Abha A. Gupta

The role of the initial bone marrow aspirate in the diagnosis of hemophagocytic lymphohistiocytosis.

The identification of hemophagocytosis (HPC) in tissue or bone marrow (BM) represents only one of 5/8 criteria needed for the diagnosis of hemophagocytic lymphohistiocytosis (HLH). Yet, confirmation of HPC in bone marrow aspirates (BMA) is often relied upon to make therapeutic decisions. There is no standardized reporting criteria for the definition of “positive” BMA, and likely differs between institutions. The purpose of this study was to quantify the number of HPC in the initial BMA in patients diagnosed with HLH at our institution.

Clinical outcome of children and adults with localized Ewing sarcoma: impact of chemotherapy dose and timing of local therapy.

As Ewing sarcoma (EWS) can affect children and adults, these patients can be treated at either a pediatric or an adult institution. This study investigated whether differences in therapeutic strategy undertaken in pediatric and adult specialty sarcoma centers correlated with clinical outcome.

The role of hemophagocytosis in bone marrow aspirates in the diagnosis of hemophagocytic lymphohistiocytosis.

HLH represents the most prevalent and clinically significant macrophage-related histiocytic disorder [1]. Although HLH was initially described as a familial disease [2], it is now clear that even patients without identifiable genetic mutations are at risk for HLH secondary to infections, malignancy, and rheumatological conditions [3,4]. The termmacrophage activation syndrome (MAS) has also been used in the literature. The diagnosis is based on a set of criteria, including genetic mutations, clinical features, laboratory abnormalities, and morphological evidence of hemophagocytosis (HPC) [5]. Genetic mutations in perforin [6], Munc 13-4 [7], and syntaxin 11 [4] can confirm the presence of familial disease, even in the older patients presenting with viral infections [8]. Children suspected ofHLH are often acutely ill and have non-specific clinical findings including fever, hyperferritinemia, hepatosplenomegaly and cytopenias. Thus a multi-disciplinary team approach is often required to confirm the diagnosis with involvement from general pediatrics, rheumatology, infectious disease and haematology/ oncology. Despite the exciting new findings related to the etiopathogenesis of this disease, until the aforementioned specialized genetic and immunological tests become available as routine clinical practice, there persists a lack of confirmatory diagnostic tests available to help the clinician in acute situations. It is often a consensus which navigates both diagnostic conclusions to rule in or out HLH and subsequent therapeutic approaches. Treatment can range from steroids and IVIG in mild cases to full protocol therapy including bone marrow transplantation for familial and severe patients, a distinction which can be anxiety-provoking both for families and the medical team. Even in institutions which perform specialized immunological and genetic testing, the results are usually not available in time to aid in immediate treatment-related decisions. The Munc-13 gene is extraordinarily long and it takes weeks to sequence the gene in its entirety. Furthermore, lowNK cell function and perforin analysis by flow cytometry, can be absent in up to 50% of patients with confirmed genetic abnormalities [9]. Thus, in order to have timely diagnosis, most practitioners continue to rely on the morphological presence of HPC in bone marrow (BM) to distinguish patients with simple infections or rheumatological disease from those with active HLH. Although sites most markedly affected include the splenic red pulp, hepatic portal areas, and lymph node sinuses [3,10], BM represents the most accessible place for morphological examination. BM examinations are relatively easy to organize, results are available the same day, and little risk is associated with the procedure compared to other tissue biopsies, especially in patients who are often acutely ill and coagulopathic. So, the multidisciplinary team often await the results of BM examinations in order to decide whether to diagnose the patient with and treat for HLH. Retrospective cohort analyses show that the majority of the patients have HPC at the time of diagnosis of HLH, suggesting that the diagnosis may be delayed until clinicians prove evidence of HPC [11]. HLH was initially identified and defined by the presence of hemophagocytosis, and some still maintain that it remains a morphological diagnosis [12]. However, it is clear that HPC are neither sensitive nor specific for HLH. The epiphenomenon of HPC is seen even following simple blood transfusions and surgery [13]. Furthermore, hemophagocytosis (HPC) is not always present at the time of the first BM examination in patients suspected of having HLH, and serial examinations are advocated [14]. HPC are found only at autopsy in some patients [15], such as in the original cases of HLH described by Farquhar and Claireaux [2]. There may be a different pattern of involvement of BM HPC in familial and secondary forms of HLH. It is possible that the familial cases are detected earlier in their disease course prior to the development of frank HPC. Others have commented that the degree of involvement is proportional to duration of symptoms and age of the patient. The later in life the disease started and the longer it lasted the ‘more apparent’ erythrophagocytic activity [16]. In young patients identified as having familial HLH due to a history of an affected sibling, HPCmay be absent until the onset of overt clinical symptomatology, and even then, may evolve over time requiring repeated marrow examinations [17]. Thus waiting for HPC to appear may unnecessarily delay appropriate therapy [5]. The number ofHPC required to define a positivemarrow inHLH also remains uncertain. The lack of standardized reporting of BM HPC, introduces variability in the interpretation of a positive finding. The attribution of HPC to the diagnosis of HLH may be more straightforward in situations where there is florid HPC [3], however, the finding of few HPC may not be informative. No quantitative data are available; however, it has been suggested that careful examination of at least three smears should reveal at least two HPC per slide to be significant [18]. Most studies lack information on the relative or absolute amount of HPC seen in tissues. Interpretation of the literature describing the prevalence of marrow involvement in HLH is limited by the variable diagnostic criteria used for study inclusion. A summary of these papers are listed in Table I, reporting variable BM involvement in aspirates or biopsies, ranging from 25 to 100% [3,15,16,19–25]. In combining the results of all the series listed in Table I, HPC inBMappearsmore likely to occur in secondary HLH compared to familial patients, with a Spearman correlation coefficient of 0.64, P1⁄4 0.046. Thus, BM are just as likely to be negative or positive for HPC in patients diagnosed with HLH. In summary, limited by the restriction of genetic and immunological testing to specialized centers and the delay in their reporting, BM HPC are often relied upon by clinicians, as early concrete diagnostic evidence to rule in and rule out HLH. HPC do not appear either sensitive nor specific, and there is marked heterogeneity in BM involvement among both familial and secondary forms of HLH. The problems are further confounded by lack of standardization and quantification of the reporting of HPC. Although there may be a

Critical review of controversial issues in the management of advanced pediatric liver tumors

Hepatocellular carcinoma (HCC) and hepatoblastoma (HB) are the most common primary tumors of liver in children. The management of patients with locally advanced, unresectable disease or those with extra‐hepatic distant metastases provides substantial challenges to pediatric oncologists, hepatologists, and surgeons. Herein, we critically debate the two sides of three specific controversies: (1) the role of chemotherapy in the treatment of advanced pediatric HCC; (2) the indications for liver transplantation in children with HCC, specifically, the appropriateness of using adult Milan criteria; and (3) the role of liver trasplantation in children with unresectable HB that present with metastatic disease. Pediatr Blood Cancer 2011;56:1013–1018.

Patterns of Chemotherapy-Induced Toxicities in Younger Children and Adolescents with Rhabdomyosarcoma: A Report from the Children’s Oncology Group Soft Tissue Sarcoma Committee

Patients aged >10 years with rhabdomyosarcoma have an inferior outcome compared with patients ages 1 to 9 years, which may be explained by toxicities (adverse events [AEs]) that result in chemotherapy dose reductions.

Pediatric Undifferentiated Sarcoma of the Soft Tissues: A Clinicopathologic Study

Pediatric undifferentiated soft tissue sarcomas represent a major challenge for pathologists and clinicians. The goal of this study was to identify cases that warranted this diagnosis by current standards of analysis and then determine if there are clinicopathological commonalities that may be useful for diagnosis, management, and prognosis. Eighteen potential patients were identified using the institutional pathology database. Three cases were reclassified as specific sarcomas, and 2 cases had insufficient material for molecular analysis, leaving 13 cases for pathological review and 12 patients for radiological and clinical review. There were 7 males and 6 females. The median age at diagnosis was 11 years (1 month to 16 years). Tumors commonly involved the trunk (7 of 13; 54%) and ranged in size from 1.7 to 14.5 cm (mean, 6.7 cm). Eleven patients received ifosfamide/etoposide chemotherapy and 4 received irradiation. Five-year event-free and overall survival (EFS and OS) rates were 54% and 74%, respectively. The predominant histological pattern was round to plump spindled cells forming sheets (9 of 13; 69%) and severe atypia was associated with decreased survival (P = 0.048). Immunohistochemistry showed positivity for vimentin (92%), CD117 (92%), and vascular endothelial growth factor (69%), and 8% to 23% showed focal positivity for epithelial, neural, or myogenic markers. Tumors were uniformly negative for translocations associated with pediatric sarcomas. The presence of certain common morphological and immunohistochemical features in the absence of specific molecular genetic abnormalities allows for a diagnosis of pediatric undifferentiated soft tissue sarcoma; however, whether this group of neoplasms forms a unique category of tumors or a common precursor pathway for a number of different sarcomas awaits further study.

Malignant pancreatic tumors in children: a single-institution series.

BACKGROUND Pancreatic tumors in children represent a very rare entity. We reviewed the clinical and pathologic features of pediatric patients with pancreatic tumors at a single institution. METHODS We conducted a retrospective review of cases diagnosed at the Hospital for Sick Children between 1986 and 2010. RESULTS Twenty-seven patients were diagnosed during the study period: 18 with solid pseudopapillary neoplasm (SPN), 6 with pancreatic endocrine neoplasia, and 3 with other tumors. Of the 27 children, 3 had associated syndromes, in specific tuberous sclerosis, von Hippel-Lindau, and polycystic ovarian syndrome. The most common symptoms were pain and vomiting in SPN and hypoglycemia and seizures in insulinomas. Magnetic resonance imaging and computed tomographic scan were equally accurate in determining size and site of origin of the tumor, and both were better than ultrasound. All patients underwent surgery (distal pancreatectomy in 14 cases, Whipple procedure in 8, other procedures in 5), which represented the only treatment for all but 3 cases. Seventeen patients (94%) with SPN are alive (median follow-up, 32 months), 3 of whom had positive margins. Two patients died: 1 male with SPN with malignant transformation and 1 with fibrosarcoma. CONCLUSIONS We describe the largest single-institution study of pediatric pancreatic tumors. Females with SPN have an excellent outcome, even in presence of positive margins, suggesting that limited surgical resection may be appropriate for these patients.

Experience with hemophagocytic lymphohistiocytosis/macrophage activation syndrome at a single institution.

Background Hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) is a serious and potentially life threatening histiocytic disorder in children and adults. The most commonly used protocol-based therapy includes corticosteroids, cyclosporine-A, and etoposide. However, patients are often started on corticosteroid alone with or without the addition of intravenous γ-globulin. The role of the various therapies in HLH/MAS remains undefined. Objective To identify patient-related factors that led to the use of full protocol therapy (HLH 1994/2004) and to determine treatment-related factors that were associated with adverse outcome including relapse and death. Design/Methods Patients who were diagnosed with HLH/MAS between January 1998 and December 2005 were included in this study. Results Thirty-eight patients had a median age of 9.1 years at diagnosis. Underlying diagnoses were: viral/other 42%; rheumatologic 37%; and malignancy 21%. Initial treatment included corticosteroids 29%; intravenous immunoglobulin (IVIG) 18%; steroids+IVIG 8%; cyclosporine 5%; etoposide 5%; HLH protocol 32%. Etoposide was eventually used in 21% (3/14) of rheumatology and 75% (18/25) viral/other patients. In all, 5/14 (36%) rheumatology and 12/16 (75%) viral/other patients required intensive care unit admission, and 1/14 (7.1%) rheumatology, and 6/16 (38%) viral/other patients died. Three children received a bone marrow transplant. Eleven of 38 (29%) patients died, despite 8 having received etoposide therapy. Three deaths were secondary to underlying malignancy and one from transplant-related complication for malignancy. Conclusions Patients with HLH are at high risk for death early in their disease course. However, corticosteroids and/or IVIG may be sufficient as first-line therapy for patients with underlying rheumatologic disease who present with HLH/MAS. Further prospective studies are required to more precisely define early risk factors for poor outcomes in this often fatal disease.

What is new in the biology and treatment of pediatric rhabdomyosarcoma

Purpose of review The purpose of this review is to highlight some of the advances in the way we think about rhabdomyosarcoma (RMS). Recent outcome and biological analyses have shifted the risk stratification and treatment paradigms for pediatric RMS. Recent findings The presence or absence of the FOXO1 translocation is one of the most important prognostic factors in RMS. Future clinical studies will incorporate FOXO1 translocation status within risk stratification criteria. Molecular analyses have identified RAS/NF1, hedgehog, IL-4R, and ALK pathway abnormalities as potential therapeutic targets in RMS. Reductions in systemic therapy are possible, although radiation therapy remains essential to prevent local failures in most patients. Summary Although survival for RMS has not improved in recent years, refinement in risk stratification, further understanding of the biological drivers of the disease, and modifications in treatment intensity have set the stage for the next generation of studies in RMS.

Clinical Features, Treatment, and Outcome in 102 Adult and Pediatric Patients with Localized High-Grade Synovial Sarcoma

Background. There remains controversy on the routine use of chemotherapy in localized SS. Methods. The records of 87 adult (AP) and 15 pediatric (PP) patients with localized SS diagnosed between 1986 and 2007 at 2 centres in Toronto were reviewed. Results. Median age for AP and PP was 37.6 (range 15–76) and 14 (range 0.4–18) years, respectively. 65 (64%) patients had large tumours (>5 cm). All patients underwent en bloc surgical resection resulting in 94 (92.2%) negative and 8 (7.8%) microscopically positive surgical margins. 72 (82.8%) AP and 8 (53%) PP received radiotherapy. Chemotherapy was administered to 12 (13.8%) AP and 13 (87%) PP. 10 AP and 5 PP were evaluable for response to neoadjuvant chemotherapy, with response rate of 10% and 40%, respectively. 5-year EFS and OS was 69.3 ± 4.8% and 80.3 ± 4.3%, respectively, and was similar for AP and PP, In patients with tumors >5 cm, in whom chemotherapy might be considered most appropriate, relapse occurred in 9/19 (47%) with chemotherapy, compared to 17/46 (37%) In those without. Conclusions. Patients with localized SS have a good chance of cure with surgery and RT. Evidence for a well-defined role of chemotherapy to improve survival In localized SS remains elusive.