364 Metastases to the Retroperitoneum in Patients with Extremity Soft Tissue Sarcoma An Unusual Metastatic Pattern Dina Lev-Chelouche, M.D.1 Richard Nakache, M.D.1 Dror Soffer, M.D.1 Ofer Merimsky, M.D.2 Joseph M. Klausner, M.D.1 Mordechai Gutman, M.D.1 1 Department of Surgery B, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 2 Department of Oncology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. BACKGROUND. Extremity soft tissue sarcoma (STS) metastasizes preferentially to the lungs via the hematogenous route. Metastases in extrapulmonary sites such as bone, brain, and subcutaneous tissues are observed less frequently. To the authors’ knowledge, limb STS primarily metastasizing to the retroperitoneum has not been described to date. The current study reviews the clinical course, management, and patient prognosis in such a pattern of metastasis. METHODS. Records of patients with retroperitoneal metastases originating from an extremity STS between 1994 –1998 were reviewed. Patient demographics, primary tumor site, other tumor sites, local recurrence, distant metastasis, treatment, and survival were analyzed. RESULTS. Ten patients were included in the study. All had primary STS of different histologic types and high histologic grade confined to a lower limb. The retroperitoneal metastases were diagnosed between 6 –120 months (mean, 45 months) after diagnosis of the primary sarcoma. At that time, one patient had evidence of local recurrence of the primary tumor site, two patients had lung metastases, and one patient had diffuse bone metastases. Eight patients were eligible for surgery. In six of these patients the metastases were excised completely. The median follow up was 12 months. Of the six patients who underwent complete resection, 3 were alive at last follow-up with no evidence of disease after 12 months, 14 months, and 24 months, respectively. Two patients with recurrent retroperitoneal disease and one patient with retroperitoneal and lung metastases died despite systemic chemotherapy. CONCLUSIONS. Extremity STS can metastasize hematogenously to the retroperitoneum, a fact that mandates a high index of suspicion and abdominal imaging studies during the follow-up of such patients. Retroperitoneal metastases necessitate aggressive surgical resection to enable prolongation of survival. Cancer 2000; 88:364 – 8. © 2000 American Cancer Society. KEYWORDS: soft tissue sarcoma, limb, retroperitoneum, metastasis, treatment, survival. oft tissue sarcomas (STS) are relatively rare, comprising ⬍ 1% of all adult solid malignancies. This low incidence rate, together with the multitude of histologic subtypes, is responsible for the relatively obscure knowledge regarding their natural history. Approximately 60% of STS occur in the extremities, mainly in the lower limb. At the time of diagnosis, the majority of patients do not have detectable distant metastases, and initial therapy therefore is directed at definitive treatment of the primary lesion.1 Use of a multimodality approach– (surgery, chemotherapy, and radiation) has resulted in a significantly lower local recurrence rate and improved local control.2,3 S Address for reprints: Mordechai Gutman, M.D., Department of Surgery B, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel. Received April 23, 1999; accepted September 27, 1999. © 2000 American Cancer Society Sarcoma Metatasizing to the Retroperitoneum/Lev-Chelouche et al. 365 TABLE 1 Patient and Tumor Characteristics Patient no. Age (yrs) Gender Histology/grade 1 2 3 4 5 6 7 8 9 10 43 42 22 38 34 58 35 83 75 47 M M M M M F M F F F Liposarcoma/2 Liposarcoma/2 Malignant schwannoma/2 Leiomyosarcoma/2 Synovial sarcoma/2 Malignant fibrous histiocytoma/2 Malignant fibrous histiocytoma/3 Malignant fibrous histiocytoma/3 Liposarcoma/2 Liposarcoma/2 Primary site TNM staging of primary tumor8 Time to retroperitoneal metastases from primary diagnosis (mos) Local recurrence/other metastatic sites Thigh Thigh Thigh and calf Thigh Calf Thigh Thigh Thigh Thigh Thigh IIB IIB IIB IIB IIB IIB IIIB IIIB IIB IIB 37 12 32 96 36 24 6 72 120 12 No Local recurrence No No No Lung Lung No No Bone M: male; F: female. However, mortality remains high and largely is attributed to the well recognized propensity of STS for hematogenous dissemination. Extremity STS appear to metastasize preferentially to the lungs and indeed the lung is the first site of spread, accounting for up to 80% of all metastases in the majority of series reported to date.4,5 This led to the recommendation that during follow-up of patients after resection of an STS of a limb, the physician’s attention should focus on the local site of the tumor and the lungs. Less frequently, metastases in extrapulmonary sites such as bone, brain, and, occasionally, subcutaneous tissues are observed. This pattern will develop in approximately 14% of patients as the initial manifestation of metastatic disease.4 Lymphatic metastases are uncommon and occur in ⬍ 5% of sarcoma patients.6 The low rate of lymph node involvement occurs as a result of the limited lymphatic supply to mesodermal structures resulting from the unusual involvement of these tissues in a host defense against invasion by pathogens.7 To our knowledge, the retroperitoneum, although a rather common site for primary STS, is a rare and poorly described target for the spread of extremity STS. Encountering patients with this disease entity led us to undertake the current study to examine the natural history, treatment, and prognosis of patients with this unique metastatic pattern. MATERIALS AND METHODS The records of patients with retroperitoneal metastases originating from an extremity STS treated in our surgical department between 1994 and 1998 were reviewed. Included were all patients with a history of histologically proven primary STS confined to the limb who developed a histologically identical secondary retroperitoneal mass. Charts and histopathologic slides were reviewed to determine clinical presentation, size, histologic type, and grade of both the extremity and the retroperitoneal tumor, treatment of the primary tumor, time to development of retroperitoneal metastasis, extent of surgical resection and use of chemotherapy, pattern of recurrence and metastases, and survival. RESULTS Ten patients were included in the study; 6 were male and 4 were female, ages 22– 83 years (mean, 48 years) (Table 1). All had primary STS confined to the lower limb, with no evidence of metastases at time of diagnosis. There were four liposarcomas, three malignant fibrous histiocytomas, one synovial sarcoma, one leiomyosarcoma, and one malignant schwannoma. All tumors were of high histologic grade (1997 AJCC Grades II–III). Staging according to the TNM system is reported in Table 1.8 The primary tumors were treated via a multimodality limb-sparing approach including complete resection plus radiotherapy (seven patients), systemic chemotherapy (four patients), and isolated limb perfusion with chemotherapeutics and/or tumor necrosis factor (four patients). Prior to the diagnosis of retroperitoneal metastases, three patients experienced local recurrence that necessitated further treatment; none underwent amputation. The retroperitoneal metastases were diagnosed between 6 –120 months (mean, 45 months) after diagnosis of the primary sarcoma. The most common presenting symptoms were abdominal pain and a palpable abdominal mass. Other symptoms included anorexia, nausea, emesis, and weight loss. Four patients were asymptomatic and were diagnosed inci- 366 CANCER January 15, 2000 / Volume 88 / Number 2 TABLE 2 Treatment and Follow-Up Patient no. Treatment Follow-up Status (D/A) 1 Complete resection, colectomy, and nephrectomy D, 12 mos 2 Resection of recurrent extremity STS and complete retroperitoneal metastases resection Laparotomy - biopsy, chemotherapy Complete resection, colectomy, splenectomy, and distal pancreatectomy Laparotomy - biopsy, chemotherapy Complete resection, nephrectomy, and lung metastectomy Chemotherapy Complete resection, sigmoidectomy, iliac vessel resection, and reconstruction Complete resection Chemotherapy Recurrent retroperitoneal and lung metastases (8 mos) Recurrent retroperitoneal metastases (12 mos) D, 18 mos NED D, 6 mos A, 14 mos 3 4 5 6 7 8 9 10 NED NED Recurrent retroperitoneal metastases (12 mos) D, 8 mos A, 12 mos D, 6 mos A, 24 mos D, 24 mos A, 3 mos D: dead; A: alive; STS: soft tissue sarcoma; NED: no evidence of disease. dentally through imaging studies performed during the follow-up of patients with a history of STS. At the time of diagnosis of the retroperitoneal mass, one patient had evidence of local recurrence of the primary site, two patients were found to have lung metastases (one had two lung lesions and the other had diffuse bilateral disease), and a fourth patient had diffuse bone metastases. The remaining six patients had no evidence of any other metastatic spread and the disease was confined to the retroperitoneum, which was the initial site of disease spread. Treatment was based on the extent of disease (Table 2). The two patients with diffuse extraabdominal disease (lung and bone) were treated with doxorubicin-based chemotherapy. The patient with limited lung disease and the patient with simultaneous local recurrence underwent combined surgery to resect all evident disease. The six patients with metastases confined to the retroperitoneum were referred for curative surgical resection. Surgical Treatment Prior to abdominal resection surgery, all eight patients had undergone preoperative assessment including ultrasonography, computed tomography, or magnetic resonance imaging, and all were considered to have resectable disease according to these imaging techniques. Six patients were found to have single lesions with an average dimension of 15 cm; all underwent complete resection necessitating en bloc excision of adjacent structures in four patients: colectomy (three patients), nephrectomy (two patients), splenectomy (one patient), distal pancreatectomy (one patient), and iliac vessel excision and reconstruction (one patient). Two patients were found to have nonresectable diffuse metastatic disease infiltrating the root of the mesentery and only a biopsy was performed. These patients later received systemic chemotherapy. There was no perioperative mortality. Two patients had wound infections but no other major complications were observed. According to the pathologic examinations performed by two separate pathologists, all resected tumors were comprised of clean microscopic margins and histologically were identical with regard to tumor type and grade to the primary extremity STS, as were those tumors that were biopsied only. There was no evidence of lymph node involvement. Follow-up The median follow-up period to date was 12 months. Of the six patients who underwent complete resection, two had recurrent retroperitoneal disease that was found to be nonresectable and one patient had retroperitoneal and lung metastases. All 3 patients received systemic chemotherapy but all died at 12 months, 18 months, and 24 months, respectively, after the initial diagnosis of retroperitoneal metastases. The remaining 3 patients were alive with no evidence of disease at 12 months, 14 months, and 24 months, respectively, after undergoing curative resection (Table 2). Both patients who underwent biopsy alone died 6 months and 8 months, respectively, after surgery. Of the 2 patients with diffuse metastatic disease who were treated with chemotherapy alone, 1 patient died Sarcoma Metatasizing to the Retroperitoneum/Lev-Chelouche et al. 6 months after diagnosis and the second patient was alive after 3 months. DISCUSSION The fact that sarcomas spread hematogenously, and that the lung is the most common site for such spread, has been well established in the literature.4-6 However, to the best of our knowledge, extremity STS primarily metastasizing to the retroperitoneum has not been described previously. In the current study we reviewed the clinical course of ten patients with such a pattern of metastasis. Although this was a small group of patients, they should be viewed differently given the rarity of STS. The estimated annual incidence rate of STS of the limb in Israel is approximately 70 patients among the entire population. The diagnosis of retroperitoneal metastases is difficult because the symptoms are vague and manifest only when the disease is very extensive. In the current study, tumors had reached a mean dimension of 15 cm at the time of diagnosis, and many patients were asymptomatic. Although the majority of systemic failures in STS occur within the first 2 years,4 the time to development of metastatic disease in the current series was 6 –120 months (mean, 45 months), emphasizing the need for the prolonged follow-up of sarcoma patients. Are we dealing with metastasis or is it a multifocal sarcoma? Blair et al.9 described six patients with multifocal sarcoma, six of whom had recurrent extremity STS with a sarcoma present in the retroperitoneum as well. However, all these patients had other sites of involvement concurrently, whereas in the majority of the patients in the current study (seven of ten patients), the retroperitoneum was an isolated and initial site of metastasis. Moreover, all retroperitoneal sarcomas in the current study were identical histologically to the primary extremity STS, making the metastatic theory more likely. We theorize that the dissemination of sarcoma from the extremity to the retroperitoneum most likely occurred via a hematogenous route because there was no evidence of direct extension from the leg to the retroperitoneum and, although the lymphatic channels also are a potential metastatic route, it is unlikely in the ten patients described in the current study because no lymph node involvement was found. Treatment of metastatic sarcoma to the retroperitoneum mainly is based on surgical resection. Experience with surgical resection of pulmonary metastases indicate that this approach may prolong patient survival.10,11 Only a small number of patients with isolated sites of involvement other than the lung (bone, subcutaneous tissue, liver, and lymph nodes) will be amenable to surgical resection and remain disease 367 free for a prolonged period. Thus the prognosis for the majority of patients developing this pattern of metastasis is far less favorable than that for patients developing an isolated pulmonary metastasis.4 The current study suggests that one could adopt the approach used for lung metastases to retroperitoneal metastases also, because 50% (3 of 6 patients) of the patients in the current study with resectable disease were alive with no evidence of disease at last follow-up, whereas those patients with nonresectable disease had a short survival period of only several months’ duration. Surgery for retroperitoneal metastases should be identical to surgery for primary retroperitoneal sarcoma, in which the main goal is complete resection of all tumor masses with macroscopic negative surgical margins.12,13 This can be accomplished using a policy of liberal en bloc resection even when contiguous organs are not invaded directly, but approximate the margin of resection. However, even this aggressive surgical approach does not eliminate the possibility of recurrence, which in our study reached 50% (3 of 6 patients). Comparing our patients with retroperitoneal metastases with those patients with primary retroperitoneal STS, we found a lower resectability rate for the former group (60% vs. 80 –95%).12,13 These results are similar to the resectability rate of recurrent retroperitoneal sarcomas, a fact that most likely reflects a more aggressive disease. Current chemotherapy modalities are not effective against retroperitoneal sarcomas, and radiation is limited by toxicity to adjacent structures. It would appear that the same can be said with regard to retroperitoneal metastases because none of the patients in the current series who were treated by chemotherapy showed improved survival. According to the literature, multiple sites of metastasis are described as developing in 14% of patients with extremity STS.4 Only 6.6% of these patients were found to be surgically rendered disease free and none enjoyed prolonged survival. In the current series, three patients developed recurrence at more than one site, one of which was found to be resectable (lung metastasectomy and complete retroperitoneal sarcoma resection). At last follow-up this patient was still alive with no evidence of disease 1 year later. Thus, we believe that, if possible, all sites of malignancy should be resected to enable prolonged survival. Abdominal imaging studies, in contrast to those of the chest, are not performed routinely during the follow-up of patients with extremity STS. However, after gathering further information regarding the true incidence rate of retroperitoneal metastases, it may prove logical to recommend the addition of such studies in 368 CANCER January 15, 2000 / Volume 88 / Number 2 the future to diagnose retroperitoneal disease as early as possible and enable efficient treatment. Our conclusions are that extremity STS can metastasize hematogenously to the retroperitoneum, a fact that mandates a high index of suspicion and may support the performance of abdominal imaging studies during the follow-up of patients with such sarcomas. Retroperitoneal metastases necessitate the same aggressive surgical treatment as retroperitoneal sarcomas to enable prolonged survival. 5. 6. 7. 8. 9. 10. REFERENCES 1. 2. 3. 4. Malawer MM, Shmookler BM. Staging, pathology and radiology of musculoskeletal tumors. 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