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Anaplasia in Wilms tumor is recognized as the most important prognostically unfavorable histological feature. It is subtyped as focal anaplastic Wilms tumor (FAWT) and diffuse anaplastic Wilms tumor (DAWT). Outcomes of patients with DAWT remain poor in patients with stage III and IV tumors. Important issues relevant to anaplasia in Wilms tumor, including prevalence, treatment, outcomes, biomarkers, anaplasia, and chemotherapy, and the concept of tumor aggressiveness, are reviewed and discussed here. We also consider the differences in clinical approaches to anaplasia in Wilms tumor between the two major renal tumor clinical research groups: the International Society of Paediatric Oncology (SIOP) Renal Tumour Study Group and the Children's Oncology Group (COG) Renal Tumor Group. We emphasize the importance and implications of recognizing FAWT and DAWT as separate clinico-pathological entities., (© 2024 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Introduction: The purpose of this study is to examine the outcomes in children with anaplastic bilateral Wilms tumor (BWT) from study AREN0534 in order to define potential prognostic factors and areas to target in future clinical trials., Methods: Demographic and clinical data from AREN0534 study patients with anaplasia (focal anaplasia [FA], or diffuse anaplasia [DA]) were compared. Event-free survival (EFS) and overall survival (OS) were reported using Kaplan-Meier estimation with 95% confidence bands, and differences in outcomes between FA and DA compared using log-rank tests. The impact of margin status was analyzed., Results: Twenty-seven children who enrolled on AREN0534 had evidence of anaplasia (17 DA, 10 FA) in at least one kidney and were included in this analysis. Twenty-six (96%) had BWT. Nineteen percent had anaplastic histology in both kidneys (four of 17 DA, and one of 10 FA). Forty-six percent with BWT had bilateral nephron-sparing surgery (NSS); one child who went off protocol therapy, eventually required bilateral completion nephrectomies. Median follow-up for EFS and OS was 8.6 and 8.7 years from enrollment. Four- and 8-year EFS was 53% [95% confidence interval (CI): 34%-83%] for DA; 4-year EFS was 80% [95% CI: 59%-100%], and 8-year EFS 70% [95% CI: 47%-100%] for FA. Three out of 10 children with FA and eight out of 17 children with DA had events. EFS did not differ statistically by margin status (p = .79; HR = 0.88). Among the six children who died (five DA, one FA), all experienced prior relapse or progression within 18 months., Conclusion: Events in children with DA/FA in the setting of BWT occurred early. Caution should be taken about interpreting the impact of margin status outcomes in the context of contemporary multimodal therapy. Future targeted investigations in children with BWT and DA/FA are needed., (© 2024 Wiley Periodicals LLC.)

Background: An objective of the Children's Oncology Group AREN0534 Study was to improve the survival of patients with bilateral Wilms tumors (BWT) by using preoperative chemotherapy of limited duration and tailoring postoperative therapy based on histopathologic response. The authors report outcomes based on postoperative histopathologic responses., Methods: Patients with BWT received treatment with vincristine, dactinomycin, and doxorubicin for 6 or 12 weeks followed by surgery. Postoperative therapy was prescribed based on the highest risk tumor according to the International Society of Pediatric Oncology classification and the Children's Oncology Group staging system., Results: Analyses were performed on data from 180 evaluable children. The 4-year event-free survival (EFS) and overall survival (OS) rates were 81% (95% CI, 74%-87%) and 95% (95% CI, 91%-99%), respectively. Seven patients who had completely necrotic tumors had a 4-year EFS rate of 100%. Of 118 patients who had tumors with intermediate-risk histopathology, the 4-year EFS and OS rates were 82% (95% CI, 74%-90%) and 97% (95% CI, 94%-100%), respectively. Fourteen patients who had blastemal-type tumors had 4-year EFS and OS rates of 79% (95% CI, 56%-100%) and 93% (95% CI, 79%-100%), respectively. Eighteen patients who had diffuse anaplasia had 4-year EFS and OS rates of 61% (95% CI, 35%-88%) and 72% (95% CI, 47%-97%), respectively; and the 4-year EFS and OS rates of 7 patients who had focal anaplasia were 71% (95% CI, 38%-100%) and 100%, respectively. There was no difference in the outcomes of patients who had different histopathologic subtypes within the intermediate-risk group (P = .54)., Conclusions: A risk-adapted treatment approach for BWT results in excellent outcomes. This approach was not successful in improving the outcome of patients who had diffuse anaplasia., (© 2022 American Cancer Society.)

We examined postoperative material from 28 patients aged 39-61 years with gliomas of different degrees of anaplasia (the diagnosis was histologically verified according to the WHO classification of CNS tumors) who had not previously received antitumor treatment. In glioma tissue, the glucose concentration was significantly higher than in the brain tissue of subjects dead from traumas (control), while lactate concentration did not differ from that in the control group or was lower. Hexokinase activity demonstrated a tendency to an increase in grade I and significant elevation in grades II and III, while in grade IV gliomas, this parameter did not differ from the control. Activities of the pentose-phosphate pathway enzymes glucose-6-phosphate dehydrogenase and transketolase increased with increasing of tumor anaplasia. Activity of glycogen synthase 3β kinase was significantly higher than in the control group. IDH1 mutation was discovered in 40% cases, the MGMT promoter methylation was detected in more than 50%, the Ki-67 level increased with increasing tumor anaplasia. The most significant correlations with glioma markers were detected for glucose-6-phosphate dehydrogenase and glycogen synthase 3β kinase. Activities of the studied enzymes of carbohydrate metabolism significantly correlated with Ki-67 marker., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare contiguous gene deletion syndrome with a 45% to 60% risk of developing Wilms tumor (WT). Currently, surveillance and treatment recommendations are based on limited evidence., Methods: Clinical characteristics, treatments, and outcomes were analyzed for patients with WAGR and WT/nephroblastomatosis who were identified through International Society of Pediatric Oncology Renal Tumor Study Group (SIOP-RTSG) registries and the SIOP-RTSG network (1989-2019). Events were defined as relapse, metachronous tumors, or death., Results: Forty-three patients were identified. The median age at WT/nephroblastomatosis diagnosis was 22 months (range, 6-44 months). The overall stage was available for 40 patients, including 15 (37.5%) with bilateral disease and none with metastatic disease. Histology was available for 42 patients; 6 nephroblastomatosis without further WT and 36 WT, including 19 stromal WT (52.8%), 12 mixed WT (33.3%), 1 regressive WT (2.8%) and 2 other/indeterminable WT (5.6%). Blastemal type WT occurred in 2 patients (5.6%) after prolonged treatment for nephroblastomatosis; anaplasia was not reported. Nephrogenic rests were present in 78.9%. Among patients with WT, the 5-year event-free survival rate was 84.3% (95% confidence interval, 72.4%-98.1%), and the overall survival rate was 91.2% (95% confidence interval, 82.1%-100%). Events (n = 6) did not include relapse, but contralateral tumor development (n = 3) occurred up to 7 years after the initial diagnosis, and 3 deaths were related to hepatotoxicity (n = 2) and obstructive ileus (n = 1)., Conclusions: Patients with WAGR have a high rate of bilateral disease and no metastatic or anaplastic tumors. Although they can be treated according to existing WT protocols, intensive monitoring of toxicity and surveillance of the remaining kidney(s) are advised., Lay Summary: WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare genetic condition with an increased risk of developing Wilms tumor. In this study, 43 patients with WAGR and Wilms tumor (or Wilms tumor precursor lesions/nephroblastomatosis) were identified through the international registry of the International Society of Pediatric Oncology Renal Tumor Study Group (SIOP-RTSG) and the SIOP-RTSG network. In many patients (37.5%), both kidneys were affected. Disease spread to other organs (metastases) did not occur. Overall, this study demonstrates that patients with WAGR syndrome and Wilms tumor can be treated according to existing protocols. However, intensive monitoring of treatment complications and surveillance of the remaining kidney(s) are advised., (© 2020 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Established prognostic indicators in rhabdomyosarcoma (RMS), the most common childhood soft tissue sarcoma, include several clinicopathologic features. Among pathologic features, anaplasia has been suggested as a potential prognostic indicator, but the clinical significance of anaplasia remains unclear., Methods: Patients enrolled on one of five recent Children's Oncology Group clinical trials for RMS (D9602, n = 357; D9802, n = 80; D9803, n = 462; ARST0331, n = 335; and ARST0531, n = 414) with prospective central pathology review were included in this study. Clinicopathologic variables including demographic information, risk group, histologic subtype, and anaplasia were recorded along with overall survival (OS) and failure-free survival (FFS) with failure defined by recurrence, progression, or death. The log-rank test was used to compare OS and FFS., Results: Anaplasia was more common in embryonal RMS (27% of all embryonal RMS) than other subtypes of RMS (11% for alveolar RMS, 7% for botryoid RMS, 11% for spindle cell RMS). On multivariate analyses, anaplasia was not an independent prognostic factor in RMS (OS:hazard ratio (HR) = 1.12, p = 0.43; FFS:HR = 1.07, p = 0.56) across all subtypes or within embryonal RMS only (OS:HR = 1.41, p = 0.078; FFS:HR = 1.25, p = 0.16). Among tumors with TP53 mutations, 69% had anaplasia, while only 24% of tumors with anaplasia had a tumoral TP53 mutation., Conclusions: Anaplasia is not an independent indicator of adverse outcomes in RMS. Emerging information on the prognostic significance of TP53 mutations raises the possibility that anaplasia may be a surrogate marker of TP53 mutations in some cases. Tumoral TP53 mutation status may be investigated as a prognostic indicator in future studies., Competing Interests: Conflict of interest statement Douglas S Hawkins has the following disclosures: Loxo Oncology, Bayer, Bristol Myers Squibb, Lilly: Clinical trial fees paid to Seattle Children's to offset costs of study conduct; reimbursed for or provided travel, housing, and food to attend medial advisory board meetings; Celgene: Reimbursed for or provided travel, housing, and food to attend medial advisory board meetings, Eisai, Glaxo Smith Kline, Sanofi, Novartis, Amgen, Seattle Genetics, Jazz Pharmaceuticals, Incyte: Clinical trial fees paid to Seattle Children's to offset costs of study conduct. All other authors have no disclosures., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

We describe a morphologically distinct pattern of tumor infarction and associated sarcoma-like changes, mimicking focal anaplasia, in otherwise WHO grade I meningiomas. The described cases (n = 9) all demonstrated a discrete spindle-cell (pseudosarcomatous) component with brisk mitotic activity (12-14 mitoses/10 HPF), elevated Ki-67 (mean 75.5 ± 25.0%, quantified), absence of PR, SSTR2A, or EMA expression, and potential SMA expression (50%). Despite these high-grade features, all nine patients remained free of progression or recurrence post resection (follow-up mean: 49.8 months). In contrast, among a comparison (control) cohort of consecutive WHO grade II and III meningiomas (n = 16), as expected, progression rate was high (68.8%, P = 0.002, Fisher's exact, average time to progression = 25 months, follow-up mean: 39.8 months). While necrosis was a frequent feature among atypical/anaplastic meningiomas (12/16, 75%), and elevated mitoses and proliferative index were present consistent with histologic grade, a well-defined zonal pattern with pseudosarcomatous component was not present among these tumors. DNA methylation-based analysis readily distinguished meningiomas by copy number profiles and DNA-based methylation meningioma random forest classification analysis (meningioma v2.4 classifier developed at University of Heidelberg); all pseudosarcomatous cases analyzed (4/9) matched with high level calibrated classifier score to "MC benign-1", with isolated loss of chromosome 22q identified as the sole copy number alteration. In contrast, multiple chromosomal losses were detected among the comparison cohort and classifier results demonstrated good concordance with histologic grade. Our findings suggest that pseudosarcomatous alterations represent reactive changes to central meningioma infarction, rather than focal anaplasia, and further support the use of DNA methylation-based analysis as a useful adjunct for predicting meningioma behavior. These indolent tumors should be distinguished from their atypical and anaplastic counterparts.

Many breakthroughs have been made in the past decade regarding our knowledge of the biological basis of the diffuse gliomas, the most common primary central nervous system (CNS) tumors. These tumors as a group are aggressive, associated with high mortality, and have a predilection for adults. However, a subset of CNS glial and glioneuronal tumors are characterized by a more circumscribed pattern of growth and occur more commonly in children and young adults. They tend to be indolent, but our understanding of anaplastic changes in these tumors continues to improve as diagnostic classifications evolve in the era of molecular pathology and more integrated and easily accessible clinical databases. The presence of anaplasia in pleomorphic xanthoastrocytomas and gangliogliomas is assigned a WHO grade III under the current classification, while the significance of anaplasia in pilocytic astrocytomas remains controversial. Recent data highlight the association of the latter with aggressive clinical behavior, as well as the presence of molecular genetic features of both pilocytic and diffuse gliomas, with the recognition that the precise terminology remains to be defined. We review the current concepts and advances regarding histopathology and molecular understanding of pilocytic astrocytomas, pleomorphic xanthoastrocytomas, and gangliogliomas, with a focus on their anaplastic counterparts.

Anaplasia may be identified in a subset of tumors with a presumed pilocytic astrocytoma (PA) component or piloid features, which may be associated with aggressive behavior, but the biologic basis of this change remains unclear. Fifty-seven resections from 36 patients (23 M, 13 F, mean age 32 years, range 3-75) were included. A clinical diagnosis of NF1 was present in 8 (22%). Alternative lengthening of telomeres (ALT) was assessed by telomere-specific FISH and/or CISH. A combination of immunohistochemistry, DNA sequencing and FISH were used to study BRAF, ATRX, CDKN2A/p16, mutant IDH1 p.R132H and H3-K27M proteins. ALT was present in 25 (69%) cases and ATRX loss in 20 (57%), mostly in the expected association of ALT+/ATRX- (20/24, 83%) or ALT-/ATRX+ (11/11, 100%). BRAF duplication was present in 8 (of 26) (31%). H3-K27M was present in 5 of 32 (16%) cases, all with concurrent ATRX loss and ALT. ALT was also present in 9 (of 11) cases in the benign PA precursor, 7 of which also had ATRX loss in both the precursor and the anaplastic tumor. In a single pediatric case, ALT and ATRX loss developed in the anaplastic component only, and in another adult case, ALT was present in the PA-A component only, but ATRX was not tested. Features associated with worse prognosis included subtotal resection, adult vs. pediatric, presence of a PA precursor preceding a diagnosis of anaplasia, necrosis, presence of ALT and ATRX expression loss. ALT and ATRX loss, as well as alterations involving the MAPK pathway, are frequent in PA with anaplasia at the time of development of anaplasia or in their precursors. Additionally, a small subset of PA with anaplasia have H3-K27M mutations. These findings further support the concept that PA with anaplasia is a neoplasm with heterogeneous genetic features and alterations typical of both PA and diffuse gliomas., (© 2018 International Society of Neuropathology.)

This study explores the genomic alterations that contribute to the formation of a unique subset of low-risk, epithelial differentiated, favorable histology Wilms tumors (WT), tumors that have been characterized by their expression of post-induction renal developmental genes (Subset 1 WT). We demonstrate copy neutral loss of heterozygosity involving 19q13.32-q13.43, unaccompanied by evidence for imprinting by DNA methylation. We further identified loss-of-function somatic mutations in TRIM28 (also known as KAP1), located at 19q13, in 8/9 Subset 1 tumors analyzed. An additional germline TRIM28 mutation was identified in one patient. Retrospective evaluation of previously analyzed WT outside of Subset 1 identified an additional tumor with anaplasia and both TRIM28 and TP53 mutations. A major function of TRIM28 is the repression of endogenous retroviruses early in development. We depleted TRIM28 in HEK293 cells, which resulted in increased expression of endogenous retroviruses, a finding also demonstrated in TRIM28-mutant WT. TRIM28 has been shown by others to be active during early renal development, and to interact with WTX, another gene recurrently mutated in WT. Our findings suggest that inactivation of TRIM28 early in renal development contributes to the formation of this unique subset of FHWTs, although the precise manner in which TRIM28 impacts both normal renal development and oncogenesis remains elusive., Competing Interests: The authors have declared that no competing interests exist.

Morbidity and mortality associated with retinoblastoma have decreased drastically in recent decades, in large part owing to better prediction of high-risk disease and appropriate treatment stratification. High-risk histopathologic features and severe anaplasia both predict the need for more aggressive treatment; however, not all centers are able to assess tumor samples easily for the degree of anaplasia. Instead, identification of genetic signatures that are able to distinguish among anaplastic grades and thus predict high- versus low-risk retinoblastoma would facilitate appropriate risk stratification in a wider patient population. A better understanding of genes dysregulated in anaplasia also would yield valuable insights into pathways underlying the development of more severe retinoblastoma. Here, we present the histopathologic and gene expression analysis of 28 retinoblastoma cases using microarray analysis. Tumors of differing anaplastic grade show clear differential gene expression, with significant dysregulation of unique genes and pathways in severe anaplasia. Photoreceptor and nucleoporin expression in particular are identified as highly dysregulated in severe anaplasia and suggest particular cellular processes contributing to the development of increased retinoblastoma severity. A limited set of highly differentially expressed genes also are able to predict severe anaplasia accurately in our data set. Together, these data contribute to the understanding of the development of anaplasia and facilitate the identification of genetic markers of high-risk retinoblastoma., (Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The current College of American Pathologists cancer template for reporting biopsies of bone tumors recommends including information that is of unproven prognostic significance for osteosarcoma, such as the presence of spontaneous tumor necrosis and mitotic rate. Conversely, the degree of cytologic anaplasia (degree of differentiation) is not reported in this template. This retrospective cohort study of 125 patients with high-grade osteosarcoma was performed to evaluate the prognostic impact of these factors in diagnostic biopsy specimens in predicting the clinical outcome and response to neoadjuvant chemotherapy. Multivariate Cox regression was performed to adjust survival analyses for well-established prognostic factors. Multivariate logistic regression was used to determine odds ratios for good chemotherapy response (≥90% tumor necrosis). Osteosarcomas with severe anaplasia were independently associated with increased overall and disease-free survival, but mitotic rate and spontaneous necrosis had no prognostic impact after controlling for other confounding factors. Mitotic rate showed a trend towards increased odds of a good histologic response, but this effect was diminished after controlling for other predictive factors. Neither spontaneous necrosis nor the degree of cytologic anaplasia observed in biopsy specimens was predictive of a good response to chemotherapy. Mitotic rate and spontaneous tumor necrosis observed in pretreatment biopsy specimens of high-grade osteosarcoma are not strong independent prognostic factors for clinical outcome or predictors of response to neoadjuvant chemotherapy. Therefore, reporting these parameters for osteosarcoma, as recommended in the College of American Pathologists Bone Biopsy template, does not appear to have clinical utility. In contrast, histologic grading schemes for osteosarcoma based on the degree of cytologic anaplasia may have independent prognostic value and should continue to be evaluated.

Objectives: The Gleason grading system measures architectural differentiation and disregards nuclear atypia and the cell proliferation index. Several studies have reported that nuclear grade and mitotic index (MI) are prognostically useful., Patients and Methods: This study included 232 radical prostatectomy specimens. Nuclear anaplasia (NA) was determined on the basis of nucleomegali (at least 20µm); vesicular chromatin; eosinophilic macronucleoli, nuclear lobulation, and irregular thickened nuclear membranei. The proportion of area of NA was recorded in each tumor in 10% increments. The MI was defined as the number of mitotic figures in 10 consecutive high-power fields (HPF)., Results: In univariate analysis, significant differences included associations between biochemical prostate-specific antigen recurrence (BCR) and Gleason score, extraprostatic extension, positive surgical margin, the presence of high-pathologic stage, NA≥10% of tumor area, MI≥3/10 HPF, and preoperative prostate-specific antigen. In a stepwise Cox regression model, a positive surgical margin, the presence of a NA≥10% of tumor area, and a MI of≥3/10 HPF were independent predictors of BCR after radical prostatectomy. NA≥10% of tumor area appeared to have a stronger association with outcome than MI≥3/10 HPF, as still associated with BCR when Gleason score was in the model., Conclusions: The results of our study showed that, in addition to the conventional Gleason grading system, NA, and MI are useful prognostic parameters while evaluating long-term prognosis in prostatic adenocarcinoma., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Cellular cannibalism has been defined as a large cell engulfing a slightly smaller one within its cytoplasm. It has been described in various cancers like bladder cancer, breast cancer, lung cancer, gastric cancer, oral squamous cell carcinoma. Cellular cannibalism has been well correlated with anaplasia, tumor aggressiveness, grading and metastatic potential. Present review focuses on significance of cannibalism in relation to cancer with special emphasis on oral squamous cell carcinoma.

The NOTCH family of membranous receptors plays key roles during development and carcinogenesis. Since NOTCH2, yet not NOTCH1 has been shown essential for murine hepatogenesis, NOTCH2 rather than NOTCH1 may be more relevant to human hepatocarcinogenesis; however, no previous studies have supported this hypothesis. We therefore assessed the role of NOTCH2 in human hepatocellular carcinoma (HCC) by immunohistochemistry and cell culture. Immunohistochemically, 19% of primary HCCs showed nuclear staining for NOTCH2, indicating activated NOTCH2 signaling. NOTCH2-positive HCCs were on average in more advanced clinical stages, and exhibited more immature cellular morphology, i.e. higher nuclear-cytoplasmic ratios and nuclear densities. Such features were not evident in NOTCH1‑positive HCCs. In human HCC cell lines, abundant NOTCH2 expression was associated with anaplasia, represented by loss of E-cadherin. When NOTCH2 signaling was stably downregulated in HLF cells, an anaplastic HCC cell line, the cells were attenuated in potential for in vitro invasiveness and migration, as well as in vivo tumorigenicity accompanied by histological maturation. Generally, inverse results were obtained for a differentiated HCC cell line, Huh7, manipulated to overexpress activated NOTCH2. These findings suggested that the NOTCH2 signaling may confer aggressive behavior and immature morphology in human HCC cells.

Background: The presence of anaplastic features has been known to correlate with poor clinical outcome in various pediatric malignancies, including Wilms tumor and medulloblastoma but not in rhabdomyosarcoma., Aim: Aim was to study the frequency of anaplasia at presentation in childhood rhabdomyosarcoma and its relationship to clinical and pathological characteristics as well as to outcome., Patients and Methods: Anaplasia was retrospectively assessed in 105 consecutive pediatric rhabdomyosarcoma patients who were registered at the Children's Cancer Hospital in Egypt (CCHE) during the period from July 2007 till the end of May 2010., Results: Anaplasia was diagnosed in 18 patients (17.1%), focal in 10 (9.5%) and diffuse in 8 (7.6%). The distribution of anaplasia was found to be more common in older patients having age⩾10 years. Also it was more likely to occur in the high risk group and in tumors with unfavorable histology (alveolar subtype), and stage IV. The 3-year failure free survival rates for patients with and without anaplasia were 27.8±10.6% and 53.4±5.8%, respectively (p=0.014) and the 3-year overall survival rates were 35.3±11.6% and 61±6%, respectively (p=0.019)., Conclusions: The frequency of anaplasia in pediatric patients with rhabdomyosarcoma in our study was 17.1%. The presence of anaplasia had statistically significant worse clinical outcome., (Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: There is a worldwide debate involving clinicians, uropathologists as well as patients and their families on whether Gleason score 6 adenocarcinoma should be labelled as cancer., Case Description: We report a case of man diagnosed with biopsy Gleason score 6 acinar adenocarcinoma and classified as low risk (based on a PSA of 5 ng/mL and stage cT2a) whose radical prostatectomy specimen initially showed organ confined Gleason score 3+3=6, WHO nuclear grade 3, acinar adenocarcinoma with lymphovascular invasion and secondary deposit in a periprostatic lymph node. When deeper sections were cut to the point that almost all the slice present in the paraffin block was sectioned, a small tumor area (<5% of the whole tumor) of Gleason pattern 4 (poorly formed glands) was found in an extraprostatic position., Conclusion: The epilogue was that the additional finding changed the final Gleason score to 3+3=6 with tertiary pattern 4 and the stage to pT3a., Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000&#95;2014&#95;190.

Primary cardiac lymphomas are exceedingly rare. The presence and extent of the intracardiac mass is determined by echocardiography, computed tomography (CT), or magnetic resonance imaging (MRI); however, the diagnosis is established by endomyocardial biopsy or by pericardial or pleural effusion cytology. We describe the pleural effusion cytologic features of a primary cardiac lymphoma in a 55-year-old woman who presented with progressive shortness of breath, fatigue, mild dizziness, dull chest ache, and lower extremity edema. Transthoracic echocardiography, CT, and MRI showed a large mass centered in the right atrium and extending into the right ventricle, associated with pericardial effusion and bilateral pleural effusions. Cytologic examination of the pleural fluid showed very large pleomorphic malignant cell, some of which were binucleated and multinucleated and had anaplastic features. Flow cytometry showed a kappa monotypic population of large cells coexpressing CD5, CD19, and CD20; and immunoperoxidase stains performed on the cell block sections showed that the large neoplastic cells were positive for CD20, PAX5, CD5, and MUM1 and showed a very high proliferation rate (over 90%) by Ki67 staining. The cytologic, flow cytometry, and immunohistochemistry findings established the diagnosis of de novo CD5-positive primary cardiac diffuse large B-cell lymphoma (DLBCL), anaplastic variant, which was confirmed by the subsequent endomyocardial biopsy. This is, to the best of our knowledge, the first report of de novo CD5-positive primary cardiac diffuse large B-cell lymphoma, and the first report of the anaplastic variant of DLBCL diagnosed by effusion cytology., (Copyright © 2012 Wiley Periodicals, Inc., a Wiley company.)

Hepatocellular carcinomas exhibit heterogeneous morphologies by routine light microscopy. Although some morphologies represent insignificant variations in growth patterns, others may represent unrecognized subtypes of hepatocellular carcinoma. Identification of these subtypes could lead to separation of hepatocellular carcinomas into discrete groups with unique underlying genetic changes, prognosis, or therapeutic responses. In order to identify potential subtypes, two pathologists independently screened a cohort of 219 unselected hepatocellular carcinoma resection specimens and divided cases into potential subtypes. One of these promising candidate subtypes was further evaluated using histological and molecular techniques. This subtype was characterized by a unique and consistent set of histological features: smooth chromophobic cytoplasm, abrupt focal nuclear anaplasia (small clusters of tumor cells with marked nuclear anaplasia in a background of tumor cells with bland nuclear cytology), and scattered microscopic pseudocysts--we designate this variant as 'chromophobe hepatocellular carcinoma with abrupt anaplasia'. Thirteen cases were identified (6% of all hepatocellular carcinomas), including 6 men and 7 women with an average age of 61 years. Six cases occurred in cirrhotic livers. Serum AFP was elevated in 6 out of 10 cases. There were a variety of underlying liver diseases, but cases were enrichment for chronic hepatitis B, P=0.006. Interestingly, at the molecular level, this variant was strongly associated with the alternative lengthening of telomere (ALT) phenotype by telomere FISH. ALT is a telomerase-independent mechanism of telomere maintenance and is found in approximately 8% of unselected hepatocellular carcinomas. In contrast, 11/12 (92%) of the cases of chromophobe hepatocellular carcinoma with abrupt anaplasia were ALT-positive. In summary, we propose that chromophobe hepatocellular carcinoma with abrupt anaplasia represents a new subtype of hepatocellular carcinoma with unique morphological and molecular features.

The anaplastic lymphoma kinase (ALK) gene has been found either rearranged or mutated in several neoplasms such as anaplastic large-cell lymphoma, non-small-cell lung cancer, neuroblastoma and anaplastic thyroid cancer. Medulloblastoma (MB) is an embryonic pediatric cancer arising from nervous system, a tissue in which ALK is expressed during embryonic development. We performed an ALK mutation screening in 52 MBs and we found a novel heterozygous germline deletion of a single base in exon 23 (3605delG) in a case with marked anaplasia. This G deletion results in a frameshift mutation producing a premature stop codon in exon 25 of ALK tyrosine kinase domain. We also screened three human MB cell lines without finding any mutation of ALK gene. Quantitative expression analysis of 16 out of 52 samples showed overexpression of ALK mRNA in three MBs. In the present study, we report the first mutation of ALK found in MB. Moreover, a deletion of ALK gene producing a stop codon has not been detected in human tumors up to now. Further investigations are now required to elucidate whether the truncated form of ALK may have a role in signal transduction.

A 52-year-old woman presented with fracture upper end of the left humerus after trivial trauma and aspiration cytology from the lytic lesion in the upper humerus seen on X-ray revealed a metastatic papillary carcinoma from the thyroid. Total thyroidectomy confirmed the papillary carcinoma thyroid. Post-operatively, she was given radioactive iodine (I-131) ablation therapy for 8 years and was asymptomatic during this period; however, for the last 1 year, she has been complaining of swelling in the shoulder, which did not respond to palliative radiotherapy and rapidly increased in size. Disarticulation of the shoulder joint was performed, which showed anaplastic carcinoma on histopathological examination. Anaplastic transformation of papillary carcinoma at the metastatic sites is well documented in the literature and is rare. However, the same has not been reported at the shoulder and from India before. Although soft tissue sarcomas are most common at this site, however, the possibility of anaplastic transformation should be kept in the differential diagnosis of rapidly enlarging painful mass in a known case of metastatic thyroid carcinoma to prevent misdiagnosis.

Background: Nuclear unrest is a term applied to Wilms' tumors (WT) that show nuclear abnormalities close to anaplasia but without abnormal mitoses. p53 is claimed to be associated with anaplasia and poor prognosis. This study was undertaken to evaluate the clinical significance of nuclear unrest and p53 immunostaining in Wilms' tumor., Material and Methods: This is a retrospective study of 63 patients who presented at NCI with Wilms' tumors, and underwent preoperative chemotherapy followed by nephrectomy. Histopathologic assessment and p53 immunohistochemistry were done., Results: WT with nuclear unrest grade III closely resembled anaplastic tumors and both of them (group 1) constituted 19% of cases. Group 1 constituted 29% of cases showing blastema dominant morphology compared to 9.4% of cases without blastema dominant morphology with significant statistical difference (p=0.047). Almost 83% of cases that achieved 1st complete remission were stages I, II and III, while 17% were stages IV and V with significant statistical difference (p<0.001). Stage affected the 3-year relapse-free-survival (RFS) significantly (p=0.014) as it was more in stages I, II and III than in stages IV and V (75.4% versus 50%). Blastema dominant morphology and high risk state significantly lowered the 3-year overall survival (OS) into 54.8% in comparison to 80.9% for cases with non-blastema dominant morphology (p=0.042). Regarding p53 immunohistochemistry, group 1 tumors showed positive p53 more than group 2 with significant statistical difference (p=0.014). p53 Positive immunostaining was significantly associated with high risk nephroblastoma (p=0.004)., Conclusion: Tumor stage and blastema dominant morphology are potent prognostic factors. p53 is linked to blastema dominant morphology. WT with nuclear unrest grade III closely resembles anaplastic WT. It may be appropriate to group tumors with nuclear unrest grade III with anaplastic histology regarding treatment stratification., (Copyright © 2011. Published by Elsevier B.V.)

Objective: To analyse the cytomorphologic spectrum of Wilms tumour (WT) on aspirates, the largest series reported to date., Study Design: Adequate aspirates from paediatric renal tumours over a period of 17 years were reviewed and selected if subsequent excision showed WT or aspirates were diagnostic for WT and clinical/radiological evidence consistent with that diagnosis. Smears were re-examined for the proportion of components, degree of pleomorphism and mitosis., Results: Of 110 aspirates, smears were triphasic in 44 (40.0%), biphasic (blastema and tubules) in 36 (32.7%) and monophasic (blastema alone) in 30 (27.3%). Stromal predominance was seen in 11 aspirates (10.0%) and five showed rhabdomyoblastic differentiation; all 11 were triphasic. Mean mitotic rate was 9.3/5000 cells (range 4-39/5000). Nuclear atypia not amounting to anaplasia and without atypical mitoses was seen in 15 (13.6%); these presented diagnostic problems. Two aspirates (1.8%) were considered anaplastic (unfavourable), both having atypical mitoses. Criteria similar to histology (i.e. 3-fold or more variation in nuclear size, marked hyperchromasia with bizarre nuclei and atypical mitoses in a biphasic or triphasic aspirate) helped in distinguishing anaplastic WT. Histopathological correlation in 67 cases showed good correlation of blastemal predominance, stromal predominance and anaplastic histology with the corresponding cytology. However, 9/27 (33.3%) triphasic tumours had only blastemal cells on corresponding aspiration because of sampling error. Cytokeratin was positive in 4 of 20 aspirates with blastema alone., Conclusions: Aspirates from WT were triphasic or biphasic in the majority (72.7%), permitting cytological diagnosis, which was improved by cytokeratin immunocytochemistry. Blastemal and stromal predominance on histology correlated well with cytology, but many triphasic tumours showed only blastema on aspiration. Anaplastic WT can be detected on aspirates using criteria similar to histology., (© 2010 Blackwell Publishing Ltd.)

Background: The aim of this study was to review institutional outcomes for anaplastic thyroid cancer treated with conformal 3-dimensional radiotherapy (3DRT) or intensity-modulated radiotherapy (IMRT)., Methods: In all, 53 consecutive patients were analyzed. Thirty-one (58%) patients were irradiated with curative intent. Median radiation dose was 55 Gray (Gy; range, 4-70 Gy). Thirteen (25%) patients received IMRT to a median 60 Gy (range, 39.9-69.0 Gy). Thirty-nine (74%) patients received chemotherapy with radiation., Results: The Kaplan-Meier estimate of overall survival (OS) at 1 year for definitively irradiated patients was 29%. Patients without distant metastases receiving >or=50 Gy had superior survival outcomes; 5 such patients had no evidence of disease at last follow-up. Use of IMRT versus 3DRT did not influence toxicity., Conclusions: Outcomes for anaplastic thyroid cancer treated with 3DRT or IMRT remain equivalent to historical results. Healthy patients with localized disease who tolerate full dose irradiation can potentially enjoy prolonged survival. Biologically targeted radiosensitization merits prioritized investigation., ((c) 2009 Wiley Periodicals, Inc.)

Clear cell meningioma (CCM) is an uncommon variant of meningioma, corresponding to WHO grade II. We present two cases of CCMs with anaplastic features in the intracranial and intraspinal region. The first case is a 65-year-old male who gradually developed changes in behavior over a period of 1 year. The second case is a 35-year-old female who presented with a 7-month history of posterior cervicothoracic pain and dysuria for 1 week. Magnetic resonance imaging revealed an intracranial lesion in the right frontal lobe in the male patient, and an intradural extramedullary lesion at C7 in the female patient. On histological examination, both tumors partly exhibited unusual anaplastic appearances with nuclear pleomorphism, high mitotic activity and necrosis, distinct from classical CCMs. Tumor cells were immunoreactive to epithelial membrane antigen (EMA) and vimentin, with a high MIB-1 index up to 40%. Total excision was performed. The male patient was found to have developed local recurrence and lateral ventricle metastasis 3 months after surgery. A diagnosis of CCM with anaplastic features was made (WHO grade III). Based on its aggressive behavior, we recommend postoperative adjuvant radiotherapy or chemotherapy even if total excision of the tumor has been performed, and MRI scans every 3-6 months during the first period of follow-up., ((c) 2009. Published by Elsevier GmbH. All rights reserved.)

Background: Cystic tumors of ovary, whether benign, borderline, or malignant may be associated with mural nodule of various types, including sarcomas, sarcoma-like mural nodules (SLMN), and foci of anaplastic carcinoma. Cases of serous borderline ovarian tumor with mural nodules of mixed type are very rare., Case: A 54-year-old woman referred with abdominal swelling. Imaging studies revealed a huge mass localized in pelvis and lower abdomen and grade 1-2 left renal hydronephrosis. Preoperative Ca-125 was 798 U/ml. In exploratory laparotomy there was a 16 cm mass adherent to lateral abdominal wall and intestines. Adhesiolysis and de-bulking surgery were performed including bilateral pelvic, para-aortic lymphadenectomy, appendectomy and omentectomy. Left ureter was found to be dilated because of the infiltration of distal part by the tumor, so distal ureteral resection and neoureterocystostomy were performed. Final pathology revealed borderline serous ovarian tumor with mural nodules which were consisted of SLMNs, multiple and sharply demarcated from the adjacent tumor, and sarcomatous nodules showing infiltrative appearance in metastatic regions. Mural nodules showed a positive reaction for vimentin and SMA but were negative for cytokeratin and also necrosis, hemorrhage, and 10-15 mitoses in 10 high power fields were noted. She had postoperative chemotherapy and follow-up is going on without metastases in her first year., Conclusion: The existence of sarcomatous nodules combined with the SLMN necessitates a careful histologic analysis for treatment and the determination of prognosis. However, too few cases of mixed type mural nodules have been published to warrant a conclusion regarding their prognosis.

Objective: Malignant intraventricular meningiomas are very rare. To the best of our knowledge, only eleven cases have been reported thus far. Seven of them developed cerebrospinal fluid (CSF) metastases. We present herein the first case of a malignant intraventricular meningioma with extraneural metastases., Clinical Presentation: We report a 44 year-old-man with a history of progressive headache and disorientation. Magnetic resonance imaging (MRI) revealed a 5-cm homogeneously-enhancing mass in the right trigone., Intervention: The lesion was totally resected via a parietooccipital transcortical approach. Histological examination demonstrated an atypical meningioma. Thereafter, the tumor recurred twice. At first recurrence, the tumor was completely removed again and external radiotherapy was administered. At surgery at second recurrence, the tumor was more aggressive, invading the brain parenchyma. Histological examination showed anaplastic meningioma. The patient was readmitted to hospital with fever and pain in right hypochondrium. Abdominal ultrasound examination disclosed multiple hypoechoic liver lesions. Biopsy was consistent with liver metastases of a malignant meningioma. The patient died of acute liver failure seven months after initial diagnosis., Conclusion: Malignant intraventricular meningiomas are prone to recur and develop metastases, mainly through the CSF. Nevertheless, our case shows that extraneural metastases are also possible. Therefore, when systemic deterioration occurs in a patient with a malignant intraventricular meningioma, metastases to extraneural organs such as the liver must be ruled out.

Dedifferentiation is a well recognized, if sometimes controversial, form of tumor progression in certain types of soft tissue and bone sarcoma, and confers a worse prognosis when compared with the low-grade counterpart. To date, dedifferentiation has not been described in solitary fibrous tumor (SFT). Among 948 cases of both intrathoracic and extrathoracic SFTs in our files accessioned between 1988 and 2008, we identified 8 cases of conventional SFT with a discrete anaplastic component, which we believe represents dedifferentiation. These occurred in 3 men and 5 women, 40 to 76 years old (median 60 y), and measured 3.4 to 20.0 cm (median 8.5 cm). Two cases were intrathoracic, 2 were located in the deep soft tissue of thigh, and single cases were located in the omentum, scalp, retroperitoneum, and abdominal wall. In addition to typical features of benign-appearing SFT there was an abrupt transition to nondistinctive high-grade sarcoma in all cases. The latter included epithelioid, round cell, and/or spindle cell components with increased mitotic activity, necrosis, and cystic degeneration. By immunohistochemistry, 7 of 8 cases were CD34 positive in the usual SFT areas, whereas 5 showed loss of CD34 in the poorly differentiated component. Six of 7 cases stained for p53 and p16 showed either negative or scattered positive cells in well-differentiated SFT areas, in contrast to positive or stronger and more diffuse staining in the high-grade component. Follow-up information available in 7 patients ranged from 1 to 58 months (mean 24 mo). Three patients with the largest tumors (9.0, 17.0, and 20.0 cm) died of disease, whereas 3 patients whose tumors measured 8.0 cm or less were treated by surgical excision only, and show no evidence of disease but with only limited follow-up. One patient with an 11.5 cm intrathoracic tumor is alive with disease at 58 months after recurrence and metastasis. We describe, apparently for the first time, what seems, at least in our view, to be dedifferentiation in primary SFT. Our results demonstrate that dedifferentiation in SFT, comparable with that in other low grade/intermediate soft-tissue tumors, poses a higher risk of tumor recurrence and/or metastasis, most notably in large and deep-seated tumors. Similar to other dedifferentiated sarcomas, abrupt transition between low grade and high-grade areas is typically observed with loss of CD34 positivity. The p53 and p16 overexpression in the high-grade component is common as in other dedifferentiated lesions, perhaps pertaining to the underlying molecular mechanism.

Background: MHC class I expression by cancer cells enables specific antigen recognition by the immune system and protection of the host. However, in some cancer types MHC class I expression is associated with an unfavorable outcome. We explored the basis of MHC class I association with unfavorable prognostic marker expression in the case of medulloblastoma., Methods: We investigated expression of four essential components of MHC class I (heavy chain, beta2m, TAP1 and TAP2) in 10 medulloblastoma mRNA samples, a tissue microarray containing 139 medulloblastoma tissues and 3 medulloblastoma cell lines. Further, in medulloblastoma cell lines we evaluated the effects of HLA class I engagement on activation of ERK1/2 and migration in vitro., Results: The majority of specimens displayed undetectable or low levels of the heavy chains. Medulloblastomas expressing high levels of HLA class I displayed significantly higher levels of anaplasia and c-myc expression, markers of poor prognosis. Binding of beta2m or a specific antibody to open forms of HLA class I promoted phosphorylation of ERK1/2 in medulloblastoma cell line with high levels, but not in the cell line with low levels of HLA heavy chain. This treatment also promoted ERK1/2 activation dependent migration of medulloblastoma cells., Conclusion: MHC class I expression in medulloblastoma is associated with anaplasia and c-myc expression, markers of poor prognosis. Peptide- and/or beta2m-free forms of MHC class I may contribute to a more malignant phenotype of medulloblastoma by modulating activation of signaling molecules such as ERK1/2 that stimulates cell mobility.

Wilms tumor can appear with a wide spectrum of morphologic features and can sometimes cover or delay the recognition of other clinicopathologic entities of the kidney. We present a case of a new tumor entity of the kidney, namely the anaplastic sarcoma of the kidney, a tumor of high malignancy.

In a 43-year-old man, an intramedullary spinal cord tumor spreading from the level of the T2 to T5 vertebrae was subtotally resected. The tumor predominantly consisted of a fascicular proliferation of spindle cells having bland nuclei and bipolar, long cytoplasmic processes, and a few perivascular pseudo-rosettes were found. Although there were no true ependymal rosettes, intracytoplasmic dot-like immunoreactivity for epithelial membrane antigen (EMA) was found in a few cells. In some areas, a dense and diffuse proliferation of anaplastic, short-spindled cells having hyperchromatic nuclei and scant cytoplasm was noted, and the Ki-67 labeling index was remarkably higher (18.2%) in these areas. Neither microvascular proliferation nor necrosis was observed. In the boundary region, these two areas showed gradual transition from one to the other. The patient has remained free from recurrence for 10 months postoperatively. This is the first documentation of tanycytic ependymoma in which tumor cells showed anaplastic cytological features.

A 5-year-old female spayed domestic shorthair cat was presented for evaluation of tetraparesis. The neurologic lesion was localized to the cervical spinal segment (C1-C6). A left axillary mass was identified, and the results of fine needle aspiration cytology indicated malignant round cell neoplasia of possible histiocytic origin. The cells were large, had marked anisocytosis and anisokaryosis, occasional bi- and multinucleation, and cytoplasmic vacuolation. Euthanasia was performed due to the poor prognosis associated with severe, progressive neurologic signs and a malignant neoplasm. Postmortem examination revealed spinal cord compression and an extradural mass at the C1-C2 spinal segment, with neoplastic cells in the adjacent vertebral bodies, surrounding skeletal muscle, left axillary lymph node, and bone marrow from the right femur. The initial histologic diagnosis was anaplastic sarcoma, but immunohistochemical results indicated the cells were CD20+ and CD45R+ and CD3-, compatible with a diagnosis of B-cell lymphoma. CD79a staining was nonspecific and uninterpretable. Weak to moderate CD18 positivity and E-cadherin positivity were also observed. Clonality of the B-cell population could not be demonstrated using PCR testing for antigen receptor gene rearrangement. To the authors' knowledge, this is the first reported case of a feline spinal anaplastic B-cell lymphoma exhibiting bi- and multinucleated cells. The prognostic significance of this cell morphology and immunophenotype is unknown.

: A 14-year-old male Labrador Retriever was presented for lethargy and collapse. On physical examination, numerous abnormalities were found, including a large ventral neck mass (100 cm(3)) in the area of the thyroid gland. Fine-needle aspirates revealed 2 apparent populations of cells: one suspected to be a well-differentiated thyroid carcinoma, and the other consisting of large pleomorphic to spindloid cells suggestive of sarcoma. Two days later, the dog died at home. A full necropsy was not performed, but examination of the head and neck revealed a well-encapsulated mass adjacent to the cranial trachea and larynx. A section of the mass was evaluated histologically and a diagnosis of anaplastic thyroid carcinoma was made. Immunohistochemical evaluation with antibodies to thyroglobulin, cytokeratin, and vimentin confirmed distinct populations of malignant epithelial and malignant mesenchymal cells, and the diagnosis was amended to thyroid carcinosarcoma. Thyroid carcinosarcoma is a rare neoplasm in dogs in which the cell type comprising the mesenchymal component can vary. Immunochemistry to demonstrate the 2 cell types may be necessary to differentiate thyroid carcinosarcoma from anaplastic thyroid carcinoma.

Background: Anaplastic thyroid carcinoma is rare but is one of the most aggressive malignancies. Therefore, accurate diagnosis is important in order to provide appropriate therapy., Purpose: To establish useful computed tomographic (CT) criteria for differentiating anaplastic carcinoma from other thyroid masses., Material and Methods: The CT scans of nine patients with anaplastic carcinomas were retrospectively reviewed and compared with those of 32 patients with papillary carcinomas (n = 12) or benign lesions (n = 20) exceeding a maximum diameter of 2.0 cm. Image analysis was performed according to the following CT parameters: size, margin (well defined or ill defined), composition (cystic, mixed, or solid), mean attenuation value, ratio of attenuation of the mass to that of the adjacent muscle (M/m attenuation ratio), necrosis (present or absent), and calcification (stippled, nodular, or absent) of the thyroid mass; and tumor-spreading patterns including the presence of surrounding normal thyroid tissue in the involved lobe, involvement of the contralateral thyroid lobe, extension into the adjacent structures, and cervical lymphadenopathy., Results: Anaplastic carcinomas appeared as large (average 4.6 cm), solid (100%), and ill-defined (88.9%) masses accompanied by necrosis (100%), nodular calcification (44.4%), direct invasion into the adjacent organs (55.6%), and cervical lymph node involvement (77.8%). Tumor necrosis was the most valuable parameter in differentiating anaplastic carcinomas from other thyroid masses. Patient age (>70 years) and low attenuation value on postcontrast scan (attenuation value <100 HU, or M/m attenuation ratio <1.3) are also helpful predictors for anaplastic carcinoma., Conclusion: If a patient is older than 70 years of age and has a large necrotic thyroid mass of low attenuation, anaplastic carcinoma should be included in the differential diagnosis.

A radiation-induced cerebellar glioma is extremely rare, and the etiology of such a tumor is unknown. We report a rare case of hemorrhagic cerebellar anaplastic glioma occurring 12 years after prophylactic cranial radiotherapy for acute lymphocytic leukemia. We discuss the etiologies of the radiation-induced hemorrhagic cerebellar glioma as a secondary malignancy after radiotherapy.

The purpose of this study was to assess the relationship between progression-free survival (PFS) in patients treated with DFMO + PCV (procarbazine, CCNU, vincristine) chemotherapy for malignant gliomas with tumor cell ornithine decarboxylase (ODC) activity. Formalin-fixed slides were obtained for study patients with anaplastic gliomas (AGs) and glioblastoma treated on protocol DM92-035. ODC levels were measured using an antibody to ODC coupled to Alexa 647 dye (Ab-ODC-Alexa 647). Ab-ODC-Alexa 647 intensity in transgenic murine hearts of differing ODC activity was used to calculate ODC activity in tumor cell nucleoplasm. In total, tumor specimens for 31 of 114 (27%) patients treated on the AG strata and 10 patients from the GBM strata were obtained. We found that tumor ODC level heterogeneity increased with increasing tumor malignancy. In a Cox proportional hazards model, PFS was found to be inversely related to median tumor ODC activity, with an unadjusted hazard ratio for median ODC group (>3.3 vs. 3.3 nmol/30 min/mug protein. Of AG tumors in which ODC activity was evaluated, 26% had ODC levels > 3.3 nmol/30 min/mug protein. This study shows that Ab-ODC-Alexa 647 fluorescence intensity can be used as a surrogate marker of ODC biochemical activity in AGs and can predict PFS to DFMO-based chemotherapy., ((c) 2007 Wiley-Liss, Inc.)

We report a case of anaplastic ganglioglioma. A 45-yr-old woman was admitted with a 5-month history of headache and dizziness, both of which progressed slowly. Preoperative magnetic resonance imaging revealed a strong enhancing mass in the left frontal lobe extending to the cingulate gyrus. Adjuvant radiation therapy and chemotherapy were given after gross total resection of the tumor. Histological and immunohistochemical studies showed an anaplastic ganglioglioma. Gangliogliomas of the central nervous system are rather uncommon tumors, and anaplastic ones are extremely rare. The pertinent literature regarding gangliogliomas is reviewed.

The authors report the case of a 7-year-old boy with a history of developmental delay who presented with aggressive behavior. A magnetic resonance (MR) image showed a mass lesion originating from the cerebellar vermis with an atypical folial pattern and contrast enhancement. Histologically, the subtotally resected specimen consisted mostly of neuropil with nodular foci of ganglion cells. Lhermitte-Duclos disease (LDD) was diagnosed in the patient. A retrospective review of the tissue sections showed a nidus of associated astrocytic proliferation, suggesting a diagnosis of ganglioglioma. Five years later, the patient experienced an altered mental state and a facial droop. An MR image revealed a cerebellar mass with cystic areas and an enhancing nodule. The resected tissue specimen consisted primarily of a mixed proliferation of glial and ganglion cells consistent with a ganglioglioma. Two years later, a third craniectomy was performed in the patient for worsening headache and ataxia. Histologically, the tumor showed progressive anaplasia and was most accurately classified as an anaplastic ganglioglioma. Immunohistochemically, most of the tumor cells were immunoreactive for anti-phospho-mammalian target of rapamycin (mTOR) and phospho-S6 ribosomal protein antibodies. In contrast, the subpopulation of neoplastic ganglion cells in the tissue, particularly from the first surgery, did not express phosphatase and tensin homolog deleted from chromosome 10 (PTEN). This immunohistochemical pattern suggests that the large dysplastic ganglion cells (the gangliocytomatous component) forming the greater part of the lesion were associated with activation of the phosphatidylinositol 3-kinase-PTEN/Akt/mTOR signaling pathway, a feature previously reported in LDD. This case represents the first report of an anaplastic ganglioglioma arising in an LDD-like lesion.

The histological appearance of a meningioma is an important predictor of tumor behavior and is frequently a factor in decisions concerning therapy. The relationship between histological features and prognosis is formalized in grading schemes such as those published by the World Health Organization (WHO), most recently in 2007. Although the latest edition is an improvement over previous grading schemes, the WHO scheme still fails to fully address a variety of important issues regarding the relationship between meningioma histological characteristics and behavior. In particular, routine histological examination fails to identify the subset of Grade I tumors that behave aggressively. Because of this, many additional prognostic markers that require immunohistochemical, cytogenetic, or molecular techniques to evaluate are under investigation. Only one, immunohistochemistry for the proliferation marker, Ki 67 (MIB-1), is used routinely and it has only limited utility. It is hoped that an understanding of the genetic changes that underlie tumor progression will improve healthcare professionals' ability to predict the behavior of meningiomas.

Large cell/anaplastic (LC/A) medulloblastoma (MB) is a recently recognized variant of medulloblastoma known to be associated with an advanced stage and a poor prognosis. Although Eberhart et al. suggested histopathologic grading of medulloblastoma in 2002, no consensus has been reached in terms of determining the criteria of an LC/A variant, and its biological behavior continues to be the subject of debate. We retrospectively analyzed 74 cases (range 0.25-15 years) of MB clinicopathologically using the criteria established by Eberhart et al. The LC/A variant was identified in 16 cases (22% of MB cases), five of which showed a poor outcome. Most LC/A variant cases revealed synaptophysin immunoexpression (75%), but no epidermal growth factor receptor (EGFR) expression. Expression of synaptophysin, NeuN, GFAP, p53, c-erbB2, and EGFR did not differ in LC/A and non-LC/A variants. Seven of the 74 cases of medulloblastoma showed erbB2 amplification by FISH, four of which were LC/A variants. N-myc amplification was observed in only one LC/A variant, but no c-myc amplification was found. In patients younger than 10 years, the LC/A variant showed a significantly poorer outcome than the non-LC/A variant (P = 0.02), while no difference was found in older patients. Multivariate analysis revealed only metastasis on MRI and p53 expression, but not anaplasia as unfavorable prognostic factors. Our study suggests that prognostic implications of anaplasia in medulloblastoma are uncertain, and that the reproducibility of the histopathologic criteria of the LC/A variant should be reassessed before they can be applied in practical use.

Medulloblastoma (WHO grade IV) is an embryonal tumour of the cerebellum and the most common malignant central nervous system tumour in children. Despite significant advances in treatment, 5-year survival rates are still less than 70%, suggesting the presence of subgroups with different response to radio/chemotherapy. In the present study, we re-evaluated a series of 347 medulloblastomas from the SIOP II clinical trial of the International Society of Paediatric Oncology to identify features predictive of clinical outcome. Relapse free survival for medulloblastomas with severe anaplasia [5-year rate: S(60)=49.5%], was significantly shorter than for tumours with moderate or mild anaplasia S(60)=65.4%; P=0.001). The difference between both groups was even larger when the presence or absence of extensive apoptosis was included (46.5 vs. 66.7%; P=0.0216). Other histological features including nodularity, necrosis, vascular proliferation and the presence of beta-catenin mutations (7% of cases) were not predictive for relapse free survival. These findings indicate that degree of anaplasia is the most significant histologic feature predictive of the survival of medulloblastoma patients.

Gangliogliomas of the spinal cord are very unusual and the anaplastic variant of these tumors is extremely rare. In spinal anaplastic gangliogliomas, malignant changes (hypercellularity, vascular proliferation, necrosis, high numbers of mitotic figures) are typically evident in the glial element of the tumor. Gangliogliomas can arise in any part of the central nervous system and the features of adult and pediatric cases differ significantly. We describe the case of a pediatric patient who had a spinal anaplastic ganglioglioma extending from the T9 to the L3 level. The signs at presentation were bilateral knee flexion (quadriceps weakness) while walking and intermittent urinary incontinence. The tumor was partially resected with an ultrasonic aspirator, but the patient's neurological status deteriorated as a result and adjuvant radiotherapy did not resolve the deficit., (Copyright 2006 S. Karger AG, Basel.)

The authors proposed a possible preoperative diagnostics of the degree of supratentorial brain gliom anaplasia using statistical analysis methods. It relies on a complex examination of 934 patients with I-IV degree anaplasias, which had been treated in the Institute of Neurosurgery from 1990 to 2004. The use of statistical analysis methods for differential diagnostics of the degree of brain gliom anaplasia may optimize a diagnostic algorithm, increase reliability of obtained data and in some cases avoid carrying out irrational operative intrusions. Clinically important signs for the use of statistical analysis methods directed to preoperative diagnostics of brain gliom anaplasia have been defined

Aim: Metastases from lung cancer to gastrointestinal tract are not rare at postmortem studies but the development of clinically significant symptoms from the gastrointestinal metastases is very unusual., Methods: Formalin-fixed, paraffin-embedded tissues were cut into 5 microm thick sections and routinely stained with hematoxylin and eosin. Some slides were also stained with Alcian-PAS. Antibodies used were primary antibodies to pancytokeratin, cytokeratin 7, cytokeratin 20, epithelial membrane antigen, vimentin, smooth muscle actin and CD-117., Results: We observed three patients who presented with multiple metastases from large cell bronchial carcinoma to small intestine. Two of them had abdominal symptoms (sudden onset of abdominal pain, constipation and vomiting) and in one case the tumor was incidentally found during autopsy. Microscopically, all tumors showed a same histological pattern and consisted almost exclusively of strands and sheets of poorly cohesive, polymorphic giant cells with scanty, delicate stromas. Few smaller polygonal anaplastic cells dispersed between polymorphic giant cells, were also observed. Immunohistochemistry showed positive staining of the tumor cells with cytokeratin and vimentin. Microscopically and immunohistochemically all metastases had a similar pattern to primary anaplastic carcinoma of the small intestine., Conclusion: In patients with small intestine tumors showing anaplastic features, especially with multiple tumors, metastases from large cell bronchial carcinoma should be first excluded, because it seems that they are more common than expected.