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Introduction Optimal management of soft tissue sarcoma (STS) remains a challenge. A nationwide survey assessed the quality of STS care in the Netherlands, thereby aiming to identify potentialities for improvement through more centralized disease management. Methods From the Netherlands Cancer Registry (NCR), data were obtained on 3317 adult STS patients (excluding gastrointestinal stromal tumor, GIST) diagnosed in 2006–2011. Logistic regression models were employed to compare outcomes on selected clinical indicators reflecting prevailing STS guidelines between high-volume (≥10 resections annually) and low-volume (

Background Nearly half of soft-tissue sarcoma (STS) patients are over the age of 65, and the behavior of cancer in these elderly patients is poorly understood. The aim of this study was to assess the impact of age, sarcoma histotype, grade, stage, and treatment modalities on survival of extremity STS (ESTS) patients. Methods Patients ≥18 years diagnosed with ESTS between 1989 and 2008 were selected from the Netherlands Cancer Registry. Survival rates and patient and treatment characteristics were analyzed for all patients. Relative survival and relative excess risk of death were estimated for young (65 years) patients. Results Overall, 3066 patients were included in this study. Histotype was different between young (65 years) patients (p 85 years)]. In multivariable analysis, age still remained a significant prognostic factor. Conclusions Different distribution of sarcoma histotypes, more high-stage and high-grade sarcomas at diagnosis, less aggressive treatment, and worse survival rates emphasize the need for optimizing sarcoma research and care of the elderly. Electronic supplementary material The online version of this article (doi:10.1245/s10434-016-5158-7) contains supplementary material, which is available to authorized users.

Background This study aimed to quantify the benefit of adjuvant radiotherapy (AXRT) for local control, distant metastasis, and long-term survival outcomes in patients with localized soft tissue sarcoma (STS). Methods This single-center retrospective observational study enrolled 433 STS patients who underwent surgery with curative intent. An inverse probability of treatment-weighted (IPTW) analysis was implemented to account rigorously for imbalances in prognostic variables between the adjuvant treatment groups. Results During a median follow-up period of 5.5 years, the study observed 38 local recurrences (9%), 73 occurrences of distant metastasis (17%), 63 STS-related deaths (15%), and 57 deaths from other causes (13%). As expected, patients receiving AXRT (n = 258, 60%) were more likely to have high-grade G3 tumors (p

e22510 Background: Ruptured GIST has poor prognosis and patients (pts) with ruptured GISTs are recommended for imatinib adjuvant therapy, however, their clinicopathological features and the prognosis in the era of imatinib are unknown. Using data obtained from two different registry studies in Japan, we examined ruptured GIST patients in clinical practice. Methods: The study cohort registered 665 pts (339 male and 326 female; median age 66 yrs) with histologically-proven primary GISTs who underwent R0 or R1 surgery between 2003 and 2007. The validation cohort included 172 pts (100 and 72; median age 62.5) between 2000 and 2014. Pathological Dx was done with H&E, KIT- and DOG1-IHC. Results: Disease located in the stomach (n = 506), small intestine (n = 119), large intestine (n = 26), or others (n = 14) in the study cohort and it was 120, 37, 14 or 2 in the validation, respectively. Median tumor size was 4.0 and 5.0 cm, median mitosis 2.6 and 5.0 /50HPF, and tumor rupture was seen in 21 pts (3.2%) and 5 pts (2.9%) in the study and validation cohorts, respectively. Rupture occurred preoperatively in 12 pts and intraoperatively in 9 of the study cohort. Ruptured GISTs showed high mitotic activities (median mitosis 13.0 vs 2.5 /50HPF; P < 0.0001), larger tumor (median size 9.6 vs 4.0 cm; P = 0.0008), and were more symptomatic than non-ruptured in the study cohort. Ruptured GIST pts had more frequent relapses (P < 0.0001) and showed shorter RFS (estimated RFS = 2.4 yrs; P < 0.0001) than non-ruptured (8.4 yrs). There were no difference in age, gender, location, surgical approach, cell type, preoperative and postoperative imatinib use between two groups.These results were confirmed in the validation cohort. Ruptured GISTs showed more frequnent relapses in the peritoneum. Multivariate analysis indicated that location (HR = 1.6), size (1.07), mitosis (1.01), and rupture (4.5) were independent prognostic factors of RFS. Rupture was not always prognostic for OS, and age (1.03), gender (2.3), and mitosis (1.01) were independent prognostic factors of OS. Conclusions: Ruptured GISTs were symptomatic larger tumors with high mitotic activity and showed frequent relapses, however, it was not independently prognostic for OS in the era of imatinib.

Background Unplanned excisions (UE) of soft tissue sarcomas (STS) carry a high risk for local recurrence (LR) due to marginal/intralesional resections. However, there are reports about improved prognosis for UE patients who have re-resection compared with patients who undergo planned surgery. The present multicentre study was designed to define characteristics of UE patients and to investigate the impact of UE on subsequent therapy and patient outcomes. Methods A total of 728 STS patients (376 males, 352 females; mean age: 58 years) who underwent definite surgery at one of three tumour centres were retrospectively included. Time-to-event analyses were calculated with log-rank and Gray’s tests, excluding patients with primary metastasis (n = 59). A propensity-score (PS) of being in the UE group was estimated, based on differences at baseline between the UE group and non-UE group. An inverse-probability-of-UE weight (IPUEW) was generated and time-to-event analyses calculated after IPUEW weighting. Results Before referral, 38.6% of patients (n = 281) had undergone UE. Unplanned excision patients were younger (p = 0.036), rather male (p = 0.05), and had smaller (p

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.

Background Limited data exist regarding the radiographic and histologic response of soft tissue sarcoma (STS) to neoadjuvant radiotherapy (RT). Methods Between February 2000 and January 2009, a total of 25 patients aged >16 years with intermediate- or high-grade primary STS of all sites were treated with neoadjuvant RT followed by definitive resection. Patients receiving chemoradiotherapy were excluded. Cross-sectional images obtained before and after RT as well as pathologic specimens were reviewed for maximal change in tumor diameter and percentage tumor necrosis, respectively. Clinicopathologic variables were analyzed for their association with pathologic and radiographic response. Results There were 18 extremity (72%) and 7 retroperitoneal (28%) tumors. Median maximal tumor size was 9 cm (range, 3.3–35 cm), and 88% were of high grade. There were 21 R0 resections (84%) and 4 R1 resections (16%). Radiographically, the median percentage change in tumor diameter was 0% (range, −25 to +86%). By Response Evaluation Criteria in Solid Tumors (RECIST), 5 patients demonstrated progressive disease, 20 demonstrated stable disease, and 0 demonstrated partial/complete response. The median pathologic percentage tumor necrosis was 30% (range, 5–100%). Two tumors (8%) demonstrated near-complete pathologic response (≥95% necrosis). Near-complete pathologic response was associated with favorable oncologic outcomes, although these associations were not statistically significant. Conclusions Radiologic and near-complete pathologic responses are rare events after preoperative RT for STS. Near-complete pathologic response may be a potentially meaningful surrogate marker for disease outcome and is not predicted by RECIST response. Knowledge of these historical response rates is important for the evaluation of novel neoadjuvant therapies for patients with STS.

Background: With the combined treatment procedure of isolated limb perfusion (ILP), delayed surgical resection and external beam radiotherapy (EBRT) for locally advanced soft tissue sarcomas (STS) of the extremities, limb salvage rates of more than 80% can be achieved. However, long-term damage to the healthy surrounding tissue cannot be prevented. We studied the late effects on the normal tissue using the LENT-SOMA scoring system.Patients and Methods: A total of 32 patients-median age 47 (range 14-71) years-were treated for a locally advanced STS with ILP, surgical resection and often adjuvant 60-70 Gy EBRT. After a median follow-up of 88 (range 17-159) months, the patients were scored, using the LENT-SOMA scales, for the following late tissue damage: muscle/soft tissue, peripheral nerves, skin/subcutaneous tissue and vessels.Results: According to the individual SOM parameters of the LENT-SOMA scales, 20 patients (63%) scored grade-3 toxicity on one or more separate items, reflecting severe symptoms with a negative impact on daily activities. Of these patients, 3 (9%) even scored grade-4 toxicity on some of the parameters, denoting irreversible functional damage necessitating major therapeutic intervention.Conclusions: In evaluating long-term morbidity after a combined treatment procedure for STS of the extremity, using modified LENT-SOMA scores, two-thirds of patients were found to have experienced serious late toxic effects.

Standard treatment for localized soft tissue sarcoma (STS) is resection plus adjuvant radiotherapy (RTx). In approximately 10% of cases, resection would cause severe loss of function or even require amputation because of the extent of disease. Isolated limb perfusion (ILP) with tumor necrosis factor alpha (TNF-alpha) and melphalan can achieve regression of the tumor, facilitating limb-saving resection. RTx improves local control but may lead to increased morbidity. In our database of over 500 ILPs, 122 patients with unifocal STS were treated by ILP followed by limb-sparing surgery. All included patients were candidates for amputation. Surgery resulted in 69 R0 resections (57%), and in 53 specimens (43%) resection margins contained microscopic evidence of tumor (R1). Histopathological examination revealed > 50% ILP-induced tumor necrosis in 59 cases (48%). RTx was administered in 73 patients (60%). Local recurrence rate was 21% after median follow-up of 31 months (2-182 months). Recurrence was significantly less in patients with > 50% ILP-induced necrosis versus a parts per thousand currency sign50% necrosis (7% vs. 33%, P = 0.001). A similar significant correlation was observed for R0 versus R1 resections (15% vs. 28%, P = 0.04). In 36 patients with R0 resection and > 50% necrosis, of whom 21 were spared RTx, no recurrences were observed during follow-up. In patients with locally advanced primary STS, treated with ILP followed by R0 resection, and with > 50% ILP-induced necrosis in the resected specimen, RTx is of no further benefit.

The integration of cytogenetics and molecular genetics into the histopathologic evaluation of soft tissue tumors has certainly represented one of the major advances of the last decade.1 It has not only served as both a validation and a refinement of available classification schemes but has also offered new diagnostic tools that have led to significant improvement of diagnostic accuracy. Among mesenchymal neoplasms, adipocytic tumor certainly represents an ideal model of such integration. In fact, with the notable exception of angiolipoma, most benign and malignant adipocytic tumors harbor distinctive genetic aberration that parallels their histomorphology. This has also proved true for adipocytic malignancies. Liposarcoma is currently subclassified genetically into three broad categories: (1) well-differentiated (WD) liposarcoma/atypical lipomatous tumors (ALT) and dedifferentiated liposarcoma featuring aberrations of the 12q13–15 chromosome region; (2) myxoid/round cell liposarcoma harboring a t(12;16) or more rarely a t(12;22) reciprocal translocation, leading to fusion of DDIT3 and FUS genes (95% of cases) or DDIT3 and EWS genes (5% of cases), respectively; and (3) pleomorphic liposarcoma showing (similarly to other pleomorphic sarcomas) complex karyotypic aberrations. With the advent (or the development) of more selective, histotype-related, systemic treatments, accurate diagnosis of mesenchymal tumors has become mandatory, as it not only provides fundamental prognostic information but also tends to determine treatment options.2,3 In the current issue of Annals of Surgical Oncology both the diagnostic and clinical impact of genetic observation is addressed by de Vreeze et al.4 The diagnostic application of 12q13–15 aberration in the differential diagnosis of well-differentiated/dedifferentiated liposarcoma dates back to the late 1990s, when pathologists first started considering the use of MDM2 and CDK4 increased protein expression (epiphenomenon of gene amplification) as a possible novel diagnostic marker.5,6 Nuclear immunopositivity for MDM2 and CDK4 appears to be restricted to well-differentiated liposarcoma/ALT, allowing separation from challenging examples of benign lipomas. The same findings in the context of dedifferentiated liposarcoma permit its distinction from other unrelated pleomorphic sarcomas that may also occur in the retroperitoneum, and have also contributed to the decline of malignant fibrous histiocytoma (MFH) as a meaningful category.6,7 Even if immunohistochemistry in expert hands appears to be acceptably reliable, fluorescence in situ hybridization (FISH) analysis as well as quantitative polymerase chain reaction (PCR)-based techniques can be used to evaluate MDM2 gene status.8 Of course a few caveats need to be underscored in order to avoid major pitfalls. First of all, MDM2 aberrations, as well as DDIT3/FUS abnormalities, whatever the technique used, should be evaluated in context with morphology. Actually this represents a general principle whenever dealing with rare form of cancers, for which diagnostic expertise is certainly crucial but also hard to achieve without access to a substantial number of cases. A second point that has been raised is related to the fact that MDM2 and CDK4 represent cell-cycle regulators, the activation of which may be not restricted to WD/dedifferentiated liposarcoma. While it is true that MDM2 gene amplification has been reported in both malignant peripheral nerve sheath tumors and undifferentiated (MFH) pleomorphic sarcomas, in the context of adipocytic malignancies it appears to be quite restricted to the well-differentiated/dedifferentiated liposarcoma category. As a consequence MDM2 analysis, as shown in the study of de Vreeze and colleagues, in addition to telling apart benign lipomas from WD liposarcomas, can also be useful in discriminating myxoid liposarcoma from well-differentiated liposarcoma with myxoid change, as well as dedifferentiated liposarcoma from pleomorphic liposarcoma. However there certainly remain a number of cases in which, despite the presence of a convincing morphology, the expected genetic aberration is missing. We have also encountered examples of classic myxoid liposarcoma or WD liposarcoma lacking any genetic aberration. However, it should be underlined that the mere absence of a given genetic abnormality may simply reflect a technical failure. As a consequence, even in the presence of state-of-the-art molecular techniques, accurate morphologic assessment should still represent the diagnostic mainstay. This assumption is supported by two very simple reasons: (1) no distinctive genetic aberration is present in 100% of cases of a given tumor (i.e., PAX2 and PAX7 aberrations in alveolar rhabdomyosarcoma), and therefore a diagnosis can be reliably rendered even if the associated genetic feature is absent, and (2) the same genetic aberration may be present in unrelated entities (i.e., ALK1 aberrations in anaplastic large lymphoma and inflammatory myofibroblastic tumor or EWSR1/CREB3/ATF1 aberrations in angiomatoid fibrous histiocytoma and clear cell sarcoma), which would be misdiagnosed if only genetic findings were to be taken into account. In conclusion, as underlined by the work of de Vreeze et al., the analysis of genetic abnormalities associated with adipocytic neoplasm is certainly a powerful tool that significantly increases diagnostic accuracy. The current role of genetic analysis is to complement and not to replace expert morphologic observation. The combination of pathology and genetics sets the rationale for appropriate clinical decision-making and possibly leads to improvement of outcome.

To the Editor: The understanding of soft tissue sarcoma has progressed impressively in the last two decades. Delineation of the biology, molecular diagnosis, and outcome have been carefully characterized with defined prognostic indicators. The challenge has been to identify if biology can predict behavior; that has now been clearly established. More importantly, can biology and predictive outcome mandate treatment change, and finally can treatment, based on biology and known outcome, be altered to reflect improved outcome? Dr Pollock and his coauthors examine this question by defining retroperitoneal liposarcoma into well-differentiated (WD) and dedifferentiated (DD) subtypes.1 They examined 135 patients over the last 10 years at their institution. This significant experience in a major sarcoma center allows important observations. As expected, WD was mostly primary and DD was mostly recurrent. Chemotherapy was rarely used in WD, and more aggressive resection was required in DD, while a third to half of all patients required multivisceral resection. The initial complete gross resection was obtained in both groups, and, as expected, recurrence was greater in the dedifferentiated group. As previously identified, metastatic disease is rare in well-differentiated liposarcoma and local recurrence can be late and prolonged. While the title of the present manuscript, “Two Different Diseases Possibly Requiring Different Treatment Approaches,” is most enticing, the data predominantly confirm that accurate diagnosis of histological subtype predicts recurrence. A recent nomogram based on 800 patients with liposarcoma has confirmed the importance of histological subtype.1 Few would challenge the authors questioning of whether, with such different outcomes, treatment should be different; however, how different is different? The real challenge, alluded to in the title, is what “different” treatment should be applied to these “different” diseases. The authors are clearly aware of the different outcomes, and that has already affected management. In both groups radiation is minimally used (

Background Epithelioid sarcoma (ES) is an extremely rare soft tissue sarcoma. Recently, the proximal variant has been reported to be a more aggressive subtype; however, as most reports of ES have involved small case series, the actual prognostic implications remain unclear. We investigated the clinicopathological features of patients with ES to identify the prognostic factors that influence survival. Methods We retrospectively analyzed the clinicopathological features of 44 patients with ES who had been treated at our institutions between 1991 and 2011. Among these patients, 26 were diagnosed histologically as having classic-type ES, whereas the remaining 18 had proximal-type ES. Thirty-three of the patients, all without distant metastases, underwent curative surgery, and the remaining 11 with distant metastases (M1) received palliative treatment. Results The proximal subtype was significantly correlated with a proximal tumor location, distant metastases at presentation, presence of rhabdoid cells, a higher tumor grade, and vascular invasion. The overall survival (OS) rate at 5 years for the 44 patients was 45 %. A superficial tumor location and lymph node metastases (N1) at presentation were independently predictive of local recurrence-free survival (LRFS), and N1 and M1 tumors were independently predictive of distant metastasis-free survival and OS, respectively. The proximal subtype was associated with unfavorable LRFS and OS, although not to a statistically significant degree. Conclusions Proximal-type ES has significantly more aggressive clinicopathological features than classic-type ES, and lymph node or distant metastasis has the most critical impact on prognosis.

Background Primary bone cancer (BC) incidence by age has not been surveyed in Asia. Methods The incidence patterns of nine subtypes of primary BCs registered between 2003 and 2010 were analyzed from Taiwan cancer registry data. More specific analyses were conducted within age groups (Group I: 0–24 years; Group II: 25–59 years; and Group III: 60–85+ years). Results A total of 1,238 newly diagnosed subjects were registered with an age-standardized incidence rate (ASR) of 6.70 per million person-years. Overall, osteosarcoma (OS: 45 %) was the most common, followed by chondrosarcoma (CS: 18 %), and Ewing sarcoma (ES: 8 %). The percentages of cases and ASRs for age groups I, II, and III were 36.3, 43.0, and 20.7 %, and 7.00, 5.48, and 10.28 per million, respectively. Significant male predilections were observed for all BCs combined, and the CS, chordoma, and malignant ameloblastoma subtypes. Our findings demonstrated an upward trend of 4.8 % per year over the study period, and was more significant for females (6.7 %). A significant increase in trend existed in the incidence of BC among females in Group II, and the incidence of OS and ES among females in Group I. Conclusions This population-based study has allowed us to confidently define the incidence rates among three age groups of Taiwanese. Despite overall low rates, the upward trend in BC incidence among females may invoke a concern. The results suggest areas for further study into the underlying causes for these cancer trends.

Background Surgical resection with curative intent for giant cell tumor of bone (GCTB) may be associated with severe morbidity. This interim analysis evaluated reduction in surgical invasiveness after denosumab treatment in patients with resectable GCTB. Methods Patients with primary or recurrent GCTB, for whom the initially planned surgery was associated with functional compromise or morbidity, received denosumab 120 mg subcutaneously every 4 weeks (additional doses on days 8 and 15 of the first cycle). Planned and actual GCTB-related surgical procedures before and after denosumab treatment were reported. Patients were followed for surgical outcome, adverse events, and recurrence following resection. Results Overall, 222 patients were evaluable for surgical downstaging (54 % were women; median age 34 years). Lesions (67 % primary and 33 % recurrent) were located in the axial (15 %) and appendicular skeleton (85 %). At the data cutoff date, most patients had not yet undergone surgery (n = 106; 48 %) or had a less morbid procedure (n = 84; 38 %) than originally planned. Median (interquartile range) time on denosumab was 19.5 (12.4–28.6) months for the 106 patients who had not undergone surgery and were continuing on monthly denosumab. Native joint preservation was 96 % (n = 24/25) for patients with planned joint/prosthesis replacement and 86 % (n = 30/35) for patients with planned joint resection/fusion. Of the 116 patients who had surgery (median postsurgical follow-up 13.0 [8.5–17.9] months), local recurrence occurred in 17 (15 %) patients. Conclusion For patients with resectable GCTB, neoadjuvant denosumab therapy resulted in beneficial surgical downstaging, including either no surgery or a less morbid surgical procedure. Electronic supplementary material The online version of this article (doi:10.1245/s10434-015-4634-9) contains supplementary material, which is available to authorized users.