Soft Tissue Sarcomas in Adults

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1 Soft Tissue Sarcomas in Adults Constantine P. Karakousis, MD, PhD Raymond P. Perez, MD Introduction Soft tissue sarcomas are relatively rare. Less than one percent of adults entering a general hospital with a diagnosis of cancer have a soft tissue sarcoma. 1 In 1994, it is estimated that 6,000 new cases will be diagnosed in the United States and 3,300 deaths will occur from this disease. 1 The relative rarity of these neoplasms complicates efforts to define their optimal management. However, the cumulative experience with soft tissue sarcomas at several large centers has allowed their clinical and biologic features to be defined, and some general principles in their management to be elucidated. Clinical Presentation Soft tissue sarcomas can occur in any anatomic region, though most develop in the extremities, usually the legs. The most common manifestations of these neoplasms are swelling and pain. Some patients attribute swelling to a minor injury, which can cause them to delay a visit to a Dr. Karakousis is Chief of the Soft Tissue Sarcoma- Melanoma and Bone Service of the Department of Surgical Oncology at Roswell Park Cancer Institute in Buffalo, New York. Dr. Perez is Assistant Professor in the Department of Medicine at Roswell Park Cancer Institute in Buffalo, New York. The authors thank Derek Raghavan, MD, PhD, for his critical review of the manuscript and helpful comments and Lynn Duewiger and Darcy Celeste for their secretarial support in preparing this manuscript. physician or cause a physician given that history to be misled and delay diagnosis. Another source of delay in diagnosis is the presumption by the examining physician of a benign growth, e.g., a lipoma. However, benign lesions of any appreciable size have typically been present for many months, if not years, and have changed very gradually in size. In any case, a mass within a muscle should not be presumed to be benign. Less frequent modes of presentation occur with intracavitary sarcomas, where the dominant symptoms may arise from the encroachment and interference of function of an adjacent organ. The median interval between the onset of symptoms and physician contact is four months, and about half of patients experience a delay of two months or more between their initial physician visit and definitive diagnosis. 2 With the exception of subcutaneous sarcomas in areas easily palpated or inspected by the patient, most lesions tend to be large, exceeding 5 cm in diameter. Pain is usually not severe and is not an early symptom for these neoplasms unless they are located close to a major nerve or in a confined anatomic space. Pelvic sarcomas may present with swelling of the leg, simulating primary iliofemoral thrombosis, or pain in the distribution of the femoral or sciatic nerve. With careful history and physical examination, it is often possible to distinguish between the acute presentation of a nonneoplastic swelling and that due to sarcoma (which is usually more indolent). 200 Ca A cancer Journal for Clinicians

2 Diagnosis For most soft tissue sarcomas, evaluation by computed tomography (CT) or magnetic resonance imaging (MRI) is initially indicated, certainly for masses situated in a muscle group or cavity. These studies are useful in outlining the size of the mass and its relationship with adjacent anatomical structures. They also provide some indication of the nature of the tumor. Areas of necrosis within a mass suggest a malignant growth. An open biopsy is usually required for a definitive diagnosis and determination of the histologic subtype. An excisional biopsy may be used for a small, superficial lesion (<2 cm in diameter), but incisional biopsy is generally employed instead of excision. However, biopsy specimens may sometimes be obtained with a tru-cut needle. Under local anesthesia, a small incision is made in the skin through which the relatively blunt tip of this needle is inserted into the mass and a core of tissue is removed. The needle is inserted several times into the mass so that several pieces of tissue are retrieved for pathologic examination. An experienced pathologist can often make a diagnosis with these small specimens. Arteriograms or venograms may be required preoperatively to delineate the relationship of major adjacent vessels with the tumor mass and to alert the surgeon to the presence of major feeding branches to the tumor. In most cases, however, the relation of vessels to the tumor mass is quite clear on CT scan. A chest x-ray and, usually, a CT scan of the chest are required to rule out pulmonary metastases, the most common manifestation of hematogenous spread for these neoplasms. For primary sarcomas adjacent to a bone, a bone scan may provide additional information as to possible involvement of the bone. However, the results of the bone scan must be interpreted carefully in conjunction with the results from the CT or MRI because a positive bone scan may simply reflect a periosteal reaction to the increased blood flow of an adjacent tumor. Pathology There are several histologic subtypes of soft tissue sarcomas. The two most common subtypes diagnosed in current series are liposarcoma and malignant fibrous histiocytoma. 3,4 The latter diagnosis was rarely made in the past, but following the clarification of histologic criteria, it has become the most common subtype in some series. Other histologic subtypes are leiomyosarcoma, fibrosarcoma, rhabdomyosarcoma, synovial sarcoma, angiosarcoma, hemangiopericytoma, alveo- The two most common histologic subtypes diagnosed are liposarcoma and malignant fibrous histiocytoma. lar soft-part sarcoma, and epithelioid sarcoma. Sarcomas originate in tissues derived from the embryonic mesoderm. One exception is the malignant schwannoma or neurofibrosarcoma, which arises in the sheath of nerves embryologically deriving from the primitive ectoderm. There are differences in the characteristics of the various subtypes as manifested by varying growth rates and capacity for hematogenous or lymphogenous metastases. Generally, for soft tissue sarcomas, the incidence of regional node metastases is low, about five percent. 5 Some subtypes (synovial sarcoma, malignant fibrous histiocytoma, epithelioid sarcoma, and clear cell sarcoma) have a higher tendency toward lymphatic dissemination to the regional nodes. 6 In contrast, liposarcomas almost never metastasize to the regional nodes. Leiomyosarcomas of the abdominal cavity have a higher tendency for intraperi- Vol. 44 No. 4 July/August

3 S o f t t i s s u e s a r c o m a s i n a d u l t s Table 1 Prognostic Factors for Soft Tissue Sarcomas Grade (low grade better than high grade) Size (smaller is better) Location (extremity better than nonextremity) Lymphatic metastasis (absence is better) DNA Ploidy? (diploid may be better; data limited to high-grade sarcomas) toneal spread than other subtypes. However, because the characteristics of these subtypes are sufficiently similar and soft tissue sarcomas are sufficiently uncommon, it is desirable to consider all soft tissue sarcomas as a group. Electron microscopy and immunohistochemical methods have helped considerably in the clarification of the various subtypes and in the differential diagnosis. Lately, further refinement of the pathologic diagnosis has been provided by the identification of nonrandom chromosomal changes characteristic of various subtypes For example, the identification of the translocation characteristic for myxoid liposarcoma can clinch the diagnosis and differentiate this entity from myxoid malignant fibrous histiocytoma. 7,8 Prognostic Factors and Staging (Table 1) The most important prognostic indicator is the grade of a sarcoma. Although some pathologists have suggested only two grades (those of well and poorly differentiated sarcomas, corresponding to a low and high grade), 13 the three-grade system (that of well, moderately, and poorly differentiated sarcomas corresponding to low, moderate, and high grade) has prevailed. 14 There is a definite correlation between grade, chance of recurrence, and survival rate. The five-year survival rates according to grade reported in one publication were 72 to 83 percent for Grade I sarcomas, 53 to 59 percent for Grade II sarcomas, and 26 to 42 percent for Grade III sarcomas. 15 The next important prognostic parameter is the size of the tumor. Tumors 5 cm or less in diameter have a better prognosis than those greater than 5 cm in diameter. The current American Joint Committee on Cancer (AJCC) staging system (Table 2) is based on grade, size, and evidence of dissemination. 16 Stages I, II, and III are localized sarcomas with Grades I, II, and III, respectively. Each stage is subdivided into A ( 5 cm) and B (>5 cm) according to the tumor diameter. Stage IVA includes regional node metastasis, and Stage IVB includes distant dissemination. A panel of the AJCC is currently reviewing the tumor-nodemetastases (TNM) staging of soft tissue sarcomas, and a revised staging classification may be forthcoming. Location of the tumor is another prognostic parameter. Extremity sarcomas have a generally better prognosis than those of other locations. Retroperitoneal sarcomas, for example, have a lower survival rate than extremity sarcomas. The influence of location on prognosis is probably not due to inherent differences in biologic propensities of the tumors at the different locations, but rather to me- 202 Ca A cancer Journal for Clinicians

4 Table 2 American Joint Committee on Cancer Staging of Soft Tissue Sarcomas Stage I Stage II Stage III Well differentiated, localized disease Moderately differentiated, localized disease Poorly differentiated or undifferentiated, localized disease Stages 1-3 are further classified on the basis of tumor size A = Tumor 5 cm in greatest dimension B = Tumor >5 cm in greatest dimension Stage IVA Stage IVB Regional lymph node metastasis, any grade or size tumor Distant metastasis, any grade or size tumor chanical differences that affect (1) the timing of diagnosis (deep-seated tumors remain obscure for longer periods of time), (2) the opportunities of successful resection (retroperitoneal sarcomas are very large when diagnosed and often involve important, adjacent anatomical structures, making them difficult to resect successfully), and (3) the risk for dissemination (in addition to lymphatic and hematogenous spread, intra-abdominal sarcomas can have intracavitary spread, which is distinct from the other two ways of dissemination). Some reports indicate that the location of the tumor in relation to the fascia of the region (i.e., whether superficial or deep to the fascia) affects survival rates, with superficial sarcomas having a better survival rate than deep sarcomas. 17,18 Lymph-node involvement 5,6,19 and DNA proliferative indices, 20 such as aneuploidy, have also been identified as potentially important prognostic factors. However, the independent predictive validity and overall clinical utility of proliferative indices are less well established than the factors outlined above. Treatment of the Primary Tumor Prior to 1975, treatment of localized soft tissue sarcomas was exclusively surgical. At that time, the amputation rate for extremity sarcomas in referral centers (biased for an increased percentage of patients with the larger tumors relative to the overall adult population of sarcoma patients) was 40 to 50 percent. 21,22 The rate of local recurrence at Roswell Park Cancer Institute (RPCI) was 35 percent after wide resection, 65 percent after local excision, and eight percent after amputation. The five-year survival rate was 45 percent. 21 In the same time period, the rate of local recurrence at Memorial Sloan-Kettering Cancer Center (MSKCC) was 28 percent after wide re- Vol. 44 No. 4 July/August

5 S o f t t i s s u e s a r c o m a s i n a d u l t s The computed tomography scan reveals the relationship of the tumor to adjacent organs, in this case displacement of the right kidney to the left of the midline. En-bloc removal of the tumor was accomplished through a midline incision with an extension to the flank. section. 22 Therefore, in this period the rate of amputation was high, but so was the rate of local recurrence after apparently wide resection. Compartmental resection was accompanied by a low rate of local recurrence, but this approach was primarily applicable in the thigh, and a large number of amputations were still performed. 23 In the current era, combination of modalities has been used to permit a higher overall rate of local control; a higher rate of limb salvage; and, generally, an improved quality of life. Resection remains the primary modality of treatment for a primary soft tissue sarcoma. However, it has undergone some evolution as a modality, and in the following section, some of the general principles and changes that have occurred will be outlined. Surgical Treatment En-bloc resection of the tumor mass with adjacent involved anatomic structures and the biopsy track, thus procuring an adequate margin, is the objective of surgical treatment. Resectability of a sarcoma depends on the vascularity and tenacity of adherence of the tumor mass to surrounding structures, as well as the size and location of the mass. Generally, sarcomas are less infiltrative than adenocarcinomas, and the tumor pseudocapsule is narrower. Thus, very large tumors can often be resected (Figure). Fixation is not a reliable sign of unresectability. Normal anatomic structures such as the psoas muscle and the pubic or iliac bone are fixed on palpation, yet both can be resected, when involved, without great difficulty. Most primary sarcomas are resectable. However, sarcomas extensively involving the suprarenal portions of the aorta and inferior vena cava and sarcomas extending into the spinal canal are often not amenable to complete surgical resection. Although subtotal resection of sarcomas in these difficult locations is feasible, and nearly complete resection combined with brachytherapy or external-beam radiation therapy may provide worthwhile palliation, cures are rare. Most sarcomas, due to their relative rarity, should probably be treated in tertiary centers where there is some experience in their management. This is more true for intra-abdominal sarcomas, where the danger of tumor spillage and dissemination is ever present. However, in our experience, prior attempts at resection of extremity sarcomas at outside institutions have not compromised the feasibility of definitive procedures or local/distant control rates (although such attempts can render definitive operations more difficult). The surgery of soft tissue sarcomas at RPCI is maximalist in its scope, both in procuring the maximum margin allowed by the local anatomy and in preserving maximum function in the context of complete resection of the tumor mass. The twin goals of maximum margin and maximum function may conflict, and successful strategies that optimize both goals re- 204 Ca A cancer Journal for Clinicians

6 quire a keen knowledge of the structural and functional anatomy of each region. A few technical surgical points, outlined in the following paragraphs, may be of interest to the reader. In the last National Institutes of Health (NIH) Consensus Conference, major vessel or nerve involvement was considered an indication for amputation. 24 This has not been the RPCI experience. 25 There is no biologic basis for the statement that involvement of one of these structures automatically requires an amputation, except for the obvious fact that true unresectability without amputation is more likely to occur in this group of patients. However, if it is found following dissection around the tumor mass that a major nerve or vessel appears to be invaded or circumferentially surrounded by tumor and that this is the only impediment to a successful resection, then that nerve can be sacrificed or the vessel resected and replaced by a graft in preference to an amputation. Resection of a major nerve results in a deficit of motor function, but the result, including the case of resection of the sciatic nerve, is vastly superior to an amputation. Similar experiences have also been reported by other centers. 26 Resection of sarcomas of the musculoaponeurotic layers of the lower abdominal wall is often followed by mesh reconstruction. It is critical that the omentum or, if free omentum is unavailable, a peritoneal graft, covers the undersurface of the mesh. Otherwise, direct contact between bowel loops and the mesh may result in fistula formation. Sarcomas involving small-bowel mesentery can be resected if the superior mesenteric vessels at the root of the mesentery are first exposed to allow ligation of branches only to involved areas and sparing the blood supply to the distal bowel. 27 Pelvic sarcomas involving portions of the inominate bone may be resected by internal hemipelvectomy. 28 Sarcomas presenting in the iliac fossa and those fixed to the wall of the lesser pelvis can be resected An open biopsy is usually required for a definitive diagnosis and determination of the histologic subtype. via an abdominoinguinal incision. 29 In the upper extremity at the lower neck, en-bloc claviculectomy may facilitate resection of a tumor in this area with limb preservation. 30 Generally in the upper extremity, resection is done in the manner of wide resection by exposing major vessels and nerves adjacent to the tumor so that uninvolved structures may be preserved. In the area of the wrist and hand, only marginal resection may be performed, and adjuvant local radiotherapy is required when these patients are treated with the intent of limb preservation. Sarcomas of the medial and posterior compartments of the thigh can be treated with compartment resection, because this does not produce functional impairment for ordinary activities. Sarcomas of the anterior thigh can be treated with modified anterior compartment resection. 31 Sarcomas of the leg are usually treated with a wide resection, which preserves some function of the respective compartment. The posterior compartment (calf) is bulky, and resection of the entire compartment is rarely necessary. Resection of the entire anterior and lateral compartments (with fibulectomy) is more commonly required for large sarcomas in these locations. These resections result in foot drop, but this is preferable to an amputation. More distal sarcomas usually are treated with local excision and adjuvant radiation therapy. In the era of multimodality treatment, the rate of amputation has been limited to about six percent at RPCI. 32,33 Vol. 44 No. 4 July/August

7 S o f t t i s s u e s a r c o m a s i n a d u l t s Patients requiring an amputation usually have massive soft tissue involvement producing swelling of the distal extremity or have sarcomas that involve a joint or major bone. In these situations, en-bloc resection of the tumor and involved tissues by dissection through clean planes is not feasible. Resection remains the primary modality of treatment for a primary soft tissue sarcoma. Combination of Modalities The major adjuvant modality to resection of a primary sarcoma has been radiation treatment. This has been employed preoperatively, 34 postoperatively, 35,36 or in a split course before and after the operation. There are pros and cons for each approach, and at present, it is not clear whether any of these various combinations is superior to others either in terms of local control or local complications. A technique combining preoperative radiation and intra-arterial chemotherapy (using doxorubicin) followed by resection has also been employed with very good results, 37 but some modifications in the protocol have been implemented over the years to reduce local complications. 4 In the most recent update of this approach, the local recurrence rate has been 10 percent. 4 Recent series of extremity sarcomas seem to employ a combination of modalities for all patients with limb preservation. At RPCI, combination of modalities for local control has been used selectively. There is rarely a need to shrink a tumor mass preoperatively. The tumor is resected with the best available margin and then critically examined by the pathologist. When the minimum margin is less than 2 cm within a compartment, adjuvant postoperative radiation is employed. A lesser margin may be adequate if composed of strong fascia and the dissection was extracompartmental. In the distal portions of the extremities and other anatomic areas where wide or radical resection is not feasible, local or marginal resection in combination with irradiation may be the only option if limb salvage is to be done. This, in our experience, provides satisfactory local control. In these areas there is little tissue intervening between the beam of radiation and the tumor bed, and the planned radiation dose can be delivered precisely to the tumor bed. In other areas this may not be the case. The question of whether radical resection with preservation of function, where feasible, is equivalent or preferable to local excision and radiation cannot be answered with certainty. Historically, the local recurrence rate after local or marginal resection has ranged from 65 percent 21 to 90 percent. 38 At RPCI, radiation therapy is used frequently with anatomic areas where wide resection is not possible and with recurrent sarcomas. In a report from MSKCC, brachytherapy in cases of heavy microscopic residual (shaving tumor off major nerve trunks or vessels) resulted in a local recurrence rate of 30 percent. 39 However, in a prospective, randomized trial from the same institution, adjuvant radiation reduced the rate of local recurrence. 40 Radiation therapy is valuable as adjuvant therapy for primary soft tissue sarcoma and appears to reduce the rate of local recurrence compared with historical surgical controls by 60 percent or more when local or marginal resection has been done. The best results for local control can be expected with surgical resection to maximally reduce the potential microscopic residual tumor followed by radiation therapy. The role of adjuvant chemotherapy is being defined. Although some trials have reported encouraging results, the 206 Ca A cancer Journal for Clinicians

8 Table 3 Active Single Agents in Patients with Soft Tissue Sarcomas* Agent Number of Patients Treated Response Rate (Percent) Range of Response Rate (Percent) Ifosfamide Doxorubicin Methotrexate Actinomycin D Dacarbazine *Agents listed are noninvestigational and have reported rates of 15 percent in a sample of at least 30 patients. Modified with permission from Antman. 45 overwhelming majority of clinical trials have failed to demonstrate a benefit for adjuvant chemotherapy in adult soft tissue sarcoma patients. 45,51 This is not entirely surprising given the lack of efficacy of chemotherapy in the metastatic setting. The use of adjuvant chemotherapy for adult soft tissue sarcoma patients remains investigational, and appropriate patients should be encouraged to participate in clinical trials. It should be noted that many adjuvant chemotherapy trials published to date may not have used optimal regimens, and the efficacy of ifosfamide in this setting is undefined. To this end, the Surgery Branch at the NCI is randomizing patients with primary or recurrent, intermediate- or high-grade, extremity soft tissue sarcomas to doxorubicin plus ifosfamide or to observation, following definitive resection. The role of neoadjuvant chemotherapy (i.e., chemotherapy administered prior to definitive local treatment) also remains to be established. At present, this approach has not proven superior to the local approaches discussed previously. Treatment of Recurrence The two most common types of recurrence are local recurrence and hematogenous recurrence, usually involving the lungs. 41 Isolated local recurrence should be treated as aggressively as a primary sarcoma. Local recurrence probably contributes little to the development of distant metastases as this development depends mostly on the inherent biologic propensities of the primary sarcoma. 21,40,42 Usually a combination of modalities is required for the treatment of a recurrence. The expected survival rate is nearly as good as for primary sarcomas. These patients, on average, have less propensity to develop metastases than patients with primary sarcomas in general, since patients with concurrent distant recurrence are excluded from consideration. Soft tissue sarcomas generally spread hematogenously, most often to the lungs. 41 The lungs may be the only metastatic site, or lung metastases may precede involvement of other sites by Vol. 44 No. 4 July/August

9 S o f t t i s s u e s a r c o m a s i n a d u l t s several months. Exceptions to this rule occur but are infrequent. In fact, this tendency for selective metastasis to the lungs has provided the rationale for the surgical treatment of pulmonary metastases, which results in a five-year survival rate of about 21 percent in highly selected cases. 2 Factors affecting prognosis in the surgical treatment of pulmonary metastases are the resectability of these metastases, the prior disease-free interval or tumordoubling time, the number of metastases, and the histologic subtype. 43 Recurrent intra-abdominal sarcomas, particularly leiomyosarcomas, often present with diffuse intraperitoneal spread. Metastasectomy in these patients may prolong survival, particularly for Grade I and II tumors. 44 Chemotherapy Chemotherapy for soft tissue sarcomas has had limited success. There is presently no accepted standard chemotherapy regimen. In general, complete responses to chemotherapy are uncommon, and responders eventually relapse and die from progressive disease. The most effective single agents in patients with soft tissue sarcomas are listed in Table Doxorubicin has historically been considered the most active single agent (objective response rates of 15 to 30 percent). More recently, ifosfamide has demonstrated activity comparable to doxorubicin. Responses to ifosfamide have been observed in patients who failed doxorubicin, which suggests that these two agents are incompletely crossresistant. 46,47 These observations have also, in part, provided a reasonable rationale to investigate the use of these drugs in combination. Active drugs have been combined in almost every conceivable way. Active combinations have generally been doxorubicin- or ifosfamide-based. At present, the superiority of combinations over single agents remains to be established. Results from two recent randomized, cooperative-group trials demonstrated increased response rates for combinations containing both doxorubicin and ifosfamide. 48,49 However, the toxicities associated with these combinations were substantial, and the survival rate was not significantly improved among patients receiving these combinations. The most frequent life-threatening toxicity in these trials was myelosuppression. Whether improved results can be obtained using combination chemotherapy in conjunction with hematopoietic growth factors remains to be determined. The RPCI approach to adult patients with unresectable metastatic soft tissue sarcomas is as follows. Since no available regimen is proven to prolong survival, patients are encouraged to participate in clinical trials. Current phase II trials at RPCI are investigating the efficacy of regimens based on paclitaxel (Taxol). Patients who are not eligible or who do not wish to participate in phase II trials are offered conventional chemotherapy. In the past, these patients were uniformly treated with MAID (mesna, doxorubicin, ifosfamide, and dacarbazine), based on initial reports indicating that this regimen had substantial activity. 50 However, in light of the results of trials discussed above, we have more recently offered these patients doxorubicin plus dacarbazine, 48 since the survival rate for patients treated with this regimen is comparable to that obtained with MAID, and its toxicity is lower. Patients who progress on either paclitaxelbased or conventional chemotherapy are encouraged to participate in phase I trials. Finally, the option to defer treatment until the time of symptomatic disease progression is offered to all patients. Conclusions Soft tissue sarcomas in adults are uncommon, which partly accounts for some delays in diagnosis and complicates deter- 208 Ca A cancer Journal for Clinicians

10 mination of optimal treatment approaches. However, with an increased awareness of their existence by the public and physicians alike, earlier diagnosis may occur in some patients, resulting in improved results. Combination of modalities has resulted in a drop in the rate of amputations, from 40 to 50 percent in the past to the current rate of about five percent. The overall five-year survival rate now also appears to be higher than in the past, but this may be due to an improvement in overall care or perhaps earlier diagnosis and may not be the result of progress in specific therapeutic modalities. However, we remain optimistic that an improved understanding of the cellular and molecular biology of soft tissue sarcomas will suggest strategies through which substantial improvements in treatment of these malignancies will occur. CA References 1. Boring CC, Squires TS, Montgomery S, Tong T: Cancer Statistics, CA Cancer J Clin 1994;44: Lawrence W Jr, Donegan WL, Natarajan N, et al: Adult soft tissue sarcomas: A pattern of care survey of the American College of Surgeons. Ann Surg 1987;205: Karakousis CP, Emrich LJ, Rao U, Krishnamsetty RM: Feasibility of limb salvage and survival in soft tissue sarcomas. Cancer 1986;57: Eilber FR, Eckardt JJ, Rosen G, et al: Neoadjuvant chemotherapy and radiotherapy in the multidisciplinary management of soft tissue sarcomas of the extremity. Surgical Oncology Clinics of North America 1993;2: Ruka W, Emrich LJ, Driscoll DL, Karakousis CP: Prognostic significance of lymph node metastatis and bone, major vessel, or nerve involvement in adults with high-grade soft tissue sarcomas. Cancer 1988;62: Weingrad DN, Rosenberg SA. Early lymphatic spread of osteogenic and soft-tissue sarcomas. Surgery 1978;84: Karakousis CP, Dal Cin P, Turc-Carel C, et al: Chromosome changes in soft tissue sarcomas: A new diagnostic parameter. Arch Surg 1987;122: Sreekantaiah C, Karakousis CP, Leong SP, Sandberg AA: Cytogenetic findings in liposarcoma correlate with histopathologic subtypes. Cancer 1992;69: Sreekantaiah C, Karakousis CP, Leong SP, Sandberg AA: Trisomy 8 as a nonrandom secondary change in myxoid liposarcoma. Cancer Genet Cytogenet 1991; 51: Sreekantaiah C, Rao UN, Karakousis CP, Sandberg AA: Cytogenetic findings in a malignant fibrous histiocytoma of the gallbladder. Cancer Genet Cytogenet 1992;59: Mrozek K, Karakousis CP, Perez-Mesa C, Bloomfield CD: Translocation t(12;22) (q13;q ) in a clear cell sarcoma of tendons and aponeuroses. Genes Chromosom Cancer 1993;6: Mrozek K, Karakousis CP, Bloomfield CD: Chromosome 12 breakpoints are cytogenetically different in benign and malignant lipogenic tumors: Localization of breakpoints in lipoma to 12q15 and in myxoid liposarcoma to 12q13.3. Cancer Res 1993;53: Hajdu SI, D Ambrosio FG: Histopathologic classification of limb sarcomas in relation to prognosis. Surgical Oncology Clinics of North America 1993;2: Suit HD: Staging systems for sarcoma of soft tissue and sarcoma of bone. Cancer Treat Symp 1985;23: Shiu MH, Brennan MF: Staging of soft tissue sarcoma, in Shiu MH, Brennan MF (eds): Surgical Management of Soft Tissue Sarcoma. Philadelphia, Lea & Febiger, 1989, pp Beahrs OH, Henson DE, Hutter RVP, Kennedy BJ: Manual for Staging of Cancer, ed 4. Philadelphia, JB Lippincott, Hajdu SI: Stage of sarcomas, in Hajdu SI (ed): Differential Diagnosis of Soft Tissue and Bone Tumors. Philadelphia, Lea & Febiger, 1986, pp Geer RJ, Woodruff J, Casper ES, Brennan MF: Management of small soft-tissue sarcoma of the extremity in adults. Arch Surg 1992;127: Ariel IM: Incidence of metastases to lymph nodes from soft-tissue sarcomas. Semin Surg Oncol 1988;4: Alvegard TA, Berg NO, Baldetorp B, et al: Cellular DNA content and prognosis of high-grade soft-tissue sarcoma: The Scandinavian Sarcoma Group experience. J Clin Oncol 1990;8: Abbas JS, Holyoke ED, Moore R, Karakousis CP: The surgical treatment and outcome of soft-tissue sarcoma. Arch Surg 1981;116: Shiu MH, Castro EB, Hajdu SI, Fortner JG: Surgical treatment of 297 soft tissue sarcomas of the lower extremity. Ann Surg 1975;182: Simon MA, Enneking WF: The management of soft-tissue sarcomas of the extremities. J Bone Joint Surg Am 1976;58: Vol. 44 No. 4 July/August

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