Biologic Diversity Research Articles

Understanding Genetics: A Primer for Occupational Health Practice

Because biologic diversity is essential for life, genes have developed many versions that may be further modified by interaction with other genes and with environmental factors. Polymorphic alterations of genetic material influence drug responses, predisposition or resistance to disease, and susceptibility to environmental toxicity. The occupational health professional should be aware of rapidly changing genetic tests, be able to distinguish between screening and diagnostic modalities, be able to access genetic resources to find the latest protocols, and should consider the ethical, legal, and social implications of genetic testing in the workplace.

Independent Validation of Prognostic Relevance of a Previously Reported Gene-Expression Signature in Acute Myeloid Leukemia (AML) with Normal Cytogenetics (NC): A Cancer and Leukemia Group B (CALGB) Study.

The heterogeneous clinical outcome of NC AML patients (pts), who constitute about 45% of AML pts and are assigned to an intermediate-risk category, likely reflects a biologic diversity. Although mutations in FLT3, MLL, CEBPA and NPM genes and overexpression of BAALC at diagnosis can stratify prognostically NC AML, novel approaches may improve the predictive value of these markers. cDNA microarrays were used recently to gain insight into the biologic and clinical heterogeneity of NC AML. Bullinger et al. (NEJM 2004; 350:1605) reported a set of 133 genes represented by 149 cDNAs (Suppl. Table 6, www.ncbi.nlm.nih.gov/geo/ , accession #GSE425) that separated NC AML into 2 cluster-based groups with significant differences in overall survival (OS) (Bullinger et al. Fig. 4D), albeit the number of pts analyzed was small. Hence, we sought to validate this signature in a larger, independent set of adults (n=64), <60 years, with primary NC AML, treated on CALGB 9621. Pretreatment samples were analyzed using Affymetrix U133 plus 2.0 GeneChips (Affymetrix, Santa Clara, CA). Normalization to a baseline array with median overall brightness and probe-set level expression computation were performed with dChip version 1.3. The log (base 2) of expression values were exported to BRB-ArrayTools v3.2.3 for analysis. Of the 133 genes from Bullinger et al., 81, represented by 157 probe sets, were on the Affymetrix chip and were expressed in ≥ 25% of our specimens. Hierarchical clustering, using the 157 probe sets, resulted in cluster I, corresponding to the poor-, and cluster II, corresponding to the good-outcome group in Bullinger et al. With a 4.7-year median follow-up, cluster I pts had lower estimated 5-year DFS (24% vs. 60%; P=.001; Fig. 1A) and OS (28% vs. 64%; P=.001; Fig. 1B) rates than cluster II pts. The 2 groups had similar complete remission rates (81% vs. 89%). With regard to pretreatment features, cluster I pts were younger (P=.06), had lower % skin infiltrates (P=.03), higher % marrow blasts (P=.06), different distribution of FAB subtypes (P=.04) with a high % M4, and higher incidence (67% vs. 12%) of FLT3 internal tandem duplication (ITD) (P<.001). A multivariable model including gene-expression cluster membership, FLT3 ITD status by Genescan analysis, and their interaction was fit to determine if the gene-expression signature added any information once accounting for FLT3 ITD status. A significant interaction of the gene-expression signature and FLT3 status was observed for DFS (P=.009) and OS (P=.01), where the gene-expression signature predicted DFS (P=.02) and OS (P=.02) only in pts with wild-type (wt) FLT3 but not in those with FLT3 ITD, who had adverse outcome irrespective of the gene-expression signature. Cluster I pts with wtFLT3 had >3x the risk of relapse and death than the corresponding cluster II pts. In conclusion, we independently validated for the first time the prognostic value of a gene-expression signature in NC AML. This expression profiling appears particularly useful in predicting outcome of pts lacking the prognostically adverse FLT3 ITD. [Display omitted]

DIVERSITY OF BAT-ASSOCIATED LEPTOSPIRA IN THE PERUVIAN AMAZON INFERRED BY BAYESIAN PHYLOGENETIC ANALYSIS OF 16S RIBOSOMAL DNA SEQUENCES

The role of bats as potential sources of transmission to humans or as maintenance hosts of leptospires is poorly understood. We quantified the prevalence of leptospiral colonization in bats in the Peruvian Amazon in the vicinity of Iquitos, an area of high biologic diversity. Of 589 analyzed bats, culture (3 of 589) and molecular evidence (20 of 589) of leptospiral colonization was found in the kidneys, yielding an overall colonization rate of 3.4%. Infection rates differed with habitat and location, and among different bat species. Bayesian analysis was used to infer phylogenic relationships of leptospiral 16S ribosomal DNA sequences. Tree topologies were consistent with groupings based on DNA-DNA hybridization studies. A diverse group of leptospires was found in peri-Iquitos bat populations including Leptospira interrogans (5 clones), L. kirschneri (1), L. borgpetersenii (4), L. fainei (1), and two previously undescribed leptospiral species (8). Although L. kirschenri and L. interrogans have been previously isolated from bats, this report is the first to describe L. borgpetersenii and L. fainei infection of bats. A wild animal reservoir of L. fainei has not been previously described. The detection in bats of the L. interrogans serovar Icterohemorrhagiae, a leptospire typically maintained by peridomestic rats, suggests a rodent-bat infection cycle. Bats in Iquitos maintain a genetically diverse group of leptospires. These results provide a solid basis for pursuing molecular epidemiologic studies of bat-associated Leptospira, a potentially new epidemiologic reservoir of transmission of leptospirosis to humans.

OC10.04: Predicting outcomes for fibroid therapies: clinical research and genetics

Despite their importance to clinical gynecology, uterine leiomyomas, commonly known as fibroids, have rarely been the subject of clinical outcomes research. Additionally the high risk of recurrent fibroid formation following conservative therapy makes predictors of outcome useful in counseling women. There is even little information regarding treatment outcomes with standard demographic and anthropometrics predictors of treatment success of failure. The increasing use of minimally invasive therapies to target specific myomas makes prediction of high-risk women more important than when hysterectomy was the standard therapy. Understanding the biologic and genetic diversity underlying the clinical heterogeneity of this disease will markedly change future treatments. Several genes including fumurate hydratase (FH) and high mobility group A2 (HMGA2) have been identified as important in the formation and growth of uterine leiomyomas. Genotype/phenotype correlations are also beginning to be identified, including several instances where the risk of malignant disease is increased. The power of advanced imaging also may provide markers of specific phenotypes allowing non-invasive genotype/phenotype correlation. A genome-wide scan such as the Finding Genes for Fibroid Project (www.fibroids.net) will also be instrumental in finding additional genes, which influence disease outcome. This is especially important because genes identified to date appear to primarily affect Caucasian women and the increased relative risk and incidence rates in AfricanAmerican women has been well documented. Furthermore, research in genetic epidemiology will set the stage for prevention strategies for high-risk young women and potentially develop new therapeutic targets.

Tissue Engineering of ACL Replacements

ACL injuries affect a large number of people, and such injuries lead to joint instability and increased risk for degenerative joint disease later in life. Reconstruction of the damaged joint using an in vitro engineered ACL replacement construct is becoming more of a reality and avoids the risk of allografts or the donor site morbidity associated with autografts. Whereas progress has been made in generating engineered tissues for ACL replacement in model systems, several challenges still remain. These include the choice of a suitable scaffold (components of normal tissue or biodegradable materials), the density and differentiation state of appropriate cells, the biomechanical environment required for optimal in vitro generation, parameters required for successful engraftment, and the biologic diversity of the host. Whereas the solutions to these challenges are being addressed by various groups and progress is being made, there are still gaps in our understanding of how to generate, implant, and ensure the success of these engineered tissues. This review discusses the current status of engineering ACL replacements and the challenges remaining.

Learning More from Microarrays: Insights from Modules and Networks

Global gene expression patterns can provide comprehensive molecular portraits of biologic diversity and complex disease states, but understanding the physiologic meaning and genetic basis of the myriad gene expression changes have been a challenge. Several new analytic strategies have now been developed to improve the interpretation of microarray data. Because genes work together in groups to carry out specific functions, defining the unit of analysis by coherent changes in biologically meaningful sets of genes, termed modules, improves our understanding of the biological processes underlying the gene expression changes. The gene module approach has been used in exploratory discovery of defective oxidative phosphorylation in diabetes mellitus and also has allowed definitive hypothesis testing on a genomic scale for the relationship between wound healing and cancer and for the oncogenic mechanism of cyclin D. To understand the genetic basis of global gene expression patterns, computational modeling of regulatory networks can highlight key regulators of the gene expression changes, and many of these predictions can now be experimentally validated using global chromatin-immunoprecipitation analysis.

Evidence for Distinct Pathomechanisms in Genetic Subgroups of Chronic Lymphocytic Leukemia Revealed by Quantitative Expression Analysis of Cell Cycle, Activation, and Apoptosis-Associated Genes

In patients with chronic lymphocytic leukemia (CLL), the VH mutation status and genomic aberrations (13q-, +12q, 11q-, 17p-) identify distinct prognostic subgroups. The aim was to elucidate biologic mechanisms through which these genetic markers may exert their pathogenic influence. Twenty-four genes involved in apoptosis, cell cycle, B-cell activation, and B-cell receptor (BCR) signaling were analyzed by real-time quantitative reverse transcription polymerase chain reaction (RQ-PCR) in 82 CLL cases constituting prototypic genetic CLL subgroups as defined by the VH mutation status and the genomic aberrations 13q-, +12, 11q-, and 17p-. The VH mutation subgroups were characterized by a differential expression of the BCR associated genes ZAP70 and PI3K. Among the subgroups defined by genomic aberrations, there was a deregulation of candidate genes from the affected critical genomic regions such as CDK4 (up), ATM (down), and TP53 (down) in the groups +12, 11q-, and 17p-, respectively. Additionally, the genomic subgroups were characterized by a significant deregulation of cell cycle and apoptosis regulators: AKT (up) in 13q, E2F1 (up) in +12, MYC (up) and BCL-2 (down) in 17p-, and CCND3 (down) in 11q- as well as 17p-. The 17p- subgroup showed an additional down-regulation of BCR-associated genes such as SYK and PI3K. The characteristic gene expression patterns observed implicate a differential regulation of cell cycle, apoptosis, and BCR signaling in the genetic subgroups illustrating distinct pathomechanisms and are evidence for a gene dosage effect being operative in CLL. These findings link the biologic diversity and clinical heterogeneity of CLL.

Ph-Chromosome-positive chronic myeloid leukemia with associated bone marrow mastocytosis

The concurrent development of chronic myeloid (CML) or myelomonocytic (CMML) leukemia in patients with systemic mastocytosis (SM) is a well recognized phenomenon. Although the leukemia often resembles CML in morphological and in clinical terms, a Ph-Chromosome-positive variant has not been reported in SM so far. We here describe a 43-year-old female patient with typical Ph-Chromosome-positive CML in whom a co-existing bone marrow mastocytosis, a special subvariant of SM, was diagnosed. RT-PCR analysis revealed the typical p210 kDa form of BCR/ABL in leukemic cells. The diagnosis SM was based on the typical focal aggregates of spindle-shaped mast cells (MC) in the bone marrow, expression of CD25 in MC, and the c- kit mutation D816V, which was detectable in microdissected bone marrow MC, but not in microdissected leukemic cells, suggesting the presence of two different (sub)clones of neoplastic cells. Therapy with the BCR/ABL-targeting drug Imatinib (STI571) resulted in complete cytogenetic remission of CML. Together, our case provides further evidence for the biologic diversity of leukemias that may occur in patients with SM. The exact knowledge of the pathology and target-profile of the associated leukemias in SM have important therapeutic implications.

Compilation of Historical Local Lymph Node Data for Evaluation of Skin Sensitization Alternative Methods

Within the toxicology community, considerable effort is directed toward the development of alternative methods for skin sensitization testing. The availability of high-quality, relevant, and reliable in vivo data regarding skin sensitization is essential for the effective evaluation of alternative methodologies. Ideally, data derived from humans would be the most appropriate source because the test methods are attempting to predict a toxicologic effect in humans. Unfortunately, insufficient human data of the necessary quality are available, so it is necessary to rely on the best available animal data. In recent years, the local lymph node assay (LLNA) has emerged as a practical option for assessing the skin sensitization potential of chemicals. In addition to accurately identifying skin sensitizers, the LLNA can also provide a reliable measure of relative sensitization potency, information that is pivotal to the successful management of human health risks. To provide a database of robust in vivo data to calibrate, evaluate, and eventually validate new approaches for skin sensitization testing. LLNA data derived from previously conducted studies were compiled from the published literature and unpublished sources. We provide a database that comprises LLNA data on 211 individual chemicals. This extensive chemical data set encompasses both the chemical and biologic diversity of known chemical allergens. To cover the range of relative allergenic potencies, the data set includes data on 13 extreme, 21 strong, 69 moderate, and 66 weak contact allergens, classified according to each allergen's mathematically estimated concentration of chemical required to induce a threefold stimulation index. In addition, there are also 42 chemicals that are considered to be nonsensitizers. In terms of chemical diversity, the database contains data pertaining to the chemical classes represented by aldehydes, ketones, aromatic amines, quinones, and acrylates, as well as compounds that have different reactivity mechanisms. In addition to two-dimensional chemical structures, the physicochemical parameters included are log Kp, log K(o/w), and molecular weight. The list of chemicals contained in the data set represents both the chemical and biologic diversity that is known to exist for chemical allergens and non-allergens. It is anticipated that this database will help accelerate the development, evaluation, and eventual validation of new approaches to skin sensitization assessment.

Enregistrement par les diatomées des variations paléoenvironnementales durant le Sarmatien dans l’aire paratéthysienne (Roumanie)

The diatom assemblages as environmental evolution recording of the Paratethys area during Sarmatian times. This paper is a detailed study based on Sarmatian (Middle Miocene) diatom assemblages, characterized by high biologic productivity and diversity from the Zarand Basin (Romania). A total of 240 diatom taxa were identified, leading to the conclusion that successive environmental variations such as changes in palaeosalinity and palaeobathimetry had taken place during this period. Water-level increases are correlated with marine influx based on the presence of boreal or subtropical marine taxa. Each marine-dominated episode is followed by one of continental influence: an isolated system where freshwater taxa are a common occurrence. To cite this article: S. Saint Martin, C. R. Palevol 4 (2005) .

Continuing evolution of H9N2 influenza viruses in Southeastern China.

H9N2 influenza viruses are panzootic in domestic poultry in Eurasia and since 1999 have caused transient infections in humans and pigs. To investigate the zoonotic potential of H9N2 viruses, we studied the evolution of the viruses in live-poultry markets in Hong Kong in 2003. H9N2 was the most prevalent influenza virus subtype in the live-poultry markets between 2001 and 2003. Antigenic and phylogenetic analysis of hemagglutinin (HA) showed that all of the 19 isolates found except one belonged to the lineage represented by A/Duck/Hong Kong/Y280/97 (H9N2). The exception was A/Guinea fowl/NT184/03 (H9N2), whose HA is most closely related to that of the human isolate A/Guangzhou/333/99 (H9N2), a virus belonging to the A/Chicken/Beijing/1/94-like (H9N2) lineage. At least six different genotypes were recognized. The majority of the viruses had nonstructural (and HA) genes derived from the A/Duck/Hong Kong/Y280/97-like virus lineage but had other genes of mixed avian virus origin, including genes similar to those of H5N1 viruses isolated in 2001. Viruses of all six genotypes of H9N2 found were able to replicate in chickens and mice without adaptation. The infected chickens showed no signs of disease, but representatives of two viral genotypes were lethal to mice. Three genotypes of virus replicated in the respiratory tracts of swine, which shed virus for at least 5 days. These results show an increasing genetic and biologic diversity of H9N2 viruses in Hong Kong and support their potential role as pandemic influenza agents.

Novel IHC reagents targeted by gene expression data predict recurrence in a retrospective breast cancer cohort at the Comprehensive Cancer Institute of Huntsville (CCIH)

9612 Background: Recent gene expression studies have identified novel classes of breast cancer including a basal/myoepithelial class and a subclass of estrogen receptor-expressing patients which have poor outcomes. It remains unclear how many genes or proteins will need to be measured in order to develop diagnostic tools for patient stratification. Methods: Several hundred affinity-purified anti-peptide antisera were generated to targets chosen on the basis of gene expression data. A selected panel of 24 were tested on tissue arrays which contained 422 diagnostic paraffin blocks from breast cancer patients diagnosed at CCIH from 1989 to 2000 (mean follow-up of 65 months). Results: A panel of only four antibodies had a sensitivity of 57% and specificity of 73% (HR=3.0 p<0.01) for identifying patients who recurred. The prognostic values of these markers were independent of ER, lymph node status, stage, grade, and each other as assessed by a Cox multivariate proportional hazard model. Included in the panel were antisera directed at a predicted “Basal” target, BPAG1 (p<0.01), at a predicted “Luminal B” target, SLC7A5 (p<0.01), at a novel cadherin-related protein (p=0.01), and at an antisera directed at a putative methyltransferase expressed in a cell cycle dependent manner (p<0.01). Furthermore, the novel cadherin-related protein and the putative cell cycle regulated methyltransferase showed significant correlations with survival. Conclusions: Novel subclasses of breast cancer associated with poor outcome identified by gene expression studies can be distinguished by a panel of novel IHC antisera. These reagents should prove useful for patient stratification in early stage breast cancer patients. The expanded panel, which distinguishes broader biologic diversity in breast cancer, should prove useful for retrospective and prospective studies designed to identify responder populations in adjuvant clinical trials. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Applied Genomics, Inc. Applied Genomics, Inc. Applied Genomics, Inc.

Novel IHC reagents targeted by gene expression data predict recurrence in a retrospective breast cancer cohort at the Comprehensive Cancer Institute of Huntsville (CCIH)

9612 Background: Recent gene expression studies have identified novel classes of breast cancer including a basal/myoepithelial class and a subclass of estrogen receptor-expressing patients which have poor outcomes. It remains unclear how many genes or proteins will need to be measured in order to develop diagnostic tools for patient stratification. Methods: Several hundred affinity-purified anti-peptide antisera were generated to targets chosen on the basis of gene expression data. A selected panel of 24 were tested on tissue arrays which contained 422 diagnostic paraffin blocks from breast cancer patients diagnosed at CCIH from 1989 to 2000 (mean follow-up of 65 months). Results: A panel of only four antibodies had a sensitivity of 57% and specificity of 73% (HR=3.0 p<0.01) for identifying patients who recurred. The prognostic values of these markers were independent of ER, lymph node status, stage, grade, and each other as assessed by a Cox multivariate proportional hazard model. Included in the panel were antisera directed at a predicted “Basal” target, BPAG1 (p<0.01), at a predicted “Luminal B” target, SLC7A5 (p<0.01), at a novel cadherin-related protein (p=0.01), and at an antisera directed at a putative methyltransferase expressed in a cell cycle dependent manner (p<0.01). Furthermore, the novel cadherin-related protein and the putative cell cycle regulated methyltransferase showed significant correlations with survival. Conclusions: Novel subclasses of breast cancer associated with poor outcome identified by gene expression studies can be distinguished by a panel of novel IHC antisera. These reagents should prove useful for patient stratification in early stage breast cancer patients. The expanded panel, which distinguishes broader biologic diversity in breast cancer, should prove useful for retrospective and prospective studies designed to identify responder populations in adjuvant clinical trials. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Applied Genomics, Inc. Applied Genomics, Inc. Applied Genomics, Inc.

Novel therapies for myelodysplastic syndromes

The assessment of patients with myelodysplastic syndromes (MDS) and the choice of therapies remain challenging. New therapies are now emerging after the identification of molecular targets that result in improvement of hematologic parameters and may hold promise for the prevention of disease progression. A review of the English literature was performed that included original articles and related reviews from MEDLINE (PubMed) and abstracts based on published meeting material. MDS is a heterogeneous group of disorders. Although current classification and prognostic schemes have proven valid to define subgroups, they are insufficient to take into consideration the significant biologic diversity of MDS. New molecular targets are identified as the mosaic of pathophysiologic pathways in MDS is being unraveled. Novel and targeted therapeutic agents, such as the inhibition of farnesyl transferases and receptor tyrosine kinases, more potent thalidomide analogs, and arsenic trioxide, have shown encouraging results and may offer durable benefit to patients with MDS. Although progress has been made in the understanding of clinical manifestations and some of the molecular pathways underlying ineffective hematopoiesis and leukemic transformation in MDS, intensive clinical and laboratory research continues to 1) identify further relevant pathophysiologic pathways, 2) better define MDS subgroups, and 3) develop new drugs based on a clearer understanding of disease biology.

The autoreactivity of anti-phosphorylcholine antibodies for atherosclerosis-associated neo-antigens and apoptotic cells.

Abs specific for phosphorylcholine (PC) are known to contribute to the immune defense against a variety of microbial infections. To assess for other types of binding interactions, we performed surveys of anti-PC Abs of diverse biologic origins and structural diversity and demonstrated a common autoreactivity for oxidatively modified low density lipoprotein and other oxidation-specific structures containing PC-Ags. We also found that cells undergoing apoptosis sequentially express a range of oxidation-specific neo-self PC determinants. Whereas natural Abs to PC recognized cells at early stages of apoptosis, by contrast, an IgG anti-PC Ab, representative of a T cell-dependent response, recognized PC determinants primarily associated with late stages of apoptosis. Cumulatively, these results demonstrate a fundamental paradigm in which Abs from both the innate and the T cell-dependent tiers of the B cell compartment recognize a minimal molecular motif arrayed both on microbes and as neo-self Ags linked to atherosclerosis and autoimmune disease.

황하강 삼각주의 습지환경이 강의 흐름에 미치는 영향

The Yellow River began ceasing affected by natural factors and the unreasonable human activities. The flow broke in the Yellow River and water and sediment flowing into the sea decreased, which lowered the speed of newly formed wetland extending to the sea. The water environment deteriorated; Its composing structure tended to be unsteady; The biologic diversity decreased and wetland function reduced. To ensure that the Yellow River delta and its ecosystem develops sustainablly, it is significant to reduce times and days of the ceasing, keep certain runoff and sediments in the river to the sea and make its watercourse stable.

Prognostic and predictive factors in oral cancer: the role of the invasive tumour front.

Most decisions for cancer patients are now made on the basis of prognostic and predictive factors. However, due to the limited prognostic value of conventional tumour/nodal/ metastasis staging and histopathological grading in oral cancer, a large group of patients are still over- or under-treated with significant personal and socioeconomical impact. Recent work indicates that morphological and functional characteristics of the invasive tumour front underlie the biological aggressiveness of oral cancer. Incorporation of these concepts into a prognostic system will better reflect the biologic diversity of oral cancer and more accurately predict clinical outcomes and responses to particular types of adjuvant therapy.

Clinical and Biologic Diversity of Leukemias Occurring in Patients with Mastocytosis

Patients with systemic mast cell (MC) disease, but not those with cutaneous mastocytosis, are at a high risk (10–30%) to develop life-threatening myelogenous malignancies. In a significant proportion of cases, myeloid leukemias occur. Using conventional criteria, such leukemias resemble acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or myelomonocytic leukemia (CMML). Mast cell leukemia (MCL) may also occur. Myeloid leukemias (AML, CML, CMML) can develop in indolent or aggressive mastocytosis (skin lesions present or absent) with a variable prephase of MC disease. By contrast, MCL (typically without skin lesions) often develops on a “de novo” basis, and, if at all recognized, a prephase resembling (malignant) mastocytosis, is short. MCL differs from myeloid leukemias (AML, CML, CMML) by morphologic and phenotypic cellular characteristics. In fact, MCL are strongly tryptase-positive, c-kit-positive, myeloperoxidase (MPO) -negative neoplasms with variable metachromasia and chloroacetate esterase expression, whereas an MPO-positive, tryptase-negative phenotype supports the diagnosis of a myeloid non-MC lineage disease. Thus, MCL, but also myeloid non-MC lineage leukemias can develop in patients with (systemic) mastocytosis. Little is known, however, about the pathophysiologic basis of co-evolution. In the present article, the concomitant occurrence of mastocytosis and leukemia is discussed in the light of the literature and of concepts proposed to explain the biologic basis of this phenomenon.

New classifications for non-Hodgkin's lymphoma.

For decades, attempts to design clinically and biologically relevant classifications of non-Hodgkin’s lymphoma have been the topic of intense debate [1, 2, 3, 4, 5]. In recent years, our understanding of the basic biological aspects of malignant lymphoma has accelerated rapidly. Unfortunately, this explosion of knowledge has imparted extreme complexity to the subject of lymphoma classification. Much of this complexity reflects the true biologic diversity of lymphoid neoplasia. At times, however, this complexity has been aggravated by variation in interobserver reliability [6] and by the use of different terms assigned by different investigators to describe biologically identical cell types or disease entities [4,6]

Atypical angiomyolipoma of the kidney

BACKGROUND The purpose of this study was to fully characterize and emphasize the salient features of an unusual variant of angiomyolipoma that the authors believe has been underrecognized. METHODS Five cases of atypical angiomyolipoma (AAML) of the kidney, two of which were reported previously, were retrieved from the consultation files of one of the authors. In one patient a small extrarenal tumor was examined in addition to the primary renal tumor. The histopathologic features of all six tumors, the immunohistochemical findings of five tumors (including the extrarenal tumor), and the ultrastructure of three tumors were analyzed. Clinical follow-up was obtained for all patients. RESULTS Two tumors occurred in children and presented as large masses (≥ 15 cm), and 2 tumors were small (< 5 cm) and affected middle-aged adults; the remaining tumor, of intermediate size (6 cm), occurred in an adolescent. One child with tuberous sclerosis also had a small (2 cm) extrarenal lesion. All tumors were circumscribed and had a red-brown cut surface. The largest tumors showed areas of hemorrhage and necrosis. The tumors were highly cellular and composed of various types of multinucleated and mononuclear cells. The most distinguishing of these, and virtually pathognomonic of this entity, were huge cells with abnormal strap-like and ameboid configurations having copious eosinophilic hyaline cytoplasm and myriad nuclei disposed peripherally in a ring-like fashion. Ganglion-like cells, polygonal cells, and spindle cells also were observed. For the most part, all cell types shared the same nuclear features, and except for one tumor, mitoses were negligible. The cells displayed a perivascular arrangement, and grew as loosely organized sheets oriented around abnormally dilated vascular channels or in a hemangiopericytic pattern; glomeruloid vessels were variably present. Notably, adipose tissue was inconspicuous. The tumors stained positive for HMB-45 protein, smooth muscle specific actin, and muscle specific actin antibodies, with a tendency for immunoreactivity to segregate along with individual cell phenotypes. Immunoperoxidase stains also disclosed a prominent and consistent intratumoral histiocytic component and a T-cell lymphoid infiltrate. Ultrastructurally, the tumor cells were replete with organelles showing highly electron-dense granules. All patients underwent radical nephrectomy; three patients with significant follow-up remain free of disease. CONCLUSIONS AAML exhibits unusual but distinctive "pseudomalignant" histomorphologic features that facilitate its recognition, and a singular immunohistochemical profile that allows diagnostic confirmation. It occurs both sporadically and in association with tuberous sclerosis, affects both the adult and pediatric populations, and has shown an indolent behavior. AAML attests to the biologic and morphologic diversity that characterizes tuberous sclerosis hamartomata in general, and to the plasticity of the yet unclarified precursor of angiomyolipoma in particular. Cancer 1998;83:1581-1592. © 1998 American Cancer Society.