James M. Woodruff

Two Hundred Gastrointestinal Stromal Tumors: Recurrence Patterns and Prognostic Factors for Survival

OBJECTIVE To analyze the outcome of 200 patients with gastrointestinal stromal tumor (GIST) who were treated at a single institution and followed up prospectively. SUMMARY BACKGROUND DATA A GIST is a visceral sarcoma that arises from the gastrointestinal tract. Surgical resection is the mainstay of treatment because adjuvant therapy is unproven. METHODS Two hundred patients with malignant GIST were admitted and treated at Memorial Hospital during the past 16 years. Patient, tumor, and treatment variables were analyzed to identify patterns of tumor recurrence and factors that predict survival. RESULTS Of the 200 patients, 46% had primary disease without metastasis, 47% had metastasis, and 7% had isolated local recurrence. In patients with primary disease who underwent complete resection of gross disease (n = 80), the 5-year actuarial survival rate was 54%, and survival was predicted by tumor size but not microscopic margins of resection. Recurrence of disease after resection was predominantly intraabdominal and involved the original tumor site, peritoneum, and liver. CONCLUSIONS GISTs are uncommon sarcomas. Tumor size predicts disease-specific survival in patients with primary disease who undergo complete gross resection. Tumor recurrence tends to be intraabdominal. Investigational protocols are indicated to reduce the rate of recurrence after resection and to improve the outcome for patients with GIST.

Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities

PURPOSE To identify specific independent adverse clinicopathologic factors for event-free survival in a cohort of consecutively treated patients with extremity soft tissue sarcomas. PATIENTS AND METHODS Prospectively collected data from a population of 1,041 adult patients with localized (American Joint Committee on Cancer [AJCC] stage IA to IIIB) extremity soft tissue sarcomas were analyzed. Patients were treated at a single institution between 1982 and 1994. Patient, tumor, and pathologic factors were analyzed by univariate and multivariate techniques to identify independent prognostic factors for the end points of local recurrence, distant recurrence, disease-specific survival, and post-metastasis survival. RESULTS The 5-year survival rate for this cohort of patients was 76%, with a median follow-up time of 3.95 years. Significant independent adverse prognostic factors for local recurrence were age greater than 50 years, recurrent disease at presentation, microscopically positive surgical margins, and the histologic subtypes fibrosarcoma and malignant peripheral-nerve tumor. For distant recurrence, intermediate tumor size, high histologic grade, deep location, recurrent disease at presentation, leiomyosarcoma, and nonliposarcoma histology were independent adverse prognostic factors. For disease-specific survival, large tumor size, high grade, deep location, recurrent disease at presentation, the histologic subtypes leiomyosarcoma and malignant peripheral-nerve tumor, microscopically positive surgical margins, and lower extremity site were adverse factors. For post-metastasis survival, only large tumor size ( > 10 cm) was an adverse prognostic factor. CONCLUSION The independent adverse prognostic factors for distant recurrence and disease specific survival differ from those identified for subsequent local recurrence. Patients with microscopically positive surgical margins or patients who present with locally recurrent disease are at increased risk for subsequent local recurrence and tumor-related mortality. Specific histopathologic subtypes are associated with increased risks for local failure and tumor-related mortality.

Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma.

PURPOSE This trial was performed to evaluate the impact of adjuvant brachytherapy on local and systemic recurrence rates in patients with soft tissue sarcoma. PATIENTS AND METHODS In a single-institution prospective randomized trial, 164 patients were randomized intraoperatively to receive either adjuvant brachytherapy (BRT) or no further therapy (no BRT) after complete resection of soft tissue sarcomas of the extremity or superficial trunk. The adjuvant radiation was administered by iridium-192 implant, which delivered 42 to 45 Gy over 4 to 6 days. The two study groups had comparable distributions of patient and tumor factors, including age, sex, tumor site, tumor size, and histologic type and grade. RESULTS With a median follow-up time of 76 months, the 5-year actuarial local control rates were 82% and 69% in the BRT and no BRT groups (P = .04), respectively. Patients with high-grade lesions had local control rates of 89% (BRT) and 66% (no BRT) (P = .0025). BRT had no impact on local control in patients with low-grade lesions (P = .49). The 5-year freedom-from-distant-recurrence rates were 83% and 76% in the BRT and no BRT groups (P = .60), respectively. Analysis by histologic grade did not demonstrate an impact of BRT on the development of distant metastasis, despite the improvement in local control noted in patients with high-grade lesions. The 5-year disease-specific survival rates for the BRT and no BRT groups were 84% and 81% (P = .65), respectively, with no impact of BRT regardless of tumor grade. CONCLUSION Adjuvant brachytherapy improves local control after complete resection of soft tissue sarcomas. This improvement in local control is limited to patients with high-grade histopathology. The reduction in local recurrence in patients with high-grade lesions is not associated with a significant reduction in distant metastasis or improvement in disease-specific survival.

Retroperitoneal soft-tissue sarcoma : analysis of 500 patients treated and followed at a single institution

OBJECTIVE To analyze treatment and survival of a large cohort of patients with retroperitoneal soft-tissue sarcomas (STS) treated and prospectively followed at a single institution. SUMMARY BACKGROUND DATA Retroperitoneal STS are relatively uncommon and constitute a difficult management problem. Although surgical resection is often difficult or impossible, current chemotherapy is not effective and radiation is limited by toxicity to adjacent structures. Thus, complete surgical resection remains the most effective modality for selected primary and recurrent disease. METHODS Five hundred patients with retroperitoneal STS were admitted and treated between July 1, 1982, and September 30, 1997, and prospectively followed. Patient, tumor, and treatment variables were analyzed for disease-specific and disease-free survival. Survival was determined with the Kaplan-Meier method. Statistical significance was evaluated using the logrank test for univariate influence and Cox model stepwise regression for multivariate influence. RESULTS Two hundred seventy-eight patients (56%) had primary disease and 222 (44%) recurrent disease. Median follow-up was 28 months (range 1 to 172 months), 40 months for survivors. Median survival was 72 months for patients with primary disease, 28 months for those with local recurrence, and 10 months for those with metastasis. For patients with primary or locally recurrent tumors, unresectable disease, incomplete resection, and high-grade tumors significantly reduced survival time. CONCLUSIONS In this study of patients with retroperitoneal STS, stage at presentation, high histologic grade, unresectable primary tumor, and positive gross margin are strongly associated with the tumor mortality rate. Patients approached with curative intent should undergo aggressive attempts at complete surgical resection. Incomplete resection should be undertaken only for symptom relief.

SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma

BACKGROUND Synovial sarcomas account for up to 10 percent of soft-tissue sarcomas and include two major histologic subtypes, biphasic and monophasic, defined respectively by the presence and absence of glandular epithelial differentiation in a background of spindle tumor cells. A characteristic SYT-SSX fusion gene resulting from the chromosomal translocation t(X;18)(p11;q11) is detectable in almost all synovial sarcomas. The translocation fuses the SYT gene from chromosome 18 to either of two highly homologous genes at Xp11, SSX1 or SSX2. SYT-SSX1 and SYT-SSX2 are thought to tunction as aberrant transcriptional regulators. We attempted to determine the influence of the two alternative forms of the SYT-SSX fusion gene on tumor morphology and clinical outcome in patients with this sarcoma. METHODS We analyzed SYT-SSX fusion transcripts in 45 synovial sarcomas (33 monophasic and 12 biphasic) by the reverse-transcriptase polymerase chain reaction and compared the results with relevant clinical and pathological data. RESULTS The SYT-SSX1 and SYT-SSX2 fusion transcripts were detected in 29 (64 percent) and 16 (36 percent) of the tumors, respectively. There was a significant relation (P=0.003) between histologic subtype (monophasic vs. biphasic) and SSX1 or SSX2 involvement in the fusion transcript: all 12 biphasic synovial sarcomas had a SYT-SSX1 fusion transcript, and all 16 tumors that were positive for SYT-SSX2 were monophasic. Kaplan-Meier analysis of 39 patients with localized tumors showed that the 15 patients with SYT-SSX2 had significantly better metastasis-free survival than the 24 patients with SYT-SSX1 (P=0.03 by multivariate analysis; relative risk, 3.0). There were no significant correlations between the type of SYT-SSX transcript and age, sex, tumor location and size, whether there were metastases at diagnosis, or whether patients underwent chemotherapy. Histologic subtype alone was not prognostically important. CONCLUSIONS The type of SYT-SSX fusion transcript correlates with both the histologic subtype and the clinical behavior of synovial sarcoma. SYT-SSX fusion transcripts are a defining diagnostic marker of synovial sarcomas and may also yield important independent prognostic information.

Lymph node metastasis from soft tissue sarcoma in adults. Analysis of data from a prospective database of 1772 sarcoma patients.

To examine the natural history of lymph node metastasis from sarcomas and the utility of therapeutic lymphadenectomy, clinical histories of all adult patients identified by a prospective sarcoma database for the 10-year period July 1982 to July 1991 were examined. Of the 1772 sarcoma patients, 46 (2.6%) were identified with lymph node metastasis. Median follow-up of all patients from diagnosis of lymph node metastasis was 12.9 months (range, 0 to 100 months). Median survival for nonsurvivors was 12.7 months (range, 0 to 40.7). The tumor types with the highest incidence of lymph node metastasis are angiosarcoma (5/37 total cases; 13.5%), embryonal rhabdomyosarcoma (ERMS) (12/88 total cases; 13.6%), and epithelioid sarcoma (2/ 12 total cases; 16.7%). Lymph node metastasis from visceral primary (p = 0.004) and malignant fibrous histiocytomas (p = 0.006) were associated with particularly poor prognosis. Thirty-one patients underwent radical, therapeutic lymphadenectomy with curative intent, whereas 15 patients had less than curative procedures, in most cases biopsy only. Patients not treated with radical lymphadenectomy had a median survival of 4.3 months (range, 1 to 32) whereas radical lymphadenectomy was associated with a 16.3 month median survival and the only long-term survivors (46% 5-year survival by Kaplan-Meier). The authors conclude that lymph node metastases from sarcoma are rare in adults, but vigilance is warranted, especially in angiosarcoma, ERMS, and epithelioid subtypes. Radical lymphadenectomy is appropriate treatment for isolated metastasis to regional lymph nodes and may provide long-term survival.

Pulmonary Metastases from Soft Tissue Sarcoma: Analysis of Patterns of Disease and Postmetastasis Survival

OBJECTIVE To report the patterns of disease and postmetastasis survival for patients with pulmonary metastases from soft tissue sarcoma in a large group of patients treated at a single institution. Clinical factors that influence postmetastasis survival are analyzed. SUMMARY BACKGROUND DATA For patients with soft tissue sarcoma, the lungs are the most common site of metastatic disease. Although pulmonary metastases most commonly arise from primary tumors in the extremities, they may arise from almost any primary site or histology. To date, resection of disease has been the only effective therapy for metastatic sarcoma. METHODS From July 1982 to February 1997, 3149 adult patients with soft tissue sarcoma were admitted and treated at Memorial Sloan-Kettering Cancer Center. During this interval, 719 patients either developed or presented with lung metastases. Patients were treated with resection of metastatic disease whenever possible. Disease-specific survival was the endpoint of the study. Time to death was modeled using the method of Kaplan and Meier. The association of factors to time-to-event endpoints was analyzed using the log-rank test for univariate analysis and the Cox proportional hazards model for multivariate analysis. RESULTS The overall median survival from diagnosis of pulmonary metastasis for all patients was 15 months. The 3-year actuarial survival rate was 25%. The ability to resect all metastatic disease completely was the most important prognostic factor for survival. Patients treated with complete resection had a median survival of 33 months and a 3-year actuarial survival rate of 46%. For patients treated with nonoperative therapy, the median survival was 11 months. A disease-free interval of more than 12 months before the development of metastases was also a favorable prognostic factor. Unfavorable factors included the histologic variants of liposarcoma and malignant peripheral nerve tumors and patient age older than 50 years at the time of treatment of metastasis. CONCLUSIONS Resection of metastatic disease is the single most important factor that determines outcome in these patients. Long-term survival is possible in selected patients, particularly when recurrent pulmonary disease is resected. Surgical excision should remain the treatment of choice for metastases of soft tissue sarcoma to the lung.

Paragangliomas of the head and neck region. A pathologic study of tumors from 71 patients.

The histopathology of 72 paragangliomas originating in the head and neck region of 71 patients is presented. There were 45 carotid body, 13 vagal body, eight jugulotympanic, and three nasal paragangliomas. In addition, two arose in the larynx and one in the area of the aortic arch. Tumors occurred in four unrelated families. The two most important histologic features leading to a diagnosis of paraganglioma were zellballen and the presence of cytoplasmic argyrophil granules in all cases in which staining with the Grimelius technique was carried out. Ultrastructural study of three carotid body and two vagal body paragangliomas revealed both light and dark chief cells. Tumor cells contained membrane bound, electron dense neurosecretory types of granules, which usually ranged in diameter from 120 to 200 nm. Follow-up information was available for 67 patients (94 per cent). Two of the three nasal paragangliomas, 50 per cent of the jugulotympanic paragangliomas, 17 per cent of the vagal body paragangliomas, and 10 per cent of those of the carotid body recurred locally following attempted surgical resection. All patients treated with radiation had persistent tumor. Four (9 per cent) of the carotid body paragangliomas were malignant, all four patients dying with widespread metastases. One vagal body paragangliomas metastasized to regional lymph nodes (the patient was alive and well at five years), and another caused death by direct intracranial extension. In contrast to the benign tumors, malignant paragangliomas tended to show foci of necrosis and vascular invasion. Mitotic figures, which usually were not identified in the benign cases, were seen in all malignant tumors.

Malignant peripheral nerve sheath tumors of the buttock and lower extremity. A study of 43 cases

Using strict clinical and pathologic criteria for the inclusion of cases, the authors have reviewed the clinicopathologic features of 43 malignant peripheral nerve sheath tumors of the buttock and extremity seen over a 35‐year period. Twentythree (53%) of the patients had neurofibromatosis (VRN), whereas 20 (47%) did not. Fifty‐one percent of the patients were women. The mean age at presentation was 36 years for patients with VRN and 44 years for patients without VRN. A nerve of origin was identified for 72% of the cases and an associated neurofibroma for 44% (65% with VRN and 20% without VRN). The mean greatest dimension of the tumors was 12.3 cm, and this did not differ significantly between the two groups. The predominant histologic pattern in 86% of the tumors was that of tightly packed spindle cells in an interlacing and woven pattern; heterologous sarcomatous elements were noticed in 12% of the cases. Surgical resection was the main modality of treatment for all patients; 65% also received adjuvant therapy. Followup evaluation was done in every case. An unexpected finding was the absence of a significant difference in survival rates between patients with and without VRN. Overall, 63% of the patients died of tumor: 65% of the patients with VRN and 60% of the patients without VRN. Large tumor size and high mitotic rate (>20 per 10 high‐power fields) portended a poor prognosis, as did the need for resection by amputation. Adjuvant radiation therapy and chemotherapy did not affect survival rates.

Prognostic factors associated with long-term survival for retroperitoneal sarcoma: implications for management.

PURPOSE Retroperitoneal soft tissue sarcomas are rare tumors. Studies characterizing long-term follow-up and patterns of recurrence are limited. The purpose of this analysis is to identify patterns of recurrence and prognostic factors associated with long-term survival after resection of retroperitoneal soft tissue sarcomas. METHODS Between July 1, 1982, and June 30, 1990, 198 adult patients were identified from our prospective soft tissue sarcoma database carrying the diagnosis of retroperitoneal soft tissue sarcoma who were eligible for > or = 5 years of follow-up. Of these, 48 patients (25%) were documented to be alive > or = 5 years from the time of operation. Statistical analysis was by log-rank or Wilcoxon test for univariate analysis. Multivariate analysis was by the Cox model. RESULTS The recurrence rate during the follow-up period was approximately 5% per year from the time of initial operation. Of the patients who were disease-free for > or = 5 years from initial surgery, 40% recurred by 10 years. Radiation therapy was the only factor significant (P = .02) for a reduction in the risk of local recurrence. Age < or = 50 years and high-grade tumors were significant factors (P = .003 and .009, respectively) for an increased risk of distant metastasis. Incomplete gross resection was the only factor significant for an increased risk of tumor mortality (P = .003). CONCLUSION Complete surgical resection at the time of primary presentation is likely to afford the best chance for long-term survival. With long-term follow-up, it is clear that recurrence will continue to occur, and a 5-year disease-free interval is not a cure. Patients with an incomplete initial resection, age less than 50 years, and high-grade tumors are candidates for investigational adjuvant therapy.