An extralingual Ectomesenchymal chondromyxoid tumor with RREB1::MRTFB fusion: a rare case report of plantar fascia involvement

Abstract

Background

Ectomesenchymal chondromyxoid tumor (ECT) is a rare benign intraoral tumor that almost exclusively presents as a small mass on the anterior dorsal tongue. Recently, the ras-responsive element-binding protein 1::myocardin-related transcription factor B (RREB1::MRTFB; previously known as MKL2) fusion gene has been identified in 90% of ECTs, all localized to the tongue, highlighting its genetic distinctiveness. Herein, we report a mesenchymal tumor involving the plantar fascia of the left foot in a young woman, harboring the RREB1::MRTFB fusion gene.

Case presentation

The tumor presented as a well-circumscribed mass. Following complete excision, no recurrence was observed at the six-month follow-up. Histological examination revealed tumor cells exhibiting mild nuclear atypia and very low mitotic activity. Immunohistochemical analysis showed diffuse positive staining for S100, glial fibrillary acidic protein (GFAP), and CD56, variable expression of smooth muscle actin, and negative staining for SOX10 and P63. Targeted RNA sequencing identified RREB1 (exon 8)–MRTFB (exon 11) fusion transcripts. Collectively, these findings suggest the possibility of a previously unreported extralingual ECT involving the plantar fascia. However, its atypical morphology and uncommon anatomical location posed significant diagnostic challenges.

Conclusions

We report, for the first time, a mesenchymal chondromyxoid tumor with an RREB1::MRTFB fusion gene occurring in the foot. This case expands the known distribution of ECT beyond the tongue. Accurate differential diagnosis should rely on thorough histological assessment, combined with immunohistochemical and molecular analyses.

Background

Ectomesenchymal chondromyxoid tumor (ECT) is an extremely rare neoplasm almost exclusively occurring in the tongue, first described by Smith et al. in 1995 [1]. A recent study reported that the average patient age is 40 years, ranging from 2.3 to 78 years, with no significant sex predilection [2]. Most ECTs are localized to the anterior dorsal surface of the tongue [2, 3]. However, rare cases involving the lateral tongue, gingiva [4], hard palate [5, 6], tonsillar bed [7], and the right mandibular body [8] have also been documented. These tumors are typically slow-growing, painless, well-circumscribed, firm submucosal nodules without ulceration. Their sizes generally range from 0.3 to 4.0 cm in diameter, with rare exceptions exceeding 4.0 cm. Microscopically, ECTs are composed of small, round-to-fusiform cells arranged in sheets within a myxoid or hyalinized stroma. Hemorrhage and cyst formation are occasionally observed.

The term “ectomesenchymal chondromyxoid tumor,” introduced in the initial publication, reflects the presumed origin of the tumor from migrated ectomesenchymal cells of the neural crest. This hypothesis is supported by the observation that the anterior tongue derives from neural crest mesenchyme of the first branchial arch, explaining the tumor’s predilection for this location. The neural crest origin theory is further corroborated by immunohistochemical markers such as GFAP, S-100, and CD56, which are commonly expressed in neural tissue. Recently, Dickson et al. [9] identified a novel RREB1::MRTFB fusion gene in 90% of 21 ECTs, all of which were located in the tongue, underscoring the genetic distinctiveness of this neoplasm.

Herein, we report a mesenchymal tumor involving the plantar fascia of the left foot harboring the RREB1::MRTFB fusion gene. Although initially unclassifiable, histological reevaluation and additional immunohistochemical studies, informed by genetic insights, revealed phenotypic similarities to ECTs of the tongue, suggesting that this case represents an extralingual counterpart of ECT.

Case presentation

A 20-year-old woman presented with swelling and pain in the left plantar region persisting for 4 years. Outpatient examination revealed a left plantar mass measuring approximately 44 mm × 20 mm × 20 mm. She was admitted to the hospital with a diagnosis of “left lower limb tumor.” The patient had no relevant personal or family medical history.

Magnetic resonance imaging (MRI) of the left foot revealed a block-shaped abnormal signal in the space between the left plantar flexor muscle tendon. The lesion demonstrated uneven, slightly low-intensity T1 signals and uneven high-intensity T2 signals, with well-defined borders and a size of approximately 44 mm × 20 mm × 20 mm (Fig. 1). Compression of adjacent flexor spaces was observed, but no significant bone destruction was detected in the calcaneus, talus, sphenoid bone, cuneiform bone, or metatarsal bones. The tarsal and metatarsophalangeal joints were free of stenosis, with smooth joint surfaces. No fluid accumulation was noted in the joints, or abnormal signals were observed in the surrounding soft tissues or tendons.

Fig. 1

Sagittal T2-weighted magnetic resonance imaging showing a well-defined, heterogeneous hyperintense lesion on the left foot

MRI findings suggested a left plantar mass with benign characteristics, potentially indicating focal bleeding or degeneration. A clinical diagnosis of a benign lesion was made, and local excision was performed. Histopathological examination confirmed tumor-free surgical margins, and the postoperative course was uneventful. The patient was referred to a local physician for follow-up care.

Pathological findings

The surgically resected specimen consisted of an elastic, soft tumor measuring 4.5 cm × 2.3 cm × 1.2 cm. The cut surface revealed a cystic and solid appearance, with bloody fluid in the cystic region and a grayish-white solid region exhibiting a focal mucinous texture. Histological examination showed that the tumor was well-circumscribed, with a thin fibrous capsule covering most areas and localized infiltration into the surrounding skeletal muscle tissue. The tumor predominantly comprised uniform, short spindle to ovoid cells with hyaline or eosinophilic cytoplasm. At high magnification, certain regions displayed cells secreting mucus, giving rise to a microcystic morphology. There was no evident nuclear atypia in the myxoid stroma. Mitotic figures were absent, and no necrosis was observed. The stroma was rich in blood-filled sinusoids, resembling vascular-related lesions, with some areas demonstrating collagenization suggestive of an osteoid matrix (Fig. 2).

Fig. 2

Histopathological findings of the surgical specimen. (A) The tumor was well circumscribed, with a thin fibrous capsule encasing most areas. (B) Localized invasion into the surrounding skeletal muscle tissue. (C) The tumor predominantly comprised uniform short spindle to ovoid cells with hyaline or eosinophilic cytoplasm. (D) Some areas exhibited microcystic morphology, with an absence of cellular atypia. (E) Regions containing blood sinusoid-like structures. (F) Collagenized regions within the tumor

Immunohistochemistry revealed diffuse positive staining for S100, GFAP, and CD56, with focal weak positivity for smooth muscle actin (SMA). The Ki-67 labeling index was 10% in hotspot areas. The tumor cells were negative for pan-cytokeratin, CD34, ERG, HMB45, Melan-A, P63, SOX10, and neuron-specific enolase (NSE) (Fig. 3). Notably, TFE3 showed nuclear weak positivity; however, fluorescence in situ hybridization (FISH) analysis for TFE3 did not detect signal separation.

Fig. 3

Photomicrographs of immunohistochemical staining. (A) Positive staining for S100. (B) Positive staining for CD56. (C) Positive staining for GFAP. (D) Weakly positive staining for SMA. (E) Negative staining for CK-pan. (F) Negative staining for SOX10. (G) Negative staining for CD34. (All images, IHC ×100 magnification)

Molecular analysis using targeted RNA-based next-generation sequencing (NGS) identified an in-frame fusion between exon 8 of RREB1 (NM_001003698.4) and exon 11 of MRTFB (NM_014048.4), a genetic event previously reported as highly recurrent in ECTs [10] (Fig. 4).

Fig. 4

RREB1::MRTFB fusion gene analysis. (A) Schematic representation of the fusion event between RREB1 (orange) and MRTFB (green). The RREB1 gene is located on chromosome 6p, and the MRTFB (formerly MKL2) gene is located on chromosome 16p. Lines and filled boxes represent intronic sequences and coding exons, respectively. BP, breakpoint. (B, C) Representative screenshots from the Integrative Genomics Viewer showing split reads mapping to the 3’ region of RREB1 exon 8 and the 5’ region of MRTFB exon 11

Based on the histopathological, immunohistochemical, and molecular findings, a diagnosis of ECT was established. At the 3-month postoperative follow-up, the patient remained recurrence-free.

Discussion and conclusions

ECT is a rare intraoral mesenchymal tumor. In this report, we describe, for the first time, an extremely rare case of ECT arising from the plantar fascia of the left foot in a young woman, a location where it can be easily misdiagnosed in clinical practice.

Unlike the painless presentation commonly reported in the literature [2], this patient experienced swelling and pain, likely attributable to the tumor’s location. Gross examination of the tumor revealed a firm-to-myxoid or gelatinous cut surface with variable coloration, including yellow and white. Cystic areas with or without hemorrhage, as described previously [11], were also observed in this case.

Morphologically, ECT typically presents as a well-defined, non-encapsulated mass composed of uniform round, ovoid, or fusiform cells embedded in a myxoid or chondromyxoid matrix, with no mitotic figures, nuclear pleomorphism, or vascular invasion [12]. In contrast, the present case showed a thin fibrous capsule and focal infiltration into the surrounding skeletal muscle. Sakurai et al. [13] previously reported involvement of striated muscle bundles and peripheral nerve fibers within ECTs, raising the question of whether these features suggest an invasive biological behavior that warrants further investigation.

Initially, we considered hemangioblastoma; however, this diagnosis was ruled out due to negative staining for α-inhibin and NSE. Microcystic/reticular schwannoma was also considered due to S100 positivity, but SOX10 negativity contradicted this diagnosis. Karamchandani et al. [14] noted that S100 and SOX10 exhibit similar sensitivity in neural crest-derived tumors, excluding malignant peripheral nerve sheath tumor. Other differential diagnoses, including monophasic spindle cell synovial sarcoma, solitary fibrous tumor, and myoepithelioma, were excluded due to negative staining for CD99, TLE1, CD34, and P63.

Non-ossifying fibromyxoid tumor, a subtype of ossifying fibromyxoid tumor (OFMT), was also considered because of its histological similarity to ECT, S100 positivity in 67% of cases, and lack of ossification. However, this diagnosis was ultimately excluded due to the absence of INI1 loss and the lack of TFE3 rearrangement on FISH analysis. Notably, OFMT is associated with recurrent gene rearrangements, predominantly involving the PHF1 gene [15, 16].

Given these challenges, we explored mesenchymal tumors with GLI1 alterations, but FISH analysis showed no changes in GLI1. NGS identified the presence of an ras-responsive element-binding protein 1::myocardin-related transcription factor B (RREB1::MRTFB; previously known as MKL2) fusion product, involving RREB1 (located at 6p24.3 [17]) and MRTFB (located at 16p13.12 [18]). (The differential diagnosis has been summarized in Table 1.)

Table 1 Pathological differential diagnosis for ECT

The RREB1::MRTFB fusion has been identified in various tumors, most commonly ECTs (Summaried in Tables 2 and 3). In a series of 21 cases, Dickson et al. [9] reported RREB1::MRTFB fusions in 19 cases (90%) of ETC, with one case showing no known genetic changes and another harboring an EWSR1::CREM fusion. Additional studies [10, 19,20,21,22,23], summarized in Table 3, have reported 11 sporadic cases with the RREB1::MRTFB fusion. Of these, two cases resembled biphenotypic sinonasal sarcoma [10, 22], two mimicked rhabdomyosarcoma [21], and the remaining cases were reported as unclassified fibromyxoid neoplasms.

Table 2 Summary all ECT cases reported with the RREB1- MRTFB gene fusion

Table 3 Summary the other cases reported with the RREB1- MRTFB gene fusion

Siegfried et al. [22] proposed that the RREB1::MRTFB fusion promotes MRTFB translation, regulating both neural and myogenic differentiation, similar to the role of PAX3 fusions in biphenotypic sinonasal sarcoma [24, 25]. This mechanism aligns with the immunophenotype of ECT, which shows neurogenic markers (S100 protein) and myogenic markers (SMA, desmin, and myosin). Further research is needed to elucidate the pathogenesis.

According to existing literature, ECT follows a benign course, with no reported metastases. However, five cases of recurrence have been documented, with follow-up durations ranging from 3 months to 10 years after initial resection [1, 2, 9, 26]. Adequate surgical excision is critical for favorable patient outcomes.

Conclusion

To the best of our knowledge, this is the first reported case of a tumor with an RREB1::MRTFB gene fusion occurring in the sole of the foot. Based on comprehensive histological, immunohistochemical, and molecular pathological analyses, the tumor was ultimately classified as an ECT. However, the atypical anatomical location and overlapping morphological features pose a significant risk of misdiagnosis. Our findings provide additional evidence that the RREB1::MRTFB fusion is not confined to tumors in the head region, thereby increasing awareness of this rare entity.