Mutation of KIT in cellular extraskeletal myxoid chondrosarcoma: a case report and literature review
Diagnostic Pathology volume 17, Article number: 42 (2022)
Extraskeletal myxoid chondrosarcomas (EMCs) are solid tumors that have been genetically and biologically characterized. Only a few studies have discussed the role of the KIT gene or CD117 expression in EMCs, identified by immunohistochemical (IHC) staining. Herein, we present a novel case of cellular EMC exhibiting an EWSR1-NR4A3 fusion, KIT exon 13 mutations and strong diffuse expression of CD117.
A 69-year-old man presented with a fist-sized tumor on his left shoulder. CT revealed a tumor in the left thoracic and dorsal muscle space. The tumor was completely resected. Histologically, the tumor cells had a nodular structure and infiltrated the peripheral fat and muscle tissues. The tumor cells were uniform in size with round nuclei, well-defined nucleoli and eosinophilic cytoplasm. Immunohistochemically, the tumor cells were positive for CD117, vimentin, CD56 and NSE and focally expressed desmin; the cells were negative for myogenin, S-100, SYN, INSM1, CD34, STAT6, INI-1, Brachyury, ERG, TLE1, AE1/AE3, WT-1, CD99 and SMA. NGS revealed an EWSR1-NR4A3 fusion and KIT exon 13 mutations. The patient had no further treatment after surgery, and no recurrence or metastasis occurred during the ~ 10 month follow-up period.
Molecular detection is an indispensable technique for diagnosing cellular EMCs. The KIT mutations noted in this case report may offer fresh insights into EMCs treatment options.
Extraskeletal myxoid chondrosarcomas (EMCs) are solid tumors that have been genetically and biologically characterized , and they comprise < 1% of all soft-tissue sarcomas . Cellular EMCs account for ~ 29% of all EMCs  and have the same nodular structure as classic EMCs; however, cellular EMCs demonstrate an abundance of compact tumor cells and a limited myxoid matrix. EWSR1-NR4A3 fusion products are detected in approximately 62–75% of patients with NR4A3 rearrangement [4,5,6]. Only a few studies have discussed the role of the KIT gene or CD117 expression in EMCs, identified by immunohistochemical (IHC) staining. Here, we present a novel case of cellular EMC in the left shoulder of a 69-year-old man who exhibited, in addition to the EWSR1-NR4A3 fusion, KIT exon 13 mutations, as revealed by next-generation sequencing (NGS). Moreover, the IHC staining results demonstrated strong diffuse expression of CD117. To the best of our knowledge, this is the first report of KIT exon 13 mutations in cellular EMC.
Six months before admission, a 69-year-old man noted a fist-sized tumor on his left shoulder without obvious fever, ulcer, night sweating, weight loss or other symptoms. We noted a palpable subcutaneous mass on the left side of the scapula, which was difficult to reach, with a clear boundary, poor mobility and no obvious tenderness. CT revealed an irregularly shaped soft-tissue mass 7.0 × 5.4 × 2.7 cm in size in the left thoracic and dorsal muscle space, and examination of the mass revealed a clear boundary and uniform density (Fig. 1a). The examination of the bone adjacent to the mass revealed slight absorption and destruction. MRI confirmed an irregularly shaped soft-tissue mass in the left thoracic and dorsal muscle space with long T1 and T2 signaling and uniform low-signal intensity on T1WI (Fig. 1b and c) and high-signal intensity with fat suppression on T2WI (Fig. 1d). During surgery, a mass approximately 7 × 6 × 3 cm in size was located in the deep surface of the latissimus dorsi muscle. Most of the mass capsule was complete, some tissues adhered to the bottom near the scapula region, and the mass was removed. The mass had a soft consistency and a pale-yellow appearance. The tissue specimen was then sent to the pathologist for analysis. The specimen comprised a block of tissues (2 blocks), which was 7.5 × 5.1 × 3.3 cm in size, without a capsule and revealed a nodular cut surface, grayish-white in color with a glossy appearance (Fig. 2).
Microscopically, the tumor cells were arranged in a nodular manner, and infiltrating growth into the surrounding fat and muscle tissue was present (Fig. 3a). The nodules were separated by a large volume of fibrous tissue, and most (> 80%) were solid in texture and comprised round, slightly short spindle cells (Fig. 3b). The cells were uniform in size and had a round nucleus, nonobvious entoblast and slightly stained cytoplasm; mitosis could be seen in high cellularity areas (Fig. 3c). Additionally, in some nodules, the cells were loosely arranged and connected into a reticulated or crossed appearance in the myxoid stroma (Fig. 3d), with no necrosis within the tumor.
IHC staining plays an essential role in this process; thus, the expression of several markers was assessed. The tumor was positive for CD117 (Fig. 3e), Vim, CD56 (Fig. 3f) and NSE and showed focal expression of desmin but was negative for myogenin, S-100, SYN, INSM1, CD34, STAT6, INI-1, Brachyury, ERG, TLE1, AE1/AE3, WT-1, CD99 and SMA.
Next-generation sequencing (NGS) was performed to detect tumor mutations. NGS detected a translocation of a fragment from exon 1 to 7 of EWSR1 and exon 2 to 5 of NR4A3 (Fig. 4a). NGS detected a single-nucleotide variant (A to G) in exon 13 of KIT (Fig. 5). Fluorescence in situ hybridization (FISH) confirmed the presence of the EWSR1-NR4A3 fusion gene. FISH for EWSR1 and NR4A3 demonstrated red–green staining, indicating the EWSR1-NR4A3 fusion (Fig. 6). A diagnosis of cellular EMC was confirmed based on the combined results of the morphological, immunophenotypic and molecular analyses.
EMCs were first defined as a class of solid tumors by Enzinger and Shiraki , and they constitute < 1% of all soft-tissue sarcomas . EMCs are commonly seen in male adults, with a mean age of onset of 50 years. Lesions are most frequently found in the deep soft tissues of the proximal extremities, especially the lower extremities; however, in some cases, EMCs can also affect the trunk, head and neck, abdominal wall, paravertebral soft tissues and bones [7,8,9,10].
Histologically, EMCs can be categorized into classical EMCs and two variants, cellular EMCs and solid nonmyxoid EMCs . The tumor cells, in this case, had a nodular structure and infiltrated the peripheral fat and muscle tissues. There were abundant fibrous tissues between the nodules, most of which were identified as solid nodules (> 90%) comprised of round or fusiform cells. The tumor cells were uniform in size and had round nuclei with well-defined nucleoli and eosinophilic cytoplasm, and their nuclear fission was 2/10 HPF. The nodular structure partly resembled that of classic EMCs, but the tumor cells were loosely arranged, forming reticular or crosswise layers in the myxoid matrix. Local necrosis was observed. Diagnosing EMC is extremely challenging because of the lack of specificity in their morphological features . Many soft tissue tumors have similar morphology to EMC. The main differential diagnosis includes cellular EMC, proximal-type epithelioid sarcoma, extrarenal malignant rhabdoid tumor, epithelioid angiosarcoma, malignant solitary fibrous tumor, extraosseous Ewing’s sarcoma, desmoplastic small round cell tumor, metastatic dedifferentiated chordoma, poorly differentiated synovial sarcoma and epithelioid malignant peripheral nerve sheath tumor. IHC staining plays an essential role in the diagnostic process. In this case, the IHC staining results suggested that the patient’s tumor was diffusely positive for CD117, vimentin, CD56 and NSE and focally positive for desmin, negative for other markers, and had a ki-67 level of ~ 40%. Despite the effectiveness of IHC staining, a definitive diagnosis of EMC cannot be made solely from positive IHC results for CD117, vimentin, CD56 and NSE as specific markers; however, IHC provided a diagnostic clue, and NGS was performed on the tumor. An EWSR1 exon 7-NR4A3 exon 2 fusion was subsequently identified. Thus, a diagnosis of cellular EMC was confirmed by considering the combined results of the morphological, immunophenotypic and molecular analyses. A recent study  reported positivity for INSM1 in up to 90% of EMC cases, which is considered evidence for the neuroendocrine differentiation of EMC cells; however, INSM1 expression was not detected in this case. In terms of molecular genetics, EWSR1-NR4A3 fusion products are detected in approximately 62–75% of patients with NR4A3 rearrangement [4,5,6]. Other studies have reported HSPA8-NR4A3 translocation , a novel t (2;22) (q34; q12) EWSR1 translocation  and SMARCA2-NR4A3 fusion .
Interestingly, along with the EWSR1 exon 7-NR4A3 exon 2 fusion, NGS detected KIT exon 13 mutations; moreover, it was noted that the IHC staining results demonstrated strong diffuse expression of CD117. Only a few studies have discussed the role of evaluating CD117 positivity and KIT gene alterations in EMC diagnostics. Hornick and Fletcher  reported that 2 of 20 patients tested positive for CD117, but did not investigate the KIT gene. Subramanian et al.  conducted IHC and ISH (In Situ Hybridization) tests, revealing that 6 of 11 EMCs were diffusely positive for CD117,KIT exons 9, 11, 13 and 17 were screened for mutations in the diffuse positive cases (6/11), and the results suggested indicated no mutations. The IHC staining results in the study by Stacchiotti et al.  suggested the presence of CD117 expression in 6 of 9 EMCs cases, however, no KIT gene analysis was conducted. Subsequently, Urbini et al.  reported the case of an EMC patient (1/20) with KIT exon 11 mutations, which, apart from the case presented in this paper, is firstly reported EMC case with KIT gene mutations; however, no IHC staining results were conducted. In the present case, the presence of KIT exon 13 mutations was established based on NGS and morphological findings, i.e., abundant tumor cells, scarce myxoid stroma and strong diffuse expression of anti-CD117 antibody in tumor cells. We hypothesize that CD117-positive (CD117+) cellular EMCs might have a higher frequency of KIT gene mutations. EMC subtypes were not elaborated in the abovementioned studies on patients without KIT gene mutations who tested positive for anti-CD117 antibodies or those with KIT gene mutations identified before anti-CD117 antibody testing. Moreover, to the best of our knowledge, no study has explored the association between anti-CD117 antibodies and the KIT gene and EMC subtypes. Therefore, it is necessary to study more EMC cases positive for anti-CD117 antibody expression and cellular EMC cases positive for CD117 expression.
In gastrointestinal stromal tumors, the location of KIT mutations is associated with tumor biological behavior, and exon 11 and 13 mutations provide evidence regarding the tumors’ malignant biological status . KIT exon 13 mutations are relatively rare, accounting for 0.8–4.1% of all KIT mutations, and patients with KIT exon 13 mutations benefit from sunitinib therapy . A patient with EMC who had KIT exon 11 mutations and had not previously received sunitinib was reported to benefit from sunitinib therapy . However, Brooke et al.  reported that stable disease was maintained with imatinib treatement for 3 years in a 55-year-old woman diagnosed with EMCs with KIT exon 11 mutations. In the present case, the patient had KIT exon 13 mutations but was not administered sunitinib; therefore, whether sunitinib would benefit this patient remains unclear. The 10-year survival rate was 70% among the patients with EMCs, and the prognosis of EMCs was not associated with histological grade or proliferative markers but with the location and size of the tumor in elderly patients . At the time of writing, follow-up on the present case had been conducted for only ~ 10 months; thus, the significance of the follow-up results is limited. We will continue to follow up with this patient.
Consequently, cellular EMC is a rare tumor type and shows some clinically and biologically unique features. Molecular detection is an indispensable technique for diagnosing cellular EMCs. The KIT mutations reported in this case report may offer fresh insights into EMCs treatment options. We firstly reported the case of KIT exon 13 mutations, and reviewed the relevant literature to make a deeper understanding of the disease, and provide useful parameters for further gene therapy.
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Extraskeletal myxoid chondrosarcomas
Fluorescence in situ hybridization
In Situ Hybridization
Magnetic resonance imaging
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Wang, C., You, ZJ., Chen, XY. et al. Mutation of KIT in cellular extraskeletal myxoid chondrosarcoma: a case report and literature review. Diagn Pathol 17, 42 (2022). https://doi.org/10.1186/s13000-022-01222-7