Intestinal Clear Cell Sarcoma-A Case Presentation of an Extremely Rare Tumor and Literature Review.

Background: Clear cell sarcoma (CCS) is an extremely rare form of sarcoma representing less than 1% of all soft-tissue sarcomas. It has morphological, structural, and immunohistochemical similarities to malignant melanoma, affecting young adults and equally affecting both sexes, and is usually located in the tendinous sheaths and aponeuroses of the limbs. Gastrointestinal localization is exceptional, with less than 100 cases reported thus far. The gene fusion of activating transcription factor 1 (ATF1) and the Ewing sarcoma breakpoint region 1 (EWSR1) are pathognomonic for clear cell sarcoma, representing the key to the diagnosis. CCS is an extremely aggressive tumor, with >30% having distant or lymphatic metastasis at the time of diagnostic, and it has a high recurrence rate of over 80% in the first year after diagnosis and a high tendency for metastatic dissemination. Given the rarity of this tumor, there is no standardized treatment. Early diagnosis and radical surgery are essential in the treatment of CCS both for the primary tumor and for recurrence or metastasis. Chemo-radiotherapy has very little effect and is rarely indicated, and the role of targeted therapies is still under investigation. Case presentation: We present an extremely rare case of intestinal CSS in a 44-year-old Caucasian female. The patient, asymptomatic, first presented for a routine checkup and was diagnosed with mild iron-deficiency anemia. Given her family history of multiple digestive cancers, additional investigations were requested (gastroscopy, colonoscopy, tumoral markers and imaging) and the results were all within normal limits. In the subsequent period, the patient experienced mild diffuse recurrent abdominal pain, which occurred every 2-3 months. Two years later, the patient presented with symptoms of intestinal obstruction and underwent an emergency laparotomy followed by segmental enterectomy and regional lymphadenectomy for stenotic tumor of the jejunum. Histology, immunohistochemistry, and genetic testing established the diagnosis of CCS. No adjuvant therapy was indicated. Initially, no signs of recurrence or metastasis were detected, but after 30 and 46 months, respectively, from the primary treatment, the patient developed liver metastasis and pericolic peritoneal implants treated by atypical hepatic resections and right hemicolectomy. The patient remains under observation.

Navigating diagnostic challenges-distinguishing malignant melanoma and clear cell sarcoma of soft tissues: a case report and review of the literature.

BACKGROUND: Within the spectrum of melanocytic-differentiated tumors, the challenge faced by pathologists is discerning accurate diagnoses, with clear cell sarcoma of soft tissues standing out as a rare and aggressive neoplasm originating from the neural crest. Accounting for 1% of all soft tissue sarcomas, clear cell sarcoma of soft tissues poses diagnostic complexities, often misidentified owing to its phenotypic resemblance to malignant melanoma. This chapter delves into the intricacies of clear cell sarcoma of soft tissues, its epidemiology, characteristic manifestations, and the imperative need for a comprehensive diagnostic approach involving immunohistochemical and molecular analyses. CASE PRESENTATION: A compelling case unfolds as a 25-year-old male from Morocco, initially misdiagnosed with malignant melanoma, experiences tumor recurrence on the second toe. With no history of trauma or familial neoplasia, the patient's clinical journey is explored, emphasizing the importance of detailed clinical examinations and radiological assessments. The chapter elucidates the histopathological findings, immunohistochemical spectrum, and the correlation between clinical parameters and diagnostic inference, ultimately leading to metatarsal amputation. This clinical vignette highlights the multidimensional diagnostic process in soft tissue neoplasms, emphasizing the synergistic role of clinical, radiological, and histopathological insights. CONCLUSION: The diagnostic challenges inherent in melanocytic-differentiated tumors, exemplified by the rarity of soft tissue clear cell sarcoma, underscore the essential role of an integrated diagnostic approach. This concluding chapter emphasizes the perpetual collaboration required across pathology, clinical medicine, and radiology for nuanced diagnostic precision and tailored therapeutic strategies. The rarity of these soft tissue malignancies necessitates ongoing interdisciplinary engagement, ensuring the optimization of prognosis and treatment modalities through a comprehensive understanding of the diagnostic intricacies presented by clear cell sarcoma of soft tissues.

Small Intestine Gastrointestinal Clear Cell Sarcoma: A Case Report and Review of the Literature.

Gastrointestinal clear cell sarcoma (GICCS)/malignant gastrointestinal neuroectodermal tumor (GNET) is an extremely rare form of cancer with aggressive clinical behavior. It has distinct pathological, immunohistochemical, ultrastructural, and molecular features. Herein, we present the case of a 20-year-old woman with no notable medical history who presented to the outpatient department with complaints of abdominal pain and vomiting. Symptoms had been evolving for 3 months. The physical examination revealed slight abdominal tenderness and melena. Biological investigations revealed iron-deficiency anemia. The upper and lower endoscopies showed no abnormalities. Magnetic resonance enterography revealed small bowel wall thickening of 15 mm × 2 mm. Exploratory laparotomy revealed an ileal mass with mesenteric lymphadenopathy. A wide resection of the mass was then performed. The final pathological report confirmed the diagnosis of small bowel GICCS/GNET. After 11 months of follow-up, the patient presented with mesenteric lymph node metastases.

MED15::ATF1-Rearranged Tumor: A Novel Cutaneous Tumor With Melanocytic Differentiation.

We recently described novel dermal tumors with melanocytic differentiation and morphologic and biological similarities to cutaneous clear cell sarcoma, including CRTC1::TRIM11 cutaneous tumor, and clear cell tumors with melanocytic differentiation and either ACTIN::MITF or MITF::CREM. Here, we describe a series of 3 patients presenting with tumors reminiscent of CRTC1::TRIM11 cutaneous tumor, found to demonstrate a novel MED15::ATF1 fusion. All 3 patients were children (5-16 years old). Primary excision of case 1 showed a circumscribed wedge-shaped silhouette with peripheral intercalation into collagen fibers and scattered lymphoid aggregates. All 3 tumors abutted the epidermis; one showed a junctional component. Tumors were highly cellular and comprised of monomorphic, oval-to-round epithelioid cells arranged in vague nests and short fascicles in variably fibrotic stroma. Mitotic rate was high (hotspot 6-12/mm2), without atypical mitoses. Necrosis was focally present in case 3. All cases showed strong, diffuse nuclear staining for SOX10 and MITF (2/2) but showed variable expression for S100 protein (1/3) and other melanocytic markers-Melan-A (focal in 2/3), HMB45 (focal in 1/3), and Pan-Melanoma (patchy in 1/1). Whole-exome RNA sequencing demonstrated a MED15::ATF1 fusion without any other notable alterations. Cases 1 and 2 were completely excised without recurrence (12 months). Case 3 developed a grossly apparent regional lymph node spread shortly after primary biopsy. The patient was treated with wide excision, radiation, cervical lymph node dissection (4/46 with >75% lymph node replacement), and neoadjuvant and adjuvant nivolumab (alive without disease at cycle 11). This series is presented to aid in future diagnosis of this novel dermal tumor with melanocytic differentiation and emphasize the potential for aggressive biologic behavior, which should be considered in patient management planning.

Clear cell sarcoma in the post-molar area: Report of an ultra-rare case and literature review of oral clear cell sarcoma.

BACKGROUND: Clear cell sarcoma of soft tissue is an exceptionally rare sarcoma. It is even rarer in the oral cavity. To our knowledge, this case is the first reported clear cell sarcoma involving the post-molar area. Pathologically, clear cell sarcoma has low mitotic activity, rare nuclear pleomorphism, and necrosis. Its biological behavior is often underestimated by morphology. It is a highly aggressive tumor. CASE REPORT: A 39-year-old female presented with an asymptomatic mass in the post-molar area. It was mistaken for a benign or low-grade malignant tumor based on frozen incisional biopsy samples. The surgical resection sample was tested by NGS, which detected a rare EWSR1::CREB1 in clear cell sarcoma. The final diagnosis was made by combining morphological, immunohistochemical, and molecular test results. The patient did not receive any adjuvant therapy after surgery and no recurrence of the disease was detected at 8 months of follow-up. CONCLUSION: The study highlights that mild histological manifestation in the oral cavity should be considered the possibility of CCS affecting young patients. Careful histological investigation, sufficient immunohistochemical staining, and molecular tests are essential to the diagnosis.

One step at a time: Melanocytic differentiation in fusion-driven cutaneous neoplasms.

As dermatopathologists, we routinely diagnose melanocytic nevi, melanomas, and occasionally melanocytomas in our daily clinical practice. However, it is now clearly established that the presence of melanocytic differentiation in a tumor does not necessarily indicate any of the aforementioned diagnoses. Tumors such as clear cell sarcoma, malignant melanotic nerve sheath tumor, PEComa, melanotic neuroectodermic tumor of infancy, and even certain translocation-associated renal cell carcinomas all share the common characteristic of melanin synthesis. Over the past two decades, with the advent of molecular diagnostics, there has been an explosion of new data and discoveries in this field. Examples such as CRTC1::TRIM11 cutaneous tumors and MITF pathway-activated melanocytic tumors (ACTIN::MITF and MITF::CREM) have been incorporated into the latest edition of the WHO classification of skin tumors (5th ed). In a recent issue, Alexandrescu et al. reported another case of a dermal/subcutaneous melanocytic tumor harboring a MITF::CREM1 translocation. In a separate paper within the current issue, Li et al. present a case of clear cell sarcoma with the rare EWSR1::CREM fusion, which had initially been misdiagnosed as melanoma with regional and distant metastases. We warmly welcome these two very interesting and high-quality articles to our journal, and we eagerly anticipate what the future holds for this fascinating category of tumors.

Clear cell sarcoma of kidney: A mimicker of Wilms' tumor.

The differential diagnosis for an abdominal mass in a 2-year-old child is broad and includes lesions of renal, hepatic, gastrointestinal, adrenal, and lymphatic origins. Of these, Wilms' tumor and neuroblastoma are the most common tumors, where Wilms' tumor represents about 92% of renal masses in children. Non-Wilms' renal tumors, rhabdoid tumors, and clear cell sarcoma of the kidney (CCSK) are uncommon. CCSK constitutes approximately 3% of all malignant renal tumors in childhood. In this report, we present a child presenting with a huge renal mass consistent with Wilms' tumor on computed tomography and initial biopsy. However, the final pathologic diagnosis after resection revealed CCSK.

Unusual Clinical Presentation of Clear Cell Sarcoma in a Young Woman.

Clear cell sarcoma (CCS) is a rare but aggressive malignancy that typically occurs in young adults and is characterized by soft tissue tumors of the extremities. CCS can be difficult to distinguish from metastatic melanoma based solely on histology and immunohistochemistry (IHC) because of the significant overlap between them. However, it is imperative to get an accurate clinical diagnosis, as it informs disease staging and treatment options for patient care. Present in approximately 75% of CCS cases, the EWSR1 gene rearrangement detected by fluorescence in situ hybridization (FISH) can help with establishing a diagnosis; the underlying reciprocal translocation has never been reported in cutaneous melanoma. We reviewed a case of a young woman who presented with a confusing picture of widespread lymphadenopathy, cutaneous metastases, and electrolyte derangements and was subsequently diagnosed with metastatic CCS.This case suggests possible value in performing molecular testing when a clinical picture does not correspond with what is expected for melanoma. It also raises the question of whether CCS cases may be underreported. This case highlights an uncommon presentation that may not be recognized as a manifestation of CCS by an oncologist who is not a sarcoma specialist. It is unclear how COVID-19 vaccination contributed to her clinical presentation, and it is also unclear whether an early diagnosis would have changed her clinical outcome.

Navigating through the diagnostic minefield of clear cell sarcoma of soft tissue: Lessons from a challenging case with literature review.

Clear cell sarcoma of soft tissue (CCSST) is a rare soft tissue sarcoma occurring in young adults with a predilection for deep soft tissues of the distal extremities. Its overlapping morphology and immunohistochemical profile pose a diagnostic challenge. Herein, we present a rare case of CCSST with a unique immunohistochemical profile arising in an uncommon location. A 36-year-old male presented with a progressively increasing painful swelling in the left supraclavicular region for the last 2 months. Positron emission tomography showed FDG-avid lesions in the left supraclavicular and scapular regions. Fine needle aspiration cytology (FNAC) followed by core needle biopsy was performed. The cytology smears showed predominantly discohesive sheets of polygonal tumor cells with prominent macronucleoli in a vacuolated background. On immunocytochemistry, tumor cells showed positivity for vimentin, HMB45, and S100, confirming the diagnosis of CCSST. Histopathological examination showed sheets of similar tumor cells that were positive for vimentin, HMB45, melan A, CD38, and CD138, representing a potential diagnostic pitfall in the index case. The index report, besides highlighting the characteristic pathologic features of CCSST and its mimics, is unique due to the diffuse positivity of the tumor cells for CD38 and CD138. It is imperative to be aware of this diagnostic pitfall as it may muddle the diagnosis of CCSST.

Compound clear cell sarcoma with EWSR1::CREM fusion.

Cutaneous clear cell sarcomas may be confused with melanomas as a result of overlapping histopathology and immunohistochemical staining. We report a case of a 41-year-old woman with a purported history of acral melanoma of the great toe. Twenty-one months after excision of the primary tumor, the patient developed a groin mass, diagnosed as metastatic melanoma on excision. Five months later, a biopsy of a lung mass was reported as metastatic melanoma. The patient was referred to our institution for treatment, which prompted molecular testing on the groin metastasis by targeted next-generation sequencing. Molecular testing results revealed TP53 and TERT promoter mutations and the absence of BRAF, KRAS, and KIT mutations; it also revealed an EWSR1::CREM fusion that was confirmed by Archer FusionPlex. The alleged acral melanoma was re-reviewed, showing an invasive amelanotic spindle cell neoplasm in the dermis with neoplastic nests at the dermal-epidermal junction; the tumor cells expressed markers of melanocytic differentiation but were negative for PRAME and BRAF immunohistochemical staining. Molecular testing of the toe and lung metastasis revealed the same EWSR1::CREM fusion. In light of the molecular findings, the diagnosis was revised to a primary acral compound clear cell sarcoma with EWSR1::CREM fusion.

Multiple metastases of clear cell sarcoma at diagnosis presented in bone marrow aspirate: A case report.

Clear cell sarcoma (CCS) is a rare and aggressive soft-tissue sarcoma that arises most commonly in adolescents and young adults of both sexes. CCS presents a diagnostic challenge due to its morphological and immunohistochemical similarity to malignant melanoma. We present a rare and severe case of CCS simultaneously with multiple bone and lymph node metastases at the time of initial diagnosis in a previously healthy 15-year-old Chinese man. Detailed information on clinical manifestations, laboratory profiles, histopathological findings and poor outcome were described. The cytomorphology of bone marrow aspirate in CCS in Wright-Giemsa staining smear was first depicted in this case. The diagnostic difficulties of the rare case was also discussed.

Clear Cell Sarcoma of the Kidney (CCSK) With BCOR-CCNB3 Fusion: A Rare Case Report With a Brief Review of the Literature.

Pediatric renal tumors are a rare entity and majority of these tumors are accounted for by Wilms tumor. The second most common renal tumor is clear cell sarcoma of the kidney (CSSK). Most of the CSSK have either BCOR-internal tandem duplication (ITD) or YWHAE-NUTM2B/E fusion. The sarcomas with BCOR-CCNB3 fusion are well documented in soft tissue and bone tumors, but are extremely rare in the pediatric renal setting. We are reporting an extremely rare case of pediatric clear cell sarcoma of the kidney (CSSK) with BCOR-CCNB3 fusion, which was a diagnostic challenge on morphological grounds. A final diagnosis could only be reached after multiple reviews and NGS based RNA fusion testing. We have also performed a brief review of literature which revealed eight (8) other cases of this rare entity.

Clear cell sarcoma of soft tissue with plasmacytoid morphology: A rare case report.

RATIONALE: Clear cell sarcoma of soft tissue (CCSST) is a rare malignant tumor that occurs in the extremities of young adults. CCSST has been documented to have atypical histopathological features, such as epidermotropism or myxoid differentiation, which may set pitfalls in the differential diagnosis. We report a case of CCSST with plasmacytoid morphology which has never been described. PATIENT CONCERNS: A 15-year-old male, presented with a 5-cm mass in his left inguinal area. DIAGNOSIS: Positron emission tomography-computed tomography examination showed nodules in the left groin and the lung, the latter was considered metastasis. A core needle biopsy with the diagnosis of CCSST with plasmacytoid morphology was made according to histology, immunostaining, and molecular analysis. INTERVENTIONS: The patient received chemotherapy of doxorubicin and ifosfamide. OUTCOMES: The patient failed to respond to the standard chemotherapy and deceased twelve months after diagnosis. LESSONS: This special case of CCSST with plasmacytoid features demonstrated a morphological variation never been documented and may easily lead to misdiagnosis. For such cases, molecular analysis is essential to provide solid evidence for accurate diagnosis.

Malignant gastrointestinal neuroectodermal tumor: A case-based review of literature.

Malignant gastrointestinal (GI) neuroectodermal tumor is an extremely rare entity that was first described by Zambrano et al. in 2003 as "clear cell sarcoma (CCS)-like tumor of the GI tract." It shares some of the histopathological features of CCS but lacks the immunohistochemical (IHC) reactivity for melanocytic markers. Most mesenchymal neoplasms of the GI tract belong to the category of GI stromal tumors and are characterized by the IHC expression of c-KIT. In cases, without detectable KIT receptor expression, several differential diagnoses have to be taken into consideration. In this article, we describe such a case and present a review of all the reported cases till date. We also present the current available knowledge on its pathology and molecular genetics along with the limitations in its diagnosis. Here, we report a case of a 32-year-old man with a tumor of the small bowel composed of polygonal tumor cells arranged in solid nests, alveolar pattern, and pseudopapillary and admixed with numerous osteoclast-like multinucleated giant cells. Immunohistochemically, the tumor cells strongly expressed S-100 protein only. HMB-45, melan-A, CD117, cytokeratin, desmin, smooth muscle actin, and CD-34 were absent. Ki-67 index was 15%. The diagnosis was further confirmed by fluorescence in situ hybridization (FISH) demonstrating the presence of EWSR1 (22q12) translocation. A final diagnosis of malignant gastroneuroectodermal tumor was rendered. The patient is disease-free for 20 months of postsurgery. The diagnosis of this entity should be considered in the presence of S-100-positivity and multinucleated osteoclastic giant cells and the absence of melanocytic differentiation in a tumor arising from GI tract. Further confirmation can be done by performing FISH analysis.

Clear cell sarcoma of the kidney with inferior vena cava thrombus: a case report.

BACKGROUND: Clear cell sarcoma of the kidney is an uncommon pediatric renal malignant neoplasm that is typically characterized in 2-3-year-olds by aggressive behavior and late relapses. Our literature review revealed fewer than ten previously reported cases of CCSK with inferior vena cava thrombus, with only five in the pediatric age group. CASE PRESENTATION: We report the case of a 14-year-old Syrian girl who complained of mild pain in the left lumbar region pain with hematuria. On physical examination, a mass was palpated in the left flank. Abdominal ultrasonography revealed a left renal mass (7 × 5 × 2 cm3), associated with dilatation of the left renal vein. Contrast abdominal computed tomography showed a mass measuring 7 × 5 × 3 cm3 with the presence of thrombus extending into the inferior cavity down to the right atrium that was initially diagnosed as Wilms' tumor. Radical right nephrectomy with excision of the thrombus was undertaken. Histological immunostaining revealed a diagnosis of the tumor as clear cell sarcoma with vascular tumor thrombus extending to the inferior vena cava. CONCLUSION: Clear cell sarcoma and Wilms' tumor are similar in terms of typical age of appearance, clinical features, and histopathology, but with different methods of treatment and prognosis. The differential diagnosis of such masses is thus very important. We present the case of a patient with clear cell sarcoma with unusual age, with complete removal of the thromboses in the inferior vena cava and the right atrium.

Systemic treatment of advanced clear cell sarcoma: results from a retrospective international series from the World Sarcoma Network.

BACKGROUND: Clear cell sarcoma (CCS) is a translocated aggressive malignancy with a high incidence of metastases and poor prognosis. There are few studies describing the activity of systemic therapy in CCS. We report a multi-institutional retrospective study of the outcomes of patients with advanced CCS treated with systemic therapy within the World Sarcoma Network (WSN). MATERIALS AND METHODS: Patients with molecularly confirmed locally advanced or metastatic CCS treated with systemic therapy from June 1985 to May 2021 were included. Baseline demographic and treatment information, including response by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, was retrospectively collected by local investigators. Descriptive statistics were carried out. RESULTS: Fifty-five patients from 10 institutions were included. At diagnosis, the median age was 30 (15-73) years and 24% (n = 13/55) had metastatic disease. The median age at diagnosis was 30 (15-73) years. Most primary tumours were at aponeurosis (n = 9/55, 16%) or non-aponeurosis limb sites (n = 17/55, 31%). The most common fusion was EWSR1-ATF1 (n = 24/55, 44%). The median number of systemic therapies was 1 (range 1-7). The best response rate was seen for patients treated with sunitinib (30%, n = 3/10), with a median progression-free survival of 4 [95% confidence interval (CI) 1-7] months. The median overall survival for patients with advanced/metastatic disease was 15 months (95% CI 3-27 months). CONCLUSIONS: Soft tissue sarcoma-type systemic therapies have limited benefit in advanced CCS and response rate was poor. International, multicentre prospective translational studies are required to identify new treatments for this ultra-rare subtype, and access to early clinical trial enrolment remains key for patients with CCS.