Childhood Soft Tissue Research Articles

An Unusual Cause of Upper Gastrointestinal Bleeding

36-year-old man was admitted after a single Aepisode of hematemesis and 2-day history of black tarry stools, dizziness, and sweats. He was afebrile and denied abdominal pain. Laboratory results were significant only for mild anemia (hemoglobin, 12.3 gm/dL). Coagulation laboratory results were normal. The patient underwent esophagogastroduodenoscopy where a large, broad-based mass with mucosal ulceration was identified in the gastric body (Figure A, B). Subsequent endoscopic ultrasound confirmed a 5.5-cm hyperechoic, submucosal mass (Figure C, arrow). Endoscopic biopsies and ultrasound-guided fine-needle aspiration were inconclusive, consisting solely of bland spindle cells and ulcer bed. The patient opted for removal of the mass through laparoscopic partial gastrectomy. The surgical pathology diagnosis of the resection specimen was gastric calcifying fibrous tumor (Figure D, H&E). Immunohistochemical staining, specifically S-100, CD34, DOG-1, C-Kit, desmin, and ALK, were all negative. Calcifying fibrous tumor (CFT) is a rare, benign mesenchymal tumor. It was originally described by Rosenthal and Abdul-Karim in 1988 as childhood fibrous tumor with psammoma bodies because the tumor is composed of dense, eosinophilic, hyalinized fibrous tissue admixed with bland fibroblastic spindle cells, scattered psammomatous and/or dystrophic calcifications, and a variable mononuclear lymphocytic infiltrate. CFT was originally described in soft tissues of children and young adults but is now known to have a wide anatomic distribution. It is rare in the gastrointestinal tract, with only 13 gastric and 3 intestinal cases documented to date. Within the gastric cases including our own, there were 8 men and 6 women with a mean age of 52 years and mean tumor size of 2.1 cm. On ultrasound, the lesion tends to be isoechoic, with hyperechoic foci and acoustic shadowing corresponding to the calcifications. Although this is not entirely clear, CFTs are thought to be a reactive process caused by abnormal tissue repair. However, because local recurrences of CFT are documented, this lesion is best classified as a CFT rather than its former designation of a pseudotumor. Recurrence has not been documented in the largest gastric case series to date. CFT has morphologic overlap with other spindle cell tumors, namely gastrointestinal stromal tumor. Both can arise in the posterior stomach wall with varying involvement of the muscularis propria. However, their immunohistochemical profiles are distinctly different. CFT does not express C-Kit, DOG-1, or CD34. Desmoids, inflammatory myofibroblastic tumors, and gastric schwannomas are also diagnostic considerations, but again, immunohistochemistry can be used to exclude these diagnoses.

Fine-Needle Aspiration Cytology of Ewing's Sarcoma of Thoracic Spine with Extension into the Intradural Space.

Ewing's sarcoma/peripheral primitive neuroectodermal tumor is a small, round, and blue cell malignancy that occurs most often in bone and soft tissues of children and young adults. The intraspinal manifestation of the disease is rare, and when present, this is often misdiagnosed with other varieties of primary spinal tumors. Fine-needle aspiration cytology (FNAC) plays important role in the early diagnosis of these cases. We report such a case of Ewing's sarcoma of thoracic spine with extension into the intradural space, which was initially suspected to be a case of metastatic lesion in an 18-year-old boy.

Targeting Wild-Type and Mutationally Activated FGFR4 in Rhabdomyosarcoma with the Inhibitor Ponatinib (AP24534)

Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. Despite advances in modern therapy, patients with relapsed or metastatic disease have a very poor clinical prognosis. Fibroblast Growth Factor Receptor 4 (FGFR4) is a cell surface tyrosine kinase receptor that is involved in normal myogenesis and muscle regeneration, but not commonly expressed in differentiated muscle tissues. Amplification and mutational activation of FGFR4 has been reported in RMS and promotes tumor progression. Therefore, FGFR4 is a tractable therapeutic target for patients with RMS. In this study, we used a chimeric Ba/F3 TEL-FGFR4 construct to test five tyrosine kinase inhibitors reported to specifically inhibit FGFRs in the nanomolar range. We found ponatinib (AP24534) to be the most potent FGFR4 inhibitor with an IC50 in the nanomolar range. Ponatinib inhibited the growth of RMS cells expressing wild-type or mutated FGFR4 through increased apoptosis. Phosphorylation of wild-type and mutated FGFR4 as well as its downstream target STAT3 was also suppressed by ponatinib. Finally, ponatinib treatment inhibited tumor growth in a RMS mouse model expressing mutated FGFR4. Therefore, our data suggests that ponatinib is a potentially effective therapeutic agent for RMS tumors that are driven by a dysregulated FGFR4 signaling pathway.

Comparison of latino and non-Latino patients with Ewing sarcoma

Ewing sarcoma (ES) is a malignancy of bone and soft tissue in children and adults. Previous registry-based studies indicate that Latino patients with ES have inferior outcomes compared to non-Latino patients, though an etiology for this difference could not be identified. To explore possible differences that might underlie this disparity, we conducted a retrospective study to compare clinical characteristics, tumor features, healthcare access, and treatment outcomes between Latino and non-Latino patients with ES. Primary data for 218 ES patients treated at two academic medical centers between 1980 and 2010 were collected. Categorical data were compared using Fisher exact tests; Wilcoxon rank-sum tests were used for continuous variables. Survival was estimated using Kaplan-Meier analysis and compared using log-rank testing. Latino patients were diagnosed at a younger age (P = 0.014). All other clinical and histological data were similar between groups, including radiologic and histologic response to neoadjuvant chemotherapy. Latino patients had lower socioeconomic status (P = 0.001), were less likely to have insurance (P = 0.001), and were more likely to present to the emergency room at onset of symptoms (P = 0.031) rather than to primary care physicians. Five-year event free survival (EFS) and overall survival (OS) were similar between Latino and non-Latino patients (EFS: 60.5% vs. 50.9% P = 0.37; OS: 77.6% vs. 68.6% P = 0.54). Latino patients with ES present at a younger age, and have evidence of impaired access to healthcare. Response to initial therapy appears similar between Latino and non-Latino patients.

Giant Cell Angioblastoma in an Adult: A Unique Presentation

Giant cell angioblastoma is a very rare, locally destructive vascular tumor of intermediate malignancy without metastatic potential. There are only a few cases reported in the literature exclusively in the soft tissue of children. For the first time, we report on an adult patient with a giant cell angioblastoma in the popliteal fossa. The therapy included tumor resection with favorable clinical, oncological and functional outcome. Due to its locally destructive nature, surgery remains the mainstay of treatment. Histologically, giant cell angioblastoma is comprised of nodular aggregates of histiocytoid cells arranged around bland angiomatous spaces. Because of insufficient available data in regard to the definition of the entity, diagnostic criteria and its biological potential, it is not included in the new World Health Organization classification of tumors of soft tissue and bone. The differential diagnosis includes plexiform fibrohistiocytic tumor, myofibroma and giant cell fibroblastoma.

Serum IL-10 and IL-12 levels reflect the response to chemotherapy but are influenced by G-CSF therapy and sepsis in children with soft tissue sarcomas

Pre-treatment serum IL-10/IL-12 balance has been recently found deregulated in childhood soft tissue sarcomas (STS). Its role in STS monitoring and assessment of response to therapy is unknown. To establish whether serum IL-10 and IL-12 levels and their reciprocal ratios reflect childhood STS course and actual activity and whether G-CSF therapy and central vein catheter (CVC)-related sepsis influence the interleukins levels. ELISA determinations of serum interleukins were performed before treatment, in remission without complications (CR), at relapse and after treatment in 59 STS patients and during G-CSF administration and CVC-related sepsis (in 18) and also in 30 healthy controls. In CR IL-10 declined and IL-12 increased as compared to pretreatment levels; in relapse IL-10 rose and IL-12 decreased significantly as compared to levels in CR. Also rates of IL-10, IL-12, and IL-10/IL-12 ratios recently estimated by us as of prognostic significance reflected well the STS course. During G-CSF therapy and CVC-related sepsis, IL-10 increased and IL-12 decreased significantly from levels in CR without complications. IL-10 levels and rates of IL-10 ≥ 11 pg/ml in sepsis could falsely suggest relapse. However, IL-12 levels, rates of IL-12 ≤ 60 pg/ml and/or simultaneous determination of both interleukins differed significantly from levels at relapse. Serial determinations of serum IL-10 and IL-12 reflected well the course of STS in children and enabled remission and relapse phases to be distinguished. To avoid G-CSF and sepsis influence, IL-12 and IL-10/IL-12 ratio and not IL-10 alone should be analysed.

Abstract 3551: CD44 expression in Ewing sarcoma is associated with reduced chemosensitivity in vitro.

Abstract CD44 is the primary hyaluronate (HA) receptor in a variety of cell types and has been implicated in several processes, such as cell-to-cell and cell-to-extracellular matrix interactions, cell migration and invasion, as well as metastasis and drug resistance. Even though CD44 expression has been studied in various types of cancer, such as prostate and lung cancer, little is known about its role in Ewing sarcoma, the second most common malignancy of bone and soft tissue in children and adolescents. We assessed the expression of CD44 in 25 cases of Ewing sarcoma by immunohistochemistry and found that CD44 is expressed in 40% of them. Furthermore, we noticed that in 4 out of 10 patients CD44 expression increased in one or more subsequent recurrent or metastatic biopsy samples. Therefore, we hypothesized that CD44+ cells in Ewing sarcoma represent cell clones, which are resistant to treatment and lead to tumor relapses. In order to study the role of CD44 in Ewing sarcoma, we cultured tumor cells for 24 to 72 hours in anchorage-independent sphere forming culture conditions, (low attachment plates), which are known to induce CD44 expression and compared them to adherent cells. CD44 mRNA and protein expression was induced in the anchorage-independent group as early as 24h in all 7 Ewing sarcoma cell lines. We then measured mRNA levels of ABCB5 and ABCC1, members of the superfamily of ATP-binding cassette (ABC) transporters related to drug resistance by real time PCR and found them increased. These data were corroborated by our finding of significantly increased efflux of the fluorescent DNA binding dye, Hoechst 33342, in the anchorage-independent group, indicating that the cells that overexpress CD44 are more effective in effluxing the chemotherapeutic drugs, thus becoming more resistant to chemotherapy. Finally, changes in the expression of efflux proteins were associated with increased resistance to doxorubicin-induced apoptotic cell death documented by increased expression of annexin V. In summary, our data indicate that CD44 is involved in drug resistance in Ewing sarcoma and may be clinically useful in making therapeutic decisions. Citation Format: Nikolina Dioufa, Guang Li, Maria Tsokos. CD44 expression in Ewing sarcoma is associated with reduced chemosensitivity in vitro. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3551. doi:10.1158/1538-7445.AM2013-3551

Primary inflammatory myofibroblastic tumor of the stomach in an adult woman: a case report and review of the literature

Inflammatory myofibroblastic tumor has been defined as a histologically distinctive lesion with uncertain behaviour. The term inflammatory myofibroblastic tumor more commonly referred to as “pseudostumor ”, denotes a pseudosarcomatous inflammatory lesion that contains spindle cells, myofibroblasts, plasma cells, lymphocytes and histiocytes. It exhibits a variable biological behavior that ranges from frequently benign lesions to more aggressive variants. Inflammatory myofibroblastic tumor mostly occurs in the soft tissue of children and young adults, and the lungs are the most commonly affected site, but it has been recognized that any anatomic localization can be involved. Inflammatory myofibroblastic tumors in adults are very rare, especially in the stomach. We present a case of a 43-year old woman with primary inflammatory myofibiroblastic tumor in the stomach and a review of the literature.

Fibrous Hamartoma Of Infancy-Case Report.

Fibrous hamartoma of infancy is an extremely rare benign proliferation of soft tissue of unknown histiogenesis, with less than 200 cases reported in medical literature, and commonly presenting as a rapidly growing solitary subcutaneous mass in an infant. More than 90% of the lesions occur during the 1 st year of life and approximately 25% being congenital. The lesion is twice as common in males and the common sites include axillae, chest wall, back, thigh, and the inguinoscrotal region. We report the case of a 9 month old male child, born out of a non- consanguineous marriage and attaining normal developmental milestones, who presented with a rapidly growing right axillary mass of 5 months duration. The tumor was excised with wide surgical margins and the wound approximated with skin flap. The histopathological examination confirmed the diagnosis of Fibrous hamartoma of infancy. We report this case because of its extreme rarity, uncanny appearance; a common mimicker of capricious childhood soft tissue neoplasms. Keywords- Fibrous hamartoma of infancy, Childhood soft tissue neoplasms.

Malignant rhabdoid tumor of the orbit

Malignant rhabdoid tumor is a rare and malignant tumor of childhood. Generally it originates from the kidney and central nervous system, but occasionally it may arise from the orbit. Differential diagnosis from other childhood soft tissue sarcomas should be done. We report here an 8-week-old female infant with malignant rhabdoid tumor of the orbit who was treated with chemotherapy and surgery. The 8 week-old girl was referred to our hospital with a history of right proptosis first noted at birth. Physical and laboratory evaluation of the patient was normal except for right proptosis. The mass was removed surgically. Histopathologic examination and immunohistochemical findings of the specimen were evaluated as malignant rhabdoid tumor. Chemotherapy was administered. While in clinical remission, she succumbed during a febrile episode. Malignant rhabdoid tumor can rarely originate from the orbit. Malignant rhabdoid tumor should be kept in mind in the differential diagnosis of orbital masses, and surgery, chemotherapy and local radiotherapy should be used as combined therapy due to the poor prognosis.

1509P - Chemotherapy is Effective in Primitive Neuroectodermal Tumor (PNET) / Ewing Sarcoma (EWS) of The Kidney

ABSTRACT Background PNET/EWS is a rare tumor that occurs most commonly in bone and soft tissues of children and young. PNET/EWS arise rarely as a primary renal neoplasm and exhibits highly aggressive biological behavior. Since its first description in 1975, less than 100 cases of EWS/PNET have been published in medical literature. We aim to collect and to analyze clinical and pathological features of this tumor. Patient and methods All cases reports of PNET/EWS published from 1975 to February 2012 were collected. When available, clinical and pathological data were extracted for each case such as previously reported (Iacovelli et al. BJU Int 2012). Survivals were estimated with Kaplan-Meier method and compared with log-rank test with 95% CI. Results A total of 117 cases were found, 55% were male and the median age was 28.0 y (IQR: 20.0 – 42.0). All patients (pts) had clinical symptoms as first presentation of disease such as pain (54%), hematuria (29%) and bulky renal mass (28%); whereas dysuria, fever, weight loss fatigue and abdomen swelling were reported rarely. 66% of pts had stage IV at diagnosis and the main sites of metastases were lung (60%), liver (37%), abdominal lymph-nodes (20%), bone and local relapse ( Conclusions PNET/EWS is a rare aggressive tumor with a well defined genetic profile. It affects principally young people with a poor prognosis for M1 pts; chemotherapy is an effective strategy in M1 and probably also in M0 pts. Disclosure All authors have declared no conflicts of interest.

A Rare Case of Inflammatory Myofibroblastoma of Diaphragm

Inflammatory myofibroblastoma is a distinctive pseudosarcomatous lesion that occurs primarily in the viscera and soft tissue of children and young adults. It is composed of myofibroblastic spindle cells accompanied by an inflammatory infiltrate of plasma cells, lymphocytes, and eosinophils. We report a 41-year-old man who presented with progressive dyspnea and pain in the right hypochondrium for 6months. USG abdomen revealed a well-defined hypoechoic rounded mass in the subdiaphragmatic region. CT thorax and abdomen revealed a large hypodense mass in posterosuperior aspect of the right lobe of liver, right pleural effusion and basal consolidation of the right lung. Right thoracotomy was performed. The tumor mass was arising from the right side of diaphragm. Total surgical excision was done. On histomorphology and immunohistochemical analysis, a diagnosis of inflammatory myofibroblastoma was done. Following excision the patient was completely relieved of dyspnea and pain. There was no recurrence on follow-up for 2years.

NKX2.2 is a Useful Immunohistochemical Marker for Ewing Sarcoma

Ewing sarcoma is a high-grade round cell sarcoma that affects bones and soft tissues in children and young adults. Its diagnosis can be challenging, and the differential diagnoses include a wide variety of small round cell tumors. CD99 and FLI-1 are the currently accepted immunohistochemical markers for Ewing sarcoma, but their accuracy has been controversial. NKX2.2 is a homeodomain-containing transcription factor that plays a critical role in neuroendocrine/glial differentiation. The NKX2.2 gene was recently identified as a target of EWS-FLI-1, the fusion protein specific to Ewing sarcoma, and was shown to be differentially upregulated in Ewing sarcoma on the basis of array-based gene expression analysis. However, the immunohistochemical diagnostic potential of this marker has not been tested. We immunostained representative sections of 30 genetically confirmed Ewing sarcomas and 130 non-Ewing small round cell tumors by using an antibody to NKX2.2. Nuclear staining in at least 5% of the cells was deemed positive. Twenty-eight (93%) of the 30 Ewing sarcomas were positive for NKX2.2. The staining was diffuse (>50%) in all the positive cases and was moderate or strong in intensity for most cases (25 of 28). NKX2.2 was also positive in 14 non-Ewing tumors, including all the olfactory neuroblastomas and a minor subset of small cell carcinomas, synovial sarcomas, mesenchymal chondrosarcomas, and malignant melanomas. All the other non-Ewing tumors tested were negative for this marker. NKX2.2 is a valuable marker for Ewing sarcoma, with a sensitivity of 93% and a specificity of 89%, and aids in the differential diagnosis of small round cell tumors.

Randomized Comparison of Intensified Six-Drug Versus Standard Three-Drug Chemotherapy for High-Risk Nonmetastatic Rhabdomyosarcoma and Other Chemotherapy-Sensitive Childhood Soft Tissue Sarcomas: Long-Term Results From the International Society of Pediatric Oncology MMT95 Study

MMT95 was the fourth of a series of International Society of Pediatric Oncology (SIOP) collaborations for children with high-risk nonmetastatic soft tissue sarcoma (STS). The principal objective was to explore survival advantage for an intensified chemotherapy strategy in a randomized trial. From July 1995 to June 2003, 457 previously untreated patients with incompletely resected embryonal rhabdomyosarcoma (RMS), undifferentiated sarcoma, and soft tissue primitive neuroectodermal tumor at all sites except paratesticular, vagina, and uterus, or with alveolar RMS were randomly assigned to receive either ifosfamide, vincristine, and dactinomycin (IVA) or a six-drug combination (IVA plus carboplatin, epirubicin, and etoposide) both delivered over 27 weeks. Cumulative doses were as follows: ifosfamide 54 g/m(2) (both arms), epirubicin 450 mg/m(2), etoposide 1,350 mg/m(2) (six-drug regimen). Poor responders after three courses of IVA were to be switched to the other arm. Delivery of radiotherapy was determined according to site and/or response to chemotherapy with or without surgery. Overall survival (OS) for all patients was 81% (95% CI, 77% to 84%) at 3 years. No significant difference in outcome in either OS or event-free survival was noted between the two arms (3-year OS: 82% [95% CI, 76% to 86%] for IVA and 80% [95% CI, 74% to 85%] for the six-drug arm). Toxicity was significantly greater (infection, myelosuppression, and mucositis) in the six-drug arm. Overall burden of local therapy was consistent with data from previous SIOP studies and showed no difference between the two chemotherapy regimens. Intensification of chemotherapy for nonmetastatic RMS and other chemotherapy-sensitive STS provides no survival advantage or reduction in the intensity of local therapy and adds toxicity.

Playing Bad Cards Properly: Challenges to Improving Cure Rates in Rhabdomyosarcoma

“Success . . . comes not from having the right cards, but from playing bad ones properly.” —Joshua Dool. At least two thirds of children and adolescents with intermediateand higher-risk nonmetastatic rhabdomyosarcoma can be cured with multidisciplinary therapy. Although a reasonably good outcome, it clearly is not good enough. The total burden of therapy is high, with substantial acute and chronic toxicity. The best established therapy is a three-drug chemotherapy combination using vincristine, dactinomycin, and an alkylator (either cyclophosphamide or ifosfamide) and local control measures that cause substantial morbidity, particularly in our youngest patients. The therapy approach and anticipated outcome have not substantially changed in the last two decades. Oberlin et al report in Journal of Clinical Oncology the results of the MMT95 trial, a well-designed prospective, randomized study comparing intensified six-drug therapy versus standard three-drug chemotherapy in nonmetastatic rhabdomyosarcoma and other chemosensitive childhood soft tissue sarcomas. Intensification of chemotherapy provided no survival advantage, no reduction in the intensity of local therapy, and added toxicity—certainly not the answer for which these investigators had hoped. Why have we been unable to make any recent progress in treating rhabdomyosarcoma? Successful clinical trials must be well designed. Most advances in pediatric oncology have used prospective, randomized comparative study designs. However, good trial design certainly does not guarantee success. The two most recently completed intermediate-risk rhabdomyosarcoma studies conducted by the Intergroup Rhabdomyosarcoma Study (IRS) Group (IRS-IV comparing vincristine, dactinomycin, and cyclophosphamide [VAC]; vincristine, dactinomycin, and ifosfamide; and vincristine, ifosfamide, and etoposide) and the Children’s Oncology Group (COG; D9803 comparing VAC v VAC plus topotecan and cyclophosphamide) were well designed and appropriately powered and evaluated agents with substantial clinical activity, yet they failed to show any improvement in the experimental arms. The MMT95 (Malignant Mesenchymal Tumor 1995) study prospectively randomly assigned patients to receive threeor six-drug therapy, with a switch to the six-drug combination in patients who had disease progression, less than 50% imaging response, or poor histologic response. This design decreased the number of patients who received either only threeor only six-drug therapy. In addition, a relatively high number of eligible patients were not randomly assigned (149 of 606; 25%). However, these flaws, while decreasing the statistical power of this study, are relatively minor and do not seem to have affected the final negative results. Selection of the right patient population is a key component of sound clinical trial design. The MMT95 study enrolled higher-risk patients with rhabdomyosarcoma with both embryonal and alveolar histologies. These two histologies are biologically distinct, yet all cooperative group trials in higher-risk rhabdomyosarcoma have included both histologies, with few data to suggest substantial differences in treatment response for the different histologic entities. In addition, the MMT95 study enrolled 72 patients with chemotherapy-sensitive nonrhabdomyosarcoma soft tissue sarcomas. Soft tissue primitive neuroectodermal tumors (27 patients enrolled onto MMT95) share morphologic, immunohistochemical, and genetic features with Ewing tumors arising in bone, are classified by WHO inclusively as Ewing sarcoma/primitive neuroectodermal tumor, and are currently treated in studies of the Ewing family of tumors. COG trials previously enrolled patients with undifferentiated sarcomas together with rhabdomyosarcomas, but these patients were recently treated on a study for other nonrhabdomyosarcoma soft tissue sarcomas (COG ARST0332: Risk-based treatment for nonrhabdomyosarcoma soft tissue sarcomas in patients under30yearsofage).Ratesofmetastasis inMMT95werehigher inthese patient subsets (P .03); the number of patients enrolled with these histologies was insufficient to provide insights into the impact of more intensive therapy. Cure rates have improved in some childhood cancers with the optimization of chemotherapy schedules and doses. Decades of empiric adjustments using a modest number of active chemotherapy

Inflammatory myofibroblastic tumor of the tongue: Report of an unusual case in a teenage patient

Inflammatory myofibroblastic tumor is a rare and distinctive lesion composed of myofibroblastic cells accompanied by an inflammatory infiltration of plasma cells, lymphocytes, and eosinophils that mainly affects viscera and soft tissues of children and young adults. It clinically manifests as a mass with rapid development that may occur at almost any site of the body, but predominantly in the lungs or the upper respiratory tract. It rarely arises in the oral cavity with approximately 15 cases reported in that location. We describe a case of an inflammatory myofibroblastic tumor of the tongue, confirmed by both histopathologic and immunohistochemical analysis, occurring in a 14-year-old boy that spontaneously regressed after the surgical procedures for its diagnosis. Because of some aggressive clinical, histological, and radiological features, this lesion may be confused with a malignant tumor. Therefore, its correct recognition is important to avoid unnecessary extensive and radical therapeutic approaches.

Vascular and Perivascular Lesions of Skin and Soft Tissues in Children and Adolescents

Vascular anomalies in children and adolescents are the most common soft tissue lesions and include reactive, malformative, and neoplastic tumefactions, with a full spectrum of benign, intermediate, and malignant neoplasms. These lesions are diagnostically challenging because of morphologic complexity and recent changes in classification systems, some of which are based on clinical features and others on pathologic findings. In recent decades, there have been significant advances in clinical diagnosis, development of new therapies, and a better understanding of the genetic aspects of vascular biology and syndromes that include unusual vascular proliferations. Most vascular lesions in children and adolescents are benign, although the intermediate locally aggressive and intermediate rarely metastasizing neoplasms are important to distinguish from benign and malignant mimics. Morphologic recognition of a vasoproliferative lesion is straightforward in most instances, and conventional morphology remains the cornerstone for a specific diagnosis. However, pathologic examination is enhanced by adjunctive techniques, especially immunohistochemistry to characterize the type of vessels involved. Multifocality may cause some uncertainty regarding the assignment of "benign" or "malignant." However, increased interest in vascular anomalies, clinical expertise, and imaging technology have contributed greatly to our understanding of these disorders to the extent that in most vascular malformations and in many tumors, a diagnosis is made clinically and biopsy is not required for diagnosis. The importance of close collaboration between the clinical team and the pathologist cannot be overemphasized. For some lesions, a diagnosis is not possible from evaluation of histopathology alone, and in a subset of these, a specific diagnosis may not be possible even after all assembled data have been reviewed. In such instances, a consensus diagnosis in conjunction with clinical colleagues guides therapy. The purpose of this review is to delineate the clinicopathologic features of vascular lesions in children and adolescents with an emphasis on their unique aspects, use of diagnostic adjuncts, and differential diagnosis.

Ewing sarcoma/peripheral primitive neuroectodermal tumor and related tumors.

Ewing sarcoma/peripheral primitive neuroectodermal tumor (EWS/pPNET) and other tumors with EWS gene rearrangements encompass a malignant and intermediate neoplasm with a broad anatomic distribution and a wide age range but a predilection for soft tissue in children, adolescents, and young adults. The overlapping histologic, immunohistochemical and cytogenetic and molecular genetic features create diagnostic challenges despite significant clinical and prognostic differences. Ewing sarcoma is the 3rd most common sarcoma in children and adolescents, and desmoplastic small round cell tumor is a rare neoplasm that occurs more often in older children, adolescents, and young adults. Pathologic examination is complemented by immunohistochemistry, cytogenetics, and molecular genetics. This article reviews the clinicopathologic features of EWS/pPNET and desmoplastic small round cell tumor in the spectrum of tumors with EWS gene rearrangements. Other tumors with different histopathologic features and an EWS gene rearrangement are discussed elsewhere in this volume.

Hyperbaric oxygen treatment of superficial soft tissue lesions in children with oncologic disease

This study aimed to assess the feasibility and results of hyperbaric oxygen therapy (HOT) as supportive treatment of lesions of superficial soft tissues in children with oncological diseases. This was a retrospective analysis and review of all records of children observed at the Pediatric Hematology-Oncology Department of the University of Padova and treated adjuvantly with HOT. Between 1996 and 2010, 12 patients (5 males and 7 females, median age 7 years, range 0.5–16) underwent HOT. The effectiveness of HOT varied according to the lesion treated. Ten out of 12 patients were cured. Efficacy was most questionable in 2 patients with skin graft and flaps at risk. Compliance to therapy was close to 100%. In just one case, HOT was interrupted for the appearance of local skin metastases close to the site of primary tumor. HOT showed itself to be safe and effective in most patients even those immunocompromised or critically ill.

Expression of therapeutic targets in Ewing sarcoma family tumors

Ewing sarcoma family tumor is an aggressive malignant tumor of bone and soft tissue in children and adolescents. Despite advances in modern therapy, metastasis occurs in 20% to 25% of cases and results in mortality in 80% of patients. Intracellular molecules mammalian target of rapamycin, Akt, vascular endothelial growth factor, nuclear factor κB, and BRAF are important kinases and transcription factors that regulate the proliferation of tumor cells. We studied the expression of these proteins in 72 Ewing sarcoma family tumors. Patients' survival data were available in 55 cases. Formalin-fixed, paraffin-embedded tumor sections were stained with antibodies against phosphorylated mammalian target of rapamycin, Akt, BRAF, vascular endothelial growth factor, and nuclear factor κB proteins. Stained sections were analyzed for percentage and strength of staining, and a composite score (0-200) was subsequently generated. Although most tumors expressed mammalian target of rapamycin, Akt, nuclear factor κB, and vascular endothelial growth factor, only 37%, 86%, 55%, and 12%, respectively, showed high expression (staining score ≥ 100). There was no significant correlation between mammalian target of rapamycin and Akt expression and clinical outcome. High nuclear factor κB expression was significantly associated with tumors in pelvic locations. Decreased vascular endothelial growth factor expression (score <100) was significantly associated with better prognosis (P < .05). BRAF was not expressed in most cases and showed negative or weak staining (score <100) in 97% of cases. Thus, except for BRAF, Ewing sarcoma family tumors may be amenable to treatment that targets the expressed proteins. High Akt expression suggests potential universal response to Akt-targeted therapy. BRAF kinase inhibitors are unlikely to be effective in the treatment of Ewing sarcoma family tumors.