The study group comprised 30 men (57.69%) and 22 women (42.30%), and patients ranged in age from 6 years to 81 years (median, 33 years). Forty-two percent of patients were aged ≤30 years, and 94% were aged <60 years.
Forty-three tumors (82.69%) were located in the extremities, eight tumors (15.38%) were located in the trunk, and one tumor was located in the scalp. The most common tumor site was the foot (19 tumors), followed by the hand (13 tumors), and the thigh (9 tumors). Fourteen tumors (26.92%) were considered proximal, and 38 tumors (73.07%) were considered distal.
Fifty patients (96.15%) had a mass that had been enlarging slowly for periods ranging from six weeks to four years (median, 15 weeks). Pain and/or tenderness were observed in 30 patients (57.69%), and this was frequently the main reason for seeking medical advice. In two patients, acute urinary retention was the first sign of the disease. No patients had a history of melanoma or unusual pigmented skin lesions.
At presentation the malignant nature of the swelling was seldom suspected, and in thirty-six patients (69.23%), a biopsy was performed. Nevertheless in sixteen patients (30.76%), the lesion was thought to be benign on clinical grounds, and initial clinical diagnosis included epithelial cyst (7 patients) exostose (4 patients), haematoma (2 patients), and neurinoma, lipoma, and carpal tunnel syndrome (1 patient each).
Initial diagnosis was made at another institution in all cases, with incisional or excisional biopsy. All cases were reviewed by the Gustave Roussy or the Bergonie Institute soft tissue pathologists.
The tumors ranged in size from 1
cm to 15
cm (median, 4, 86
cm). The tumors measured <4
cm in 30 patients (57.69%) and between 4
cm and 15
cm in 21 patients (40.38%). Tumor size was unknown in one patient.
In all cases, the tumor cells were arranged in nests, clefts, and an alveolar pattern, separated by fibrous septa. Some dyscohesive cells were seen lying in spaces. The cells showed necrosis less than 50% in 33 patients (63.46%), more than 50% in 14 patients (26.92%), and no evidence of necrosis in 5 patients (09.61%). Of the fourteen patients who had necrosis more than 50%, ten patients died. The number of mitoses was less than 10 per high power fields (10 HPF) in 27 patients (51.92%), between 10 and 20 per 10 HPF in 21 patients (40.38%), and more than 20 per HPF in 4 patients (7.69%). Forty tumors (76.92%) were grade 2, and twelve tumors (23.07%) were grade 3 using the FNCLCC grading system.
HMB45 was diffusely positive in forty-four tumors (84.61%) and focally positive in 8 patients (15.38%). S100 protein was largely positive in forty-four patients (84.61%), focally positive in 5 cases (09.61%), and negative in 3 cases (5.76%). Melan A and MITF were expressed in many cases (76.92% and 84.6% of cases, resp.) including S100 protein-negative tumors. Vimentin could be detected in 3 cases (5.76%). None of our cases had expressions of keratin. Only one of the 22 CCS harboured a BRAF mutation (V599E); it was the well-known valine to glutamic acid change in position 599. No exon 11 mutation were found. One mutation of NRAS (codon 61) was also found with no overlap with the BRAF mutation. The EWS/ATF-1 fusion transcript was detected in 28 patients of the 31 paraffin-embedded CCS, and 3 of the 31 patients were negative. The two tumours that presented a BRAF or NRAS mutation also presented the ATF1-EWS fusion gene and were considered atypical. However, the absence of cutaneous involvement, histologic features (spindle and a few epithelioid cells arranged in a nested pattern), and immunohistochemistry (diffuse positivity for S100 protein and HMB45) strongly suggested a diagnosis of CCS.
Forty-nine patients (94.23%) presented with localized disease; forty-four patients (84.61%) of them underwent surgical resection of primary tumor. Nineteen patients (36.53%) underwent complete surgical resection with negative margins; twenty-five patients (48.07%) had residual microscopic disease and underwent adjuvant therapy especially radiotherapy.
The last five patients with localized disease received neoadjuvant chemotherapy before surgical resection in order to reduce tumors size and make surgical resection possible.
Two patients (3.84%) presented with disease metastatic to lymph nodes. One patient presented with disease metastatic to both lymph nodes and lung.
Definitive surgical management included wide local excisions in 29 patients, local excision in 11 patients, radical compartment resection in 4 patients, and amputation in 3 patients. Adjuvant treatment was given to 42 patients and consisted of radiotherapy in 40 patients (76.92%) with a median of 50 grays. This radiotherapy was associated to adjuvant chemotherapy in 10 patients, and 2 patients received adjuvant chemotherapy alone.
29 patients (55, 76%) developed local recurrence. The time interval from initial treatment to local relapses ranged from 1 month to 20 years, with a median of 38 months. Local recurrence was seen in 55% of the 29 patients at 5 years and 63% at 10 years. Sixteen of these patients received additional surgical treatment and 3 had amputation. Of the other 10 patients (19.23%), they were already known to have regional lymph node metastases and/or had disseminated disease. Of the 29 patients (55, 76%) who had local recurrences, 19 (36.53%) died of the tumors, three (5.76%) are alive with disease, but only seven (13.46%) patients are alive free of disease.
No local recurrences occurred in 23 patients (44.23%) who had surgical resection with negative margins (16 patients) or with positive margins associated to adjuvant radiotherapy (7 patients). The overall survival rate without local recurrence was 30% at 5 years and 16% at 10 years.
Nineteen patients developed regional lymph node metastases at 5 years in 34% and at 10 years in 41% of them. Of these patients, six (11.53%) had lymph node metastases within less than 1 year of the followup, three patients (5.76%) between 1 and 2 years, and 10 patients (19.23%) between 2 and 7 years of the followup. Regional lymph node dissection was performed on fourteen patients and was associated with regional isolated limb perfusion with melphalan and tumor necrosis factor alpha in one case. Five patients had already distant metastases.
Thirty patients developed distant metastases: 43% of them at 5 years and 62% at 10 years. Of them, twenty-seven patients died because of disease and three are alive with disease (time of followup: 09, 63, 84 months). Distant metastases most frequently involved the lungs (27 patients), bones (2 patients), and distant lymph nodes (1 patient).
Twenty-four patients received some form of chemotherapy, and three patients had surgical treatment (accessible metastases sites and single localisation).
Various chemotherapeutic regimens for musculoskeletal sarcomas or for malignant melanoma, in adjuvant aim or in curative one, were employed, including actinomycin, Adriblastina, cyclophosphamide, carboplatine, cisplatine; dacarbazine, etoposide, fotemustine; iosfamide, interleukin 2, ifosfamide (3
g/m²) + dactinomycin (1,5
mg/m²) + vincristine (1,5
mg/m²); regional isolated limb perfusion with melphalan and tumor necrosis factor alpha, methotrexate, MAID: doxorubicine (15
mg/m²) + dacarbazine (250
mg/m²/j) + ifosfamide (2–2,85
g/m²/j), vincristine; VACA: cyclophosphamide (1,2
g/m²) + doxorubicine (30
mg/m²) + dactinomycin (0,5
mg/m²) + vincristine 1,5
mg/m²; intrferon and taxol.
In twenty-one patients, chemotherapy was discontinued, usually after three courses, because of tumor progression (18 patients) or major hematotoxicity (3 patients). Local radiotherapy for distant metastases sometimes briefly alleviated the pain and was mostly given to patients with skeletal metastases.
The overall survival rate was 59% at 5 years and 41% at 10 years (). Median time of follow up was 120 months (11–348). On multivariate analysis, only tumor size (P : 0.01) emerged as a significant prognostic factor ( and ).
Overall survival of 52 patients with clear cell sarcoma.
Multivariate analysis of overall survival.
Event-free survival of 52 patients with clear cell sarcoma according to tumor size (P = 0.01).