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ORIGINAL ARTICLES |
From the Sarcoma and Melanoma Unit, Royal Marsden NHS Trust, United Kingdom.
Correspondence: Address correspondence and reprint requests to: Kasim A. Behranwala, MS, DNB, FRCS (Ed), FRCS (Glas), Sarcoma and Melanoma Unit, Royal Marsden NHS Trust, 203 Fulham Road, London SW3 6JJ, UK; Fax: 44-0-20-7808-2673, E-mail: kbehranwala{at}hotmail.com
| ABSTRACT |
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Methods: All patients with RLNM from soft tissue sarcoma were identified from the Royal Marsden Hospital Sarcoma Unit prospective database from January 1990.
Results: A total of 73 (3.4%) of 2127 patients had RLNM. Fifty-seven patients (78.1%) had RLNM as the first site of spread, and 16 patients (21.9%) presented with RLNM and distant metastasis synchronously. The most common histologies were rhabdomyosarcoma, epithelioid sarcoma, and angiosarcoma. There were 9 T1 and 36 T2 tumors, and tumor size was not available in 28 patients. There were 6 grade 1, 16 grade 2, and 51 grade 3 tumors. Forty-two patients presented with RLNM along with the primary tumor. Of the remaining patients, the median time to development of RLNM from diagnosis of the primary tumor was 13.5 months (95% confidence interval [CI], 1100 months). The 1-year survival for patients with isolated RLNM was 77.49% (95% CI, 62.99%86.88%), compared with 36.27% (95% CI, 13.32%60.04%) for patients who presented with RLNM and distant metastasis (P = .005). The 1-year survival for metachronous and synchronous RLNM was 94.44% (95% CI, 66.64%99.20%) and 67.54% (95% CI, 47.89%81.12%), respectively (P = .05).
Conclusions: Lymph node metastasis is rare. Patients who present with isolated RLNM have an improved survival compared with patients who present with regional and distant metastasis at diagnosis. Synchronous RLNM with the primary tumor have a poorer outcome than metachronous RLNM in the absence of distant metastasis.
Key Words: Lymph node metastasis Soft tissue sarcoma Prognosis Survival
| INTRODUCTION |
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| MATERIALS AND METHODS |
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Diagnosis and Treatment
Lymph nodes were evaluated by fine-needle aspiration cytology, core biopsy, or excisional biopsy to obtain histological diagnoses. Occasionally, nodal metastases were discovered incidentally in the resected specimen when the tumor lay adjacent to a lymph node field. Involvement of lymph nodes by disease (>2 cm) was also judged by evaluation of computed tomography scans.
Patients with isolated lymph node metastases were mainly treated by surgery as the primary modality. A few patients with RLNM with suitable histology (primitive neuroectodermal tumor/Ewings sarcoma or embryonal rhabdomyosarcoma), a surgically inaccessible location, or extensive unresectable nodal disease, with or without systemic disease, were treated primarily by chemotherapy or radiotherapy.
Pathology
Tumor-related factors, including histological type, size, and grade, were noted. Tumor size was recorded from the pathologic specimen or imaging analysis. Tumors were classified as T1 (<5 cm) or T2 (>5 cm). Tumor grade was classified as low (grade 1), intermediate (grade 2), or high (grade 3) on the basis of the degree of cellularity, differentiation and vascularity, nuclear pleomorphism, number of mitoses per high-power field, and amount of stromal necrosis.
Follow-Up
Careful surveillance was based on guided history and thorough physical examination. Plain chest radiographs were initially performed every 4 months (for the first 2 years if high grade and otherwise for 1 year) and then yearly. Axial imaging studies for detection of recurrence were not part of the follow-up protocol for the patients in this study and were indicated only if a patient was symptomatic or if clinical examination findings were abnormal. Follow-up data are presented as time in months from the diagnosis of nodal disease.
Statistical Analysis
Generic grouping of site was accepted; extremities and superficial trunk were combined. Visceral sites were analyzed as separate, as were the remainder (head and neck, breast, and retroperitoneum). There were therefore three categories: extremity plus superficial trunk, visceral, and the remainder. According to the AJCC 6th ed./UICC 5th ed. guidelines,16 the patient with dermatofibrosarcoma protuberans (DFSP) was excluded from statistical analysis. Analysis of the effect of site, the extent of treatment (radical vs. limited lymph node dissection), and the timing of RLNM detection on survival (synchronous vs. metachronous to the primary tumor) was undertaken with Coxs regression. Survival after lymph node metastasis was the primary end point. Survival rates were analyzed, and life-table curves were constructed according to the Kaplan-Meier method. The log-rank test was used to compare differences in survival distributions observed in subsets of patients. No adjustment was made for multiple significance tests, because the interpretation of the P values should be evident.17
| RESULTS |
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Simultaneous distant metastasis at the time of presentation of RLNM was present in 16 patients. Therefore, the basic series to evaluate the prognostic significance of regional lymph node involvement consisted of 56 patients (excluding 1 patient with DFSP) who had isolated RLNM at the time of their discovery. Of these, 31 went on to have distant metastasis after treatment of lymph node metastasis, with a median time to development of distant metastasis of 21 months (range, 735 months). At last follow-up, 10 patients were healthy, 48 patients had died of disease, 12 patients were alive with disease, and 3 patients were dead because of medical reasons.
Survival From Lymph Node Metastasis
No survival difference was observed among the various sites of the primary tumor with RLNM. Thus, the entire group could be studied as a whole irrespective of disease site. The 1- and 2-year survival for patients with isolated RLNM were 77.49% (95% confidence interval [CI], 62.99%86.88%) and 47.36% (95% CI, 32.67%60.69%), respectively. The 1- and 2-year survival for patients with distant metastases present at the time of presentation of RLNM were 36.27% (95% CI, 13.32%60.04%) and 21.76% (95% CI, 5.31%45.29%), respectively (P = .005; Fig. 1). The 5-year survival for patients with isolated RLNM was 23.9% (95% CI, 12.6%37.1%) and was 0% for patients who presented with RLNM and distant metastasis.
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| DISCUSSION |
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Fine et al.21 commented that regional lymphadenopathy seldom manifests clinically at the time of initial therapy and that on occasion it becomes evident years after the primary tumor has been excised or has recurred locally. In our study, 42 of 73 patients presented with RLNM synchronously with a primary tumor (7 had synchronous distant metastasis). Certainly, the clinical impression that elective lymphadenectomy is not warranted for STS is supported by the low incidence (3.4%) of nodal metastasis found in this study. Radiotherapy is not given prophylactically to the lymph nodedraining areas in sarcoma. Regional lymph nodes as the first site of disease recurrence was observed in 31 (1.5%) of 2127 cases. There was a borderline significance in 5-year survival between local recurrence and regional lymph nodes as the site of first recurrence of disease in the study by Vezeridis et al.15 The presence of RLNM seems to be associated with a high incidence of relapse in metastatic sites and with poor outcome.
The 5-year overall and disease-free survival for stage III in the Memorial Sloan-Kettering Cancer Center study (AJCC 6th ed.) were 56.29% and 51.77%, respectively. The 2- and 5-year survival for patients with isolated RLNM for extremity STS in our study were 47.36% and 23.9%, which was less than with patients with stage III disease. Concomitant distant metastases significantly altered survival for patients with lymph node metastases in our study (2-year survival, 21.76%; 95% CI, 5.31%45.29%). In the study by Billingsley et al.,22 the 2- and 5-year survival for patients with pulmonary metastases were 30% and 16%, respectively. The 2- and 5-year survival from the Royal Marsden Hospital Sarcoma database for the group with only distant metastases were 36.7% (SE, 2%) and 18.5% (SE, 2%), respectively. These findings suggest that the current AJCC/UICC staging system for STS should be re-examined. Patients with isolated RLNM could be assigned to stage IVa and those with distant metastases to stage IVb.
The conclusion derived by Fong et al.12that radical lymphadenectomy is appropriate treatment for isolated metastases to the regional lymph nodes and may provide long-term survivalis confounded by the fact that 12 of the 16 patients in the limited lymphadenectomy group had unresectable disease or distant metastatic disease.
In our study it was demonstrated that primary surgical treatment of lymph nodes gives a better survival than that for patients treated by chemotherapy and radiotherapy in the group with RLNM only. Patients treated only by chemotherapy and radiotherapy did worse, probably because they presented with worse disease (higher tumor burden) than those treated with surgery. Limited regional node dissection was performed at referring hospitals or for positive lymph nodes detected incidentally on histology when they were removed in continuity with the primary tumor. Radical lymphadenectomy did not confer a significant survival benefit over limited involved regional node dissection for patients with only RLNM in this study. The possible explanation would be that involvement of lymph nodes, irrespective of the number involved, translates into equal biological aggressiveness. The data are not statistically significant because the numbers are small, and we would still recommend radical lymphadenectomy for treatment of RLNM.
Three patients in our series received adjuvant treatment (two patients were treated by chemotherapy, and one received radiotherapy to the lymph node basin). The combined multimodality therapy did not seem to improve survival rates in our patients, although it is difficult to assess its effect because it was not applied in a randomized fashion. Thus, the data according to adjuvant treatment are not shown and are not discussed further. Forty of 48 patients in our series died of disseminated disease. Therefore, adjuvant chemotherapy after lymphadenectomy may be the most reasonable treatment. Lymph node involvement in sarcoma patients is a poor prognostic sign, and such patients require systemic therapy in an attempt to control future development of metastatic disease.
| CONCLUSION |
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| FOOTNOTES |
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Received for publication April 28, 2003. Accepted for publication March 26, 2004.
| REFERENCES |
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