Blueish indurated nodule of the tongue in a teenager

A 14-year-old boy with no prior medical history, presented with a 2-month history of a painless tongue lesion and a 1-month history of a painful left pelvic swelling, associated with functional limitation. Clinical examination revealed an undernourished adolescent with a sizable, indurated tumefaction in the left pelvic area, coupled with restricted mobility of the left leg, which was held in an externally rotated and abducted position. Additionally, a bluish nodular indurated lesion at the right side of the tongue base (Figure 1) and palpable right cervical adenopathy were noted. Faciocervical scanner demonstrated a contrast-enhanced mass, measuring 46 × 26 mm, located at the right lateral border of the tongue, as well as two rounded images with hypodense centers, suggestive of necrotic lymphadenopathies, in the right cervical jugulocarotid and submandibular regions. Abdominopelvic imaging revealed a substantial, infiltrative osteolytic mass centered on the left iliac bone, accompanied by extensive invasion of adjacent soft tissues (Figure 2a). The positron emission tomography scan did not reveal any metastases beyond the aforementioned lesions (Figure 2b). Laboratory assessments revealed a profile consistent with systemic inflammation, characterized by elevated levels of C-reactive protein (118.8 mg/L) and fibrinogen (8.02 g/L), Thrombocytosis (860 G/L) and microcytic anemia (hemoglobin 10.9 g/dL, mean corpuscular volume 72.8 fL). HIV testing returned negative results. Subsequently, incisional biopsies of the tongue and hip were performed for histopathologic examination (Figure 3a,b). Clear cell sarcoma (CCS) of soft tissue (of the tongue). Analysis of the biopsies from the tongue and hip bone revealed a tumoral proliferation of epithelioid clear cells in a diffuse pattern, rich in melanin deposits (Figure 3a,b). Immunohistochemistry exhibited positive staining for melanocytic markers (Melan A, HMB45, SOX10, S100), while 85 PRAME, CD99, and pancytokeratine were negative. Subsequent negative NGS melanoma panel results prompted extended RNA sequencing studies, identifying an EWSR1/ATF1 fusion transcript. Based on clinical and histological examinations, the initial diagnosis of melanoma was made, thus prompting the initiation of immunotherapy using nivolumab. The subsequent identification of an EWSR1/ATF1 fusion transcript led to the revised diagnosis of cutaneous clear-cell sarcoma of soft tissue of the tongue with bone metastasis. Unfortunately, the patient's condition deteriorated, resulting in a fatal outcome. Clear cell sarcoma of soft tissue (CCSST) is an exceedingly uncommon malignant neoplasm, accounting for only 1% of soft tissue sarcomas.1 Previously considered a melanoma subtype, CCSST was reclassified as a distinct entity. It predominantly affects young adults with a median age of 39 years.1 In children, most cases manifest after the age of 14.2 Typically originating from tendinous sheaths and aponeuroses, CCSST primarily affects the lower limbs.1, 2 Its occurrence within the tongue is extraordinarily rare, with only three documented cases in adults, along with an additional case described by Breton et al., wherein the distinction between CCSST and gastrointestinal neuroectodermal tumor remains unresolved.3-6 Our case notably represents the first reported occurrence of CCSST of the tongue in a teenager, to the best of our knowledge. CCSST is associated with a high rate of local recurrence, distant metastasis, mainly to the lungs and bones, and lymph node involvement, which is uncommon in other types of soft tissue sarcoma.1, 2 Microscopically, CCSST is made of neoplastic cells with abundant cytoplasm, often exhibiting a polygonal or fusiform shape. The "clear-cell" characteristic appearance is due to intracellular glycogen accumulation.7 Some cases, as seen in our patient, also demonstrate melanin pigment.2, 7 Immunohistochemistry reveals positivity for melanin synthesis markers, including HMB45, S100, and Melan A, which can be misleading suggestive of malignant melanoma.2, 7 CCS shares many features with melanoma, including histological, immunophenotypic, ultrastructural and similarities in gene expression patterns although genetic profiling can provide clarity.2, 7 Unlike melanoma, CCSST harbors characteristic recurrent chromosomal translocations involving the EWSR1 gene, serving as cytogenetic hallmark. In majority of the cases, a t(12;22)(q13;q12) is found resulting in an EWSR1/ATF1 chimeric gene; less commonly, a t(2;22)(q34;q12) translocation is found fusing EWSR1 and CREB1.7 Here, the young age of the patient and atypical presentation should have been an important clue raising the possibility of CCSST rather than melanoma, which prevalence in children accounts for around 1% of all malignant pediatric tumors.8 CCSST presents a therapeutic challenge, as evidenced by the poor 5-year survival rate of 50% in localized forms, decreasing to 20% in metastatic disease. Due to its rarity, clinical trials are scarce, and a standardized systemic treatment protocol is lacking. Complete excision with a wide margin is deemed the optimal approach for localized CCSST, with or without radiotherapy.9 Current therapeutic options for advanced disease yield limited efficacy and a dismal response rate. CCSST is generally characterized by minimal responsiveness to standard chemotherapy.9, 10 Targeted therapies like sunitinib have shown some promise.10 Immunotherapy, specifically immune checkpoint inhibitors, is being researched as a potential treatment for CCS.10 This case underlines the diagnostic complexity in differentiating CCSST from melanoma and emphasizes the importance of considering CCSST in cases with melanocytic features, especially in young patients. Genetic profiling, particularly the identification of the EWSR1/ATF1 fusion transcript, plays a pivotal role in confirming the diagnosis and guiding appropriate management. All authors had full access to all of the data in the case. Laura Mengeot and Antoine Bertolotti take responsibility for the integrity of the data and the accuracy of the data analysis. Laura Mengeot was involved in conceptualization and design. Laura Mengeot was involved in drafting the manuscript. Laura Mengeot, Philippe Drabent and Antoine Bertolotti were involved in critical revision, validation, and visualization of the manuscript. The authors declare no conflict of interest. The parents/guardians of minor patients have given written informed consent for their child's participation in the study, as well as for the use of their child's deidentified, anonymized, aggregated data, and case details (including photographs) for publication. Ethical Approval: not applicable. Not applicable to this article as no datasets were generated or analyzed.