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Inhibition of proliferation and induction of apoptosis in soft tissue sarcoma cells by interferon-alpha and retinoids.

Uncontrolled proliferation and a defect of apoptosis constitute crucial elements in the development and progression of tumours. Among many other biological response modifiers known to influence these mechanisms, the efficacy of retinoids and interferons in the treatment of various malignant entities is currently matter of discussion. In the present study, we have investigated the effects of 9-cis-retinoic acid (9cRA), 13-cis-retinoic acid (13cRA), all-trans-retinoic acid (tRA) and interferon-alpha on proliferation and apoptosis of human soft tissue sarcoma (STS) cell lines HTB-82 (rhabdomyosarcoma), HTB-91 (fibrosarcoma), HTB-92 (liposarcoma), HTB-93 (synovial sarcoma) and HTB-94 (chondrosarcoma) in relation to p53 genotype as well as p53 expression. HTB-91, HTB-92 and HTB-94 STS cells exhibited mutant p53, whereas wild-type p53 was found in HTB-93 STS cells, and a normal p53 status in HTB-82 STS cells, carrying a silent point mutation only. Interferon-alpha, irrespective of p53 status, inhibited the proliferation of all five cell lines dose- and time-dependently. Similarly, 9cRA, 13cRA and tRA decreased the proliferation of HTB-82 and HTB-93 STS cells, whereas the proliferation of p53-mutated HTB-91, HTB-92 and HTB-94 STS cells remained unchanged. Furthermore, only 9cRA and tRA were capable of inducing apoptosis in HTB-82 and HTB-93 STS cells, whereas HTB-91, HTB-92 and HTB-94 STS cells did not undergo apoptosis under the influence of 9cRA or tRA. Retinoic acid receptor (RAR)-alpha and RAR-beta mRNA were not detectable by Northern blot analysis in the five STS cell lines, whereas mRNA for the universal retinoic acid receptor, RAR-gamma, was expressed in all STS cell lines indicating that retinoid resistance was not associated with a lack of RAR expression. Apoptosis was not induced by interferon-alpha or 13cRA in any of the five STS cell lines tested. Our results indicate that within the panel of tested STS cell lines, inhibition of proliferation and induction of apoptosis result from different mechanisms which differ in their dependence upon the presence of intact p53.

Apoptosis↗

S-100 protein as a marker for melanocytic and other tumours.

The majority of melanocytic tumours are easily diagnosed but they become a problem when they are amelanotic and the tumour cells resemble those of other tumours. This applies particularly to secondary melanoma. Detection of S100 protein is a useful identifying marker. S100 protein, so named for its solubility in saturated ammonium sulphate, is derived from brain tissue. It is a dimer and belongs to a calcium binding group of proteins. The protein was first thought to be in neural or neural crest derived tissues but has been found in chondrocytes, adipocytes, myoepithelial cells, dendritic cells of lymphoid tissue, Langerhans cells and T lymphocytes. The protein is present in a high proportion of malignant melanomas and nevocytic nevi of skin, but is less positive in eye melanomas. It is present in gliomas, Schwannomas and neurofibromas but not in neurone derived tumours such as neuroblastomas. Chondromas, chondrosarcomas, liposarcomas, some osteogenic sarcomas and some histiocytic tumours are positive. The tumours that do not contain S100 protein are listed. Pending development of melanoma-directed monoclonal antibodies, the use of anti-serum to S100 protein plus anti-keratin and anti-leukocyte reagents is useful in the identification of tumours of doubtful histogenesis.

Body Fluids↗

Platelet-derived growth factor receptor (beta-subunit) immunoreactivity in soft tissue tumors.

Using a well characterized monoclonal antibody (PR7212) to the beta-subunit of the platelet-derived growth factor receptor (PDGF-R(beta) and the avidin-biotin peroxidase method on frozen sections, we analyzed PDGF-R(beta) expression in 71 nonepithelial lesions as well as normal mesenchymal tissues. PDGF-R(beta) reactivity was observed in normal salivary gland, normal cutaneous and visceral fibroblasts, muscularis mucosa of bowel, and endothelial cells; squamous carcinoma was negative. Interestingly, hepatocytes and lymph node histiocytes were also positive. Positive tumors included malignant fibrous histiocytoma (6/6), benign and malignant smooth muscle tumors (5/6 leiomyoma, 8/9 leiomyosarcoma), liposarcoma (4/4), synovial sarcoma (6/7), angiosarcoma (2/2), and sarcoma NOS (2/2). Fibromatosis cases were also positive (2/2). In many tumors, the reactive fibroblasts and vascular components were also reactive. The characteristic pattern of reactivity in fibroblastic lesions highlighted thin cytoplasmic extensions or strands not visible in normal hematoxylin and eosin-stained sections. Expression of PDGF-R(beta) was not necessarily correlated with the presence of PDGF. We conclude that PDGF-R(beta) expression can be identified in a wide variety of mesenchymal lesions and postulate that its presence may be important in the mechanism of growth of these tumors.

Adenocarcinoma↗

[Clinical studies on preoperative continuous intra-arterial chemotherapy in the treatment of malignant soft tissue tumors].

Preoperative continuous intra-arterial chemotherapy combined with surgery in the treatment of malignant soft tissue tumors has been used since 1971 in our clinic. We treated thirty-eight patients, and twenty-five of them underwent preoperative intra-arterial chemotherapy and surgery. The diagnoses were liposarcoma (5), synovial sarcoma (4), rhabdomyosarcoma (2), angiosarcoma (2), malignant schwannoma (2), malignant lymphoma (2) and 8 other types of tumors. From the standpoint of local failures, there was only one recurrent case. Eighteen patients are alive now without evidence of disease. The 10-year cumulative survival rate for cases treated with intra-arterial chemotherapy was 69.5%, as compared with 24.9% of cases without intra-arterial chemotherapy. Therefore we conclude that preoperative continuous intra-arterial chemotherapy is a very effective method in the treatment of malignant soft tissue tumors.

Adolescent↗

[DNA cytofluorometry of soft tissue tumors].

We carried out DNA cytofluorometry with propidium iodide stain on the 17 cases of soft tissue tumors including giant cell tumor of the tendon sheath, pigmented villonodular synovitis, 2 hemangiomas, 3 lipomas, 5 schwannomas, 3 neurofibromas, liposarcoma and synovial sarcoma. The benign tumors were characterized by regular polyploidization with very few S-phase cells, indicating slow tumor growth. Most of the malignant soft tissue tumors were associated with remarkable polyploidization with an increase in S-phase cells. However, some malignant tumors did not show polyploidization. We concluded, therefore, that an increase in S-phase cells is an important, cytofluorometric criterion for malignancy of soft tissue tumors.

Adult↗

Intra-abdominal spindle cell lesions: a review and practical aids to diagnosis.

Intra-abdominal spindle cell lesions are uncommon and often present a diagnostic challenge. An important group of such lesions are the gastrointestinal stromal tumours. Other intra-abdominal spindle cell lesions include fibromatosis, various sarcomas-in particular, leiomyosarcoma, liposarcoma, and malignant peripheral nerve sheath tumour-and, in women, endometrial stromal sarcoma. Less common lesions are inflammatory myofibroblastic tumours, the mesenteric spindle cell reactive lesions, retroperitoneal fibrosis, and solitary fibrous tumour. A variety of intra-abdominal tumours of nonmesenchymal origin may have a spindle cell/sarcomatoid morphology; these include sarcomatoid carcinoma, malignant melanoma and, in women, sarcomatoid granulosa cell tumour. Finally, metastatic sarcomas from pelvic or extra-abdominal organs need also be considered. A set of practical aids to the diagnosis of intra-abdominal spindle cell lesions is presented to assist pathologists dealing with such lesions, particularly with regards to the consideration of differential diagnoses.

Abdominal Neoplasms↗

Grading of soft tissue sarcomas: review and update.

CONTEXT: Histologic grading is the most important prognostic factor and the best indicator of metastatic risk in adult soft tissue sarcomas. The most commonly used systems are the French grading and the National Cancer Institute grading. Both are 3-grade systems and are mainly based on histologic type and subtype, tumor necrosis, and mitotic activity. Rules for using grading should be strictly respected and limitations of grading should be known to obtain the best performance. The most controversial point is the respective values of histologic typing and grading. Histologic typing should be clearly defined before any attempt at grading, and grading should not be used on tumors of intermediate malignancy such as atypical fibroxanthoma and on some sarcomas such as dedifferentiated liposarcoma. However, grading is useful in more than 90% of adult soft tissue sarcomas and has been adapted to pediatric nonrhabdomyosarcomatous sarcomas. Current grading is not suitable for core needle biopsies. OBJECTIVE: To review the current value and limitations of histologic grading in soft tissue sarcomas. DATA SOURCES: The reviews on grading and original studies on prognostic factors in soft tissue sarcomas were analyzed. CONCLUSIONS: Grading is the best predictor of metastasis outcome in adult soft tissue sarcomas and should be part of the pathologic report. Grading should be adapted to the modern management of patients and complemented by radiologic and molecular parameters.

Biopsy, Fine-Needle↗

[Dedifferentiated liposarcoma. A clinico-pathologic study of 6 cases].

During a period of 15 years, 6 cases of dedifferentiated liposarcomas were found among 542 cases of adult soft tissue sarcomas, 77 of which were liposarcomas. They were huge tumors of the retroperitoneum, containing distinct areas of well-differentiated liposarcoma most often of sclerosing type and malignant fibrous histiocytoma or undifferentiated sarcoma most often of high grade malignancy. Immunohistochemistry on the dedifferentiated component showed a positivity with anti-vimentin and alpha-1-antichymotrypsin in 5 cases and with anti-alpha smooth muscular actin in 4 cases. Three patients developed local recurrence and a fourth one quickly died with bone metastasis. Other types of dedifferentiated sarcomas, the process of dedifferentiation and links between malignant fibrous histiocytoma and dedifferentiated sarcomas are discussed.

Aged↗

Uncommon sarcomas of the uterine cervix: a review of selected entities.

Sarcomas constitute less than 1% of all cervical malignancies. With over 150 reported cases, rhabdomyosarcomas represent the most commonly reported sarcoma at this location. In this report, a select group of the more uncommon sarcomas of the uterine cervix are reviewed, including all previously reported examples of leiomyosarcoma, liposarcoma, alveolar soft part sarcoma, Ewing sarcoma/primitive neuroectodermal tumor, undifferentiated endocervical sarcoma, and malignant peripheral nerve sheath tumor (MPNST). Emphasis is placed on any distinctive clinicopathologic features of these entities at this unusual location.

Journal Article↗

[Retroperitoneal liposarcoma].

Retroperitoneal soft-tissue sarcomas are a heterogeneous group of rare and peculiar mesenchymal tumors. They are locally invasive and have a peak incidence in the fifth decade of life. They account for 0.1-0.2% of all solid tumors and 15% of all soft-tissue tumors. Liposarcomas are usually large and occur most frequently in the lower extremities, in the retroperitoneal, perineal and mesenteric region. In the retroperitoneum they grow slowly due to the ability of the abdominal cavity to accommodate these slowly expanding masses. They don't produce symptoms until they are very large and have invaded local tissues. The case of a 61-year old man with a retroperitoneal liposarcoma is reported. The tumor was discovered due to the association of abdominal mass, weight loss and persistent fever. The fever, especially, is present due to a wide tumor necrosis. The diagnosis was suggested by computed tomography. Normally, the interval between start of symptoms and diagnosis is included within three weeks and one year. Surgical complete resection of the mass with splenectomy and local postoperative radiotherapy were performed. The weight of the mass was 8.56 kilograms and the pathological evaluation showed a pleomorphic highly undifferentiated liposarcoma. This histological type normally presents many tumor giant cells, some of which have the features of lipoblasts. The single most important prognostic factor in patients with soft-tissue sarcomas is the histologic grade of the primary lesion. In the last AJCC Staging System the grades are assigned from grade 1 (well differentiated) to grade 3 (poorly differentiated). The present case is grade 3. In the treatment of sarcoma of the retroperitoneum or genitourinary tract, the conventional chemotherapy does not seem effective, while radiotherapy has a little improvement on survival. Local recurrences are frequent, especially in the first three years, often in the absence of distant metastases. When the tumor recurs locally, the best therapy is still to remove the mass. Sometimes, two or more operations may be necessary for the patient. Generally, the prognosis is poor with overall 5-year survival of 15-50%. The patient was admitted in our division 4 months after the first operation with poor medical condition. The patient died nine months after surgery.

Follow-Up Studies↗

Histopathology peer review of high-grade soft tissue sarcoma: the Scandinavian Sarcoma Group experience.

From 1981 to 1986, a total of 240 patients with a primary soft tissue sarcoma with malignancy grade III or IV were entered into an adjuvant chemotherapy multicenter trial conducted by the Scandinavian Sarcoma Group (SSG). Histopathologic peer review of all the specimens was performed by an expert pathology committee. The most common soft tissue sarcoma after review was malignant fibrous histiocytoma (MFH) (40%), followed by synovial sarcoma (15%), leiomyosarcoma (9%), liposarcoma (8%), and malignant Schwannoma (6%). In 25% of the cases the histologic type of sarcoma was reclassified, and in 40% of the cases the malignancy grade was changed. By survival analyses, the reclassification of malignancy grade seemed to be valid. Also, grading highly malignant soft tissue sarcoma in two grades (III and IV) increased the prognostic information. Of 164 tumors from the centers with the most reported cases (five centers with 25 to 51 tumors each), eight tumors were found to be ineligible for the adjuvant study (5%); of 76 tumors from 13 centers with few tumors (one to 16 tumors per center), 12 tumors were ineligible (16%). We conclude that histologic peer review is important in studies of soft tissue sarcoma.

Follow-Up Studies↗

Genomic alterations in sarcomas: a histologic correlative study with use of oncogene panels.

Amplification and rearrangement of cellular proto-oncogenes are two of the several possible genetic alterations implicated in carcinogenesis and tumor progression. Although morphologically similar tumors may be heterogeneous at the level of the genome, some tumor types have shown relatively frequent and consistent abnormalities of specific oncogenes. In order to determine the frequency of oncogene amplification and rearrangement in several types of human sarcomas and to determine if histologically similar tumors have common genetic alterations, we analyzed 26 primary sarcomas by Southern hybridization. The oncogene probes utilized were N- and H-ras, sis, EGF-R (erb-B-1), neu (erb-B-2), fos, N- and c-myc, mos, and yes. The tumors studied included: five rhabdomyosarcomas (one alveolar, four embryonal), six malignant fibrous histiocytomas, six leiomyosarcomas, four liposarcomas, two Ewing's sarcomas, one osteosarcoma, and two fibrosarcomas. Oncogene abnormalities were identified in three tumors. One rhabdomyosarcoma showed 12-fold amplification and concurrent rearrangement of sis. This particular tumor also revealed rearrangement of H-ras and 15-fold amplification of c-myc. A second rhabdomyosarcoma revealed rearrangement of neu. A liposarcoma had a sis rearrangement. These findings suggest that many sarcomas show no common structural oncogene abnormalities. The presence of differing oncogene alterations within the rhabdomyosarcoma group indicates genetic heterogeneity among histologically similar sarcomas. The finding of a sis rearrangement in both a liposarcoma and a rhabdomyosarcoma, however, may suggest common oncogenesis among different tumor types.

Adolescent↗

Treatment of soft-tissue sarcomas of the hand.

We studied the clinical features, radiographic and pathological findings, treatment, and results for twenty-three patients who had been managed for a soft-tissue sarcoma of the hand between 1982 and 1990. The ages of the patients ranged from sixteen to seventy-six years (median age, thirty-one years). The most common clinical finding was a small, painless soft-tissue mass. Twenty of the tumors were high-grade, and eighteen were less than five centimeters in diameter. The most common diagnosis was synovial sarcoma, which was identified in eight patients. Leiomyosarcoma, rhabdomyosarcoma, and malignant fibrous histiocytoma developed in three patients each; epithelioid sarcoma, in two patients; and angiosarcoma, liposarcoma, neuroectodermal tumor, and clear-cell sarcoma, in one patient each. Curative wide excision or amputation was attempted in twenty-two patients; the margins were positive for tumor cells in eight, and local recurrence was seen in nine. Of the twenty-three patients, fourteen had survived, without evidence of disease, after a median duration of follow-up of forty-nine months, and nine had died of disease. The median rate of survival did not differ significantly on the basis of the size or grade of the tumor or the use of adjuvant treatment. However, the rate of survival of the patients who had a soft-tissue sarcoma of the hand that was less than five centimeters in diameter was significantly lower (p = 0.0008) than that of 152 patients who had a similar tumor at another site in an extremity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

Primary liposarcoma of esophagus: a case report.

Liposarcoma is the most common soft tissue sarcoma in adult life while esophageal liposarcoma is an extremely rare tumor. In the world literature, only 14 cases of esophageal liposarcomas have been described. We report a 72-year old male patient who was urgently admitted to our hospital for acute epigastric pain with a burning retrosternal sensation, persistent nausea, vomiting and dysphagia. Barium swallow, upper gastrointestinal (GI) endoscopy, esophageal manometry and CT scan, failed to accurately diagnose the lesion. After surgical resection of an esophageal polypoid tumor, the histological examination revealed a well-differentiated grade I liposarcoma. Diagnostic and therapeutic tools were discussed and the results of literature were reviewed.

Aged↗

Intussusception secondary to metastasis from a low-grade retroperitoneal liposarcoma.

Liposarcomas are the most prevalent soft tissue sarcomas in adults. Low-grade liposarcomas are the most frequent and least aggressive and are noted as having a low risk of metastasis. We present a case of low-grade myxoid liposarcoma that metastasized to the small bowel resulting in intussusception. This case involves a 44-year-old woman with a recurrent retroperitoneal liposarcoma. Approximately 30 months after initial diagnosis, the patient was found to have a solitary metastasis to the small bowel that presented as a jejunal intussusception. Interestingly, there was no indication of a round cell component in either the metastasis or recurrent tumor, although the original tumor did contain a small round cell component. This is the first report in the English literature of liposarcoma metastasizing to the small bowel. We suggest that atypical presentations of liposarcoma metastases should always be considered in the management of patients with a history of liposarcoma.

Adult↗

High grade soft tissue sarcoma of the flexor fossae. Size rather than compartmental status determine prognosis.

BACKGROUND: High grade soft tissue sarcoma arising in the popliteal space, axilla, and antecubital fossae (flexor fossae tumors) have by convention been classified as extracompartmental tumors by the accepted staging and grading criteria of the Musculoskeletal Tumor Society (MSTS). Advances in neoadjuvant chemotherapy and radiation therapy have made surgical resection more feasible. The hypothesis to be tested is that compartmental status may not be of prognostic significance if the tumor is adjusted for size, histologic grade, and distant metastasis after undergoing adjuvant chemotherapy and radiation. METHODS: From June 1976 to December 1992, 22 patients with high grade soft tissue sarcomas of the flexor fossae (Group A) were treated at UCLA Medical Center. The histologic subtypes were liposarcoma (five), synovial cell sarcoma (eight), malignant fibrous histiocytoma (four), leiomyosarcoma (two), angiosarcoma (two), and rhabdomyosarcoma (one). The popliteal fossa was the location in 11, the axilla in 10, and the antecubital fossa in 1. Wide resection was attempted in all patients after preoperative chemotherapy and radiation therapy. Amputation was performed in 5 patients because of repeated or extensive recurrent tumor. A group of 77 patients (Group B) with high grade soft tissue sarcoma located within an extremity compartment were chosen to test the hypothesis that survival of patients with tumors in the flexor fossae is equal to that of patients with intracompartmental tumors of similar size and grade if both are given adjuvant therapy. This group was chosen so that histologic subtype, size, sex, and location would be similar in the two groups. The authors selected thigh and calf tumors for comparison with popliteal fossa tumors and periscapular, deltoid, and arm tumors for comparison with axilla and antecubital fossae tumors. All of these patients had similar treatment and follow-up protocols. The median follow-up of survivors in Group A was 104 months and for patients in Group B was 79 months. RESULTS: The 5-year cumulative survival rate (Kaplan-Meier method) of patients in Group A was 76%, and 67% for those in Group B. The difference was not significant. Three patients in Group A (14%) and 17 (22%) in Group B had local tumor recurrence. Eight patients in Group A (36%) and 27 (35%) in Group B had lung metastases. Age, sex, histologic subtype, and surgical margins did not affect survival outcomes, lung metastasis, and local recurrence. However, patients with larger tumors (maximum dimension > or = 8 cm or cross-sectional area > or = 40 cm2) had significantly poorer survival, more metastases, and local recurrences. CONCLUSION: Flexor fossae sarcomas do not have a poorer prognosis than extremity intracompartmental tumors when adjusted for size, distant metastasis, and histologic grade when they are treated with adjuvant radiation therapy, chemotherapy, and surgery.

Adolescent↗