatient examination showed a left plantar mass, approximately 44 * 20 * 20mm in size, and was admitted to the hospital for "left lower limb tumor ". The patient had no personal or family medical history. The left foot MRI plain scan results showed a block shaped abnormal signal in the space between the left plantar flexor muscle tendon, showing uneven slightly short T1 and uneven long T2 signals, with clear boundaries and a range of about 44 * 20 * 20mm(Fig. 1). Adjacent flexor spaces are compressed; No significant bone destruction was observed in the remaining calcaneus, talus, talus, sphenoid bone, cuneiform bone, metatarsal bone, and metatarsal bone. There was no stenosis in the tarsal joint, tarsal joint, and metatarsophalangeal joint, and the joint surface was smooth. No fluid accumulation was found in the joint. There is no significant swelling in the soft tissue around the remaining joints, and no abnormal signals are observed in the tendons. The diagnosis result of MRI: Left plantar mass, with a benign tendency, indicating focal bleeding or degeneration.

A benign lesion was suspected clinically, and local excision was performed. The surgical margin was free of tumor cells and the postoperative course was uneventful. The patient was referred to a local physician for follow-up treatment.

Pathological findings

The surgically resected specimen consisted of an elastic soft tumor measuring 4.5*2.3*1.2cm. The cut surface exhibited cystic and solid appearance, with bloody fluid contained in the cystic area, and the solid area was grayish white with a focal mucinous sensation. Histological observation showed the tumor was well circumscribed, with a thin fibrous capsule attached to most areas and localized infiltration of surrounding skeletal muscle tissue. The tumor was predominantly composed of uniform short, spindle to ovoid cells with hyaline or eosinophilic cytoplasm. Under high power lens, some cells in certain areas secrete mucous exhibition of a microcystic morphology. There was no obvious nuclear atypia in a myxoid stroma. Mitotic figures were not apparent, and no necrosis was detected. The stroma was rich in blood-sinusoid, resembling a vascular related lesions and some area was collagenized, resembling an osteoid matrix (Fig. 2).

Immunohistochemistry revealed that the tumor cells were diffusely positive for S-100, glial fibrillary acidic protein (GFAP), CD56 protein and focal weakly positive for smooth muscle actin protein (SMA). The Ki-67 labeling index was 10% in hotspot area. The tumor cells were negative for pan-cytokeratin, CD34, ERG, HMB45, Melan-A, P63 or SOX10, NSE. Specifically, TFE3 appeared to be nuclear positive, but TFE3 (FISH) detection lacked signal separation (Fig. 3).

Molecular analysis by targeted RNA-based next-generation sequencing (NGS) was performed finally, and identified an in-frame fusion between exon 8 of RREB1 (NM_001003698.4) and exon 11 of MRTFB (NM_014048.4), a genetic event that was reported to be a highly recurrent fusion in ECTs [10].

A diagnosis of ECT was rendered based on the findings obtained from the histopathological, IHC and NGS analyses. The patient was reviewed after 3 months of surgery, and she remains no recurrence to date.

ECT is a rare intraoral mesenchymal tumor. In this report, we first describe an extremely rare lesion of ECT arising from the bottom of the left foot of young female, which is very easy to misdiagnose in our daily work.

Unlike the painlessness described in the literature[2], the patient in this case experienced swelling and pain, which may be related to the location of the tumor. Grossly, the tumor revealed a firm-to-myxoid or gelatinous cut surface with various colors, such as yellow or white. Cystic areas with or without hemorrhage were described[11]. These features were also observed in the present case. Morphologically, ECT generally exhibits a well-defined, non-encapsulated mass with uniform round, ovoid or fusiform cells embedding in a myxoid or chondromyxoid matrix, without mitotic figures, nuclear pleomorphism, or vascular invasion[12]. The different feature in our tumor is a thin fibrous capsule attached, and focal infiltrate into the surrounding skeletal muscle. Sakurai K et al [13] reported that bundles of striated muscle and peripheral nerve fibers were involved within the tumor. Whether these features suggest invasive biological behavior remains to be observed.

At first, we thought it might be a hemangioblastoma, but it was quickly rejected because a-inhibin and NSE were negative expression. Then we considered it maybe a microcystic/reticular schwannoma due to S-100 positivity, but SOX10 negativity did not support this diagnosis. Karamchandani JR et al [14]reported that S100 and Sox10 showed similar sensitivity in tumors of neural crest origin, excluding malignant peripheral nerve sheath tumor (MPNST). In addition, the differentiation diagnosis included monophasic spindle cell synovial sarcoma (SS), solitary fibrous tumor (SFT), and myoepithelioma. All of them were ruled out because of the CD99, TLE1, CD34 and P63 negativity in the present case. Notably, non-ossifying fibromyxoid tumor, which is a subtype of ossifying fibromyxoid tumors (OFMT), shows about 67% of cases S-100 positive. The histological morphology is similar to ECT and without ossification. But eventually the diagnosis was ruled out because of no absence expression of INI1 and no signal separation of TFE3 Fish detection. In recent years, OFMT has been shown to be associated with recurrent gene rearrangements, mostly involving the PHF1 gene (including in typical, atypical, and malignant neoplasms)[15, 16]. Finally, the mesenchymal tumor with GLI1 changes caught our attention, so we provided GLI1 fish testing, and the result did not show any changes. Ultimately, we recommended NGS testing, which showed the presence of an RREB1::MRTFB fusion product; this involved RREB1 (Ras-responsive element-binding protein 1, mapped to 6p24.3[17]), and MRTFB (myocardin-related transcription factor B, mapped to 16p13.12[18]).(Summarized in Table1)

Table 1

Pathological differential diagnosis for ECT
Tumor	Clinical feathers	Histopathology	Immunohistochemistry	Molecular findings
ECT	Occurring in the tongue, no significant sex predilection	Small round-to-fusiform cells arranged in sheets, with a myxoid or hyalinized stroma. Occasionally, hemorrhage, and cyst formation can be seen.	Most show GFAP, S-100, and CD56 expression; Variable expressed for CD56, SMA; negative for CK, SOX10, P63	Most show RREB1- MRTFB fusion; subset show EWSR1 rearrangement
Hemangioblastoma	Occurring in the central nervous system	Rich in small blood vessels and large vacuolar stromal cells, with clear boundaries	Most positive for a-inhibin, variable positive for NSE, S-100, calretinin; negative for GFAP, CD10	VHL
Microcystic/reticular schwannoma	Predilection for the head, neck, and limbs;young patients	Bland ovoid, spindled cells; may demonstrate reticular or focal Microcapsules architectural patterns	Positive for S-100, SOX10, CD56; negative for CK, EMA, SMA, CD34	Not applicable
Monophasic spindle cell synovial sarcoma	The lower extremities; young adults with a male preponderance	Spindle cells arranged in fascicles with nuclear atypical	Expression TLE1, CD99, Bcl2, CD56; patchy positive for EMA, S-100	t(X;18)(p11;q11)translocation; SYT-SSX gene fusion
Solitary fibrous tumor	Intra-thoracic is the most common location; predilection for female	Oval to spindle-shaped nuclei cells;display a hemangiopericytic growth pattern, known as “staghorn” blood vessels, and perivascular sclerosis	Positive for CD34, BCL-2, CD99, STAT6; negative for CK, S-100, SOX10, SMA	NAB2-STAT6 gene fusion; GRIA2 highly expression
GLI1-Altered Mesenchymal Tumors	Predilection for the tongue; present in younger to middle-aged adults	Ovoid-to-round or vaguely epithelioid cells arranged in compact or ill-defined nests that are separated by a well-developed arborizing capillary network	Variable expression of SMA, CD56, S-100, NSE, P16, GFAP, calponin	GLI1-fusion-positive tumors (eg. ACTB::GLI1); GLI1-amplified tumors
Non-ossifying fibromyxoid tumor	Often based within the subcutaneous tissues of proximal limbs and limb girdles	Well-circumscribed; absent ossifying; uniform, round, or ovoid epithelioid cells with defined cytoplasmic borders, within a myxohyaline or fibromyxoid stroma	Positive for vimentin, CD10, S-100, NSE, desmin, TFE3; negative for CK, SOX10; variable expression INI-1	PHF1 gene rearrangement (eg.PHF1-TFE3)
Soft tissue myoepithelioma	Most common in the limb girdles and extremities;in younger age group on average	Epithelioid cells with a chondromyxoid stroma; ductal differentiation or plasmacytoid morphology	Positive for AE1/AE3, Cam5.2, S-100, SOX10, GFAP, SMA, Calponin; Variable expression INI-1	EWSR1 gene rearrangement or FUS abnormalities
ECT, ectomesenchymal chondromyxoid tumor; GFAP, glial fibrillary acidic protein; SMA, smooth muscle actin; CK, keratin; RREB1: ras responsive element binding protein 1; MRTFB, myocardin related transcription factor B; EWSR1, EWS RNA binding protein 1; NSE, neuron-specific enolase; VHL, Von Hippel-Lindau; EMA, epithelial membrane antigen; TLE1, transducin-like enhancer protein 1; SYT: synaptotagmin; SSX, synovial sarcoma X breakpoint; NAB2, NGFI-A binding protein 2; STAT6, signal transducer and activator of transcription 6; GRIA2, glutamate receptor lonotropic AMPA 2; GLI1, glioma-associated oncogene homolog 1; ACTB, beta-actin; INI-1, Integrase interactor-1; PHF1, PHD finger protein 1; FUS: fused in sarcoma.

The RREB1::MRTFB fusion has been reported in various tumors, among which ECT is most commonly associated with it. In a series of 21 cases Dickson et al. [9]identified RREB1- MRTFB fusion gene in 19 cases (90%), of which 1 case did not show any known genetic changes, and the remaining 1 case contained EWSR1-CREM gene fusion. In addition to the study by Dickson et al., there were 12 sporadic cases reported with the RREB1- MRTFB gene fusion (including our case)[8, 10, 19–22](summarized in Table 2), of which 2 cases were considered to be ETC based on histological morphology and immunohistochemical detection results, 2 cases were morphologically similar to biphenotypic sinonasal sarcoma[10, 22], and 2 cases mimicked rhabdomyosarcoma[21], the remaining reported as unclassified fibromyxoid neoplasm. Siegfried et al[22] reported that the fusion gene RREB1– MRTFB promotes the translation of MRTFB, which regulates both neural and myogenic differentiation, like the role of PAX3 (commonly fusion with MAML3) in biphenotypic sinonasal sarcoma[23, 24]. It seems to be consistent with the immunophenotype of ECT, which expresses neurogenic type (S100 protein) and myogenic type (SMA, desmin, and myosin). Of course, further research is needed to clarify the pathogenesis.

Table 2

Summary of 12 sporadic cases reported with the RREB1- MRTFB gene fusion
Authers	Case NO.	Location	Reported as
Siegfried et al. 2017	Case1	Oropharyngeal	Biphenotypic “oropharyngeal” sarcoma
Naohiro Makise et al.2020	Case2	Paravertebral	Mesenchyme tumor with RREB1– MRTFB fusion
Naohiro Makise et al.2020	Case3	Superior mediastinum	Mesenchyme tumor with RREB1– MRTFB fusion
Gunhild Mechtersheimer et al 2021	Case4	Biphenotypic sinonasal	Biphenotypic sinonasal sarcoma
Justin Bubola et al. 2021	Case5	Mandible	ECT
Abbas Agaimy et al. 2022	Case6	Inguinal	Unclassified fibromyxoid neoplasm
	Case7	Presacral region	Unclassified fibromyxoid neoplasm
	Case8	Jaw	Chondromyxoid sinonasal hamartoma
	Case9	Parapharyngeal space	Unclassified spindle and round cell neoplasm
	Case10	Osterior nasopharyngeal wall	Low-grade mesenchymal neoplasm with rhabdomyoblastic differentiation and RREB:: MRTFB fusion, not RMS
Nuttavut Sumransub et al. 2022	Case11	Oropharyngeal tongue	rhabdomyosarcoma with RREB1-MRTFB fusion
Present case	Case12	The bottom of foot	ECT
NO., numero; RREB1: ras responsive element binding protein 1; MRTFB, myocardin related transcription factor B; ECT, ectomesenchymal chondromyxoid tumor

According to literature reports, mesenchymal chondromyxoid tumors follow a benign course with no metastases reported. 5 cases recurrence have been reported and follow up duration ranges from 3 months to 10 years after the original resection[1, 2, 9, 25]. Adequate surgical resection plays an important role in the prognosis of patients.

In summary, to our knowledge, this is the first case of a tumor with RREB1-MRTFB gene fusion occurring in the sole of the foot. Based on the comprehensive histological features, immunohistochemistry, and molecular pathological changes, ECT was ultimately considered. However, ECT is prone to misdiagnosis because of its special occurrence site, and overlapped morphology. Our report further provided the evidence that RREB1–MRTFB fusion is not limited to tumors in the head region, enhancing the awareness of this disease.

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The images did not contain the patient records and information. This study obtained ethical approval and participation consent by the Clinical Research Ethics board of the First Affiliated Hospital, Zhejiang University School of Medicine

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Written informed consent for publication was obtained from all participants.

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The authors declare that they have no conflicts of interest.

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This study has no funding source.

Author Contribution

Each author made critical contributions to the conception and design of this paper. Y.D. wrote the main original manuscript text and W. Z. prepared Figs. K.S. reviewed and edited manuscript text. All authors read and approved the final manuscript.

Acknowledgements

This article constitutes first presentation to this case report.

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An extra-glossal ectomesenchymal chondromyxoid tumor with RREB1::MRTFB fusion-positive: A case report of a rare tumor at a rare site

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