Peter Bergh

Extraskeletal myxoid chondrosarcoma: A reappraisal of its morphologic spectrum and prognostic factors based on 117 cases

Extraskeletal myxoid chondrosarcoma (EMC), a phenotypically and genotypically distinctive entity, has generally been viewed as a low-grade sarcoma. No studies regarding clinical and morphologic prognostic factors have been performed on a large series of cases with long-term follow-up because of the rarity and protracted clinical course of EMC. The clinical, morphologic, and immunohistochemical features of 117 previously unreported cases were studied and statistically analyzed. The male-to-female ratio was 2:1. The median patient age was 52 years (range, 6-89 years), and the median tumor size was 7 cm (range, 1.1-25 cm). All tumors occurred within the deep subcutis or deeper soft tissues, with 80% occurring in the proximal extremities or limb girdles and 20% in the trunk. Most initial tumor excisions were intralesional or marginal. Follow-up information was available in 99 cases (median, 9 years: range, 2 months-22 years). Forty-eight patients were disease-free, and 41 patients had evidence of disease (18 of these had died of disease). Ten additional patients survived, but their disease status was unknown. There were local recurrences in 40 (48%) of 83 patients, 23 (58%) of whom had multiple local recurrences. Metastases occurred in 35 (46%) of 76 patients. The estimated 5-, 10-, and 15-year survival rates were 90%, 70%, and 60%, respectively. All cases had histologic features characteristic of classical EMC, at least focally. Cellular foci devoid of myxoid matrix and reminiscent of chondroblastoma, Ewings sarcoma, monophasic and poorly differentiated synovial sarcoma, fibrosarcoma, and rhabdoid tumor were identified in 29% cases. Older patient age, larger tumor size, and tumor location in the proximal extremity or limb girdle were adverse prognostic factors identified by multivariate analysis. Metastasis also adversely affected survival, although local recurrence did not. This study shows that EMC has a unique clinical course, including a high rate of local recurrence, prolonged survival after metastasis in some cases, and eventually a high rate of death due to tumor. These features distinguish EMC from low-grade sarcomas. This study shows that histologic grading is of no prognostic value in EMC because prognosis is dictated primarily by certain clinical features. Histologic recognition of classical EMC and cellular and solid, nonmyxoid variants is important, however, in view of EMCs distinctive biologic behavior.

Prognostic factors and outcome of pelvic, sacral, and spinal chondrosarcomas: A center-based study of 69 cases

The surgical treatment of chondrosarcoma of the pelvis, sacrum, and spine is complex and technically demanding. As such, adequate surgical margins have been difficult to achieve, resulting in poor local control and survival. The objective of this study was to assess the outcome of patients with chondrosarcomas in these sites who were treated at a tumor center by using modern, aggressive surgical techniques and to identify prognostic factors.

Cement is recommended in intralesional surgery of giant cell tumors : A Scandinavian Sarcoma Group study of 294 patients followed for a median time of 5 years

Background Giant cell tumors of bone rarely metasta-size but often recur locally after surgery. There is limited knowledge about the risk of recurrence related to different types of treatment. Patients and methods We analyzed factors affecting the local recurrence rate in 294 patients with giant cell tumors of the extremities using prospectively collected material from 13 centers. The median follow-up time was 5 (0.2–18) years. Results A local recurrence was diagnosed in 57 of 294 patients (19%). The overall 5-year local recurrence rate was 0.22. Univariate analysis identified young age and intralesional surgery to be associated with a higher risk of recurrence. Based on multivariate analysis, the relative risk was 2.4-fold for intralesional surgery compared to more extensive operative methods. There was no correlation between tumor size, tumor extension, sex of the patient, tumor location, or fracture at diagnosis and outcome. In the subgroup of 200 patients treated with intralesional surgery, the method of filling (cement or bone) was known for 194 patients and was statistically highly significant in favor of the use of cement. Interpretation Intralesional surgery should be the first choice in most giant cell tumors, even in the presence of a pathological fracture. After thorough evacuation, the cavity should be filled with cement.

Studies on the Molecular Pathogenesis of Extraskeletal Myxoid Chondrosarcoma—Cytogenetic, Molecular Genetic, and cDNA Microarray Analyses

Extraskeletal myxoid chondrosarcomas (EMCs) are characterized by recurrent chromosome translocations resulting in fusions of the nuclear receptor TEC to various NH(2)-terminal partners. Here we describe the phenotypic, cytogenetic, and molecular genetic characteristics of a series of 10 EMCs. Using spectral karyotyping and fluorescence in situ hybridization, clonal chromosome abnormalities were detected in all but one tumor. A t(9;22)(q22;q12) translocation was found in three cases; a del(22)(q12-13)in one case; and variant translocations, including t(9;17)(q22;q11-12), t(7;9;17)(q32;q22;q11), and t(9;15)(q22;q21), were detected in one case each. Recurrent, secondary abnormalities, including trisomy 1q, 7, 8, 12, and 19, were found in seven tumors. All tumors contained translocation-generated or cryptic gene fusions, including EWS-TEC (five cases, of which one was a novel fusion), TAF2N-TEC (four cases), and TCF12-TEC (one case). cDNA microarray analysis of the gene expression patterns of two EMCs and a myxoid liposarcoma reference tumor revealed a remarkably distinct and uniform expression profile in both EMCs despite the fact that they had different histologies and expressed different fusion transcripts. The most differentially expressed gene in both tumors was CHI3L1, which encodes a secreted glycoprotein (YKL-40) previously implicated in various pathological conditions of extracellular matrix degradation as well as in cancer. Our findings suggests that EMC exhibits a tumor-specific gene expression profile, including overexpression of several cancer-related genes as well as genes implicated in chondrogenesis and neural-neuroendocrine differentiation, thus distinguishing it from other soft tissue sarcomas.

Treatment of local recurrences of giant cell tumour in long bones after curettage and cementing: A SCANDINAVIAN SARCOMA GROUP STUDY.

We retrospectively studied local recurrence of giant cell tumour in long bones following treatment with curettage and cementing in 137 patients. The median follow-up time was 60 months (3 to 166). A total of 19 patients (14%) had at least one local recurrence, the first was diagnosed at a median of 17 months (3 to 29) after treatment of the primary tumour. There were 13 patients with a total of 15 local recurrences who were successfully treated by further curettage and cementing. Two patients with a second local recurrence were consequently treated twice. At the last follow-up, at a median of 53 months (3 to 128) after the most recent operation, all patients were free from disease and had good function. We concluded that local recurrence of giant cell tumour after curettage and cementing in long bones can generally be successfully treated with further curettage and cementing, with only a minor risk of increased morbidity. This suggests that more extensive surgery for the primary tumour in an attempt to obtain wide margins is not the method of choice, since it leaves the patient with higher morbidity with no significant gain with respect to cure of the disease.

Desmoid tumors: A clinical review of 30 patients with more than 20 years' follow-up

We retrospectively studied the outcome in a consecutive series of 30 patients with desmoid tumors who were followed for more than 20 years after treatment (surgery in 29 patients). A local recurrence occurred in 12 patients and more than 1 recurrence occurred in 8. 3 patients had spontaneous complete regression of the tumor. At follow-up after mean 28 (20-54) years, all patients were tumor-free except 1 who had had a stable tumor for at least 11 years. Symptoms were related more to treatment than to the tumor. We conclude that desmoid tumors may have a high capacity for self-limitation and that conservative therapy should be considered in symptom-free patients.

Insight opinion to surgically treated metastatic bone disease: Scandinavian Sarcoma Group Skeletal Metastasis Registry report of 1195 operated skeletal metastasis.

The number of cancer patients living with metastatic disease is growing. The increased survival has led to an increase in the number of cancer-induced complications, such as pathologic fractures due to bone metastases. Surgery is most commonly needed for mechanical complications, such as fractures and intractable pain. We determined survival, disease free interval and complications in surgically treated bone metastasis. Data were collected from the Scandinavian Skeletal Metastasis Registry for patients with extremity skeletal metastases surgically treated at eight major Scandinavian referral centres between 1999 and 2009 covering a total of 1195 skeletal metastases in 1107 patients. Primary breast, prostate, renal, lung, and myeloma tumors make up 78% of the tumors. Number of complications is tolerable and is affected by methods of surgery as well as preoperative radiation therapy. Overall 1-year patient survival was 36%; however, mean survival was influenced by the primary tumor type and the presence of additional visceral metastases. Patients with impending fracture had more systemic complications than those with complete fracture. Although surgery is usually only a palliative treatment, patients can survive for years after surgery. We developed a simple, useful and reliable scoring system to predict survival among these patients. This scoring system gives good aid in predicting the prognosis when selecting the surgical method. While it is important to avoid unnecessary operations, operating when necessary can provide benefit.

The Presence of Local Mesenchymal Progenitor Cells in Human Degenerated Intervertebral Discs and Possibilities to Influence These In Vitro: A Descriptive Study in Humans

Low back pain is common and degenerated discs (DDs) are believed to be a major cause. In non-degenerated intervertebral discs (IVDs) presence of stem/progenitor cells was recently reported in different mammals (rabbit, rat, pig). Understanding processes of disc degeneration and regenerative mechanisms within DDs is important. The aim of the study was to examine the presence of local stem/progenitor cells in human DDs and if these cell populations could respond to paracrine stimulation in vitro. Tissue biopsies from the IVD region (L3-S1) were collected from 15 patients, age 34-69 years, undergoing surgery (spinal fusion) and mesenchymal stem cells (MSCs) (iliac crest) from 2 donors. Non-DD cells were collected from 1 donor (scoliosis) and chordoma tissue was obtained from (positive control, stem cell markers) 2 donors. The IVD biopsies were investigated for gene and protein expression of: OCT3/4, CD105, CD90, STRO-1, and NOTCH1. DD cell cultures (pellet mass) were performed with conditioned media from MSCs and non-degenerated IVD cells. Pellets were investigated after 7, 14, 28 days for the same stem cell markers as above. Gene expression of OCT3/4 and STRO-1 was detected in 13/15 patient samples, CD105 in 14/15 samples, and CD90 and NOTCH1 were detected 15/15 samples. Immunohistochemistry analysis supported findings on the protein level, in cells sparsely distributed in DDs tissues. DDs cell cultures displayed more undifferentiated appearance with increased expression of CD105, CD90, STRO-1, OCT3/4, NOTCH1, and JAGGED1, which was observed when cultured in conditioned cell culture media from MSCs compared to cell cultures cultured with conditioned media from non-DD cells. Expression of OCT3/4 (multipotency marker) and NOTCH1 (regulator of cell fate), MSC-markers, CD105, CD90, and STRO-1, indicate that primitive cell populations are present within DDs. Furthermore, the possibility to influence cells from DDs by paracrine signaling /soluble factors from MSCs and from nondegenerated IVD cells was observed in vitro indicating that repair processes within human DDs may be stimulated.

Liposarcoma : Outcome Based on the Scandinavian Sarcoma Group Register

The aim was to study the clinicopathological characteristics, treatment, and outcome of liposarcoma in an unselected, population‐based patient sample, and to establish whether treatment was according to the Scandinavian Sarcoma Group (SSG) treatment guidelines.BACKGROUND The aim was to study the clinicopathological characteristics, treatment, and outcome of liposarcoma in an unselected, population-based patient sample, and to establish whether treatment was according to the Scandinavian Sarcoma Group (SSG) treatment guidelines. METHODS The SSG Pathology Board reviewed 319 liposarcoma cases reported between 1986 and 1998. After the review, 237 patients without metastasis were analyzed for local recurrence rate in relation to surgical margins, radiotherapy, occurrence of metastasis, and survival. RESULTS Seventy-eight percent of the patients were primarily operated on at a sarcoma center, 45% with wide margins. All patients operated on outside the center had nonwide margins. Low-grade lesions constituted 67% of cases. Despite nonwide surgery, only 58% of high-grade lesions were treated with postoperative radiotherapy. The risk of local recurrence after nonwide surgery, without irradiation, was 47% for high-grade lesions. The estimated 10-year, local recurrence-free and metastasis-free survival in the low-grade group was 87% and 95%, respectively. In the high-grade group, it was 75% and 61%, respectively. Independent adverse prognostic factors for local recurrence were surgery outside a sarcoma center and histological type dedifferentiated liposarcoma. For metastases, they were old age, large tumor size, high grade, and histological type myxoid liposarcoma with a round cell component. Radiotherapy showed significant effect on local recurrence rate for the same grade and margin. CONCLUSIONS Patients with liposarcoma should be treated at specialized centers. Postoperative radiotherapy decreases the local recurrence rate. To maintain quality and provide support for further trials, reporting to quality registers is crucial.

Irradiation of myxoid/round cell liposarcoma induces volume reduction and lipoma-like morphology

The aim of the study was to investigate the clinical and morphological effects of radiotherapy in the treatment of myxoid/round cell liposarcoma (MLS/RCLS). Thirty-three primary and metastatic MLS/RCLS tumours in 15 patients were treated with radiation therapy. Twenty-seven of the 33 tumours were surgically removed after preoperative radiation (34–46 Gy) while six tumours were treated with radiotherapy alone (44–60 Gy). The pretreatment diagnosis was established in all 15 patients based on fine needle aspirates or histological findings. Tumour size was measured by CT or MRI before and after radiotherapy in 30 tumours. Thirteen tumours from 11 patients were genetically characterised before and/or after radiation therapy. Twenty-three of 30 irradiated tumours showed a median reduction in tumour volume of 52% and seven lesions a median progression of 36%. All 27 surgically removed tumours revealed histological features of radiation response. The most striking morphological changes were lipoma-like appearance, paucicellularity and hyalinisation. Twelve of 13 tumours analysed before and/or after radiation therapy showed the FUS-DDIT3 translocation. Radiation therapy of MLS/RCLS induces histopathologic accumulation of mature lipoma-like areas and tumour volume reduction that may facilitate resectability.