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PubMed1995

Preoperative regional therapy for extremity sarcoma. A tricenter update.

BACKGROUND: Preoperative radiation with sensitizing doxorubicin has been popularized in the treatment of high grade sarcoma of the extremity. A multiinstitutional experience with this protocol that was initiated by the Southeastern Cancer Study Group in 1984 and maintained in three institutions was updated by the authors. METHODS: Patients with biopsied sarcoma had intraarterial infusion with doxorubicin hydrochloride (Adriamycin) 30 mg/24 hrs x 3 days and were allocated by the institution to receive radiation 30-35 Gy in 10 fractions or 46 Gy in 23-25 fractions followed by resection. Surgery was performed within 10 days or 30 days depending on the radiation dose. Postoperative chemotherapy was administered to 31 patients. RESULTS: Of 66 patients, 32 were female and 34 were male. The median age was 46 years (range, 14-77 years); 73% had lower and 27% had upper extremity tumors. There were 55 soft-tissue and 9 malignant bone tumors. Common types were malignant fibrous histiocytoma 20%; liposarcoma, 17%; synovial sarcoma 18%; and 14% were osteosarcoma. American Joint Committee on Cancer stages were: I, IIB (17%), IIIA/B (59%), and IIIC/4A (24%). Limb salvage surgery was performed on 60 patients including radical resection in 21 with extensive tumors, wide local excision in 30, and limited excision in 2 patients. Primary amputation was performed on four patients and delayed amputation in two because of wound complications. Three patients had pulmonary metastasectomy in conjunction with primary surgery (2 are long term survivors > 5 years). There were no postoperative deaths, but wound complications occurred in 41% of the patients. Overall survival and disease free survival at 5 years was 59 and 49%. One patient (1.5%) had local recurrence 9 years after resection of an extensive synovial sarcoma of the shoulder. This was resected with limb salvage techniques. Among 23 patients who failed primarily in the lung, the median survival was 7 months with 4 surviving more than 5 years, after demonstration of the pulmonary metastases. Multivariant analysis of prognostic factors showed that extent of disease and stage correlated with disease free survival, whereas only extent of surgical resection correlated with overall surgical survival. CONCLUSION: Combined therapy for extremity sarcoma in a multicenter setting using preoperative radiation with sensitizing chemotherapy and adequate resection was associated with an excellent local control rate (98.5%) and reasonable long term tumor control, although distant metastases continued to be a major challenge.

Adolescent↗

PubMedDate not supplied

Relationship between doxorubicin binding ability and tumor volume decrease after chemotherapy in adult malignant soft tissue tumors in the extremities.

We have previously reported that the doxorubicin (DOX) binding ability detected by the DOX (or adriamycin) binding assay closely correlated with the chemosensitivity of human osteosarcomas (1). We performed the present study to clarify the relationship between the DOX binding ability (%DB) and the histologic response, rate of decrease in tumor volume of malignant soft tissue tumors after preoperative chemotherapy and prognosis. Nine malignant soft tissue tumors (4 liposarcomas, 3 synovial sarcomas, one malignant fibrous histiocytoma (MFH) and one extraskeletal osteosarcoma (EOS)) which arose at the extremities of adult patients were analyzed by the DOX binding assay using freshly biopsied specimens. After preoperative chemotherapy including DOX or pirarubicin (THP), the rate of decrease in tumor volume was measured using magnetic resonance imaging, and the histologic response expressed as tumor necrosis to chemotherapy was also investigated. All the patients, apart for one, were continuously disease-free after treatment. One patient with EOS died of metastatic disease before surgery. The histologic response in 8 tumors without EOS was poor. The %DB of 5 tumors was greater than 80% (average: 95.90%), whereas that of 4 tumors was less than 80% (average: 38.33%). Although there was no correlation between the %DB and the histologic response, or prognosis, a significantly positive correlation was found between the %DB and the rate of decrease in tumor volume (r = 0.7455, p < 0.05). These results suggest that in malignant soft tissue tumors, the rate of decrease in tumor volume after chemotherapy might be a better indicator for chemosensitivity than the histologic response and also that the DOX binding ability might be a good predictor for chemosensitivity before chemotherapy.

Adult↗

PubMed2002

Sensitization of sarcoma cells to doxorubicin treatment by concomitant wild-type adeno-associated virus type 2 (AAV-2) infection.

Doxorubicin-based chemotherapy is used in the treatment of sarcomas. Toxic side effects and poor response rates underline the demand for an improvement in current chemotherapeutic protocols. Recently, it has been reported that parvoviruses confer various antineoplastic properties to infected cells, and that adeno-associated virus type 2 (AAV-2) infection sensitizes malignant epithelial cells to radiation- or chemotherapy-based genotoxic treatment. Thus, we analyzed whether AAV-2 infection leads to an improved efficacy of doxorubicin chemotherapy in malignant mesenchymal cells, using 13 human sarcoma cell lines. Therapeutic effects were analyzed by measuring cell viability and proliferation (WST-1, colony forming, and propidium iodide assays). Additionally, permissivity for AAV-2 infection was determined by Southern dot blot analysis. AAV-2 infection strongly increased the efficacy of doxorubicin treatment in rhabdomyo-, fibro-, osteo- and chondrosarcoma cells in a dose-dependent manner. This effect was not observed in liposarcoma and synovial sarcoma cells, although a susceptability to AAV-2 infection was documented. Our results indicate that the sensitization effects towards genotoxic treatment exerted by non-pathogenic AAV-2 infection are not restricted to epithelial malignancies but may also be exploited for the improvement of chemotherapy in patients suffering from rhabdomyo-, fibro-, osteo-, or chondrosarcomas.

Antibiotics, Antineoplastic↗

PubMed1996

Retroperitoneal liposarcoma in two siblings.

We report here on two cases of retroperitoneal liposarcoma which heterochronously occurred in two siblings. A huge myxoid liposarcoma, 20 x 14 cm size, was noticed in a 33-year-old female, who died with multiple liver metastasis in about half a year. Two years later after the death of the younger sister, pleomorphic liposarcoma, 8 x 8 cm in size, was noticed in a 39-year-old male who died with local recurrence and multiple metastasis one year after the operation. Their mother (69 years old) had had an operation for malignant fibrous histiocytoma of the right thigh at age 66. There was no evidence of multiple lipomatosis, an autosomal dominant trait, in the siblings or their family. Diverse soft-tissue sarcomas, but not liposarcoma, occur excessively in siblings with the syndrome of Li-Fraumeni. To our knowledge this is the first such report of its sibship occurrence.

Adult↗

PubMed2003

[Recent entities in soft tissue tumor pathology. Part 2].

The second part of this review on the pathology of soft tissue tumors focuses on malignant entities of recent description, including the following: soft tissue giant cell tumor, inflammatory myxohyaline tumor, inflammatory fibroblastic sarcoma, low grade fibromyxoid Evans sarcoma and its variant, the hyalinizing spindle cell tumor with giant rosettes, spindle cell liposarcoma, proximal type epithelioid sarcoma, sclerosing epithelioid fibrosarcoma. For each entity, the diagnostic criteria, the clinical presentation and the differential diagnosis are described. The role of immunohistochemistry and molecular pathology in the identification and delineation of these new entities is emphasized.

Diagnosis, Differential↗

PubMed1992

Expression of disialogangliosides GD2 and GD3 on human soft tissue sarcomas.

METHODS: Fifty-six freshly frozen human sarcomas were studied for expression of disialogangliosides by avidin-biotin immunohistochemical staining with purified monoclonal antibodies (MoAb) 3F8 (antidisialoganglioside GD2) and R24 (antidisialoganglioside GD3). RESULTS: Ninety-three percent of the tumors tested by the immunohistochemical staining expressed GD2 and 88% expressed GD3. The intensity of expression varied among sarcomas of different histologic types. Liposarcoma, fibrosarcoma, malignant fibrous histiocytoma, leiomyosarcoma, and spindle cell sarcoma reacted strongly with 3F8 and R24. Embryonal rhabdomyosarcoma and synovial sarcoma demonstrated substantially weaker staining by either MoAb. Weakly reactive or nonreactive tumors were, in general, high-grade or metastatic sarcomas. Ganglioside extraction and thin-layer chromatography/immunothin-layer chromatography of two liposarcomas confirmed the identities of these gangliosides. CONCLUSIONS: GD2 and GD3 may indicate sites for MoAb-targeted imaging and therapy for sarcomas. The association of a diminished stainability by 3F8 and R24 with aggressive sarcomas may indicate prognostic significance.

Gangliosides↗

PubMed2006

ET-743: a novel agent with activity in soft-tissue sarcomas.

PURPOSE OF REVIEW: ET-743 (ecteinascidin-743, trabectedin, Yondelis) is a natural marine product that has shown clinical activity in sarcoma. This paper reviews the current knowledge on this compound. RECENT FINDINGS: ET-743 interferes with several transcription factors, traps protein from the nucleotide-excision repair system, thus resulting in DNA damage, modulates gene expression, and blocks cells in the G2-M phase. In the clinical setting, after failure of standard treatment, ET-743 at 1.5 mg/m2 in 24 h continuous infusion every 21 days yielded an overall response rate close to 8% and stabilization rates of 30-40%, some lasting beyond 3 years. Leiomyosarcomas, liposarcomas, and synovial sarcomas may be the more sensitive histotypes. The major toxicities of ET-743 are hepatic--through biliary duct destruction--and hematologic. They are not cumulative and a significant number of patients may receive 12 courses or more. In a randomized Phase II study testing weekly ET-743 with treatment every 3 weeks, an improved progression-free survival rate was observed in the 3-weekly arm; the results of the follow-up Phase III trial should be available at the American Society of Clinical Oncology meeting of 2006. Phase I combination studies are in currently progress. SUMMARY: ET-743 is a novel active drug for sarcoma which yields prolonged disease-free survival in subsets of patients.

Antineoplastic Agents, Alkylating↗

PubMed1988

Expression of nerve growth factor receptor in paraffin-embedded soft tissue tumors.

Identification of growth factors and receptors in mesenchymal tumors may be crucial to understanding of growth regulation in sarcomas. During an immunohistochemical study of the expression of growth factors and receptors in human soft tissue tumors (STT), only 1 antisera capable of working in paraffin-embedded tissue was noted. A detailed study of 141 STT was undertaken to determine the frequency of expression of nerve growth factor receptor (NGF-R), its specificity and sensitivity for neural tumors, and the effect of fixation on detection. In normal mesenchymal tissue, only nerve sheath and perivascular staining was seen. No immunoreactivity was seen in many tumors including rhabdomyosarcoma, angiosarcoma, liposarcoma, Ewing's sarcoma, and alveolar soft part sarcoma. Less than 15% of tumors of smooth muscle, fibrous, or fibrohistiocytic origin showed immunoreactivity, usually focal. In contrast, a high frequency of immunoreactivity was noted in tumors of neural origin (74%). This included granular cell tumors (100%), Schwannoma/neurofibroma (91%), malignant Schwannoma (78%), neuroblastoma/neuroepithelioma (60%), and paraganglioma (57%). A high rate of reactivity was also seen in synovial sarcomas (80%), undifferentiated sarcomas (60%), and hemangiopericytomas (43%), suggesting a potential relationship to the neural phenotype. Among the neural tumors, Bouin's fixation was superior to formalin, suggesting that immunoreactivity for NGF-R is affected by fixation. This antibody may be a useful adjunct marker diagnostically.

Histological Techniques↗

PubMed2000

Medical management of unresectable, recurrent low-grade retroperitoneal liposarcoma: integration of cytotoxic and non-cytotoxic therapies into multimodality care.

Liposarcomas of the retroperitoneum are rare tumors, and best managed by an expert multidisciplinary team consisting of a surgical oncologist with appropriate medical oncology and radiation oncology collaboration. For large tumors, surgical excision with wide margins is difficult to achieve, and even wide margins cannot ensure that microscopic remnants of residual disease will not grow back in the future. For these reasons, even following expert resection, local recurrence is common. For patients with recurrent and unresectable liposarcoma, treating the sarcoma while maintaining quality of life becomes the major therapeutic goal. Importantly, patients with advanced recurrent disease demonstrate the need for multidisciplinary team involvement, with timely consideration of palliative surgical, radiation therapy, and chemotherapy options. Such patients also represent ideal candidates for investigational approaches aimed at identifying new agents with which to treat this disease. In addition to the development of new cytotoxic agents, patients may be candidates for novel strategies such as differentiation therapies or anti-angiogenic approaches. The recent explosion of knowledge regarding the cytogenetics, molecular, and cellular biology of liposarcomas allows us to remain positive that new translational therapies will be developed to improve the clinical outcomes of patients with these diseases. Current strategies, such as the use of PPARgamma ligands to differentiate liposarcomas, will soon be tested in major national collaborative trials, and the cooperation of surgeons and medical oncologists at all levels of community and academic practice will be crucial to obtain answers in this field. This review will summarize an illustrative case in the process of describing the natural history and potential interventions which should be considered for patients with this disease.

Chromans↗

PubMed1993

The 12q13-q15 translocation breakpoints in pleomorphic adenoma and clear-cell sarcoma of tendons and aponeuroses are different from that in myxoid liposarcoma.

The transcription factor gene CHOP was recently shown to be rearranged in myxoid liposarcoma with t(12;16)(q13;p11). We have analyzed whether the CHOP gene is the target of rearrangements in pleomorphic adenoma and clear-cell sarcoma of tendons and aponeuroses with chromosome abnormalities of 12q13-q15. Restriction fragment analysis showed that the CHOP gene and its flanking sequences were not rearranged in any of these tumor types, indicating that the 12q translocation breakpoints in pleomorphic adenoma and clear-cell sarcoma are different from that in myxoid liposarcoma.

Adenoma↗

PubMed2003

Definitive intraoperative radiotherapy for musculoskeletal sarcomas and malignant lymphoma in combination with surgical excision.

BACKGROUND: . The purpose was to estimate retrospectively the outcome of patients with musculoskeletal sarcoma or malignant lymphoma treated with intraoperative radiotherapy (IORT). METHODS: Between 1988 and 1999, definitive IORT in combination with surgical excision was performed in 24 patients with musculoskeletal sarcoma (malignant fibrous histiocytoma, 10; osteosarcoma, 6; liposarcoma, 2; chondrosarcoma, 1; synovial sarcoma, 1; Ewing's sarcoma, 1; angiosarcoma, 1; epithelioid sarcoma, 1; malignant schwannoma, 1) and 3 patients with malignant lymphoma. The tumor was excised by marginal margin excision, intralesional margin excision, or wide margin excision; 15-45 Gy electrons was then delivered to the affected sites. RESULTS: In the 8 patients without distant metastases at the first visit, 4 patients are alive 6.5-11.5 years after IORT, and 4 patients died <4.5 years after IORT. The incidence of local recurrence was 13%. In the 19 patients with distant metastases at the first visit, 3 patients are alive 2.5-6.7 years after IORT, and 16 patients died 0.2-5.7 years after IORT. The incidence of local recurrence was 45%. Complications after IORT were found in 5 patients: neuropathy, 1 patient; skin necrosis, 1 patient; myelopathy, 1 patient; enteritis ileus, 1 patient; and edema, 1 patient. CONCLUSION: IORT with a radiation dose of 15-45 Gy in combination with surgical excision appeared to be useful for local control and to be more effective in patients without distant metastases at the first visit than in patients with distant metastases.

Adolescent↗

PubMed1991

Melanocyte-marker-HMB-45 is regularly expressed in angiomyolipoma of the kidney.

HMB-45 (melanocytic cell-specific monoclonal antibody) immunoreactivity was investigated in 10 cases of angiomyolipoma (AML) (1 with massive regional lymph node involvement) of the kidney and detected in all of them. No HMB-45 immunoreactivity was found in other tumors of the region which can occasionally be confused with AML, such as renal cell carcinoma, Wilms' tumor, and retroperitoneal sarcoma (leiomyosarcoma and liposarcoma). These findings indicate that HMB-45 is not a melanocyte-restricted marker and suggest that its expression might be useful in distinguishing AML from other tumors of the kidney and retroperitoneum.

Antibodies, Monoclonal↗

PubMed2004

High-dose chemotherapy with autologous peripheral blood stem cell transplantation for bone and soft-tissue sarcomas.

The role of high-dose chemotherapy (HDCT) with PBSCT in the treatment of bone and soft-tissue sarcomas is not established. In total, 27 patients (15 female, median age at TPL 30.6 years (range: 13-59)) were analyzed (Ewing sarcoma family n=8, osteosarcoma n=6, MPNST (malignant peripheral nerve sheath tumor) n=4, synovial sarcoma n=3, liposarcoma n=2, leiomyosarcoma n=2, rhabdomyosarcoma n=1, meningosarcoma n=1). Following chemotherapy and surgery complete remission (CR) (n=9), partial remission (PR) (n=10), stable disease (SD) (n=2) and progressive disease (PD) (n=6) were reached prior HDCT. Different HDCT conditioning regimens were used. One patient died due to cardiac arrest after HDCT. Except hematologic side effects, no WHO grade III-IV complications were observed. Four patients died within 6 months due to PD, disease recurred in another seven patients and led to death, 15 patients are alive with/without disease. The median progression-free survival (PFS) is 12.0 months (range: 0-58), in nine CR patients median PFS is 25.8 months (range: 3-58). Although the role of HDCT in the treatment of sarcomas is not defined, a subgroup of patients who achieved CR before HDCT could benefit from this therapy.

Adolescent↗

PubMed2000

Hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan in advanced soft-tissue sarcomas: histopathological considerations.

BACKGROUND: Hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan was used as induction treatment in locally advanced extremity soft-tissue sarcomas for limb sparing surgery. The typical histopathological changes that occur in these tumoral masses are described in a series of 30 patients. METHODS: Fresh tumor specimens of 27 high grade extensive soft-tissue sarcomas and 3 recurrent desmoid tumors of the extremities were collected 6 to 8 weeks after hyperthermic isolated limb perfusion with tumor necrosis factor-alpha plus melphalan. The specimens were studied for surgical margins, extent and type of tumor necrosis, lymph node involvement, perineural and vascular invasion, and the effects on adjacent normal tissues such as nerves, muscles, and blood vessels. RESULTS: The typical histological changes were central cystic hemorrhagic necrosis with pericystic extensive fibrosis. Some nonspecific changes were noted in the soft tissues around the mass. In eight cases, more than 90% necrosis was found. In 17 cases, the extent of necrosis ranged between 60% and 90% (80%-90% in 4 of 17 cases). In five cases, less than 60% necrosis was noted. The best responses (>90% necrosis) were observed in distally located tumors. The responsive types were malignant fibrous histiocytoma, followed by myxoid liposarcoma and synovial sarcoma. Desmoid tumors showed less necrosis than high grade sarcomas. Vascular invasion was observed in two cases and intralesional venous thrombosis in one case. No perineural invasion or lymph nodes involvement were observed. The soft tissues adjacent to the tumor bed did not show major morphological changes. No correlation was found between the histological changes and each of the following: the anatomical (upper vs. lower limb) or compartmental location of the tumor; whether the tumor was primary or recurrent; and the types of previous treatment (systemic chemotherapy or radiotherapy) and tumor size. CONCLUSIONS: This is the first serial histological description of the effects of tumor necrosis factor-alpha and melphalan administered via hyperthermic isolated limb perfusion on the tumoral masses of limb soft-tissue sarcomas. The small number of specimens and, especially, the variability of tumors preclude definite conclusions. Larger numbers and more homogeneity are needed in future studies.

Adolescent↗

PubMed1998

Intramuscular myxoma: a clinicopathologic study of 51 cases with emphasis on hypercellular and hypervascular variants.

Intramuscular myxoma (IM) is a benign soft-tissue tumor that presents as a deeply seated mass confined to skeletal muscle. Surgical excision is virtually always curative. Recurrence, even after incomplete resection, is exceptional. Intramuscular myxoma is classically described as hypocellular and hypovascular, and is composed of cytologically bland stellate and bipolar fibroblasts separated by abundant extracellular myxoid matrix. What is underemphasized, however, is that IMs often show areas of increased cellularity and vascularity that can lead to a mistaken diagnosis of sarcoma, especially myxofibrosarcoma, low-grade fibromyxoid sarcoma, and myxoid liposarcoma. In this report, we describe the clinicopathologic features of 51 IMs with special emphasis on those that exhibit these "hypercellular regions." The patients included 35 women and 16 men who ranged in age from 27 to 89 (mean 52) years. The tumors measured from 2 to 15 (average 5.6) cm and all had a gelatinous, lobulated cut surface. Histologically, they all demonstrated classic hypocellular, hypovascular regions. Thirty-eight tumors contained areas of relative increased cellularity that occupied from 10 to 80% of the tumor. These foci had increased numbers of cells, more prominent vascularity, and often increased collagen content. The hypercellular regions were not associated with cytologic atypia of the constituent cells, mitotic activity, or necrosis. Follow-up information was available for 32 patients and ranged from 3 to 108 (average 30) months. No tumor recurred or metastasized. Areas of hypercellularity are common in IMs. Their recognition is important to avoid an erroneous diagnosis of sarcoma.

Actins↗

PubMedDate not supplied

CT findings of retroperitoneal malignant mesenchymoma.

Malignant mesenchymoma (MM) is a rare mesenchymal neoplasm which, by definition, demonstrates at least two distinct types of malignant mesenchymal differentiation. We present the computed tomographic (CT) findings of a 42-year-old female with a pathologically proven retroperitoneal MM consisting of osteoid production combined with foci of liposarcoma and Kaposi sarcoma. MM should be considered along with extraosseous osteosarcoma and teratoma in the differential diagnosis for unusual large heterogeneous retroperitoneal masses with massive calcification.

Adult↗

PubMed1986

Fibrohistiocytic tumors of soft tissues. An immunohistochemical study of 183 cases.

183 cases of soft tissue tumors were studied utilizing the immunoperoxidase technique to demonstrate alpha-1-antitrypsin, ferritin and lysozyme. The series comprises 50 malignant lesions, 34 intermediate malignancy lesions, 99 benign lesions of fibrohistiocytic origin, and 23 malignant tumors of non fibrohistiocytic origin. The actual results of the study are as follows: alpha-1-antitrypsin, ferritin and lysozyme were always absent in 10 fibrosarcomas, 2 liposarcomas, 2 Ewing sarcomas, 3 synovial sarcomas, 4 neurofibrosarcomas, and 2 rhabdomyosarcomas, but in 24 malignant fibrous histiocytomas, 34 cases of dermatofibrosarcoma protuberans and 102 benign fibrohistiocytic lesions, these activities were present in a percentage that ranged between 12% and 38% (average 25%). Differences in the frequency of positive reactions did not occur between benign and malignant fibrohistiocytic lesions. The immunohistological examinations carried out have, therefore, only a very limited value for the practical diagnostic evaluation, but, when positive, are important to clarify the histogenesis of the tumor.

Ferritins↗

PubMed2003

Trail-induced apoptosis and interaction with cytotoxic agents in soft tissue sarcoma cell lines.

Five human soft tissue sarcoma (STS) cell lines (HTB-82 rhabdomyosarcoma, HTB-91 fibrosarcoma, HTB-92 liposarcoma, HTB-93 synovial sarcoma and HTB-94 chondrosarcoma) were analysed for their sensitivity to tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and the function of the TRAIL apoptotic pathway in these cells. TRAIL induced significant apoptosis (>90%) in HTB-92 and HTB-93 cells, whereas no effect was observed in HTB-82, HTB-91 and HTB-94 cells. TRAIL-Receptor 1 (TRAIL-R1) was expressed in TRAIL-sensitive HTB-92 and HTB-93 cell lines, but not in TRAIL-resistant HTB-91 and HTB-94 cells. HTB-82 cells, which expressed the long (c-FLIP(L)) and short (c-FLIP(S)) splice variants of the FLICE-like inhibitory protein (FLIP), were resistant to TRAIL in spite of the presence of TRAIL-R1. TRAIL-R2,-R3,-R4 and osteoprotegerin (OPG) expression did not correlate with TRAIL sensitivity. Coincubation of TRAIL and doxorubicin led to the overexpression of TRAIL-R2 resulting in a synergistic effect of doxorubicin and TRAIL in TRAIL-sensitive cell lines and in the overcoming of TRAIL-resistance in all of the TRAIL-resistant cell lines, except HTB-91, which lacked caspase 8 expression. These data suggest that TRAIL, either as a single agent or in combination with cytotoxic agents, might represent a new treatment option for advanced STS, which constitutes a largely chemotherapy-resistant disease.

Antineoplastic Combined Chemotherapy Protocols↗