Oral contraceptive use, parity, and constitutional characteristics in soft tissue sarcoma: a Swedish population-based case-control study 1988-2009.

PURPOSE: The study was designed to investigate the influence of surrogate factors associated with sex (SH) and growth hormones (GH) on the risk of developing soft tissue sarcomas (STS). BACKGROUND AND METHODS: The etiology of soft tissue sarcoma is largely unknown. We have studied the effect of hormone related factors on STS in the Swedish population between 1988 and 2009 using a population-based matched case-control design. RESULTS: Our study is the largest on this topic to date, including 634 cases in a primary matched analysis and 855 cases in an unmatched sensitivity analysis. We identified protective effects connected to constitutional characteristics, hormonal and reproductive factors. Being shorter than your peers at age 11 was associated with an odds ratio (OR) of 0.51 (0.36-0.74). Having used oral contraceptives (OC), OR 0.75 (0.49-1.15), and high parity, OR 0.16 (0.04-0.63), comparing three or more children to two or less, also appeared to reduce the risk of STS. The risk was further reduced with the duration of OC use (p = 0.01), comparing use for 11 years or more to use for 3 years or less yielded an OR of 0.10 (0.02-0.41). No effect was observed for ever having had perimenopausal hormone therapy OR 1.02 (0.70-1.47). The effect of BMI varied significantly with subtype (p = 0.03) and tumor location (p < 0.001). CONCLUSIONS: We observed surrogates of SH, GH, and insulin-like growth factor 1 to be associated with STS development. These findings are important as they may connect STSs to the group of hormone-dependent tumors, potentially revealing common treatment and prevention targets.

Small soft tissue sarcomas do metastasize: identification of high-risk tumors.

BACKGROUND: Small (≤ 5 cm) soft tissue sarcomas (STS) of the extremities and the trunk wall generally have a favorable prognosis. However, 1 of 10 patients do develop metastases, and we therefore aimed to determine predictors of metastasis in a population-based cohort of patients with small STSs. PATIENTS AND METHODS: In the southern Sweden health care region, 848 adult patients with STS of the extremities or the trunk wall were diagnosed between 1986 and 2010. Of these, 243 STS (29 %) were ≤5 cm. Prognostic evaluation was performed in 229 patients with localized disease at diagnosis, 181 of whom had histologic high-grade tumors. RESULTS: None of the 48 patients with low-grade tumors developed metastases, whereas 24 of 181 patients with high-grade tumors (13 %) tumors did. Presence of either tumor necrosis or vascular invasion predicted development of metastases with a hazard ratio of 2.9 (95 % CI, 1.0-7.9), and tumors with both factors had a hazard ratio of 12 (95 % CI, 4.1-37) for metastasis (adjusted for size). CONCLUSIONS: Our population-based series of STSs ≤5 cm demonstrate an overall good prognosis with metastases developing in 13 % of the patients with high-grade tumors. Tumor necrosis and vascular invasion were the major predictors of metastatic disease in this subset. Tumors with both these risk factors metastasized in 8 of 18 patients, which corresponds to a 12-fold increased risk of metastasis. These findings suggest that although small STS generally are linked to a good prognosis, necrosis and vascular invasion are features indicating biologically aggressive tumors for which treatment and surveillance should equal that for larger tumors.

Radiation-associated angiosarcoma after breast cancer: high recurrence rate and poor survival despite surgical treatment with R0 resection.

BACKGROUND: Secondary angiosarcoma of the breast is a rare but severe long-term complication of breast cancer treated with breast-conserving surgery and radiotherapy. We characterized a population-based cohort of patients with secondary angiosarcomas from two tertiary hospitals to investigate this complication with respect to surgical treatment and outcome. METHODS: We identified 35 patients with a history of radiation for breast cancer that developed angiosarcoma in the irradiated field from 1990 to 2009. Of these, 31 underwent surgery and were included for analysis. RESULTS: Angiosarcoma developed after median 7 years (range 3-25 years). R0 resection was obtained in 23 of 31 patients after primary treatment. Local recurrence developed in 19 patients after median 6 months (range 1-89 months). Regional and distant metastases occurred in 13 patients after median 17 months (range 2-50 months); nine which also had local recurrence. Patients whose local recurrence could be operated on had a better survival after treatment than those who were not considered for surgical treatment, median 34 months (range 6-84 months) compared with 6 months (range 5-24 months). The median disease-free survival and disease-specific survival was 16 and 37 months, respectively. CONCLUSIONS: Despite R0 resection, two-thirds of the patients developed a local recurrence. Survival among those with local recurrence was better if the patient could be treated with surgery. Overall, the prognosis was dismal and median DSS was just over 3 years.

Reliability of Margin Assessment after Surgery for Extremity Soft Tissue Sarcoma: The SSG Experience.

Surgery remains the mainstay of soft tissue sarcoma (STS) treatment and has been the primary treatment for the majority of patients in Scandinavia during the last 30 years although the use of adjuvant radiotherapy has increased. Patient and treatment characteristics have been recorded in the Scandinavian Sarcoma Group (SSG) Register since 1987. When the effect of new radiotherapy guidelines from 1998 was evaluated, the reliability of surgical margin assessments among different Scandinavian institutions was investigated. Margins were reevaluated by a panel of sarcoma surgeons, studying pathology and surgical reports from 117 patients, randomly selected among 470 recorded patients treated between 1998-2003. In 80% of cases, the panel agreed with the original classification. Disagreement was most frequent when addressing the distinction between marginal and wide margins. Considered the element of judgment inherent in all margin assessment, we find this reliability acceptable for using the Register for studies of local control of STS.

Mesenchymal stromal cells from primary osteosarcoma are non-malignant and strikingly similar to their bone marrow counterparts.

Mesenchymal stromal cells (MSC) are multipotent cells that can be isolated from a number of human tissues. In cancer, MSC have been implicated with tumor growth, invasion, metastasis, drug resistance and were even suggested as possible tumor-initiating cells in osteosarcoma (OS). However, MSC from OS and their possible tumor origin have not yet been thoroughly investigated. Therefore, primary OS mesenchymal progenitors and OS-derived MSC were studied. OS samples contained very high frequencies of mesenchymal progenitor cells as measured by the colony-forming unit fibroblast (CFU-F) assay (median: 1,117 colonies per 10(5) cells, range: 133-3,000, n = 6). This is considerably higher compared to other human tissues such as normal bone marrow (BM) (1.3 ± 0.2 colonies per 10(5) cells, n = 8). OS-derived MSC (OS-MSC) showed normal MSC morphology and expressed the typical MSC surface marker profile (CD105/CD73/CD90/CD44/HLA-classI/CD166 positive, CD45/CD34/CD14/CD19/HLA-DR/CD31 negative). Furthermore, all OS-MSC samples could be differentiated into the osteogenic lineage, and all but one sample into adipocytes and chondrocytes. Genetic analysis of OS-MSC as well as OS-derived spheres showed no tumor-related chromosomal aberrations. OS-MSC expression of markers related to tumor-associated fibroblasts (fibroblast surface protein, alpha-smooth muscle actin, vimentin) was comparable to BM-MSC and OS-MSC growth was considerably affected by tyrosine kinase inhibitors. Taken together, our results demonstrate that normal, non-malignant mesenchymal stroma cells are isolated from OS when MSC culture techniques are applied. OS-MSC represent a major constituent of the tumor microenvironment, and they share many properties with BM-derived MSC.

Changing clinical presentation of angiosarcomas after breast cancer: from late tumors in edematous arms to earlier tumors on the thoracic wall.

Angiosarcoma is a rare complication of breast cancer treatment. In order to define predictors, clinical presentation, and outcome, we characterized a population-based 50-year cohort of angiosarcomas after breast cancer. Clinical data were collected from all females with previous breast cancer who developed angiosarcomas/lymphangiosarcomas on the thoracic wall/upper extremity between 1958 and 2008 in the Southern Swedish health care region. In total, 31 angiosarcomas developed at a median age of 71 years. The patients formed two distinct groups; 14 females treated for breast cancer with radical mastectomy and radiotherapy 1949-1988 developed angiosarcomas in edematous arms (Stewart-Treves syndrome) after median 11 years, and 17 females treated by segmental resection, anti-hormonal treatment and radiotherapy 1980-2005 developed angiosarcomas in the irradiated field on the thoracic wall after median 7.3 years. The clinical presentations were heterogeneous and included hematoma-like lesions, multiple bluish-reddish nodules, and asymptomatic lumps. The overall 5-year survival was 16%. In this population-based cohort, the early angiosarcomas developed in edematous arms after radical mastectomies, whereas more recent cases occurred after a shorter time period in the irradiated fields following breast conserving surgery. We conclude that the clinical presentation of angiosarcomas has changed, parallel with altered treatment principles for breast cancer.

Two genetic pathways, t(1;10) and amplification of 3p11-12, in myxoinflammatory fibroblastic sarcoma, haemosiderotic fibrolipomatous tumour, and morphologically similar lesions.

Myxoinflammatory fibroblastic sarcoma (MIFS) is a low-grade malignant neoplasm for which limited genetic information, including a t(1;10)(p22;q24) and amplification of chromosome 3 material, is available. To further characterize these aberrations, we have investigated eight soft tissue sarcomas diagnosed as MIFS, haemosiderotic fibrolipomatous tumour (HFT), myxoid spindle cell/pleomorphic sarcoma with MIFS features, and inflammatory malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma with prominent inflammation (IMFH) harbouring a t(1;10) or variants thereof and/or ring chromosomes with possible involvement of chromosome 3. Using chromosome banding, fluorescence in situ hybridization, array-based comparative genomic hybridization, global gene expression, and real-time quantitative PCR analyses, we identified the breakpoint regions on chromosomes 1 and 10, demonstrated and delineated the commonly amplified region on chromosome 3, and assessed the consequences of these alterations for gene expression. The breakpoints in the t(1;10) mapped to TGFBR3 in 1p22 and in or near MGEA5 in 10q24, resulting in transcriptional up-regulation of NPM3 and particularly FGF8, two consecutive genes located close to MGEA5. The ring chromosomes contained a commonly amplified 1.44 Mb region in 3p11-12, which was associated with increased expression of VGLL3 and CHMP2B. The identified genetic aberrations were not confined to MIFS; an identical t(1;10) was also found in a case of HFT and the amplicon in 3p was seen in an IMFH.

Delays in the management of retroperitoneal sarcomas.

Retroperitoneal sarcomas are rare and treatment should optimally be centralized. Despite successful centralization with 90% of the patients referred prior to surgery, delays occur, which led us to assess lead times in a population-based series. Method. Patients diagnosed with retroperitoneal sarcoma in the southern Sweden health care region 2003-2009 were eligible for the study. Data on referrals and diagnostic investigations were collected from clinical files from primary health care, local hospitals, and from the sarcoma centre. Lead times were divided into patient delays and health care delays caused by primary health care, local hospitals, or procedures at the sarcoma centre. Results. Complete data were available from 33 patients and demonstrated a median patient delay of 23 days (0-17 months) and median health care delay of 94 days (1-40 months) with delays of median 15 days at the general practitioner, 36 days at local hospitals, and 55 days at the sarcoma centre. Conclusion. Centralization per se is not sufficient for optimized and efficient management. Our findings suggest that delays can be minimized by direct referral of patients from primary health care to sarcoma centers and indicate that development of coordinated diagnostic packages could shorten delays at the sarcoma centre.

Indistinguishable genomic profiles and shared prognostic markers in undifferentiated pleomorphic sarcoma and leiomyosarcoma: different sides of a single coin?

Soft tissue sarcoma (STS) diagnostics and prognostics are challenging, particularly in highly malignant and pleomorphic subtypes such as undifferentiated pleomorphic sarcoma (UPS) and leiomyosarcoma (LMS). We applied 32K BAC arrays and gene expression profiling to 18 extremity soft tissue LMS and 31 extremity soft tissue UPS with the aim of identifying molecular subtype signatures and genomic prognostic markers. Both the gains/losses and gene expression signatures revealed striking similarities between UPS and LMS, which were indistinguishable using unsupervised hierarchical cluster analysis and significance analysis for microarrays. Gene expression analysis revealed just nine genes, among them tropomyosin beta, which were differentially expressed. Loss of 4q31 (encompassing the SMAD1 locus), loss of 18q22, and tumor necrosis were identified as independent predictors of metastasis in multivariate stepwise Cox regression analysis. Combined analysis applying loss of 4q31 and 18q22 and the presence of necrosis improved the area under receiver operating characteristic curve for metastasis prediction from 0.64 to 0.86. The extensive genetic similarities between extremity soft tissue UPS and LMS suggest a shared lineage of these STS subtypes and the new and independent genetic prognosticators identified hold promise for refined prognostic determination in high-grade, genetically complex STS.

Radiotherapy to improve local control regardless of surgical margin and malignancy grade in extremity and trunk wall soft tissue sarcoma: a Scandinavian sarcoma group study.

PURPOSE: Adjuvant radiotherapy has during the past decades become increasingly used in the treatment of localized soft tissue sarcoma. We evaluated the effect of radiotherapy (RT) on local recurrence rates (LRRs) in Scandinavia between 1986 and 2005. METHODS AND MATERIALS: A total of 1,093 adult patients with extremity or trunk wall soft tissue sarcoma treated at four Scandinavian sarcoma centers were stratified according to the treatment period (1986-1991, 1992-1997, and 1998-2005). The use of adjuvant RT, quality of the surgical margin, interval between surgery and RT, and LRR were analyzed. The median follow-up was 5 years. RESULTS: The use of RT (77% treated postoperatively) increased from 28% to 53%, and the 5-year LRR decreased from 27% to 15%. The rate of wide surgical margins did not increase. The risk factors for local recurrence were histologic high-grade malignancy (hazard ratio [HR], 5), an intralesional (HR, 6) or marginal (HR, 3) surgical margin, and no RT (HR, 3). The effect of RT on the LRR was also significant after a wide margin resection and in low-grade malignant tumors. The LRR was the same after preoperative and postoperative RT. The median interval from surgery to the start of RT was 7 weeks, and 98% started RT within 4 months. The LRR was the same in patients who started treatment before and after 7 weeks. CONCLUSION: The results of our study have shown that adjuvant RT effectively prevents local recurrence in soft tissue sarcoma, irrespective of the tumor depth, malignancy grade, and surgical margin status. The effect was most pronounced in deep-seated, high-grade tumors, even when removed with a wide surgical margin.

Diagnostic and prognostic gene expression signatures in 177 soft tissue sarcomas: hypoxia-induced transcription profile signifies metastatic potential.

BACKGROUND: Soft tissue sarcoma (STS) diagnosis is challenging because of a multitude of histopathological subtypes, different genetic characteristics, and frequent intratumoral pleomorphism. One-third of STS metastasize and current risk-stratification is suboptimal, therefore, novel diagnostic and prognostic markers would be clinically valuable. We assessed the diagnostic and prognostic value of array-based gene expression profiles using 27 k cDNA microarrays in 177, mainly high-grade, STS of 13 histopathological subtypes. RESULTS: Unsupervised analysis resulted in two major clusters--one mainly containing STS characterized by type-specific genetic alterations and the other with a predominance of genetically complex and pleomorphic STS. Synovial sarcomas, myxoid/round-cell liposarcomas, and gastrointestinal stromal tumors clustered tightly within the former cluster and discriminatory signatures for these were characterized by developmental genes from the EGFR, FGFR, Wnt, Notch, Hedgehog, RAR and KIT signaling pathways. The more pleomorphic STS subtypes, e.g. leiomyosarcoma, malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma and dedifferentiated/pleomorphic liposarcoma, were part of the latter cluster and were characterized by relatively heterogeneous profiles, although subclusters herein were identified. A prognostic signature partly characterized by hypoxia-related genes was identified among 89 genetically complex pleomorphic primary STS and could, in a multivariate analysis including established prognostic markers, independently predict the risk of metastasis with a hazard ratio of 2.2 (P = 0.04). CONCLUSION: Diagnostic gene expression profiles linking signaling pathways to the different STS subtypes were demonstrated and a hypoxia-induced metastatic profile was identified in the pleomorphic, high-grade STS. These findings verify diagnostic utility and application of expression data for improved selection of high-risk STS patients.

Standardizing evaluation of sarcoma proliferation- higher Ki-67 expression in the tumor periphery than the center.

Soft tissue sarcomas often present as large and histopathologically heterogenous tumors. Proliferation has repeatedly been identified as a prognostic factor and immunostaining for Ki-67 represents the most commonly used proliferation marker. There is, however, a lack of consensus on how to evaluate Ki-67 staining regarding optimal cut-off levels, selection of tumor areas, and the number of tumor cells to evaluate. We assessed the impact of targeting peripheral versus central tumor areas using tissue microarray-based staining for Ki-67 throughout the tumor diameter in 25 leiomyosarcomas. In 18/25 tumors, Ki-67 expression was higher in the tumor periphery. If 10% staining tumor nuclei was used as cut-off and the maximal Ki-67 staining section in the tumor periphery was considered, 21/25 tumors would have been classified as highly proliferative compared to 14/25 if the tumor center had been analyzed. Similar results were obtained also when higher cut-off levels were used and if the mean expression rather than the maximal expression was considered and the differences were neither caused by necrosis nor by hypoxia (assessed as HIF-1alpha expression). Our findings suggest that the determination of proliferation in soft tissue sarcomas should be standardized for clinical application of Ki-67 as a prognostic marker.

Unstable translocation (8;22) in a case of giant cell reparative granuloma.

Giant cell reparative granuloma (GCRG) is an uncommon lesion most often affecting the jaw but also the small bones of the hands and feet. GCRG overlaps clinically and radiographically with other giant cell-rich tumors such as giant cell tumor of bone (GCTB) and aneurysmal bone cyst (ABC). In the only case of a cytogenetically investigated GCRG reported previously, a balanced translocation involving chromosomes 4 and X was found. In the present study, chromosome banding and fluorescence in situ hybridization (FISH) analyses were used to characterize the primary lesion and local recurrence of a GCRG in the thumb and skin biopsy of a 45-year-old woman. The skin showed a normal karyotype. Various forms of a dic(8;22) containing 8q, 22q, and smaller or larger parts of 8p were found in both GCRG samples. In addition, ring chromosomes, most often composed of chromosome 11 material, and telomeric associations were found. The latter aberrations were more frequent in the primary lesion. Normal FISH signals were seen when using probes capable of detecting USP6 rearrangements. The variant 8;22 aberrations were interpreted to originate from an unstable dic(8;22)(p23;p11) that gradually evolved into a functionally monocentric chromosome in the dominating subset of cell populations. We conclude that our case of GCRG shared several cytogenetic characteristics with GCTB but none with ABC.

Fine-needle aspiration of neurilemoma (schwannoma). A clinicocytopathologic study of 116 patients.

The preoperative fine-needle aspiration cytology (FNAC) diagnoses in 116 surgically excised neurilemomas were reviewed and compared with the corresponding histopathologic diagnoses made on surgical specimens and with clinical data. In addition, the utility of adjunctive techniques was analyzed and other spindle-cell lesions in the differential diagnoses were discussed. An unequivocal, benign diagnosis was rendered by FNAC in 80 cases, 67 of which were correctly labelled as neurilemoma in a review of the original cytology reports. There were 6 false-positive malignant diagnoses while 23 smears were considered insufficient and 7 inconclusive as to whether benign or malignant. On reevaluation, the diagnostic smears in most cases contained spindle cells with wavy nuclei embedded in a fibrillar, occasionally collagenous, and/or myxoid matrix and Antoni A/Antoni B tissue fragments. A moderate to abundant admixture of round to oval cells was also frequent. Nuclear palisading was seen in 41 smears with distinctive Verocay bodies in 10. Markedly pleomorphic nuclei were seen in smears from 8 ancient and 6 conventional neurilemomas, and slight to moderate nuclear pleomorphism was observed in 38 additional cases. Thus most neurilemomas have distinct cytomorphologic features that allow correct diagnosis. The major problem in FNAC of neurilemoma is to obtain sufficient material. Furthermore aspirates showing predominantly Antoni A features, nuclear pleomorphism, and/or myxoid changes can easily be confused with other types of benign or malignant soft-tissue tumors.