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In this overview, topics addressed include cellular overgrowth; recent molecular advances; problems of "lumping" and "splitting"; classification systems; relationship of neoplasia to overgrowth syndromes; vascular malformations; and problems in designation of overgrowth syndromes.
PURPOSE: The process of metastasis has been elucidated by thorough morphological studies on resection specimens and new findings in the field of molecular biology in recent years. The successful surgical removal of distant metastases lead to the necessity of a detailed and precise classification system of distant metastases. PATIENTS AND METHODS: The new molecular findings as well as data obtained from morphological studies and the results of a international field study on behalf of the UICC lead to the proposed system presented here as a new classification system for metastases. RESULTS: A general classification of distant metastases of any primary tumor should separate 5 different categories: M1 for non-regional lymph node metastases only, M2 for liver metastases only, M3 for lung metastases only, M4 for bone metastases only and M5 for metastases in 2 or more of these organs or others. In case of liver metastases of colorectal carcinoma, 2 different classifications were proposed; a clinical classification based on locoregional tumor status, number of liver metastases and involved lobes and a post-surgical classification depending on locoregional tumor status and size of metastases removed surgically and assessed by the pathologist. CONCLUSION: More detailed knowledge of the metastatic process and success in surgical treatment makes a detailed and exact classification system for distant metastases essential. This should be used as a fundamental base for future therapeutical and prognostic studies.
Amelogenesis imperfecta (AI) is a collective term for a number of conditions with abnormal enamel formation. Many cases are inherited, either as an X-linked, autosomal dominant or autosomal recessive trait. Several classifications have evolved since 1945, based primarily on phenotype with the mode of inheritance being used in some systems as a secondary factor in allocating a case into a particular category. The benefits and shortcomings of these systems are reviewed. As we move into an era of establishing the molecular basis of AI we propose a robust mechanism for classification and cataloguing of the disorder which parallels systems used in medical genetics. This system is applicable to individuals and families irrespective of current or future knowledge of the molecular defect involved. We argue that this system is of more benefit to these individuals and families than previous classifications.
Pneumocystis carinii and Toxoplasma gondii are opportunistic pathogens of immunosuppressed patients that are susceptible to therapy with inhibitors of dihydrofolate reductase (DHFR). The DHFR of these two organisms was characterized to facilitate the identification of more selective inhibitors. Similar to all reported protozoa, T. gondii has a bifunctional enzyme, of 120,000 Da, that possesses both DHFR and thymidylate synthase (TS) activity. Unexpectedly, P. carinii DHFR activity was present on a small molecule, of 26,000 Da. T. gondii DHFR and TS activity coeluted during affinity chromatography using a methotrexate-Sepharose column, whereas P. carinii DHFR and TS activity could be separated by affinity chromatography using the same column. P. carinii DHFR could be easily distinguished from rat DHFR, which is similar in size, by the differences in Km for dihydrofolate (P. carinii, 17.6 +/- 3.9 microM; rat, 4.0 +/- 2.2 microM). Since all protozoa reported have a large molecular weight, bifunctional DHFR, these studies support the classification of P. carinii as a fungus. These studies also provide a basis for the development of more effective therapeutic agents for these pathogens.
An international consultation on the diagnosis of non-invasive urothelial neoplasms was held in Ancona, Italy in May 2001. Besides histology and problems of classification, one group of experts (Committee no. 3) discussed the molecular pathology and cytometry of non-invasive urothelial carcinomas. In the following first part, special immunohistochemical and molecular markers for stratifications in bladder cancer were discussed including different cytokeratins (clone 34betaE12, CK 20), cell proliferation markers (Ki67/MIB-1, PCNA, AgNOR, DNA-cytometry), tumor suppressor genes and oncogenes (p53, p21, erb-B2, bcl-2), different receptor expressions of epidermal growth factor and vascular endothelial growth factor and others. These molecular markers were analyzed in diagnosis of urothelial carcinomas, recurrences, progression and response to treatment.
In the preface, the World Health Organization (WHO) classification vows to offer pathologists, oncologists and geneticists worldwide a system of classification for human neoplasms based on histopathological and genetic features. Standardization of nomenclature and agreed-upon criteria for definition of the various types of cancer are felt to be a prerequisite for progress in clinical oncology, multicentre therapy trials and comparative studies in different countries. In fact, the WHO effort represents the first worldwide comprehensive consensus classification of the haematological malignancies. Consensus was reached among a subgroup of investigators, carefully selected for their experience and contributions to existing classifications. In the present climate of daily new discoveries that yield a constant stream of fascinating insights into the biology of leukaemias and lymphomas and, above all, resulting in an explosion of potential therapeutic targets, the WHO system has taken the stand of compiling established classification approaches and providing order to known facts. This furnishes an essential skeleton upon which to build in the future. The WHO committee decided that sorting neoplasms according to prognosis was neither practical nor necessary and could be misleading. While justifiable at the present time, it is important to realize that the classifications of the haematological malignancies are a moving target and that the trend is to move away from currently accepted gold standards, such as morphological evaluations, in favour of genetic characterizations, especially those with therapeutic relevance. The goal of this chapter is to fill in some gaps that, as per the author's opinion, exist in the WHO classification, predominantly, where it concerns the role of immunophenotyping as a complementary discipline for genotyping through its potential to generate surrogate marker profiles for molecular lesions. By introducing some state-of-the-art classification modalities, some of which are still awaiting confirmation, this chapter also aims to spark excitement and provide a glimpse at the future.
In the 14 years since the first higher-level bird phylogenies based on DNA sequence data, avian phylogenetics has witnessed the advent and maturation of the genomics era, the completion of the chicken genome and a suite of technologies that promise to add considerably to the agenda of avian phylogenetics. In this review, we summarize current approaches and data characteristics of recent higher-level bird studies and suggest a number of as yet untested molecular and analytical approaches for the unfolding tree of life for birds. A variety of comparative genomics strategies, including adoption of objective quality scores for sequence data, analysis of contiguous DNA sequences provided by large-insert genomic libraries, and the systematic use of retroposon insertions and other rare genomic changes all promise an integrated phylogenetics that is solidly grounded in genome evolution. The avian genome is an excellent testing ground for such approaches because of the more balanced representation of single-copy and repetitive DNA regions than in mammals. Although comparative genomics has a number of obvious uses in avian phylogenetics, its application to large numbers of taxa poses a number of methodological and infrastructural challenges, and can be greatly facilitated by a 'community genomics' approach in which the modest sequencing throughputs of single PI laboratories are pooled to produce larger, complementary datasets. Although the polymerase chain reaction era of avian phylogenetics is far from complete, the comparative genomics era-with its ability to vastly increase the number and type of molecular characters and to provide a genomic context for these characters-will usher in a host of new perspectives and opportunities for integrating genome evolution and avian phylogenetics.
The literature on gastrointestinal stromal tumors (GISTs) has rapidly expanded and has demonstrated how scientific advancements in diagnosis can revolutionize the understanding of disease, while paving the way for effective treatment. While KIT (CD117) immunohistochemistry has established our definition of GISTs, molecular genetics continue to refine it. Elucidation of the aberrant receptor tyrosine kinase (RTK) model of GIST pathogenesis through mutations in c-kit and platelet-derived growth factor alpha PDGFRalpha proto-oncogenes has been prerequisite to the use of imatinib mesylate (STI571, Gleevec; Novartis, Switzerland), a molecular inhibitor of several tyrosine kinases, in the treatment of GISTs. In addition to providing a means for effective treatment, clarification of the molecular pathology of GISTs may potentially offer a new classification of these tumors by correlating genotype with histological, immunohistochemical, and clinical phenotype. This article seeks to review current knowledge of GISTs, offering a practical guide to their diagnosis and describing current epidemiological, molecular biological, and therapeutic aspects.
Type 2A of von Willebrand disease refers to qualitative variants with decreased platelet dependent function that is associated with the absence of high molecular weight forms of von Willebrand factor (vWF) multimers. Type 2B refers to qualitative variants with increased affinity for platelet glycoprotein Ib. In this report we describe the study of a patient who has been previously diagnosed as having subtype 2A von Willebrand disease (vWD), because she had no heightened ristocetin-induced platelet aggregation, no large and intermediate molecular weight von Willebrand factor (vWF) multimers in plasma, and no increase in plasma vWF capacity to bind to normal platelets in the presence of low ristocetin concentrations. The DNA sequencing of the 3' part of the exon 28 of the vWF gene where most of the subtype 2A mutations have already been identified, did not detect any nucleotide change. At variance, a G to A transition changing the encoded amino acid residue from Val 553 to Met in mature vWF, was found in the 5' part of this exon. This mutation which has already been found in several unrelated families with 2B vWD and the increased binding of the patient platelet vWF on normal platelets in the presence of low ristocetin concentrations provide evidence for subtype 2B vWD. This study thus illustrates the importance of the molecular characterization of patients in the correct diagnosis and classification of type 2 vWD.
The origin and histological classification of embryonal tumors, which make up the largest group of malignant pediatric brain malignancies, are two controversial issues. However, in recent years, progress has been made in our understanding of the molecular genetic abnormalities that govern their onset and/or progression. Several of these abnormalities appear to involve alterations in the signaling system controlling normal cerebellar development. An improved understanding of both the biology and clinical relevance of these molecular defects is probably the only means by which neuro-oncologists will improve the management of these tumors, thus reducing disease- and treatment-related morbidity and mortality.
A cytoplasmic polyhedrosis virus (CPV) infecting Manduca sexta was characterized. The genome consisted of ten equimolar RNA segments ranging in estimated molecular mass from 0.7 to 3.84 Mdaltons and with a total estimated molecular mass of 21.75 Mdaltons . The sizes of the individual RNA segments provisionally placed this CPV within the type 8 classification of Payne and Rivers. The polyhedrin protein had an estimated molecular mass of 28 kdaltons . Six virion-associated proteins were observed, ranging in size from 27.1 to 160 kdaltons . The RNA and protein profiles were compared to profiles observed from two other CPVs infecting Orgyia pseudotsugata and Bombyx mori. In addition, the nucleic acid sequence homology, using 32P-labeled cDNA to the total M. sexta CPV genome, demonstrated no homology with the B. mori CPV or the O. pseudotsugata CPV. The M. sexta CPV was transmitted by per os inoculation to O. pseudotsugata larvae.
Insight into the molecular basis of inherited photoreceptor cell degeneration has been rapidly evolving during the last decade. The Drosophila Rh1 rhodopsin gene was the first gene shown to cause retinal degeneration when mutated. Many more degeneration-causing mutations in genes encoding rhodopsin and other photoreceptor proteins have been isolated since then in both, Drosophila and humans. To date some 70 mutations of the Drosophila Rh1 gene have been isolated, most of them have been characterized at the molecular level, and more than 60% of them cause retinal degeneration. This review lists the known Rh1 mutations that cause retinal degeneration up to April 1998, gives an overview on the ultrastructural and biochemical correlates of photoreceptor cell degeneration, and suggests a system for the classification of degeneration-causing Rh1 mutations.
Myelodysplastic syndromes (MDS) are heterogeneous group of neoplastic clonal stem cell diseases characterized by dysplastic morphological features and clinical bone marrow failure. The FAB (French-American-British) system served as the gold standard for MDS classification for more than two decades. The WHO classification, built on the backbone of FAB classification, is an attempt to further improve the prognostic value of MDS classification as well as establish its clinical utility as a tool to select different treatments. In this article we review the epidemiology, pathogenesis, molecular biology, diagnosis and classification of MDS. We highlight the major differences between the FAB classification and the WHO MDS classification. We discuss in more detail the experience of using the new WHO classification since its publication and review the studies that tried to validate the prognostic value of the new classification or apply it to predict clinical responses to various treatments.
For a set of 220 phenols with literature data on their toxicity and associated mode of action (MOA) toward the ciliate Tetrahymena pyriformis, a stepwise classification scheme was developed that allows the identification of four MOAs from molecular hydrophobicity and AM1-based quantum chemical descriptors, employing linear discriminant analysis or binary logistic regression. Taking the AM1 lowest unoccupied molecular orbital energy as the only parameter, an initial separation of polar narcotics and proelectrophiles from oxidative uncouplers and soft electrophiles is correct to 97%, and for the subsequent discrimination between polar narcotics and proelectrophiles as well as between oxidative uncouplers and soft electrophiles, 99 and 98% correct classifications are achieved using three and two molecular descriptors, respectively. The results are discussed in terms of detailed contingency table statistics and with respect to relationships between molecular descriptors and mechanisms of toxicity. Statistical model evaluation includes simulated external validation employing complementary subset models.
Histopathology remains the gold standard technique for the diagnosis of intraepithelial neoplasia (dysplasia) in Barrett's oesophagus, but it is highly subjective and relies on blind biopsy targeting. The aim of this study was to evaluate Raman spectroscopy, a rapid, non-invasive, molecular, specific analytical technique, for the objective identification and classification of Barrett's neoplasia in vitro. A secondary objective was to demonstrate the need for a rigorous gold standard in the development of new diagnostic techniques. Forty-four patients with a mean age of 69 years (range 34-89 years) undergoing surveillance for Barrett's oesophagus were included in the study. Three consultant pathologists independently assessed snap-frozen oesophageal biopsy specimens. Raman spectra were measured on 87 histopathologically homogeneous samples. Spectral classification models were developed using multivariate analysis for the prediction of pathology. Histopathology and Raman classification results were compared. Raman spectral prediction with a consensus pathology classification model gave sensitivities between 73% and 100% and specificities of 90-100%. A high level of agreement (kappa = 0.89) was demonstrated between the three-subset biopsy targeting model and consensus pathology opinion. This compares favourably with the agreement measured between an independent pathologist and the consensus pathology opinion for the same spectra (kappa = 0.76). Raman spectroscopy appears to provide a highly sensitive and specific technique for the identification and classification of neoplasia in Barrett's oesophagus.
During the recent 20 years the improvement of the methodological research basis including the molecular and genetic analysis of microorganisms parasites of eukaryotic cells, led to considerable changes in the taxonomy and classification of rickettsiae. This problem was not discussed in the Russian literature. At present the term "rickettsiae" conventionally embraces the group of microorganisms of the class Proteobacteria, nominated as species belonging to the genera Rickettsia, Orientia, Ehrlichia, Coxiella and Bartonella. An original scheme of the modern taxonomy of rickettsiae, pathogenic for man, is presented. The scheme is made with due regard to their phenotypic, clinico-epidemiological and genetic features.
In this paper we propose a classification of the amphipathic helical repeats occurring in the plasma apolipoprotein sequences. It is based upon the calculation of the molecular hydrophobicity potential around the helical segments. The repeats were identified using a new autocorrelation matrix, based upon similarities of hydrophobic and hydrophilic properties of the amino acid residues within the apolipoprotein sequences. The helices were constructed by molecular modeling, the molecular hydrophobicity potential was calculated, and isopotential contour lines drawn around the helices yielded a three-dimensional visualization of the hydrophobicity potential. Two classes of apolipoproteins could be differentiated by comparing the hydrophobic angles obtained by projection of the isopotential contour lines on a plane perpendicular to the long axis of the helix. The isopotential contour lines around apo AI, AIV, and E are more hydrophilic than hydrophobic, whereas they are of similar intensity for apo AII, CI, and CIII. In both cases discoidal lipid-protein complexes are generated, with the amphipathic helices around the edge of the lipid core. The long axis of the helices is oriented parallel to the phospholipid acyl chains and the hydrophilic side of the helix toward the aqueous phase. As a result of the differences in hydrophobicity potential, the contact between the hydrophobic side of the helices and the phospholipid acyl chains is larger for apo AII, CI, and CIII than for the other apolipoproteins. This might account for the greater stability of the discoidal complexes generated between phospholipids and these apoproteins.
A new WHO classification of renal cell carcinoma has been introduced in 2004. This classification includes the recently described renal cell carcinomas with the ASPL-TFE3 gene fusion and carcinomas with a PRCC-TFE3 gene fusion. Collectively, these tumors have been termed Xp11.2 or TFE3 translocation carcinomas, which primarily occur in children and young adults. To further study the characteristics of renal cell carcinoma in young patients and to determine their genetic background, 41 renal cell carcinomas of patients younger than 22 years were morphologically and genetically characterized. Loss of heterozygosity analysis of the von Hippel-Lindau gene region and screening for VHL gene mutations by direct sequencing were performed in 20 tumors. TFE3 protein overexpression, which correlates with the presence of a TFE3 gene fusion, was assessed by immunohistochemistry. Applying the new WHO classification for renal cell carcinoma, there were 6 clear cell (15%), 9 papillary (22%), 2 chromophobe, and 2 collecting duct carcinomas. Eight carcinomas showed translocation carcinoma morphology (20%). One carcinoma occurred 4 years after a neuroblastoma. Thirteen tumors could not be assigned to types specified by the new WHO classification: 10 were grouped as unclassified (24%), including a unique renal cell carcinoma with prominently vacuolated cytoplasm and WT1 expression. Three carcinomas occurred in combination with nephroblastoma. Molecular analysis revealed deletions at 3p25-26 in one translocation carcinoma, one chromophobe renal cell carcinoma, and one papillary renal cell carcinoma. There were no VHL mutations. Nuclear TFE3 overexpression was detected in 6 renal cell carcinomas, all of which showed areas with voluminous cytoplasm and foci of papillary architecture, consistent with a translocation carcinoma phenotype. The large proportion of TFE3 "translocation" carcinomas and "unclassified" carcinomas in the first two decades of life demonstrates that renal cell carcinomas in young patients contain genetically and phenotypically distinct tumors with further potential for novel renal cell carcinoma subtypes. The far lower frequency of clear cell carcinomas and VHL alterations compared with adults suggests that renal cell carcinomas in young patients have a unique genetic background.