Genetic variants and copy number changes in soft tissue leiomyosarcoma detected by targeted amplicon sequencing.

AIMS: Leiomyosarcomas (LMSs) occur in various tissues and harbour potential for metastases. The genomic landscape of LMS is poorly understood. In an effort to improve understanding of the LMS genome, we analysed 11 LMSs of somatic soft tissue including matching tissue of normal phenotype. METHODS: DNA derived from microdissected tumour domains and matching normal tissue underwent amplicon sequencing of 409 tumour suppressors and oncogenes using the Ion Torrent Comprehensive Cancer Panel. RESULTS: Genomic changes were heterogeneous with few recurrent abnormalities detected. Coding variants were identified in genes involved in signal transduction, transcriptional regulation and DNA repair. There were variants in several genes related to angiogenesis and GPR124 variants (TEM5) were confirmed by immunohistochemical analysis of a LMS tissue microarray. Surprisingly, there were shared coding variants in tumour and corresponding normal tissue. CONCLUSIONS: LMSs are a very heterogeneous population lacking recurrent somatic abnormalities. The presence of damaging mutations in normal tissue may reflect either a germline predisposition or field effect rather than tissue contamination. Hopeful therapeutic targets appear to be those related to AKT/MTOR pathway.

Cytoreductive Surgery and HIPEC as a Treatment Option for Laparoscopic Resection of Uterine Leiomyosarcoma with Morcellation: Early Results.

BACKGROUND: A new and frequently utilized treatment option for symptomatic uterine leiomyoma is laparoscopic resection with morcellation so the specimen can be extracted through a small abdominal incision or through the vagina. Some of these tumors (approximately 0.2 %) have malignant foci of uterine leiomyosarcoma (ULMS) that is widely disseminated in the process of resection. These patients are in need of effective additional treatments. METHODS: Patients with ULMS were treated with a standardized cytoreductive surgery (CRS), hyperthermic perioperative chemotherapy (HIPEC), and early postoperative intraperitoneal chemotherapy (EPIC) specifically designed for sarcomatosis. Distribution of disease by Peritoneal Cancer Index was recorded by preoperative computed tomography or magnetic resonance imaging and at the time of CRS. Completeness of cytoreduction score was determined after completion of CRS. Morbidity and mortality, as well as interval to start systemic chemotherapy, were prospectively recorded. RESULTS: Six patients with disseminated ULMS after morcellation or slicing underwent CRS and HIPEC plus EPIC. All six patients had complete visible clearing of sarcoma prior to perioperative chemotherapy. Early intervention after morcellation was associated with a lesser extent of disease. No serious morbidity or mortality was observed in early referral patients, and patients eligible for systemic chemotherapy were treated with perioperative chemotherapy within 6 weeks of the CRS. CONCLUSIONS: The future use of laparoscopic resection of ULMS with morcellation is currently under debate. However, patients after laparoscopic resection and morcellation have CRS and HIPEC plus EPIC as a treatment option. Results regarding short-term benefit are suggested by these early data, especially with early referral.

Aggressive locoregional management of recurrent peritoneal sarcomatosis.

BACKGROUND AND OBJECTIVES: Peritoneal sarcomatosis responds poorly to systemic chemotherapy and demonstrates high rates of recurrence after resection. We sought to determine perioperative and oncologic outcomes after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) for recurrent sarcomatosis. METHODS: We reviewed 15 patients undergoing 17 CRS/HIPEC for recurrent sarcomatosis from a prospective database. RESULTS: There were four synovial cell sarcomas, five liposarcomas, three leiomyosarcomas, two gastrointestinal stromal tumors (GIST), and three other sarcomas. Adequate cytoreduction (CC-0/1) was achieved in all patients, with a median intra-operative Simplified Peritoneal Carcinomatosis Index of 6 (range: 3-9). Median blood loss and operative time were 1 L (range: 450-5,200) and 402 min (range: 324-680), respectively. Chemoperfusion drug was mitomycin C, cisplatin, or doxorubicin. Significant post-operative complications (Clavien-Dindo III/IV) occurred in four (24%) patients, with no 60-day mortalities and three (18%) 60-day re-admissions. Median intra-abdominal disease-free and overall survival after CRS/HIPEC was 17.2 (95% CI: 2.4-19.7 months) and 22.6 months (95% CI: 6.1-62.6 months), respectively. There was a trend towards delayed recurrence after combined CRS/HIPEC than after prior CRS alone (17.2 months vs. 10.7 months, respectively; P = 0.52). CONCLUSION: Cytoreduction combined with HIPEC may improve loco-regional disease control in patients with recurrent sarcomatosis.

Uterine leiomyosarcoma diffusely express disialoganglioside GD2 and bind the therapeutic immunocytokine 14.18-IL2: implications for immunotherapy.

Uterine leiomyosarcoma comprises <1 % of uterine malignancies and is known for its clinically aggressive course. Extrapelvic recurrences are common and often lethal. No adjuvant therapies have been shown to significantly improve overall survival, highlighting the need for new and novel therapies. Our objective was to determine whether GD2-specific immunocytokine therapy may be explored for the treatment for uterine leiomyosarcoma. To do so, frozen tissue sections were obtained from the Gynecologic Oncology Group tumor bank and evaluated by immunohistochemistry (IHC) for GD2 expression using both the parent mouse monoclonal antibody 14G2A and immunocytokine 14.18-IL2 generated from the 14G2A sequence. Immunoreactivity was detected by avidin-biotin complex with DAB substrate. Specimens were reviewed by a pathologist with light microscopy and classified as negative, 1+, 2+ or 3+, compared to human melanoma cells as positive control and tissue incubated in the absence of primary antibody as negative control. GD2 was diffusely present in all evaluable samples. 10 tumors (67 %) demonstrated 3+ IHC intensity for GD2, two tumors (13 %) demonstrated 2+ intensity, and 3 (20 %) tumors demonstrated 1+ intensity. Eleven cases had sufficient tissue to assess 14.18-IL2 binding. All 11 cases bound 14.18-IL2 in a pattern identical to the parent antibody. Uterine leiomyosarcoma diffusely express GD2 and bind the therapeutic immunocytokine 14.18-IL2. This warrants further exploration to determine whether immunocytokine therapy may have a clinical role in the management of these aggressive tumors.

Iterative procedures combining cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for peritoneal recurrence: postoperative and long-term results.

OBJECTIVE: Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is the best treatment of several peritoneal surface malignancies. Isolated peritoneal recurrence may be treated by iterative procedures. The aim of this study was to evaluate immediate postoperative and long-term results after iterative CRS-HIPEC. METHODS: From 1990 to 2010, 30 patients with isolated peritoneal recurrence underwent iterative procedures combining CRS-HIPEC. RESULTS: Origins of peritoneal carcinomatosis were ovarian, colorectal, pseudomyxoma peritonei, peritoneal mesothelioma, gastric cancer, cholangiocarcinoma, leiomyosarcoma, and primary peritoneal serous carcinoma. Median recurrence-free survival (RFS) was 16.2 months from the first procedure. After the second procedure, one (3.3%) postoperative death occurred. Severe morbidity following the second procedure was 40% versus 30% after the first procedure (P = 0.37). At most recent follow up, 11 patients were disease-free, 10 were alive with recurrence, and 9 were dead with recurrence. Five-year overall survival after initial CRS with HIPEC was 65%, and overall median survival from diagnosis was 140 months. CONCLUSION: Iterative procedures combining CRS-HIPEC are feasible and allow long-term survival but may result in significant morbidity and mortality. Patients must be carefully selected, based on the following criteria: Origin of carcinomatosis, magnitude of first procedure, length of RFS, physiological age, co-morbidity, and possibility of complete cytoreduction.

Peritoneal sarcomatosis: is there a subset of patients who may benefit from cytoreductive surgery and hyperthermic intraperitoneal chemotherapy?

BACKGROUND: Unlike novel molecular-targeted therapies for metastatic gastrointestinal stromal tumors (GIST), conventional treatments for peritoneal sarcomatosis (PS) are mostly ineffective. As with carcinomatosis of epithelial origin, a rationale base supports an aggressive locoregional treatment of PS, but the use of CRS and HIPEC in this setting is still controversial. We assessed the outcome of clinically and pathologically homogeneous subsets of patients with PS uniformly treated by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: A prospective database of 37 patients who underwent CRS and close-abdomen HIPEC with cisplatin and doxorubicin or mitomycin-C was reviewed. PS originated from GIST (pre-imatinib era) in 8 patients, uterine leiomyosarcoma (ULS) in 11, retroperitoneal liposarcoma (RPLP) in 13, and other sarcoma in 5. RESULTS: CRS was macroscopically complete in 28 patients (75.7%). Operative mortality was 3.7% and morbidity 21.6%. After median follow-up of 104 (range, 1-131) months, peritoneal disease progression occurred in 16 patients, distant metastases in 5, and both in 13. For all patients, median overall survival was 26.2 months; 7 patients were alive at 46-130 months (ULS, n = 4; RPLP, n = 2; GIST, n = 1). RPLP had the best overall survival (median, 34 months) but 100% peritoneal relapse; GIST had dismal overall, local-regional-free and distant-free survival; ULS had the higher proportion of long survivors and best local-regional-free survival. CONCLUSIONS: Overall, results of CRS and HIPEC did not compare favorably to those of conventional therapy. In a subgroup analysis, the combined approach did not change GIST and RPLS natural history. The interesting results with ULS may warrant further investigations.

Diagnosis and management of primary pulmonary leiomyosarcoma.

Leiomyosarcomas are cancers of smooth muscle cells that can arise from any location but occur most often in the uterus, retroperitoneum, or intraabdominal region. Primary leiomyosarcomas of the lung are extremely rare and are often diagnosed as a mass on routine chest radiography. Metastasis is uncommon and typically occurs late in the disease process, indicating the importance of early detection. Surgical excision is generally curative, offering patients optimal prognoses. The authors describe a 56-year-old asymptomatic man who was found to have a pulmonary mass on routine chest radiography. Further testing revealed a primary pulmonary leiomyosarcoma. The tumor was excised and postoperative osteopathic manipulative treatment was applied to help facilitate patient recovery. A brief discussion of the typical clinical presentation, prevalence, and medical management of these tumors is included.

[Bladder leiomyosarcoma. Partial cystectomy and adjuvant treatment]. / Leiomiosarcoma de vejiga: cistectomía parcial y tratamiento complementario.

OBJECTIVE: We report a new case of bladder leiomyosarcoma in an old patient. METHODS: We present the case of a 75-year-old man with bladder leiomyosarcoma treated by partial surgery followed by adjuvant treatment. RESULTS: Partial surgery of the primary tumor followed by concomitant chemoradiotherapy was the approach for this patient. Nowadays, patient is free of tumor and living without any problems. CONCLUSIONS: Bladder leiomyosarcoma is an uncommon tumor (only about 1% of all bladder cancers) treated basically with radical surgery. Nowadays, partial surgery is a usual approach in other tumors and there is a trend toward less aggressive surgery with preservation of function (such as head and neck cancer, bladder cancer).

Recurrent episodes of hematuria: a rare presentation of leiomyosarcoma of prostate.

Leiomyosarcoma of the prostate is an extremely rare entity. Sarcomas account for about 1% of all malignant tumors and less than 5% of them arise from the genitourinary tract. Majority of patients present with urinary obstructive symptoms. The outcome is generally poor. Surgery with or without radiotherapy/chemotherapy forms the mainstay of treatment for patients with operable tumors. We report a patient presenting with recurrent episodes of hematuria.

Interventional radiology in Carney triad.

Interventional therapeutic methods are presented in Carney triad, which is a syndrome defined as the simultaneous presence of gastric leiomyosarcoma, extra-adrenal paraganglioma, and pulmonary chondroma. The paragangliomas in the carotid bifurcation and the mediastinum were successfully treated via transarterial embolization with particles. Three intrapulmonary chondromas were ablated using MRI-guided laser-induced thermotherapy (LITT) after previous devascularization via transvenous pulmonary particle embolization. In summary, interventional techniques could be a therapeutic option in patients suffering from Carney triad.

c-Kit expression in patients with uterine leiomyosarcomas: a potential alternative therapeutic treatment.

PURPOSE: Uterine leiomyosarcomas are rare tumors characterized by their resistance to chemotherapy and radiation treatment. Surgery is the primary method of treatment, but for patients with unresectable disease, alternate therapeutic options are clearly warranted. According to initial observations of c-KIT expression, correlation with a bad prognosis, and the successful therapeutic possibility of STI571 in gastrointestinal stromal tumors, the data have encouraged us to study c-KIT expression in these tumors. EXPERIMENTAL DESIGN: We analyzed the expression of c-KIT and genetic assessment of exon 11 of c-kit gene in 32 uterine leiomyosarcomas. RESULTS: In 17 cases (53.1%), we observed a c-KIT expression in tumor cells. Of the 17 patients with distinct c-KIT-positive immunoreactivity, eight had I or II stage disease and nine had III or IV stage disease. Molecular genetic analysis of exon 11, analyzed by direct DNA sequencing, was performed for all of the c-KIT-positive uterine leiomyosarcomas. No mutations were found. CONCLUSION: The conventional chemotherapy in leiomyosarcomas appears to be ineffective for patients with metastatic or unresectable disease, and the management of these patients poses a special problem. In these women, new therapeutic strategies are warranted. The treatment with STI571 in leiomyosarcoma patients might be hypothesized, because uterine leiomyosarcomas also express c-KIT.

Aggressive recurrence after radiofrequency ablation of liver neoplasms.

Radiofrequency ablation is considered safe for inoperable liver neoplasms; with small lesions the rate of success is very high, the local recurrence is marginal and generally suitable for a retreatment. We have little information about the possibility of rapid regrowth of the tumor after a response judged as complete. We present four patients, affected by primary (3 patients) and metastatic (1 patient) uninodular cancer. All the lesions were small, superficial and well suited for surgery, but were treated by radiofrequency ablation elsewhere. The early instrumental evaluations stated a complete result in all the patients. Cancer regrowth was diagnosed at 3, 4, 6 and 12 months after radiofrequency ablation, always starting from the treated lesion. In case 1 the whole right lobe was involved together with a controlateral multinodular recurrence; cases 2 and 3 presented an extensive liver and parietal wall involvement; while in the fourth patient a diffuse biliary colonization was observed. Only 1 patient was suitable for surgery; the others died 6, 2 and 4 months, respectively, after recurrence. Recurrence after radiofrequency ablation may show an aggressive evolution precluding any possibility of cure. Radiofrequency ablation must not be considered a suitable alternative to surgery in patients with a low surgical risk.

Soft tissue sarcoma of the vulva: A clinical study.

The purpose of this study is to report clinical aspects and treatment results of patients seen at Johns Hopkins. A search of the tumor registry of the Sidney Kimmel Comprehensive Cancer Center found 453 patients with malignancies of the vulva registered between 1977 and 1997. Patient and tumor characteristics, treatment methods, and follow-up were obtained from charts. Seven patients were identified with sarcoma of the vulva. Of these, one was removed from analysis due to histology. Three patients had leiomyosarcoma, two had fibrosarcoma, and one had epithelioid sarcoma. The mean age was 41. Mean time to diagnosis was 6 months. All but one of the tumors was located on the labia majora. Median tumor size was 3.5 cm. Surgery varied from wide local excision to radical vulvectomy with inguinal lymph node dissection. Surgical margins were microscopically negative in five of the six cases. Two patients had received adjuvant external beam radiation. One of them had a tumor greater than 5 cm and close surgical margins and the other had high-grade tumor, which recurred after previous surgery. Mean follow-up was 127.8 months. There have been no recurrences to date.

[Radiofrequency ablation of liver tumours]. / Hochfrequenz-Thermoablation bei Lebertumoren.

BACKGROUND: A variety of local treatment modalities exists for the palliative therapy of inoperable primary or secondary liver tumours. In this connection the promising use especially of thermal ablation methods has been reported recently. Numerous procedures and technical terms have been mentioned in this context giving us the opportunity of a review on this subject. METHODS: From the literature of the last five years (Medline/PubMed) including the lists of references physical principles and application techniques, indications and contraindications, possibilities of evaluation and results of high frequency thermotherapy (HFTT) respectively radiofrequency ablation (RFA) were investigated and compared to our own first experiences. Survival and recurrence rates were estimated from the study results. RESULTS: Most authors describe the HF-thermoablative treatment as a technically uncomplicated and relatively low-risk procedure. After a mean follow-up of about 10 months the mean survival rate was about 90 % and tumor recurrence was seen in approximately 30 % of the patients. The main problems occurred in view of the complete registration of all tumors with imaging techniques before RFA and the complete ablation, especially of larger tumours. CONCLUSIONS: In most of the clinical studies RFA promises an advantage of survival and improvement of quality of life compared to the known courses of untreated liver tumours. Therefore this method should be practiced on a larger scale in suitable patients. At the same time its efficacy must be proven by comparative studies.

Sarcomas metastatic to the liver: response and survival after cisplatin, doxorubicin, mitomycin-C, Ethiodol, and polyvinyl alcohol chemoembolization.

PURPOSE: To evaluate the response to and survival after chemoembolization with cisplatin, doxorubicin, mitomycin-C, Ethiodol, and polyvinyl alcohol for patients with sarcomas metastatic to the liver that are surgically unresectable. MATERIALS AND METHODS: Sixteen patients were treated. Primary tumors included 11 gastrointestinal leiomyosarcomas, two splenic angiosarcomas, one leiomyosarcoma of the broad ligament, one leiomyosarcoma of the inferior vena cava, and one malignant fibrous histiocytoma of the colon. Chemoembolization with cisplatin, doxorubicin, mitomycin-C, Ethiodol, and polyvinyl alcohol particles was performed 1-5 times at approximately monthly intervals (mean, 2.8). Pre- and posttreatment cross-sectional imaging was performed 1 month after completion of treatment and then every 3 months. Thirty-day response was graded according to World Health Organization/Eastern Cooperative Oncology Group criteria. Survival was calculated with use of Kaplan-Meier analysis. RESULTS: Two patients (13%) exhibited partial morphologic response, 11 patients (69%) were morphologically stable, and three (19%) demonstrated progression of disease 30 days after completion of treatment. Among the 13 responders, two underwent partial hepatectomy after initial treatment. Seven developed intrahepatic progression at a mean of 10 months and a median time of 8 months. The remaining four patients had no documented intrahepatic progression at the time of last imaging follow-up. Nine patients developed extrahepatic progression at a mean time of 6.3 months and a median time of 6 months, of whom four underwent additional surgical resection. Response to therapy was based on time of first intervention. Cumulative survival from time of diagnosis with use of Kaplan-Meier analysis was 81% at 1 year, 54% at 2 years, and 40% at 3 years. Median survival time was 20 months. Cumulative survival from initial chemoembolization was 67% at 1 year, 50% at 2 years, and 40% at 3 years, with a median survival time of 13 months. The thirty-day mortality rate was zero. CONCLUSION: Durable tumor response with chemoembolization is possible in this form of metastatic disease, which is highly resistant to systemic chemotherapy.

Metástasis hepáticas secundarias a leiomiosarcoma de recto. Presentación de un caso / Liver metastases secondary to rectal leiomyosarcoma. A case report

Se presenta un caso de metástasis hepáticas en una paciente afectada por un leiomiosarcoma de localización rectal. Se incide en la rareza de este tipo de tumores, así como en su agresividad y posibilidades terapéuticas (AU)

Multiple organ dysfunction syndrome induced by whole-body hyperthermia and polychemotherapy in a patient with disseminated leiomyosarcoma of the uterus.

OBJECTIVE: Whole-body hyperthermia (WBH) in combination with chemotherapy is a relatively new promising treatment modality for patients with cancer. The objective of this report is to present the development of an acute systemic inflammatory response syndrome (SIRS) with multiple organ dysfunction syndrome (MODS) following WBH in combination with chemotherapy. Although WBH can also induce cytokine production, MODS has not been described before in association with WBH. DESIGN: Case report. The patient was treated with WBH (core temperature 41.8 degrees C using a radiant heat device (Aquatherm) ) in combination with polychemotherapy (ifosfamide, carboplatin and etoposide (ICE) ) in the context of a clinical trial for metastatic sarcomas. SETTING: Department of medical oncology and intensive care unit of a university hospital. PATIENT: A 58-year-old Caucasian woman treated for disseminated leiomyosarcoma of the uterus, who developed SIRS with brain dysfunction, hypotension, respiratory failure and renal dysfunction following WBH/ICE. INTERVENTIONS: She was successfully treated in the intensive care unit by mechanical ventilation, inotropics and antibiotics. MEASUREMENTS AND RESULTS: There was a remarkable recovery within 2 days: she regained full conciousness, could be extubated, inotropic support was stopped and creatinine levels returned to pre-treatment levels. All cultures remained sterile. After almost complete recovery, 5 days later a second episode of fever during neutropenia occurred and, despite antibiotic treatment, she died of Bacteroides distasonis sepsis. CONCLUSION: WBH should be added as a new cause to the already known list of physical-chemical insults which can result in MODS.

[Leiomyosarcoma of the bladder. Report of a new case and review of the literature]. / Leiomiosarcoma de vejiga. Aportación de un nuevo caso y revisión de la literatura.

Contribution of a new case of bladder leiomyosarcoma due to the rarity of its presentation. There are barely one hundred cases reported in the medical literature. Clinico-pathological, therapeutic and prognostic assessment of this type of bladder sarcoma and discussion on the convenience of complementary therapy after surgery.

Unusual cutaneous malignancies.

The most commonly occurring cutaneous malignancies are basal cell and squamous cell carcinoma. There are, however, other rare malignancies that are encountered and should be included in the differential, in which both the clinical and the histological diagnosis may be difficult. Here, the clinical and histological features, management, and prognostic factors of merkel cell carcinoma, microcystic adnexal carcinoma, leiomyosarcoma, dermatofibrosarcoma protuberans, and angiosarcoma are reviewed.