Eberhard Stoeckle

Primary Retroperitoneal Sarcomas: A Multivariate Analysis of Surgical Factors Associated With Local Control

PURPOSEnTo define the optimal initial management and the best extent of surgery that would optimize margins on primary retroperitoneal sarcomas (RPS).nnnPATIENTS AND METHODSnA total of 382 patients with primary RPS were analyzed. Sixty-five patients had a simple resection of the tumor, 120 patients had a complete compartmental resection (systematic resection of noninvolved contiguous organs), 130 patients had a contiguously involved organ resection, 21 patients had a systematic re-excision, 38 patients had an incomplete gross resection, and eight patients had a biopsy alone. Radiotherapy and chemotherapy were administered to 121 and 145 patients, respectively.nnnRESULTSnOne, 3-, and 5-year overall survival (OS) rates were 86% (95% CI, 0.82 to 0.89), 66% (95% CI, 0.61 to 0.71), and 57% (95% CI, 0.51 to 0.62), respectively. Median overall survival was 6 years. In the multivariate analysis, high grade, tumor rupture, gross residual disease, and positive margins were associated with decreased OS. Low grade, no tumor rupture, negative histologic margins, a high number of patients undergoing operation per center, and compartmental resection compared with standard procedures were associated with decreased abdominal recurrences. Compartmental resection is a significant variable, predicting a 3.29-fold lower rate of abdominal recurrence compared with simple complete resection.nnnCONCLUSIONnComplete compartmental surgery without tumor rupture should be performed when possible to achieve clear margins. This surgery should be performed in a high-volume center. The role of adjuvant treatments should be evaluated in a randomized trial in association with this optimal surgery.

Prognostic Factors Influencing Progression-Free Survival Determined From a Series of Sporadic Desmoid Tumors: A Wait-and-See Policy According to Tumor Presentation

PURPOSEnDesmoid tumors are mesenchymal fibroblastic/myofibroblastic proliferations with locoregional aggressiveness and high ability to recur after initial treatment. We present the results of the largest series of sporadic desmoid tumors ever published to determine the prognostic factors of these rare tumors.nnnPATIENTS AND METHODSnFour hundred twenty-six patients with a desmoid tumor at diagnosis were included, and the following parameters were studied: age, sex, delay between first symptoms and diagnosis, tumor size, tumor site, previous history of surgery or trauma in the area of the primary tumor, surgical margins, and context of abdominal wall desmoids in women of child-bearing age during or shortly after pregnancy. We performed univariate and multivariate analysis for progression-free survival (PFS).nnnRESULTSnIn univariate analysis, age, tumor size, tumor site, and surgical margins (R2 v R0/R1) had a significant impact on PFS. PFS curves were not significantly different for microscopic assessment of surgical resection quality (R0 v R1). In multivariate analysis, age, tumor size, and tumor site had independent values. Three prognostic groups for PFS were defined on the basis of the number of independent unfavorable prognostic factors (0 or 1, 2, and 3).nnnCONCLUSIONnThis study clearly demonstrates that there are different prognostic subgroups of desmoid tumors that could benefit from different therapeutic strategies, including a wait-and-see policy.

Most malignant fibrous histiocytomas developed in the retroperitoneum are dedifferentiated liposarcomas: A review of 25 cases initially diagnosed as malignant fibrous histiocytoma

Forty-four samples from 25 cases of retroperitoneal sarcoma initially diagnosed as malignant fibrous histiocytoma were histologically reviewed. Immunohistochemistry for mdm2 and cdk4 was performed on 20 cases. Comparative genomic hybridization was performed on 18 samples from 13 patients. Seventeen cases were reclassified as dedifferentiated liposarcoma. Twenty-one of 32 samples from these patients showed areas of well-differentiated liposarcoma, allowing the diagnosis of dedifferentiated liposarcoma. Immunohistochemistry performed in 15 of these cases showed positivity for mdm2 and cdk4. Comparative genomic hybridization analysis performed on 15 samples from 11 of these patients showed an amplification of the 12q13–15 region. Eight cases were reclassified as poorly differentiated sarcoma. Twelve samples from these patients showed no area of well-differentiated liposarcoma. Immunohistochemistry showed positivity for mdm2 and cdk4 in one of six of these patients and showed positivity for CD34 in another one. Comparative genomic hybridization analysis performed on three samples from two of these patients showed no amplification of the 12q13–15 region but showed complex profiles. This study shows that most so-called malignant fibrous histiocytomas developed in the retroperitoneum are dedifferentiated liposarcoma and that a poorly differentiated sarcoma in this area should prompt extensive sampling to demonstrate a well-differentiated liposarcoma component, immunohistochemistry for mdm2 and cdk4, and if possible, a cytogenetic or a molecular biology analysis.

Technical considerations in surgery for retroperitoneal sarcomas: Position paper from E-Surge, a master class in sarcoma surgery, and EORTC-STBSG

BackgroundSurgery is the principal treatment for retroperitoneal sarcoma. These tumors typically involve or abut multiple organs and therefore require multivisceral resections. Despite the complexity of such operations, a standardized approach has not been described. As a result, referral centers often see patients who have undergone suboptimal surgery, with gross disease left behind. This is one of the causes of the dismal prognosis of this disease.MethodsThese consensus statements came out from E-Surge, an educational symposium with live sarcoma surgery, performed by European and North American expert sarcoma surgeons illustrating an optimal technique to an international audience, held in 2010 and 2011. The content was then shared among members of the local subcommittee of European Organization for Research and Treatment of Cancer (EORTC)–Soft Tissue and Bone Sarcoma Group (STBSG).ResultsAn attempt to describe a reproducible and standardized approach to these tumors is illustrated. A detailed description of the different procedures according to the variety of different presentations is made.ConclusionsThe approach described herein should be used as the reference standard in clinical practice and serve to perform quality check of local treatment in future trials.

MED12 Alterations in Both Human Benign and Malignant Uterine Soft Tissue Tumors

The relationship between benign uterine leiomyomas and their malignant counterparts, i.e. leiomyosarcomas and smooth muscle tumors of uncertain malignant potential (STUMP), is still poorly understood. The idea that a leiomyosarcoma could derive from a leiomyoma is still controversial. Recently MED12 mutations have been reported in uterine leiomyomas. In this study we asked whether such mutations could also be involved in leiomyosarcomas and STUMP oncogenesis. For this purpose we examined 33 uterine mesenchymal tumors by sequencing the hot-spot mutation region of MED12. We determined that MED12 is altered in 66.6% of typical leiomyomas as previously reported but also in 11% of STUMP and 20% of leiomyosarcomas. The mutated allele is predominantly expressed in leiomyomas and STUMP. Interestingly all classical leiomyomas exhibit MED12 protein expression while 40% of atypical leiomyomas, 50% of STUMP and 80% of leiomyosarcomas (among them the two mutated ones) do not express MED12. All these tumors without protein expression exhibit complex genomic profiles. No mutations and no expression loss were identified in an additional series of 38 non-uterine leiomyosarcomas. MED12 mutations are not exclusive to leiomyomas but seem to be specific to uterine malignancies. A previous study has suggested that MED12 mutations in leiomyomas could lead to Wnt/β-catenin pathway activation however our immunohistochemistry results show that there is no association between MED12 status and β-catenin nuclear/cytoplasmic localization. Collectively, our results show that subgroups of benign and malignant tumors share a common genetics. We propose here that MED12 alterations could be implicated in the development of smooth muscle tumor and that its expression could be inhibited in malignant tumors.

Neoadjuvant Imatinib in Locally Advanced Gastrointestinal Stromal Tumors (GIST): The EORTC STBSG Experience

BackgroundPreoperative imatinib therapy of locally advanced GIST may facilitate resection and decrease morbidity of the procedure.MethodsWe have pooled databases from 10 EORTC STBSG sarcoma centers and analyzed disease-free survival (DFS) and disease-specific survival (DSS) in 161 patients with locally advanced, nonmetastatic GISTs who received neoadjuvant imatinib. OS was calculated from start of imatinib therapy for locally advanced disease until death or last follow-up (FU) after resection of the GIST. DFS was calculated from date of resection to date of disease recurrence or last FU. Median FU time was 46xa0months.ResultsThe primary tumor was located in the stomach (55xa0%), followed by rectum (20xa0%), duodenum (10xa0%), ileum/jejunum/other (11xa0%), and esophagus (3xa0%). The tumor resection after preoperative imatinib (median time on therapy, 40xa0weeks) was R0 in 83xa0%. Only two patients have demonstrated disease progression during neoadjuvant therapy. Five-year DSS/DFS rates were 95/65xa0%, respectively, median OS was 104xa0months, and median DFS was not reached. There were 56xa0% of patients who continued imatinib after resection. Thirty-seven GIST recurrences were diagnosed (only 5 local relapses). The most common mutations affected exon 11 KIT (65xa0%). Poorer DFS was related to primary tumor location in small bowel and lack of postoperative therapy with imatinib.ConclusionsOur analysis comprising the largest group of GIST patients treated with neoadjuvant imatinib in routine practice indicates excellent long-term results of combined therapy in locally advanced GISTs.

Management of Recurrent Retroperitoneal Sarcoma (RPS) in the Adult: A Consensus Approach from the Trans-Atlantic RPS Working Group

IntroductionRetroperitoneal soft tissue sarcomas (RPS) are rare tumors. Surgery is the mainstay of curative therapy, but local recurrence is common. No recommendations concerning the best management of recurring disease have been developed so far. Although every effort should be made to optimize the initial approach, recommendations to treat recurring RPS will be helpful to maximize disease control at recurrence.MethodsAn RPS transatlantic working group was established in 2013. The goals of the group were to share institutional experiences, build large multi-institutional case series, and develop consensus documents on the approach to this difficult disease. The outcome of this document applies to recurrent RPS that is nonvisceral in origin. Included are sarcomas of major veins, undifferentiated pleomorphic sarcoma of psoas, ureteric leiomyosarcoma (LMS). Excluded are desmoids-type fibromatosis, angiomyolipoma, gastrointestinal stromal tumors, sarcomas arising from the gut or its mesentery, uterine LMS, prostatic sarcoma, paratesticular/spermatic cord sarcoma, Ewing sarcoma, alveolar/embryonal rhabdomyosarcoma, sarcoma arising from teratoma, carcinosarcoma, sarcomatoid carcinoma, clear cell sarcoma, radiation-induced sarcoma, paraganglioma, and malignant pheochromocytoma.ResultsRecurrent RPS management was evaluated from diagnosis to follow-up. It is a rare and complex malignancy that is best managed by an experienced multidisciplinary team in a specialized referral center. The best chance of cure is at the time of primary presentation, but some patients may experience prolonged disease control also at recurrence, when the approach is optimized and follows the recommendations contained herein.ConclusionsInternational collaboration is critical for adding to the present knowledge. A transatlantic prospective registry has been established.

Maximal cytoreduction in patients with FIGO stage IIIC to stage IV ovarian, fallopian, and peritoneal cancer in day-to-day practice: a Retrospective French Multicentric Study

Objectives To evaluate the outcome of maximal cytoreductive surgery in patients with stage IIIC to stage IV ovarian, tubal, and peritoneal cancer regarding overall survival (OS) and disease-free survival (DFS). Materials and Methods Five hundred twenty-seven patients with stage IIIC (peritoneal) and stage IV (pleural) ovarian, fallopian tube, and peritoneal carcinoma underwent surgery between January 2003 and December 2007 in 7 gynecologic oncology centers in France. Patients undergoing primary and interval debulking surgery were included, whichever the number of chemotherapy cycles. The extent of disease, type of surgical procedure, and amount of residual disease were recorded. A multivariate analysis of the outcome was performed, taking into account the stage, grade, and timing of surgery. Results Median DFS was 17.9 months, but median OS was not reached at the time of analysis. Complete cytoreductive surgery, without evident residual tumor at the end of the procedure, was obtained in 71% of all patients (primary surgery, 33%). After neoadjuvant therapy, the rate of complete debulking surgery was higher (74%) compared to primary cytoreductive surgery (65%). Twenty-three percent of patients needed “ultra radical surgery” to achieve this goal. The most significant predictive factor for DFS and OS was complete cytoreductive surgery compared to any amount, even minimal (1–10 mm), of residual disease. In the group of patients with complete cytoreductive surgery, the patients undergoing surgery before chemotherapy showed better DFS than those having first chemotherapy. Conclusion The findings confirm that complete cytoreduction is the criterion standard of surgery in the management of advanced ovarian, peritoneal, and fallopian tube cancer, whatever the timing of surgery. With experienced teams, surgery was completed, without evident residual tumor in 71% of the cases.

Dedifferentiated liposarcomas with divergent myosarcomatous differentiation developed in the internal trunk: a study of 27 cases and comparison to conventional dedifferentiated liposarcomas and leiomyosarcomas.

Dedifferentiated liposarcoma (DLPS) is one of the most frequent sarcomas of the retroperitoneum and represents most undifferentiated sarcomas of the internal trunk. In about 5% cases, the dedifferentiated component is an heterologous sarcoma such as leiomyosarcoma or rhabdomyosarcoma. We reviewed a series of 65 sarcomas with a myogenic differentiation developed in the internal trunk for which initial diagnoses were leiomyosarcoma (37), rhabdomyosarcoma (6), malignant mesenchymoma (6), and DLPS (16). Immunostainings for MDM2, CDK4, alpha smooth actin, desmin, caldesmon, myogenin, c-kit, and progesterone receptor were performed. In 48 cases, the amplification status of MDM2 and CDK4 could be evaluated with quantitative polymerase chain reaction on paraffin-embedded tissues extracted DNAs. After review of the cases, final diagnoses were leiomyosarcoma (35), rhabdomyosarcomatous (20) or leiomyosarcomatous (7) DLPS, probable DLPS (2), and malignant mesenchymoma (1). DLPS were bigger tumors (median: 18.2u2009cm) than leiomyosarcomas (median: 12u2009cm). They had a lower 5-year recurrence-free survival than leiomyosarcomas (45% vs. 71%) but a higher 5-year metastasis-free survival (73% vs. 39%). There was no significant difference in overall survival (57% vs. 34%). Outcome of patients with a DLPS with a myosarcomatous component did not differ from conventional DLPS. In conclusion, most sarcomas with a rhabdomyosarcomatous differentiation occurring in the internal trunk of adults are DLPS. Moreover, DLPS with a myogenic component have a low metastatic potential, similar to conventional DLPS and significantly lower to the metastatic potential of leiomyosarcomas.

Multi-Center Evaluation of Post-Operative Morbidity and Mortality after Optimal Cytoreductive Surgery for Advanced Ovarian Cancer

Purpose While optimal cytoreduction is the standard of care for advanced ovarian cancer, the related post-operative morbidity has not been clearly documented outside pioneering centers. Indeed most of the studies are monocentric with inclusions over several years inducing heterogeneity in techniques and goals of surgery. We assessed the morbidity of optimal cytoreduction surgery for advanced ovarian cancer within a short inclusion period in 6 referral centers dedicated to achieve complete cytoreduction. Patients and Methods The 30 last optimal debulking surgeries of 6 cancer centers were included. Inclusion criteria included: stage IIIc- IV ovarian cancer and optimal surgery performed at the site of inclusion. All post-operative complications within 30 days of surgery were recorded and graded using the Memorial secondary events grading system. Student-t, Chi2 and non-parametric statistical tests were performed. Results 180 patients were included. There was no demographic differences between the centers. 63 patients underwent surgery including intestinal resections (58 recto-sigmoid resection), 24 diaphragmatic resections, 17 splenectomies. 61 patients presented complications; One patient died post-operatively. Major (grade 3–5) complications requiring subsequent surgeries occurred in 21 patients (11.5%). 76% of patients with a major complication had undergone an ultraradical surgery (Pu200a=u200a0.004). Conclusion While ultraradical surgery may result in complete resection of peritoneal disease in advanced ovarian cancer, the associated complication rate is not negligible. Patients should be carefully evaluated and the timing of their surgery optimized in order to avoid major complications.