Current World Health Organization Classification Research Articles

Comparison of Clinical Outcomes Between Pediatric Aplastic Anemia and Refractory Cytopenia of Childhood

In the diagnosis of childhood bone marrow failures (BMFs), differentiating aplastic anemia (AA) from hypoplastic myelodysplastic syndrome (MDS) is challenging. The 2008 World Health Organization (WHO) classification has proposed a provisional entity, "refractory cytopenia of childhood (RCC)". The spectrum of patients with RCC is wide, ranging from patients with severe hypocellular bone marrow (BM) and mild dysplasia to those with normocellular BM and distinct dysplasia meeting the criteria for refractory cytopenia with multilineage dysplasia (RCMD) defined for adults with MDS. Currently, it is recommended that children who meet the criteria for RCMD should be classified as RCC in the WHO classification until the number of lineages involved has been fully evaluated with regard to their relative importance as prognostic factors. Until now, few studies have addressed the question whether the current WHO classification reflects clinical outcomes of childhood BMFs.To determine the clinical differences among AA, RCC, and RCMD, we compared clinical outcomes for patients with AA, RCC, and RCMD in Japan. From February 2009 to December 2013, 252 patients were registered to the central morphology review system of the Japanese Society of Hematology and Oncology and were diagnosed with BMFs. Peripheral blood (PB) and BM smears were reviewed by two pediatric hematologists, and BM trephine biopsies were reviewed by a hematopathologist. RCC is defined as persistent cytopenia with <2% and <5% blasts in PB and BM, respectively. BM aspirate smears show dysplastic changes in >2 cell lineages or >10% within one cell lineage. On the other hand, the criteria of RCMD is defined as persistent cytopenia with <1% and <5% blasts in PB and BM, respectively. BM smears show >10% dysplastic changes in >2 cell lineages. Patients with inherited BMFs were excluded by family history and physical examination. Further, Fanconi anemia was excluded by chromosome fragility test and Dyskeratosis congenita was screened by measuring the telomere length of the peripheral lymphocytes by flowcytometry.Out of 252 patients, 63 were classified as AA, 131 as RCC, and 58 as RCMD. Median ages in AA, RCC, and RCMD groups were 10, 8, and 7 years, respectively (p=0.07). The median of leukocyte, neutrophil, reticulocyte, and platelet count, and mean corpuscular volume were significantly lower in AA than in RCC and RCMD groups (p<0.01). Chromosomal abnormalities were detected in 1 patient with AA (trisomy 8), 3 patients with RCC (trisomy 8, n=2; other, n=1), and 9 patients with RCMD (trisomy 8, n=5; monosomy 7, n=1; other, n=3) at the time of diagnosis (p<0.01). Out of 252 patients, 82 (AA, n=3; RCC, n=46; RCMD, n=33) were observed without any treatments (watch and wait, WW). 5-year overall survival (OS)/failure free survival (FFS) rates in WW group were 67%/67% in AA, 98%/54% in RCC, and 100%/69% in RCMD patients (p<0.01/p=0.97). Immunosuppressive therapy (IST) with rabbit antithymocyte globulin and cyclosporine was performed in 110 (AA, n=39; RCC, n=57; RCMD, n=14) patients. Six months after the IST, the response rates to the IST were not significantly different among AA (40%), RCC (63%), and RCMD (64%) (p=0.08). The development of additional chromosomal aberrations was found in 2 patients with RCC, and 1 with RCMD. The 5-year OS/FFS rates in IST group were 89%/36% in AA, 94%/38% in RCC, and 93%/23% in RCMD patients (p=0.64/p=0.86). Stem cell transplantation (SCT) as a first line therapy was performed in 19 patients with AA, 10 with RCC, and 5 with RCMD. The rejection was found in 2 patients with RCC and 3 with RCMD. Although 5-year OS rates in patients who underwent SCT were not different among 3 groups (p=0.26), FFS rate (30%) in patients with RCMD was significantly lower than in those with AA (100%) and RCC (78%) (p<0.01).In conclusion, we could not find any clinical relevance of separating RCC from AA because response rates to IST and the development of clonal evolution did not significantly differ between AA and RCC. The entity of RCMD should be adopted to childhood MDS classification because children with RCMD exhibited a distinct characteristic of morphology and a frequent chromosomal aberration at the time of diagnosis. The optimal treatment strategy including preconditioning regimen of SCT should be established for children with acquired BMFs based on the BM cellularity and morphological classification. DisclosuresKojima:SANOFI: Honoraria, Research Funding.

Aggressive B-cell lymphomas: frequency, immunophenotype, and genetics in a reference laboratory population.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma worldwide. The current World Health Organization classification includes several subtypes based on a combination of clinical, immunohistochemical, and genetic differences. Other aggressive variants of B-cell lymphomas, including Burkitt lymphoma and double-hit lymphomas are part of the differential diagnosis and often have overlapping features with DLBCL. In this study, we evaluated 760 of cases of DLBCL and other aggressive B-cell lymphomas using a relatively uniform immunohistochemical panel and genetic methods. We assessed the frequency of different subtypes and locations and documented distinctive immunophenotypic and genetic findings of these cases. Most cases in the study group were DLBCL (89%), including 38 CD5+ DLBCL, 28 T-cell/histiocyte-rich large B-cell lymphomas, and 33 Epstein-Barr virus-positive DLBCL (including 6 cases in elderly patients). The study also included 39 Burkitt lymphoma and 39 cases of double-hit lymphoma. In general, our results support the World Health Organization classification approach as well as other studies of DLBCL. In this study, we focus on specific issues of interest including cell-of-origin classification testing, comparing the Hans classifier with the tally classifier, correlation of MYC immunohistochemistry with MYC fluorescence in situ hybridization, and Epstein-Barr virus positivity in aggressive B-cell lymphomas.

Brain Invasion in Meningiomas: Incidence and Correlations with Clinical Variables and Prognosis

In meningioma, correlation of brain invasion with prognosis and clinical variables remains controversial. Correlation of brain invasion with clinical and histopathologic variables was investigated in 467 patients with primary intracranial meningioma. Diffuse (n= 3; 10%), clusterlike (n= 11; 34%) or fingerlike (n= 18; 56%) invasion was detected in 32 patients (7%). Brain invasion was more common in males than in females (13% vs. 5%; odds ratio, 2.75; 95% confidence interval, 1.29-5.89; P= 0.009) and pattern of invasion differed between genders (P= 0.037). Brain invasion was absent in 401 benign meningiomas and present in 48% of 60 atypical (n= 29) and 50% of 6 anaplastic (n= 3) meningiomas (P < 0.001) but was independent of tumor location and extent of resection. Progression occurred in 11% and was more frequent (31% vs. 15%; P= 0.036) in invasive than in noninvasive tumors, but only after gross total resection and in univariate analyses, and independent of invasion pattern. In atypical meningiomas, frequency of adjuvant irradiation was similar comparing invasive and noninvasive tumors and grading solely based on brain invasion (n= 20; 33%), other World Health Organization (WHO) criteria (n= 31; 52%) or a combination of both (n=9; 15%). Risk of recurrence was lower (hazard ratio, 0.258, 95% confidence interval, 0.09-0.734; P= 0.011) when grading exclusively based on brain invasion than when further WHO criteria were in addition present and the progression-free interval among the first was similar to benign tumors. Brain invasion and its patterns are correlated to gender. In contrast to the current WHO classification, invasion was associated with recurrence only after gross total resection and not independent of further histopathologic criteria of atypia.

A new prognostic histopathologic classification of nasopharyngeal carcinoma.

BackgroundThe current World Health Organization (WHO) classification of nasopharyngeal carcinoma (NPC) conveys little prognostic information. This study aimed to propose an NPC histopathologic classification that can potentially be used to predict prognosis and treatment response.MethodsWe initially developed a histopathologic classification based on the morphologic traits and cell differentiation of tumors of 2716 NPC patients who were identified at Sun Yat-sen University Cancer Center (SYSUCC) (training cohort). Then, the proposed classification was applied to 1702 patients (retrospective validation cohort) from hospitals outside SYSUCC and 1613 patients (prospective validation cohort) from SYSUCC. The efficacy of radiochemotherapy and radiotherapy modalities was compared between the proposed subtypes. We used Cox proportional hazards models to estimate hazard ratios (HRs) with 95% confidence intervals (CI) for overall survival (OS).ResultsThe 5-year OS rates for all NPC patients who were diagnosed with epithelial carcinoma (EC; 3708 patients), mixed sarcomatoid-epithelial carcinoma (MSEC; 1247 patients), sarcomatoid carcinoma (SC; 823 patients), and squamous cell carcinoma (SCC; 253 patients) were 79.4%, 70.5%, 59.6%, and 42.6%, respectively (P < 0.001). In multivariate models, patients with MSEC had a shorter OS than patients with EC (HR = 1.44, 95% CI = 1.27–1.62), SC (HR = 2.00, 95% CI = 1.76–2.28), or SCC (HR = 4.23, 95% CI = 3.34–5.38). Radiochemotherapy significantly improved survival compared with radiotherapy alone for patients with EC (HR = 0.67, 95% CI = 0.56–0.80), MSEC (HR = 0.58, 95% CI = 0.49–0.75), and possibly for those with SCC (HR = 0.63; 95% CI = 0.40–0.98), but not for patients with SC (HR = 0.97, 95% CI = 0.74–1.28).ConclusionsThe proposed classification offers more information for the prediction of NPC prognosis compared with the WHO classification and might be a valuable tool to guide treatment decisions for subtypes that are associated with a poor prognosis.

Myeloproliferative neoplasms (BCR-ABL1 negative) and myelodysplastic/myeloproliferative neoplasms: current diagnosticprinciples and upcoming updates.

Since the publication of the latest World Health Organization (WHO) classification in 2008, there has been a significant effort for clarification of unresolved questions, especially with the help of the rapidly developing field of molecular genetic studies, next-generation sequencing in particular. Numerous entities within the WHO categories of myeloproliferative neoplasms (MPNs) and myelodysplastic (MDS)/MPNs have been extensively studied, with large published series attempting to characterize and better define their morphologic and molecular genetic features. This emerging genetic landscape maintains a robust correlation with the various disease entities recognized by the WHO classification scheme based on a careful integration of detailed clinical information, bone marrow and peripheral blood morphology, immunohistology, and genomics. This brief review summarizes the current guidelines as they apply to diagnosing both the classical BCR-ABL1 negative MPN (polycythemia vera, essential thrombocythemia, and primary myelofibrosis) and the more common subtypes of MDS/MPN overlap syndromes. The more important recent molecular updates as well as the upcoming changes to the current WHO classification, expected to be published in late 2016, will also be briefly reviewed.

Sclerosing Meningioma : Radiological and Clinical Characteristics of 21 Cases.

ObjectiveA rare subtype of meningioma, sclerosing meningioma is not included in the current World Health Organization classification of meningiomas and is classified into the category of other morphological variation subtypes. Sclerosing meningioma is often misdiagnosed to other non-benign meningioma or malignant neoplasm, so it is important to diagnose sclerosing type correctly. We analyzed the radiological and clinical characteristics of a series of sclerosing meningiomas.MethodsTwenty-one patients who underwent surgery in one institute with a histopathologically proven sclerosing meningioma were included from 2006 to 2014. Eighteen tumors were diagnosed as a pure sclerosing-type meningioma, and 3 as mixed type. Magnetic resonance image was taken for all patients including contrast enhancement image. Computed tomography (CT) scan was taken for 16 patients. One neuroradiologist and 1 neurosurgeon reviewed all images retrospectively.ResultsIn the all 16 patients with preoperative CT images, higher attenuation was observed in the meningioma than in the brain parenchyma, and calcification was observed in 11 (69%). In 15 of the 21 patients (71%), a distinctive very low signal intensity appeared as a dark color in T2-weighted images. Nine of these 15 tumors (60%) exhibited heterogeneous enhancement, and 6 (40%) exhibited homogeneous enhancement that was unlike the homogeneous enhancing pattern shown by conventional meningiomas. Ten patients had a clear tumor margin without peritumoral edema.ConclusionAlthough these peculiar radiological characteristics are not unique to sclerosing meningioma, we believe that they are distinctive features that may be helpful for distinguishing sclerosing meningioma from other subtypes.

Comparison of Clinical and Laboratory Features Between Pediatric Aplastic Anemia and Refractory Cytopenia of Childhood

In the diagnosis of childhood bone marrow failure (BMF), differentiating aplastic anemia (AA) from hypoplastic myelodysplastic syndrome (MDS) is challenging. The 2008 World Health Organization (WHO) classification has proposed a provisional entity, "refractory cytopenia of childhood (RCC)". The spectrum of patients with RCC is wide, ranging from patients with severe hypocellular bone marrow (BM) and mild dysplasia to those with normocellular BM and distinct dysplasia meeting the criteria of refractory cytopenia with multilineage dysplasia (RCMD) defined for adults with MDS. Currently, it is recommended that children who meet the criteria for RCMD should be classified as RCC in the WHO classification until the number of lineages involved has been fully evaluated with regard to their relative importance as prognostic factors. Until now, no studies have addressed the question whether the current WHO classification reflects clinical outcomes of childhood BMF.The Japanese Society of Pediatric Hematology and Oncology has established a central review system of morphology. Peripheral blood (PB) and BM smears were reviewed by two pediatric hematologists, and BM trephine biopsies were reviewed by a hematopathologist. In addition, the telomere length of lymphocytes and paroxysmal nocturnal hemoglobinuria (PNH) clones in PB were measured by flowcytometry. RCC is defined as persistent cytopenia with <2% and <5% blasts in PB and BM, respectively. BM aspirate smears show dysplastic changes in >2 cell lineages or >10% within one cell lineage. On the other hand, the criteria of RCMD is defined as persistent cytopenia with <1% and <5% blasts in PB and BM, respectively. BM smears show >10% dysplastic changes in >2 cell lineages. We classified childhood BMF into AA, RCC, and RCMD in our central review.From February 2009 to February 2015, 1,300 cases were prospectively reviewed. Of the 1,300 cases, 582 were classified as BMF. Among them, 99 were classified as AA, 230 as RCC, 128 as RCMD, 50 as hepatitis-related BMF, 4 as PNH, and 71 as inherited BMF. Of the 71 cases with inherited BMF, 35 were diagnosed as Fanconi anemia, 14 as Shwachman-Diamond syndrome, and 12 as dyskeratosis congenita. To determine the clinical differences among AA, RCC, and RCMD, we compared laboratory and clinical findings for 457 patients classified with AA, RCC, and RCMD. Median ages in the AA, RCC, and RCMD groups were 10, 9, and 7 years, respectively (p<0.01). The male/female ratio in AA, RCC, and RCMD groups was 1.3, 1.4, and 1.1. The median of leukocyte, neutrophil, reticulocyte, and platelet count, and mean corpuscular volume were significantly lower in AA than in RCC and RCMD groups (p<0.01). Chromosomal abnormalities were detected in 1 patient with AA (trisomy 8), 6 patients with RCC (trisomy 8, n=4; monosomy 7, n=1; other, n=1), and 18 patients with RCMD (trisomy 8, n=5; monosomy 7, n=4; other, n=9) (p<0.01). Out of the 457 patients, 69 (AA, n=29; RCC, n=34; RCMD, n=6) were treated with immunosuppressive therapy (IST) with rabbit antithymocyte globulin and cyclosporine. Six months after the IST, the response rate to the IST was not significantly different between AA (38%) and RCC (47%) (p=0.47). Although the number of patients was limited, the response rate to the IST was 100% in patients with RCMD. One patient with RCC developed PNH at 26 months after the IST. Stem cell transplantation was performed in 15 patients with AA, 16 with RCC, and 3 with RCMD. Two patients with AA and 1 patient with RCC died of transplant-related toxicities.In conclusion, the entity of RCMD should be adopted to childhood MDS classification because children with RCMD exhibited a distinct characteristic of morphology and laboratory findings. Further efforts to clarify molecular events and clinical outcomes are necessary to establish the classification system for childhood BMF. DisclosuresNo relevant conflicts of interest to declare.

Cytogenetic Profile of Adult and Pediatric Acute Myeloid Leukemia in Oman: 10-Year Data From a Tertiary Care University Referral Hospital

Acute myeloid leukemia (AML) is the most common acute leukemia diagnosed in adults. Diagnostic karyotype is one of the most powerful independent prognostic indicators in AML, and the current World Health Organization (WHO) classification of AML is heavily dependent on the underlying cytogenetic profile. Herein we aim at reviewing the cytogenetic profile of adult and pediatric AML patients diagnosed in our …

Omental mesenteric myxoid hamartoma, a subtype of inflammatory myofibroblastic tumor? Considerations based on the histopathological evaluation of four cases.

Omental mesenteric myxoid hamartoma (OMH) is a distinctive myxoid lesion of infancy, characterized by a benign clinical behavior. In the current World Health Organization (WHO) classification of soft tissue tumors, it is considered as part of the morphologic spectrum of inflammatory myofibroblastic tumors (IMT), but this relationship with IMT is still subject to debate. Four lesions with histologic features of OMH occurring in newborns and toddlers are described and compared with classic, ALK-positive IMT. All OMH showed a peculiar dot-like immunostaining for ALK, which, in one of the cases, was cytogenetically found to be associated with an inversion of the ALK gene. While OMHs were positive for smooth muscle actin (SMA), desmin, WT1, podoplanin, and cytokeratins (CAM5.2 and AE1-3), IMT were consistently positive only for SMA (10 cases). ALK-1 displayed cytoplasmic staining in IMT and characteristic paranuclear dot-like staining in OMH.

Acute leukemias of ambiguous origin.

This session of the Society for Hematopathology/European Association for Haematopathology Workshop focused on acute leukemias of ambiguous origin. We provide an overview of mixed-phenotype acute leukemia (MPAL) as recognized in the current World Health Organization classification and summarize diagnostic criteria for major categories of MPAL: B/myeloid, T/myeloid, B/T, and B/T/myeloid. Most MPAL cases submitted were B/myeloid and T/myeloid MPAL, the most frequent types, but three cases of B/T MPAL were also submitted, and examples of all categories are illustrated. We emphasize that a comprehensive approach to immunophenotyping is required to accurately establish the diagnosis of MPAL. Flow cytometry immunophenotyping using a large panel of antibodies is needed as well as confirmatory immunohistochemical analysis and cytochemistry studies for myeloperoxidase and nonspecific esterase. We discuss technical issues in determining blast lineage and possible pitfalls in MPAL diagnosis. In particular, rare cases of B-acute lymphoblastic leukemia (B-ALL) can express myeloperoxidase but are otherwise consistent with B-ALL and should be treated as such. Last, we review the differential diagnosis between acute undifferentiated leukemia and acute myeloid leukemia with minimal differentiation. There was an agreement that diagnosis of MPAL can be challenging, especially if applied flow cytometry panels are not comprehensive enough.

Histological criteria for atypical pituitary adenomas - data from the German pituitary adenoma registry suggests modifications.

IntroductionThe term atypical pituitary adenoma (APA) was revised in the 2004 World Health Organization (WHO) classification of pituitary tumors. However, two of the four parameters required for the diagnosis of APAs were formulated rather vaguely (i.e., “extensive” nuclear staining for p53; “elevated” mitotic index). Based on a case-control study using a representative cohort of typical pituitary adenomas and APAs selected from the German Pituitary Tumor Registry, we aimed to obtain reliable cut-off values for both p53 and the mitotic index. In addition, we analyzed the impact of all four individual parameters (invasiveness, Ki67-index, p53, mitotic index) on the selectivity for differentiating both adenoma subtypes.MethodsOf the 308 patients included in the study, 98 were diagnosed as APAs (incidence 2.9 %) and 10 patients suffered from a pituitary carcinoma (incidence 0.2 %). As a control group, we selected 200 group matched patients with typical pituitary adenomas (TPAs). Cut-off values were attained using ROC analysis.ResultsWe determined significant threshold values for p53 (≥2 %; AUC: 0.94) and the mitotic index (≥2 mitosis within 10 high power fields; AUC: 0.89). The most reliable individual marker for differentiating TPAs and APAs was a Ki-67-labeling index ≥ 4 % (AUC: 0.98). Using logistic regression analysis (LRA) we were able to show that all four criteria (Ki-67 (p < 0.001); OR 5.2// p53 (p < 0.001); OR 3.1// mitotic index (p < 0.001); OR 2.1// invasiveness (p < 0.001); OR 8.2)) were significant for the group of APAs. Furthermore, we describe the presence of nucleoli as a new favorable parameter for TPAs (p = 0.008; OR: 0.4; CI95 %: 0.18; 0.77).ConclusionsHere we present a proposed rectification of the current WHO classification of pituitary tumors describing an additional marker for TPA and specific threshold values for p53 and the mitotic index. This will greatly help in the reliable diagnosis of APAs and facilitate further studies to ascertain the prognostic relevance of this categorization.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0229-8) contains supplementary material, which is available to authorized users.

Abstract IA01: Clinical significance of molecular findings in acute myeloid leukemia.

Abstract Acute myeloid leukemia (AML) is a very heterogeneous disease. Cytogenetics and molecular findings are currently the most important factors for selecting therapy. They allow improved diagnosis, prognosis, and therapy. Their importance in diagnosis is reflected in the current World Health Organization (WHO) classification,(1) which first identifies specific types of AML by specific recurrent genetic abnormalities; in a number of genetic subtypes the diagnosis is AML regardless of percent blasts. The 2008 WHO classification includes, for the first time, provisional entities based solely on molecular findings, and overall increases the percent of AML genetically classified from ~30% in the last classification (in 2001) to more than 75%. The 2008 version of the WHO classification is currently undergoing revision with planned publication in 2015. It is likely to further expand the use of cytogenetics and molecular findings for classification. Currently only one of the WHO genetic subtypes is managed almost totally based on molecular markers: acute promyelocytic leukemia (APL). This has changed the outcome for APL patients from a median survival of two weeks to a cure rate of more than 90%. Increasingly two other genetic subtypes,—those with t(8;21)(q22;q22) or inv(16)(p13.1q22) or t(16;16)(p13.1;q22) that are collectively designated core-binding factor AML —which make up ~15% of AML, are being separated from other types of AML and treated using molecularly targeted therapy. Early results from on-going trials suggest improved outcome. For the remaining types of primary AML, cytogenetics and molecular genetics are the most important prognostic findings and are often used to determine therapy. Approximately 45% of AML cases are cytogenetically normal (CN-AML); numerous molecular abnormalities have been identified in CN-AML that are highly prognostic and increasingly being used to select therapy. The therapy is increasingly molecularly targeted when feasible. Recently, international guidelines for reporting clinical data in AML have mandated correlation with cytogenetic and molecular genetic data.(2) Studies of the prognostic use of the European LeukemiaNet guidelines have demonstrated it's significant correlation with outcome. Treatment trials for about two-thirds of AML are currently genotype/molecular specific. Early data suggest that as a result we are increasing the percent of cured adult patients, especially those under the age of 60 years.

Acute myeloid leukaemia and myelodysplastic syndromes with 50% or greater erythroblasts: a diagnostic conundrum

Acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) with ≥50% erythroblasts comprise up to 5% of all cases of AML and 15% of MDS. The classification of these entities is currently fraught with difficulty and requires integration of clinical, morphological and cytogenetic features. The current World Health Organization classification of haematopoietic tumours recognises the entities of pure erythroid leukaemia and acute erythroid leukaemia (erythroid/myeloid), however, some cases of AML with erythroid predominance may also fulfil criteria for AML with myelodysplasia-related changes or therapy-related myeloid neoplasms. Among these entities, pure erythroid leukaemia remains poorly characterised due to its rarity. In addition, there is significant clinicopathological overlap between acute erythroid leukaemia and cases of MDS with ≥50% erythroblasts. In this review, we discuss current areas of controversy regarding these disorders and present our approach to their diagnosis and classification.

The World Health Organization Classification of Skeletal Muscle Tumors in Pediatric Rhabdomyosarcoma: A Report From the Children's Oncology Group

The World Health Organization Classification Since 1995, the International Classification of Rhabdomyosarcoma has provided prognostically relevant classification for rhabdomyosarcoma (RMS) and allowed risk stratification for children with RMS. The International Classification of Rhabdomyosarcoma includes botryoid and spindle cell RMS as superior-risk groups, embryonal RMS as an intermediate-risk group, and alveolar RMS as an unfavorable-risk group. The 2013 World Health Organization (WHO) classification of skeletal muscle tumors modified the histologic classification of RMS to include sclerosing RMS as a type of spindle cell RMS separate from embryonal RMS. The current WHO classification includes embryonal, alveolar, spindle cell/sclerosing, and pleomorphic subtypes of RMS and does not separate the botryoid subtype. To determine if the WHO classification applies to pediatric RMS. To accomplish this goal, we reviewed 9 consecutive Children's Oncology Group clinical trials to compare the WHO and International Classification of Rhabdomyosarcoma classifications with outcome and site of disease. Except for a subset of low-risk RMS, the outcome for botryoid was not significantly different from typical embryonal RMS when analyzed by primary site. Similarly, pediatric spindle cell and sclerosing patterns of RMS did not appear significantly different from typical embryonal RMS, with one exception: spindle cell RMS in the parameningeal region had an inferior outcome with 28% event-free survival. Our data support use of the WHO RMS classification in the pediatric population, with the caveat that histologic diagnosis does not necessarily confer the same prognostic information in children as in adults.

Outcomes of curative nephrectomy against renal cell carcinoma based on a central pathological review of 914 specimens from the era of cytokine treatment.

The purpose of this study was to determine the state of modern practice with regard to renal cell carcinoma (RCC) outcomes and to assess the effects on survival of such clinical and pathological factors such as histological subtype (HS) and nuclear grade by conducting a central pathological review based on the current World Health Organization classification and the staging system of the American Joint Committee on Cancer/Union for International Cancer Control. We collected glass slides and clinical data sets for 914 cases of RCC treated with curative nephrectomy from 1995 to 2000. Overall (OS), cancer-specific (CSS), and relapse-free (RFS) survival were compared for HS and nuclear grades determined by a central pathology review board comprising 5 board-certified pathologists, pathological staging, and a variety of clinical factors. The 5 and 7-year CSS in this study were 96 and 93 %, respectively, values superior to those reported in Western countries. Concordance between the original and reviewed HS and nuclear grades were 90.9 and 21.1 %, respectively. HS correlated with OS (P = 0.043) but was not an independent prognostic factor in the multivariate analysis (P = 0.820). Tumor size, Fuhrman grade, and infiltration type were common independent prognostic factors for OS, CSS, and RFS. This study revealed RCC outcomes in the era of cytokine treatment for metastasis. Central pathological review is an essential component of a multicenter study with long-term follow-up. Tumor size, Fuhrman grade, and infiltration type had much greater effects than HS on survival after curative nephrectomy.

The applicability of the WHO classification in paediatric AML. A NOPHO-AML study.

The World Health Organization (WHO) classification of myeloid leukaemia was revised in 2008. It incorporates newly recognized entities and emphasizes the pivotal role of cytogenetic abnormalities. The aim of this study was to evaluate the usability of the WHO classification when applied to a large population-based paediatric acute myeloid leukaemia (AML) cohort. We included children diagnosed with de novo AML, 0-18years of age from the Nordic countries and Hong Kong from 1993 to 2012. Data were retrieved from the Nordic Society for Paediatric Haematology and Oncology AML database and patients classified according to the WHO 2008 classification. A successful karyotype was available in 97% of the cases. AML with recurrent genetic abnormalities were present in 262 (41%) and 94 (15%) were classified as AML with myelodysplasia-related changes (AML-MDS). WHO classifies patients with monosomy 7 and del(7q) into one group. We found that -7 (n=14) had significantly poorer outcome than del(7q) (n=11); 5-year event-free survival 26% vs. 67%, (P=0·02), and 5-year overall survival 51% vs. 90%, (P=0·04). The largest group was the highly heterogeneous AML not otherwise specified (NOS) (n=280) (44%). In conclusion, the WHO classification allocated 15% to AML-MDS, 44% to NOS and grouped together entities with clearly different outcome, therefore limiting the applicability of the current WHO classification in children with AML.

Practical Applications in Immunohistochemistry: Evaluation of Diffuse Large B-Cell Lymphoma and Related Large B-Cell Lymphomas

Diffuse large B-cell lymphoma is the most commonly diagnosed subtype of lymphoma worldwide. The current World Health Organization (WHO) classification includes several subtypes, based on a combination of clinical, immunohistochemical, and genetic differences. Immunohistochemical staining is essential in evaluating diffuse large B-cell lymphoma and many related large B-cell lymphomas and aggressive B-cell lymphomas. To address different immunohistochemical features used for identification, subclassification, prognosis and in some cases, therapy, of diffuse large B-cell lymphoma and related lymphomas. The information outlined in this review article is based on our experiences with routine cases, on the current WHO classification of hematopoietic and lymphoid tumors, and on a review of English-language articles published throughout 2014. Features and diagnostic criteria of diffuse large B-cell lymphoma, aggressive variants of B-cell lymphomas, including Burkitt lymphoma and "double-hit" lymphomas, are discussed. Identification of cell of origin (germinal center type versus activated B-cell type) is discussed at length. Finally, practical approaches for diagnosis are discussed.

Pathology and genetics of diffuse gliomas in adults.

The current World Health Organization (WHO) classification of tumors of the central nervous system (CNS) is essentially a lineage-oriented classification based on a presumable developmental tree of CNS. A four-tiered WHO grading scheme has been successfully applied to a spectrum of diffusely infiltrative astrocytomas, but it is not fully applicable to other gliomas, including oligodendrogliomas and ependymomas. Recent genetic studies have revealed that the major categories of gliomas, such as circumscribe astrocytomas, infiltrating astrocytomas/oligodendrogliomas, and glioblastoma, roughly correspond to major genetic alterations, including isocitrate dehydrogenases (IDHs) 1/2 mutations, TP53 mutations, co-deletion of chromosome arms 1p/19q, and BRAF mutation/fusion. These genetic alterations are clinically significant in terms of the response to treatment(s) and/or the prognosis. It is, thus, rational that future classification of gliomas should be based on genotypes, rather than phenotypes, although the genetic features of each tumor are not sufficiently understood at present to draw a complete map of the gliomas, and genetic testing is not yet available worldwide, particularly in Asian and African countries. This review summarizes the current concepts of the WHO classification, as well as the current understanding of the major genetic alterations in glioma and the potential use of these alterations as diagnostic criteria.

An update on gnathic pathology.

An update on gnathic pathology.

Non-anaplastic peripheral T-cell lymphoma in children and adolescents--a retrospective analysis of the NHL-BFM study group.

Mature (peripheral) T-cell lymphoma (PTCL) other than anaplastic large cell lymphoma is a heterogeneous group of diseases and exceedingly rare in children and adolescents. Survival rates range between 46% and 85%. This study reports the disease characteristics, treatment and outcome of all patients with the diagnosis of mature TCL registered in the Berlin-Frankfurt-Munster non-Hodgkin lymphoma database between 1986 and 2012. All diagnoses were centrally reviewed and revised by clinico-pathological correlation according to the criteria of the current World Health Organization classification. Of the 69 patients originally registered as having PTCL, the diagnosis was confirmed in 38 of them. Most patients were treated with an anaplastic large cell lymphoma (ALCL)-like therapy regimen. Patients with PTCL-not otherwise specified comprised the largest group and showed a 5-year event-free survival rate of 61±11%. Patients suffering from Natural Killer/T-cell- and hepatosplenic TCL had the poorest outcome. Our results suggest that the outcomes of children with mature TCL other than ALCL depend on the subtype and are worse than in all other paediatric lymphomas. The clinical experience presented in this largest study on paediatric mature TCL may serve as basis for future collaborative international prospective clinical trials.