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Clear Cell Sarcoma

Melanoma Malignant of Soft Parts

Clear cell sarcoma is a very rare but highly malignant tumor that arises in soft tissues, and is histologically resembling malignant melanoma. The symptoms depend on the involved tissues, and most common sites include the tendons and aponeuroses of feet and ankles. Imaging studies reveal a solitary, well-defined mass. Once the diagnosis is confirmed, immediate surgical and adjuvant therapy is necessary, but this tumor carries a poor prognosis.


Presentation

Clinical presentation of clear cell sarcoma depends on its location, and the feet and ankles are the most common sites of occurrence. The humerus, as well as other parts of the skeleton have been reported, but the kidneys, the gastrointestinal tract, and the peritoneum are also locations in which primary development of tumor occurred. This tumor usually grows near tendons, aponeuroses, or fascia, which is why symptoms are functional-related. Initially, patients may be asymptomatic, but as the size of the tumor increases, symptoms such as local pain, swelling, and limited movement of the affected limb may be observed. In the case of extraskeletal involvement, but also in advanced stages of disease, constitutional symptoms such as malaise, fatigue, weight loss and anorexia may be observed, while gastrointestinal tumors may present with abdominal pain, hematochezia, and anemia [11]. 

Larger tumors may be palpable on physical examination, and together with accompanying symptoms, appropriate imaging techniques and laboratory tests should be performed to establish the diagnosis.

Turkish
  • Copyright 2016 Turkish Association of Orthopaedics and Traumatology. Production and hosting by Elsevier B.V. All rights reserved.[ncbi.nlm.nih.gov]
Splenectomy
  • The patient underwent distal pancreatectomy and splenectomy for the same. Follow-up imaging 6 months later showed a metastatic liver lesion, for which he also underwent a liver resection. BRAF mutational analysis was found to be negative.[ncbi.nlm.nih.gov]
Rectal Bleeding
  • CASE PRESENTATION: We report the case of a 69-year-old woman who presented with active rectal bleeding. After a negative colonoscopy, the patient underwent a video-capsule endoscopy. The latter detected an ileal mass that was surgically resected.[ncbi.nlm.nih.gov]
Jaundice
  • A 36-year-old man presented with jaundice for one month. A preoperative abdominal computer tomography showed a low-density mass in the head of pancreas. Whipple procedure was performed and the tumor was resected.[ncbi.nlm.nih.gov]
Papule
  • We report a case of a 13-year-old boy with cutaneous CCS who presented with a few months history of an asymptomatic papule on the lower lip that was suggestive of a mucocele.[ncbi.nlm.nih.gov]
Blurred Vision
  • A 63-year-old woman with multiple systemic metastasis secondary to clear cell sarcoma of the tendons and aponeuroses in her right knee presented with a 3 days history of blurred vision in her left eye.[ncbi.nlm.nih.gov]
  • The most common treatment-related adverse events were nausea [18/34 (52.9%)], fatigue [17/34 (50.0%)], vomiting [12/34 (35.3%)], diarrhoea [11/34 (32.4%)], constipation [9/34 (26.5%)] and blurred vision [7/34 (20.6%)].[ncbi.nlm.nih.gov]

Workup

The diagnostic workup of clear cell sarcoma comprises imaging studies and histopathology findings.

Imaging techniques reveal a solitary, well-defined mass up to 5 cm in diameter. Because plain X-rays may reveal normal findings in these patients, CT scan and MRI are imaging techniques of choice, to assess the location of the tumor, as well as local tissue involvement and potential presence of metastases. In more challenging cases, positron emission tomography (PET) scans may be used to identify metastatic changes.

A definite diagnosis is made by obtaining a biopsy of the tumor, and subsequent immunohistochemical techniques. On microscopic investigation, clear cell sarcoma shows highly infiltrative characteristics and nests of neoplastic cells in the dense connective tissue. These neoplastic cells are either polygonal or fusiform in shape, and have "clear" appearance because of glycogen accumulation. As mentioned previously, immunohistochemistry will reveal expression of S-100 protein is seen in all cases, and HMB-45, Melan-A, and MiTF in the majority of patients, while CD57, bcl-2 and synaptophysin expression is also commonly encountered [12].

Treatment

The recommended treatment in patients with clear cell sarcoma is wide surgical resection. Resection is usually a sufficient treatment method, but if wide resection cannot be performed, or if tumors are more than 5 cm in diameter, poorer outcomes are expected [13], and adjuvant therapy is indicated [14]. Chemotherapy and radiation therapy is recommended under such circumstances, and in case of proximal lymph node involvement or presence of metastases. Doxorubicin and cisplatin have been used as potential chemotherapeutic drugs, while interferon alpha is proposed as adjuvant therapy as well [15]. In the case of clear cell sarcoma of the kidney, nephrectomy is indicated in some patients, while patients with CCS of the bones, or patients in whom wide resection is not possible (proximity to large blood vessels), limb amputation is sometimes indicated [16].

Prognosis

Clear cell sarcoma is a tumor that has very high rates of metastasis, and generally carries a poor long-term prognosis. Survival rates have been reported to be 67% for 5-year survival, and 10% for 20-year survival, while metastatic development of disease has been reported in more than 60% of cases [10]. Several factors are involved in predicting the survival of patients, such as staging of the tumor at the time of diagnosis, size, and location of the tumor. Despite wide surgical resection, larger tumors have higher chances of local regrowth.

Etiology

A distinct chromosomal entity was established as one of the main causes of clear cell sarcoma. The reciprocal translocation  t(12;22)(q13;q12) has been observed in almost all patients. This translocation leads to fusion of two genes - the activating transcription factor gene (ATF-1) located on the long arm of chromosome 12 (12q13), and the Ewing's sarcoma oncogene R1 (EWSR1) on chromosome 22 (22q12) [4]. This development creates oncogenic potential, and leads to development of clear cell sarcoma

Several entities identical to malignant melanoma have been established, such as expression of S100 protein in virtually 100% of cases, and expression of melanoma-associated antigen (HMB-45), Melan-A and MiTF in more than 80% of cases [5].

Epidemiology

Clear cell sarcoma comprises less than 1% of all soft tissue tumors in adults, and is quite rarely encountered in clinical practice. Nevertheless, its prompt diagnosis can be life-saving, because of its metastatic potential. This tumor is diagnosed most commonly in adults between 20 to 40 years of age, but patients can be of any age [6]. Children are rarely affected, as only 2% of CCS are diagnosed in the pediatric population [7], but clear cell sarcoma of the kidney (CCSK) is seen almost exclusively in children between 2 and 3 years of age [8]. Gender distribution has not been established, but predilection toward Caucasian race has been noted in some studies.

Sex distribution
Age distribution

Pathophysiology

Initially, clear cell sarcoma was classified as "malignant melanoma of soft tissue parts", because of its striking genetic and etiologic resemblance. Shared entities included S-100 protein and HMB-45 expression, and several other immunohistochemical features have been established, but genomic profiling additionally revealed chromosomal translocation (12;22)(q13;q12), leading to fusion of EWSR1 and ATF-1 [9]. This genetic feature is observed in more than 90% of patients with clear cell sarcoma, and this tumor is now a distinct entity.

Prevention

Prevention of CCS is currently not achievable, but early diagnosis, and long-term follow-up of treated patients is imperative in preventing tumor recurrences and development of metastases.

Summary

Clear cell sarcoma (CCS) is a rare soft tissue tumor with very high malignant potential. It was initially described in the 1960s [1], as a tumor that affects tendons and aponeuroses [2], and the distinct appearance of "clear" cells on microscopy due to accumulation of glycogen. This tumor resembles malignant melanoma, because almost all tumors exhibit melanocytic differentiation, but under different mechanisms. Namely, translocation t(12;22)(q13;q12) is observed in almost all clear cell sarcomas, while other genetic factors have been established in the pathogenesis of this tumor as well. This tumor is most commonly diagnosed in younger and middle-aged adults, but can be observed in patients of any age. Gender predilection is not established, while Caucasians are more commonly affected. Clear cell sarcoma comprises less than 1% of all soft tissue tumors, but establishing the diagnosis and differentiating this tumor from malignant melanoma may be difficult [3].

Clinical presentation may be initially asymptomatic, and the location of the tumor most commonly includes the lower extremities, such as the feet and the ankles. Other parts of the skeleton, but also the gastrointestinal tract and the kidneys have been reported as the site of primary development. Symptoms may be related to functional impairment this tumor may cause, such as pain and limited movement. X-rays may not show pathological findings, while computed tomography (CT) or magnetic resonance imaging (MRI) may identify a well-demarcated, solitary, benign mass, usually up to 5 cm in diameter. This tumor lacks cutaneous invasion, and primarily metastasizes in the lymphoid tissue and the lungs, so the tumor may not be discovered until metastatic involvement has developed. The prognosis is variable, with 5-year survival rates between 60-70%, since clear cell sarcoma readily metastasizes, but long-term survival rates are below 10%. For these reasons, prompt diagnosis is vital, and wide surgical resection is the initial treatment of choice, while radiation and chemotherapy is indicated in patients in whom resection margins were closer to the tumor. In severe cases, limb amputations may be performed, while regional lymphadenectomy is discussed as a preventive measure in reducing the chance for metastasis.

Patient Information

Clear cell sarcoma is a very rare type of cancer that arises in soft tissues, most commonly in tendons and tissue around the bones. Because of its striking resemblance to malignant melanoma in terms of malignant potential and cellular features, it was classified as a subtype of melanoma when it was initially discovered. However, genetic mutations that were observed in this tumor made it a distinct medical entity from melanoma.

Clear cell sarcoma is most commonly diagnosed in adults between 20 to 40 years of age, and the most common site include the feet and the ankles. On the other hand, clear cell sarcoma may also occur in the kidneys, and it is diagnosed almost exclusively in children between 2-3 years of age. Other sites include other parts of the skeleton and the gastrointestinal tract. This tumor is shown to be more commonly diagnosed in Caucasians, while gender predilection has not been established.

Patients with clear cell sarcoma may initially have no complaints, but when the tumor increases in size, pain, swelling, and reduction in movement of local structures is reported. Patients may also report malaise, fatigue, weight loss, while patients in whom gastrointestinal involvement is present, bloody stools and anemia may be reported. 

Because this tumor commonly metastasizes, primarily to the lymph nodes and lungs, the prognosis is poor if not treated promptly and adequately. Size of the tumor, staging at the time of diagnosis, and presence of metastases are factors which influence outcome of patients. The diagnosis is made by imaging techniques, such as MRI or CT scan, which can assess the size and location of the tumor, but these techniques are also used to assess local structures and evaluate the presence of metastases. A definite diagnosis, however, is obtained by biopsy, and microscopic examination of the tumor.

Once the diagnosis is made, the recommended treatment is surgery. The tumor is removed along with a large amount of surrounding tissue (wide surgical excision), to reduce the chances of recurrence and development of metastases. For patients that developed metastases, or in whom surgical treatment is insufficient, chemotherapy and radiation are indicated.

References

Article

  1. Enzinger FM. Clear-cell sarcoma of tendons and aponeuroses. An analysis of 21 cases. Cancer. 1965;18(9):1163-74.
  2. Rodriguez-Martin J, Ortiz-Cruz E, Del Rio J, Vivanco T, Lopez-Amor C. Clear cell sarcoma of tendons and aponeuroses. Advances in Orthopaedics. 2011;2(4):156-160.
  3. Ipach I, Mittag F, Kopp H, Kunze B, Wolf P, Kluba T. Clear-cell sarcoma of the soft tissue – a rare diagnosis with a fatal outcome. Eur J Cancer Care. 2012;21(3):412-420. 
  4. Segal N, Pavlidis P, Noble W et al. Classification of clear-cell sarcoma as a subtype of melanoma by genomic profiling. J Clin Oncol. 2003;21:1775–1781.
  5. Mavrogenis A, Bianchi G, Stavropoulos N, Papagelopoulos P, Ruggieri P. Clinicopathological features, diagnosis and treatment of clear cell sarcoma/melanoma of soft parts. Hippokratia. 2013;17(4):298-302.
  6. Chung EB, Enzinger FM. Malignant melanoma of soft parts. A reassessment of clear cell sarcoma. Am J Surg Pathol. 1987;(5)7:405–413.
  7. Clark MA, Johnson MB, Thway K, Fisher C, Thomas JM, Hayes AJ. Clear cell sarcoma (melanoma of soft parts): The Royal Marsden Hospital experience. Eur J Surg Oncol. 2008;34(7):800-4.
  8. Franco A, Dao TV, Lewis KN, Biddinger P.W. A case of clear cell sarcoma of the kidney. J Radiol Case Rep .2011;5(2):8-12.
  9. Zucman J, Delattre O, Desmaze C et al. EWS and ATF-1 gene fusion induced by t(12;22) translocation in malignant melanoma of soft parts. Nat Genet. 1993;4:341–345.
  10. Lagmay J, Ranalli M, Arcila M, Baker P. Clear cell sarcoma of the stomach.
    Pediatr Blood Cancer. 2009;53(2):214-216.
  11. Malchau SS, Hayden J, Hornicek F, Mankin HJ. Clear cell sarcoma of soft tissues. J Surg Oncol. 2007;95:519–522.
  12. Hisaoka M, Ishida T, Kuo TT, et al. Clear cell sarcoma of soft tissue: a clinicopathologic, immunohistochemical, and molecular analysis of 33 cases. Am J Surg Pathol. 2008;32(3):452-60.
  13. Kuiper DR, Hoekstra HJ, Veth RP, Wobbes T. The management of clear cell sarcoma. Eur J Surg Oncol. 2003;29:568–570.
  14. Finley JW, Hanypsiak B, McGrath B, et al. Clear cell sarcoma: the Roswell Park experience. J Surg Oncol. 2001;77:16–20.
  15. Steger GG, Wrba F, Mader R, et al. Complete remission of metastasised clear cell sarcoma of tendons and aponeuroses. Eur J Cancer. 1991;27:254–256.
  16. Liu X, Zhang H, Dong Y. Primary clear cell sarcoma of humerus: Case report. World J Surg Oncol. 2011;9(163):1-4.

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Last updated: 2018-06-22 06:07