Germline Mutations in Cancer Predisposition Genes are Frequent in Sporadic Sarcomas.

Associations of sarcoma with inherited cancer syndromes implicate genetic predisposition in sarcoma development. However, due to the apparently sporadic nature of sarcomas, little attention has been paid to the role genetic susceptibility in sporadic sarcoma. To address this, we performed targeted-genomic sequencing to investigate the prevalence of germline mutations in known cancer-associated genes within an Asian cohort of sporadic sarcoma patients younger than 50 years old. We observed 13.6% (n = 9) amongst 66 patients harbour at least one predicted pathogenic germline mutation in 10 cancer-associated genes including ATM, BRCA2, ERCC4, FANCC, FANCE, FANCI, MSH6, POLE, SDHA and TP53. The most frequently affected genes are involved in the DNA damage repair pathway, with a germline mutation prevalence of 10.6%. Our findings suggests that genetic predisposition plays a larger role than expected in our Asian cohort of sporadic sarcoma, therefore clinicians should be aware of the possibility that young sarcoma patients may be carriers of inherited mutations in cancer genes and should be considered for genetic testing, regardless of family history. The prevalence of germline mutations in DNA damage repair genes imply that therapeutic strategies exploiting the vulnerabilities resulting from impaired DNA repair may be promising areas for translational research.

Prognostic significance of KIT exon 11 deletion mutation in intermediate-risk gastrointestinal stromal tumor.

AIM: Benefit of adjuvant imatinib therapy following curative resection in patients with intermediate-risk gastrointestinal stromal tumor (GIST) is unclear. GIST-specific exon mutations, in particular exon 11 deletions, have been shown to be prognostic. We hypothesize that specific KIT mutations may improve risk stratification in patients with intermediate-risk GIST, identifying a subgroup of patients who may benefit from adjuvant therapy. METHODS: In total, 142 GIST patients with complete clinicopathologic and mutational data from two sites were included. Risk classification was based on the modified National Institute of Health (NIH) criteria. RESULTS: In this cohort, 74% (n = 105) of patients harbored a KIT mutation; 61% (n = 86) were found in exon 11 of which nearly 70% were KIT exon 11 deletions (n = 60). A total of 18% (n = 25) of cases were classified as having intermediate-risk disease. Univariate analysis confirmed tumor size, mitotic index, nongastric origin, presence of tumor rupture and modified NIH criteria were adversely prognostic for relapse-free survival (RFS). Among KIT/PDGFRA mutants, KIT exon 11 deletions had a significantly worse prognosis (hazard ratio 2.31; 95% confidence interval, 1.30-4.10; P = 0.003). Multivariate analysis confirmed KIT exon 11 deletion (P = 0.003) and clinical risk classification (P < 0.001) as independent adverse prognostic factors for RFS. Intermediate-risk patients harboring KIT exon 11 deletions had RFS outcomes similar to high-risk patients. CONCLUSION: The presence of KIT exon 11 deletion mutation in patients with intermediate-risk GIST is associated with an inferior clinical outcome with RFS similar to high-risk patients.

Pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma - a rare vascular neoplasm with deceptive morphology and distinctive immunophenotype

Pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma is a rare, low grade vascular(endothelial) neoplasm typically presenting as multicentric, superficial to deep nodules in extremitieswith a slight tendency of affecting young adult males. We report a case of pseudomyogenichemangioendothelioma in a 15-year-old boy presenting initially with a 1 cm right thigh painlesscutaneous lump. The lump was excised with the clinical impression of a sebaceous cyst. On microscopy,a poorly circumscribed, mild to moderately atypical spindle cell lesion in fascicular and storiformpatterns with strikingly myoid-like eosinophilic cytoplasm was identified. The spindle cells werehighlighted by pancytokeratin AE1/AE3, CD31, and ERG with retained INI-1, while being negativefor MNF116, S100, CD34, EMA, desmin, SMA, caldesmon, myogenin, MyoD1, HHV-8 and CD163.Following the first diagnostic report, a positron emission tomography–computed tomography(PET-CT) scan revealed another 4 cm ill-defined nodule accompanied by a smaller adjacent 0.7cm ipsilateral satellite nodule within the right psoas muscle that displayed similar morphologyand immunophenotype as the cutaneous lump, supporting the multicentric feature of this uniqueentity. It is an uncommon yet increasingly recognised neoplasm of endothelial origin possessing amisleading myoid morphology and distinctive immunophenotype worth notifying.

Successful treatment of solitary intraosseous haemangioma of the femoral neck

Intraosseous haemangiomas (IOHs) are benign vascular bone tumours that account for 1% of all primary bone tumours. They are most frequently seen in the vertebrae and skull, and are rarely found in long bones. Herein, we present an uncommon case of a 25-year-old woman with a solitary IOH that occupied the left femoral neck. We describe the clinical, radiological and histological details of the case, as well as the three-year outcome of the surgical treatment, which successfully preserved the femoral head. We also conducted a review of the literature on this uncommon entity.

Laparoscopic grasper for intramedullary biopsy: a technique to improve tissue sampling

Fluorodeoxyglucose (FDG) hepatic superscan refers to the diffuse intense uptake of 18F-FDG in the liver on positron emission tomography (PET), with reduced physiological activity in the brain and heart. The common causes include lymphoma and metastasis. In this case report, we describe the imaging features of tuberculosis as a rare cause of FDG hepatic superscan. PET imaging may be the only clue to a diagnosis of hepatic tuberculosis, as other imaging modalities may demonstrate only nonspecific hepatomegaly. It is important to consider this entity in the differential diagnosis of patients presenting with FDG hepatic superscan and proceed with liver biopsy for a definitive diagnosis.

Positive ProbeTec tests in fresh specimens from malignant musculoskeletal tumors: a case series.

OBJECTIVE: To report a case series of patients with high-grade musculoskeletal sarcomas whose biopsies of fresh specimens yielded positive Becton Dickinson ProbeTec tests, in addition to confirming diagnoses of high-grade sarcomas. METHODS: Fresh biopsies of high-grade musculoskeletal sarcomas were subjected to ProbeTec tests. RESULTS: The biopsies of three Chinese patients aged 65, 49 and 78 years with high-grade musculoskeletal sarcomas had positive Becton Dickinson ProbeTec tests. These patients' overall clinical pictures were not consistent with active tuberculous infections, which suggested that the ProbeTec test results were false-positives. The reason for this is not known but it is postulated that there is homology between the primers used for the ProbeTec test and the molecular properties of high-grade sarcomas. CONCLUSION: With the increasing use of the ProbeTec test in clinical practice, fellow surgeons and pathologists are encouraged to be aware of this phenomenon.

Giant labial fi broepithelial stromal polyp

We report an18-year-old girl with a four-year history of a slow-growing labial mass with a sudden increase in size in the last year. Examination revealed a large fl eshy 20 cm perineal mass centering on the left labia majora and attached to it by a 1cm pedicle. It was associated with pain, ulceration and discharge. The lesion was excised via diathermy at the base of the stalk. The excised specimen weighed 1.112kg and measured 20.5 x 17 x 5cm. The lesion showed a solid, soft whitish, cut surface. Histology revealed a hypocellular tumour with focally oedematous fi brous stroma in which were scattered large and small blood vessels, mast cells and other chronic infl ammatory cells. True myxoid matrix was not observed. The stromal cells had a spindle to stellate morphology. There was no signifi cant cytological atypia, mitotic activity or necrosis. The tumour cells were negative for SMA, desmin, CD34, S100 protein, EMA and PR. The diagnosis was clinically and histologically challenging because various vulvovaginal soft tissue tumours often have overlapping clinicopathological features. However, based on strict histological criteria and the absence of worrisome cytological features, a diagnosis of fi broepithelial stromal polyp was rendered despite the unusual size. A review of the literature shows that whilst vulvovaginal fi broepithelial stromal polyps are well described, giant variants are rare. Awareness of the extraordinary size that can be attained by such polyps can fascilitate swift clinical and histological diagnosis.

Outcome after curative resection of large (>or=10 cm) gastric gastrointestinal stromal tumors: how frequent is adjacent organ involvement and is concomitant distal pancreatectomy necessary?

INTRODUCTION: Complete tumor resection with clear margins including adjacent organs is the treatment of choice for gastrointestinal stromal tumors (GISTs). However, true tumor invasion of adjacent organs has been reported to be rare. Concomitant distal pancreatectomy (DP) for suspected tumor infiltration is not infrequently performed during resection of large gastric GISTs. This study aims to determine the true frequency of adjacent organ involvement by large gastric GISTs with particular attention to the pancreas and compares the outcome after curative resection with and without a concomitant DP in order to determine if DP is truly necessary. METHODS: A retrospective review of 37 patients who underwent curative resection of large (>or=10 cm) gastric GISTs was conducted. RESULTS: Wedge resections were performed in 22, partial gastectomies in nine, and total gastrectomies in six patients. The median operative time was 180 min (range, 60-330 min), and the patients had a median postoperative stay of 8 days (range, 4-29 days). Overall, there were eight (22%) morbidities including two (5%) mortalities. Nineteen (51%) had concomitant adjacent organ resection, and these included 15 (41%) DPs with splenectomies. Direct organ invasion was demonstrated in 5/19 patients (26%) and 7/30 organs (23%) resected. Only 1/15 (6.7%) DP specimens demonstrated tumor infiltration. Comparison between the patients with and without a concomitant DP demonstrated that performance of a DP was associated with a longer operation time [225 min (range, 105-305 min) vs 158 min (60-330 min), P=.002)], increased postoperative stay [9 days (range, 7-29 days) vs 7.5 days (4-19 days), P=.042], and increased postoperative morbidity [6 (40%) vs 2 (9%), P=.025]. The DP cohort also had a statistically significant poorer 5-year recurrence free survival (22% vs 60%, P=.017). CONCLUSION: Although adjacent organ involvement is not uncommon with large gastric GISTs, concomitant DP is usually unnecessary as direct pancreatic invasion is rare. Furthermore, concomitant DP with splenectomy is associated with an increase in postoperative morbidity.

A single-institution experience with eight CD117-positive primary extragastrointestinal stromal tumors: critical appraisal and a comparison with their gastrointestinal counterparts.

INTRODUCTION: Gastrointestinal stromal tumors (GISTs) arising from outside the gut wall also termed extragastrointestinal stromal tumors (EGISTs) are reported to be rare. Presently, their pathogenesis remains controversial, and recently, it has been proposed that EGISTs may be the result of extensive extramural growth of GISTs which lose contact with the gut wall. This study presents a single-institution experience with eight EGISTs and compares their clinicopathological features with mural GISTs in order to determine further insight to their possible origin. METHODS: Between 1997 and 2008, 156 patients with pathologically proven CD117-positive primary GISTs were retrospectively reviewed. Eight tumors were identified as EGISTs, 104 were gastric GISTs, and 44 were small-bowel GISTs. Mural GISTs were classified as extramural or intra/transmural according to their gross pattern of growth. RESULTS: There were five male and three female patients with a median age of 58 years (range, 42-81 years). All patients were symptomatic, and the tumors were located in the greater omentum (n = 2), lesser sac (n = 2), lesser omentum, retroperitoneum, small-bowel mesentery, and pancreas. The median tumor size was 140 mm (range, 55 to 220 mm). Seven of eight EGISTs were found to be in close association to the adjacent gut wall. Pathological examination demonstrated that two tumors demonstrated focal involvement of the muscularis propria of the adjacent gut wall. Four tumors demonstrated tumor abutting or adherent to the serosa but no muscle involvement and one tumor was separated from the serosa. Comparison between the clinicopathological features of EGISTs with extramural GISTs and intra/transmural GISTs demonstrated that EGISTs were significantly larger [140 range (55-220) mm vs 80 (5-260) mm vs 50 (15-190) mm, P = 0.049, P < 0.001 respectively]. CONCLUSION: The occurrence of true EGISTs is rare. Most cases demonstrate some form of communication or contact with the gut wall, and EGISTs are significantly larger than extramural or intra/transmural GIST. These observations suggest that most, if not all, cases of EGISTs are likely to represent mural GISTs with extensive extramural growth with eventual loss of contact with the muscle layer of the gut.

Which is the optimal risk stratification system for surgically treated localized primary GIST? Comparison of three contemporary prognostic criteria in 171 tumors and a proposal for a modified Armed Forces Institute of Pathology risk criteria.

BACKGROUND: This study aims to validate and compare the performance of the National Institute of Health (NIH) criteria, Huang modified NIH criteria, and Armed Forces Institute of Pathology (AFIP) risk criteria for gastrointestinal stromal tumors (GISTs) in a large series of localized primary GISTs surgically treated at a single institution to determine the ideal risk stratification system for GIST. METHODS: The clinicopathological features of 171 consecutive patients who underwent surgical resection for GISTs were retrospectively reviewed. Statistical analyses were performed to compare the prognostic value of the three risk criteria by analyzing the discriminatory ability linear trend, homogeneity, monotonicity of gradients, and Akaike information criteria. RESULTS: The median actuarial recurrence-free survival (RFS) for all 171 patients was 70%. On multivariate analyses, size >10 cm, mitotic count >5/50 high-power field, tumor necrosis, and serosal involvement were independent prognostic factors of RFS. All three risk criteria demonstrated a statistically significant difference in the recurrence rate, median actuarial RFS, actuarial 5-year RFS, and tumor-specific death across the different stages. Comparison of the various risk-stratification systems demonstrated that our proposed modified AFIP criteria had the best independent predictive value of RFS when compared with the other systems. CONCLUSION: The NIH, modified NIH, and AFIP criteria are useful in the prognostication of GIST, and the AFIP risk criteria provided the best prognostication among the three systems for primary localized GIST. However, remarkable prognostic heterogeneity exists in the AFIP high-risk category, and with our proposed modification, this system provides the most accurate prognostic information.

Outcome after surgical treatment of suspected gastrointestinal stromal tumors involving the duodenum: is limited resection appropriate?

INTRODUCTION: Present surgical opinion is divided regarding the optimal method for the treatment of duodenal gastrointestinal stromal tumor (GIST) with some supporting the selective use of limited resection (LR) versus others who prefer pancreaticoduodenectomy (PD). METHODS: A retrospective review of 22 patients who underwent surgery for suspected GIST involving the duodenum. RESULTS: There were 15 GISTs, 1 leiomyosarcoma and 6 other non-GIST benign submucosal tumors. Seven patients underwent LR and seven underwent PD for GIST. The median follow-up was 42 (range, 2-174) months. Patients who underwent LR versus PD had similar mean disease-specific survival [144 (95% CI, 92-196) vs. 130 (95% CI, 82-127) months, P = 0.808] and recurrence rates (14% vs. 29%, P = 0.515). All recurrences occurred at distant sites. Comparison between LR versus PD demonstrated that LR was associated with a significantly shorter operation time [125 (range, 50-305) vs. 350 (range, 210-465) min., P = 0.001] but similar morbidity rate (23% vs. 43%, P = 0.357). Comparison between GIST and other benign tumors demonstrated that size was the only statistically significant distinguishing factor [8.5 (range, 2.5-18.0) vs. 2.5 (range, 1.5-8.0) cm, P = 0.014]. CONCLUSION: Benign non-GIST tumors may be distinguished from duodenal GIST as they are smaller in size. LR is a viable treatment option for suspected GIST involving the duodenum.

Intraabdominal schwannomas: a single institution experience.

INTRODUCTION: Intraabdominal schwannomas are rare, benign tumors. This study presents a single institution experience with 12 such tumors. METHODS: Between 1991 to 2006, 12 patients with a pathologically proven intraabdominal schwannoma were identified from a series of 216 mesenchymal tumors and were reviewed retrospectively. RESULTS: There were nine females and three male patients with a median age of 58 years (range 35-88 years). Eleven patients were symptomatic, and the tumors were located in the stomach (n = 8), jejunum, colon, rectum, and lesser sac. Multiple preoperative investigations including endoscopies with biopsies and computed tomography (CT) scans were performed, but none yielded a correct definitive preoperative diagnosis. The median tumor size was 52 mm (range 18-95 mm). Pathological examination demonstrated the 11 gastrointestinal tract (GIT) schwannomas to be solid homogenous tumors, which were highly cellular and were composed of spindle cells with positive staining for S100 protein. The pathological appearance of the lesser sac schwannoma was distinct as it demonstrated cystic degeneration with hemorrhage and Antoni A and B areas on microscopy typical of soft tissue schwannomas. All 12 patients were disease-free at a median follow-up of 22 months (range 1-120 months). CONCLUSION: Intraabdominal schwannomas are rare tumors, which are most frequently located within the GIT. GIT schwannomas are difficult if not impossible to diagnose preoperatively as endoscopic and radiologic findings are nonspecific. The treatment of choice is complete surgical excision because of diagnostic uncertainty, and the long-term outcome is excellent as these lesions are uniformly benign.

Epstein-Barr virus-associated smooth muscle tumors are distinctive mesenchymal tumors reflecting multiple infection events: a clinicopathologic and molecular analysis of 29 tumors from 19 patients.

Epstein-Barr virus-associated smooth muscle tumors (EBV-SMT) are rare lesions that occur in immunocompromised patients. Because they have not been fully characterized pathologically or at the molecular level, we have studied 29 tumors from 19 patients, the largest series to date. Cases coded as EBV-SMT were identified in 19 patients from consultation files and from the renal transplant database at Singapore General Hospital. EBV-SMT occurred in adults (mean age 39 years; range, 21-57 years) and predominantly affected males (12 male, 7 female). Causes of immunocompromise were renal transplantation (10), AIDS (8), and steroid therapy (1). Tumors were located in soft tissue (5), lung (5), liver (4), and miscellaneous sites (15). In 13 patients (68%), the tumors were multiple. Infection with EBV was confirmed in all cases by in situ hybridization for EBV early RNAs (EBER). EBV-SMT were typically well-differentiated smooth muscle tumors with little atypia and usually a low level of mitotic activity. Unlike classic leiomyosarcomas, they lacked significant pleomorphism but frequently displayed primitive round cell areas and prominent intratumoral T lymphocytes. No consistent relationship between histologic features and clinical outcome was noted. All expressed actin (29 of 29) and less frequently desmin (14 of 26). Multiple tumors in a given patient were clonally distinct as assessed by the long terminal repeat region of the virus, supporting the view that multifocal tumors arise from multiple infection events rather than from metastasis. Strain typing by analysis of the EBNA-3C gene confirmed the presence of EBV type 2. Two of four tumors assessed were positive for a 30-bp deletion in the LMP1 gene. EBV copy number per cell ranged greatly between patients and between tumors from the same patient. Follow-up information was available in 18 of 19 patients (mean, 25 months; range, 1-105 months). Fifteen patients were alive: 11 with disease and 4 without. Three patients died, 1 due to disease. We conclude that EBV-SMT are histologically distinct from classic soft tissue smooth muscle tumors, are not readily evaluated by means of conventional histologic criteria, and in the case of multifocal tumors are the result of multiple infection events rather than metastasis. EBV-2 can transform smooth muscle cells, independent of the presence of the LMP1 deletion associated with greater virulence.