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PubMedDate not supplied

Neurofibromatosis. Nosological considerations.

The neurofibromatosis (NF) represent a set of conditions having different clinical manifestations, prognosis and inheritance. It has been presented--on clinical grounds--seven types of NF, but for only two of these National Institute of Health Consensus Development Conference (NIHCDC) advent a set of diagnostic criteria. The genes responsible for NF1 and NF2 were mapped to the long arm of chromosome 17 (17q11.2) and respectively 22 (22q11.2), and their protein product (neurofibromin and respectively merlin or schwanomin) was identified. Recent studies are proved that NF1 and NF2 genes act as a tumour suppressor gene. Up to now, only a limited number of mutations in these genes have been characterized but even in these cases the genotype/fenotype correlation has not provided enough information to allow speculation on the etiologic role NF1 or NF2 mutations might play in the variant forms of NF. Further studies are required to elucidate the genes functions and mutation spectrum. This should provide a framework for the molecular classification and diagnosis and the development of new therapy for NF.

Chromosomes, Human, Pair 17↗
PubMed1992

A cystic partially differentiated nephroblastoma producing alpha-fetoprotein.

A case of cystic partially differentiated nephroblastoma with immunohistochemical and serological demonstration of alpha-fetoprotein (AFP) production is described. To our knowledge, this is the first such case reported. The morphological heterogeneity of this rare tumor led us to describe the criteria of its nosological classification and of its differential diagnosis with intrarenal teratoma. AFP, besides being a marker of germline-derived tumor, was associated to this rare variant of Wilm's tumor. Although the tumor did not show regression either on clinical or pathologic assessments, serum AFP levels decreased after preoperative chemotherapy and returned to normal limits after nephrectomy.

Biomarkers, Tumor↗
PubMed1983

[Melanotic ectodermal tumor of infancy (melanotic progonoma)--an unusual soft tissue tumor].

In rare cases an utmost uncommonly pigmented lesion is found in young infants which is mostly located in the anterior maxilla. The histogenesis of this unusual soft tissue tumor has provoked a long-lasting debate, which is reflected in many synonyms. There is no anatomical precursor and the possibility of a phylogenetic ancestral form is discussed. Therefore, the term melanotic progonoma was proposed. Because of the derivation from neural crest cells the designation melanotic neuroectodermal tumor of infancy was introduced. This name is now generally accepted. In this study, two typical cases of this rare tumor are described. The tumors are composed of large epithelial-like melanin-producing cells and small nonpigmented cells, so-called lymphocyte- like cells resembling neuroblasts. The diagnostic relevant histological pattern is characterized by intensely pigmented cells arranged either in strands or clusters often forming the lining of small cleft-like or tubular spaces, or by alveolar structures surrounded by a fibrovascular stromal component. At ultrastructural level, the pigment corresponds to the cutaneous type of neural crest type of melanin. The histogenesis of these lesions and the classification of pigmented benign and malignant neuroectodermal tumors of the soft tissues are discussed especially taking into consideration the concept of the soft tissue variant of melanomas. The melanotic neuroectodermal tumor of infancy is a benign growth Only in very few cases a fatal outcome is reported in the literature. The melanotic neuroectodermal tumor of infancy must be distinguished from other types of benign and malignant neuroectodermal tumors. From histological point of view and with regard to its biological behaviour this lesion is a particular entity of pigmented neuroectodermal tumors of the soft tissues, and for subclassification the term melanotic progonoma should be maintained, too.

Female↗
PubMed1978

Preservation of pre-excitation despite acute myocardial infarction complicated by complete heart block.

In a 53-year-old man with ventricular pre-excitation (normal PR interval, QRS interval of 0.12 seconds and delta-waves) acute inferior wall myocardial infarction was complicated by, successively, first-degree atrioventricular block, second-degree atrioventricular block (Wenckebach type) and complete heart block. The QRS pattern of pre-excitation was preserved throughout these events. The classification of ventricular pre-excitation is reviewed and the correlation between the various electrocardiographic patterns (the Wolff-Parkinson-White syndrome and its variants and the Lown-Ganong-Levine syndrome) and the anomalous conduction pathways of Kent, James and Mahaim are discussed. In this case the best possible explanation for preservation of pre-excitation during complete heart block was the existence of accessory fibres of Mahaim.

Acute Disease↗
PubMed1969

Bence Jones proteins and light chains of immunoglobulins. II. Immunochemical differentiation and classification of kappa-chains.

Three distinct classes of kappa light polypeptide chains have been detected immunochemically by an antiserum (R185) prepared against a kappa Bence Jones protein with a glutamyl amino terminal residue. This antiserum had specificity for kappa light chains with glutamyl amino terminal residues and differentiated kappa-chains with aspartyl amino terminal residues into two classes: the three kappa-chain classes have been designated as kappa(glu), kappa(aspII), and kappa(aspI). The ability of antiserum R185 to detect these antigenic differences on the intact immunoglobulin molecule, as well as on the isolated light chain or Bence Jones protein, made feasible the direct classification of type K myeloma proteins and M-macroglobulins (Waldenström). The multispecificity of the antiserum permitted the quantitation of type kappa(glu) light chains in normal, hypergammaglobulinemic, and hypogammaglobulinemic sera. Whereas the distribution of myeloma proteins and Bence Jones proteins in the kappa(glu) class correlated with the distribution of kappa(glu) chains in normal and hypergammaglobulinemic sera, the M-macroglobulins in the kappa(glu) class represented 90% of the total M-macroglobulins tested and revealed a marked divergence from the range of 24-31% of kappa(glu) immunoglobulins in normal sera. A preponderance of kappa(glu) chains was detected in the sera from patients with non-sex-linked hypogammaglobulinemia and represented 60-77% of the total type K light chain content. The controlled cleavage of a Bence Jones protein representative of each kappa-chain class into its variant half and constant half made possible the localization on the light polypeptide chain, the reactive sites for which antiserum R185 had specificity. The correlations between immunochemical and structural classification of kappa light chains are discussed.

Bence Jones Protein↗
PubMed2001

The new World Health Organization classification of lung tumours.

Tumour classification systems provide the foundation for tumour diagnosis and patient therapy and a critical basis for epidemiological and clinical studies. This updated classification was developed with the aim to adhere to the principles of reproducibility, clinical significance, and simplicity in order to minimize the number of unclassifiable lesions. Major changes in the revised classification as compared to the previous one (WHO 1981) include the addition of two pre-invasive lesions to squamous dysplasia and carcinoma in situ; atypical adenomatous hyperplasia and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Another change is the subclassification of adenocarcinoma: the definition of bronchioalveolar carcinoma has been restricted to noninvasive tumours. There has been substantial evolution of concepts in neuroendocrine lung tumour classification. Large cell neuroendocrine carcinoma (LCNEC) is now recognized as a histologically high grade non small cell carcinoma showing histopathological features of neuroendocrine differentiation as well as immunohistochemical neuroendocrine markers. The large cell carcinoma class has been enriched with several variants, including the LCNEC and the basaloid carcinoma, both with a dismal prognosis. Finally, a new class was defined called carcinoma with pleomorphic, sarcomatoid, or sarcomatous elements, which brings together a number of proliferations characterized by a spectrum of epithelial to mesenchymal differentiation. Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but our intention was to render the classification simple and practical to every surgical laboratory, so that most lung tumours could be classified by light microscopic criteria.

Adenocarcinoma↗
PubMed2002

A variant of congenital muscular dystrophy.

We analyzed three Japanese patients (two boys and a girl) from two families with congenital muscular dystrophy (CMD) and brain involvement. One of the two families had two affected siblings of different sexes. Parental consanguinity was not documented in either family. All patients showed generalized hypotonia and weakness from infancy, delayed psychomotor development, facial muscle involvement, and joint contractures. Serum creatine kinase levels were markedly elevated. The histological change seen on muscle biopsy was characteristic of a dystrophic process, although dystrophin and merosin staining were normal. On MR imaging, cortical dysplasia and cerebral white matter abnormalities were observed. Although these clinical, myopathological and neuroradiological findings were typical of Fukuyama-type CMD (FCMD), full mutational analysis of the fukutin gene revealed neither a 3 kb insertion (Japanese founder mutation) nor point mutations. RT-PCR analysis of RNA isolated from lymphoblasts of a patient revealed normal expression of the FCMD transcript. As classification of CMD should be based on genetic background, our present cases with typical clinical, myopathological and neuroradiological findings of FCMD without mutation of the fukutin gene may represent a new variant (or variants) of CMD that is different from FCMD.

Brain↗
PubMed1997

Morphology of acute promyelocytic leukemia with cytogenetic or molecular evidence for the diagnosis: characterization of additional microgranular variants.

Early diagnosis of t(15;17) acute promyelocytic leukemia (APL) is essential because of the associated disseminated intravascular coagulation and the unique response of the disease to all-trans retinoic acid (ATRA) therapy. Early diagnosis depends primarily on morphological recognition. The French-American-British (FAB) classification, however, does not describe all morphological variations that occur in APL. In 25 cases with evidence of APL confirmed by cytogenetic and/or molecular analysis, we found a heterogeneous morphological group. The most common form of APL was heterogeneous and consisted of various combinations of cells in which hypergranular cells and some cells with multiple Auer rods were obvious. In some cases, one cell predominated. This led to the description of five subcategories. These included the classical FAB M3 with hypergranular cells and multiple Auer rods; the FAB variant with hypogranular bilobed cells; the basophilic cell type of McKenna et al. [Br. J. Haematol 50:201, 1982]; and two additional subtypes, one consisting of differentiated promyelocytes and a few blast cells (M2-like), and the other consisting largely of blast cells and a few early promyelocytes (M1-like). Immunophenotyping revealed a pattern of CD33 and/or CD13 positivity, and CD14 and HLA-DR negativity in 96% of cases. CD2 was positive in the FAB variant and in the subtype with basophilic cells, but negative with other subtypes. Three out of five cases with basophilic cell predominance [McKenna et al.: Br J Haematol 50:201, 1982], and one out of two M2-like cases, responded to ATRA therapy. Awareness of the heterogeneity and the atypical morphologic subtypes found in t(15;17) APL will contribute to improved recognition and early institution of ATRA therapy.

Adolescent↗
PubMed2026

Somatic likelihood tiering: an interpretable post-calling triage protocol for tumor-only whole-exome variant review.

Tumor-only whole-exome sequencing (WES) is used when matched normal tissue is unavailable, but one sample can produce thousands of variants. Somatic likelihood tiering (SLT) is an interpretable post-calling protocol that ranks Mutect2 calls into four review-priority tiers using population-frequency, germline-quality, cancer-knowledge, PureCN posterior, and clonal-hematopoiesis evidence. Layer 2 distinguishes common, rare-callable, and unevaluable gnomAD states; missing or unmatchable gnomAD evidence is not positive rarity evidence. On the SEQC2 HCC1395 benchmark, the callability-aware SLT-A row contained 101 calls, 78 truth variants, 77.2% PPV (95% Wilson confidence interval 68.1%-84.3%), and a Number Needed to Review (NNR) of 1.29 (1.19-1.47). The conservative SLT-C catchment retained 352 of 455 truth variants (77.4%, 73.3%-81.0%) and all tiers together retained 430 of 455 truth variants. SNV performance is the primary calibration frame: SLT-C retained 341 of 439 SNV truth variants, whereas indel results were exploratory because only 16 truth indels were available. Clinical cohorts are reported as recall and concordance versus partially dependent matched-normal Mutect2 references, not independent clinical sensitivity. Patient-level bootstrap intervals were principal: HdM-BLCA-1 SLT-A recall was 18.2% (14.0%-23.5%), and LUAD-TW SLT-A recall was 49.1% (26.6%-63.3%) among 32 evaluable patients. The HdM-BLCA-1 median SLT-A queue remained 1277 variants per patient, so SLT reduces first-pass candidate counts but does not measure review time or eliminate FFPE candidate-count burden. SLT provides an auditable tumor-only WES review queue, not a substitute for matched-normal sequencing, independent orthogonal validation, or definitive somatic classification.

Humans↗
PubMed1993

[Question of differential diagnosis in a case of chronic B-cell lymphopathy].

We have reported the case of a woman aged 76 years suffering from pancytopenia, splenomegaly, relative lymphocytosis, lymphocytes with villous projection in the peripheral blood. On the basis of membrane phenotype, cytochemistry, ultrastructural examination of blood and marrow lymphocytes, differential diagnosis was between chronic lymphatic leukemia (CLL), CLL of mixed cell type, hairy cell leukemia (HCL), HCL variant, splenic lymphoma with circulating villous lymphocytes (SLVL), Non-Hodgkin lymphoma of mantle zone (NHL). The application of morphologic and immunological methods has reinforced the value of cytomorphology and has proved advantageous in increasing our understanding of the heterogeneity of B CLL itself. A new classification of chronic B leukemias has been proposed on the basis of clinical, cytomorphological, histological, cytochemical, immunological criteria: CLL; CLL of mixed cell type including cases with more than 10% and less than 55% prolymphocytes (CLL/P) and a less well defined form with pleomorphic lymphocytes (CLL/P) and a less well defined form with pleomorphic lymphocytes but less than 10% prolymphocytes; prolymphocytic leukemia (PLL); hairy cell leukemia (HCL); HCL variant; splenic lymphoma with circulating villous lymphocytes (SLVL); leukemic phase of NHL (follicular lymphoma, intermediate or mantle zone lymphoma, and others); lymphoplasmacytic lymphoma; plasma cell leukemia. Even if the application of cytomorphological and immunological criteria has increased our knowledge of the heterogeneity of chronic B leukemias, in some cases, as in the one reported, exact classification may be very difficult. However, on the basis of clinical and laboratory criteria this case can be classified as SLVL, notwithstanding some discrepancies of the immunophenotype.

Aged↗
PubMed1986

The use of monoclonal antibodies for the identification and classification of acute myeloid leukemias.

We reviewed a library of monoclonal antibodies (MoAbs) detecting antigens on myelomonocytic cells and analysed their reactivity patterns as reported in the literature. On the basis of the frequency of positivity with the myelocytic variants (FAB M1-3) or monocytic variants (FAB M4/5) of acute myeloid leukemias, the MoAbs were assigned to one of four groups. MoAbs of Group I identified most cases of both the myelocytic and the monocytic cell lineages ('pan-myelomonocytic' reactivity) and can be used to identify acute myeloid leukemias regardless of the subtype. Group II comprised MoAbs which reacted with the majority of FAB M1-3 cases, but showed a preference in reactivity with AMMoL/AMoL cases (reactivity: myelocytic partly, monocytic predominantly). MoAbs of Group III stained most cases with monocytic phenotypes, but labelled only a small percentage of non-monocytic cases. These MoAbs are valuable tools for the detection of cases with monocytic features. Group IV MoAbs reacted with a small to intermediate percentage of myelocytic and/or monocytic cases. Besides their diagnostic application MoAbs might be used in new therapeutic approaches such as in-vivo serotherapy with MoAbs and purging of autologous bone marrow for transplantation. None of the described MoAbs appear to be leukemia-specific. Many MoAbs have been produced against non-myelomonocytic cells and were reactive with cells outside the myelomonocytic cell lineages and the hematopoietic system. Other MoAbs with apparent cell lineage-restricted reactivity regarding normal cells stained leukemic cells of other cell lineages. This phenomenon of translineage reactivity of leukemic cells with mutually exclusive markers indicating a biphenotypic marker profile might be the result of abnormal, disregulated gene expression. New classification systems of acute myeloid leukemias based on immunological marker profiles have been proposed. The analysis of reactivity of normal and malignant myelomonocytic cells with MoAbs has led to refined differentiation schemes of the normal hematopoiesis.

Antibodies, Monoclonal↗
PubMed2006

Adult variant of self-healing papular mucinosis in a patient with rheumatoid arthritis: predominant proliferation of dermal dendritic cells expressing CD34 or factor XIIIa in association with dermal deposition of mucin.

According to a recent classification, self-healing papular mucinosis (SHPM) is a subtype of papular mucinosis (also known as lichen myxedematosus), which is in turn a type of idiopathic localized cutaneous mucinosis. SHPM tends to occur in children, but there have been a few reports of an adult type. We report a 70-year-old Japanese woman who presented with reddish, rice-kernel-sized papules of a few days' duration on her right arm. She had a 25-year history of rheumatoid arthritis, which had been well treated with a low dose of corticosteroid as well as some other medications. No paraproteinemia or thyroid dysfunction were observed. The eruptions spontaneously resolved within 2.5 months of onset. Histological findings showed a well-circumscribed mucinous stroma surrounded by dermal mesenchymal cells, such as fibroblast-like cells in the middle of the dermis. Immunohistochemically, these cells were positive only for vimentin on the mucinous lesion. On the circumference of the mucinous lesion, these cells expressed either CD34 or factor XIIIa (FXIIIa). Because vimentin was common to dermal mesenchymal cells, we defined the cells expressing CD34 or FXIIIa, except for vimentin+ cells lacking CD34 or FXIIIa, as dermal dendritic cells (DDC). The findings of the present case suggest that CD34+ or FXIIIa+ DDC and tryptase-positive mast cells on the perilesional area in combination with vimentin+ cells on the mucinous lesion might have given rise to the dermal deposition of mucin in our case. These cells, which are possibly activated in an autoimmune manner associated with rheumatoid arthritis, might play important roles in the development of dermal deposition of mucin in SHPM.

Aged↗
PubMed1998

Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21-22.

OBJECTIVE: The clinical and pathologic features of hereditary dysphasic disinhibition dementia (HDDD) are described to determine whether it is a variant of known dementias. BACKGROUND: Several dementing disorders have clinical and pathologic similarities with AD, Pick's disease, and the "nonspecific" dementias. A detailed description of clinical and pathologic presentation will aid classification, but ultimately the discovery of causative gene(s) will define these disorders. METHODS: The authors performed a clinical assessment: gross and microscopic pathologic evaluation of brain tissue, genetic linkage studies, and sequence analyses. RESULTS: HDDD is an autosomal-dominant frontotemporal dementia with many similarities to Pick's disease. Salient clinical features are global dementia with disproportionate dysphasia and "frontotemporal" symptoms. A linkage between HDDD and 17q21-22 was shown, with a maximum lod score of 3.68 at zero recombination. CONCLUSIONS: Several dementias have been linked to the same region and have been termed frontotemporal dementia with parkinsonism linked to chromosome 17. These disorders may represent phenotypic variants arising from mutations within a common gene.

Adult↗
PubMedDate not supplied

Plasmacytoid urothelial carcinoma of the bladder. A case report and the first description of urinary cytology.

BACKGROUND: Plasmacytoid carcinomas are rare variants, and there are only a few reported examples of plasmacytoid carcinoma of the urinary bladder in the English-language literature. We now report another such case and the first in which there was examination of urinary cytology. CASE: A 79-year-old, Caucasian woman who presented with gross hematuria following a revascularization procedure on the right arm was found to have an extensive, diffuse carcinoma of the bladder. On biopsy, there were single, round and polygonal tumor cells with a striking plasmacytoid appearance infiltrating diffusely throughout the edematous lamina propria. Immunocytochemical stains confirmed an epithelial classification, and carcinoma in situ was demonstrated in the contiguous urothelium. Voided urine cytology before and after cystoscopy and biopsy demonstrated large, dyshesive tumor cells with plasmacytoid features. CONCLUSION: A case of plasmacytoid variant of urothelial carcinoma of the bladder is reported, with the first description of its urinary cytology.

Aged↗
PubMed1996

Immunophenotypic characterization of acute leukemias and chronic lymphoproliferative disorders: practical recommendations and classifications.

Immunophenotypic characterization of leukemic cells has become essential for the diagnosis of acute leukemias (AL) and chronic lymphoproliferative disorders (CLPD). Immunophenotyping allows to classify AL according to (i) lineage assignment of the leukemic clone based on the degree of specificity (or "score") of expressed markers, (ii) the differentiation level of the clone and (iii) the presence of irrelevant markers. In addition, some rare AL subtypes may be identified, such as M0, M6 "variant" and M7 FAB types, as well as "biphenotypic" (hybrid) AL. Finally particular immunophenotypic profiles are of pronostic value or associated with specific cytogenetic abnormalities. In leukemic phase CLPD setting, some circulating lymphoid cell immunophenotypic profiles are strongly correlated with morphology as defined by the FAB and REAL classifications. In addition, some marker expressions are of pronostic value. However, proper choices of sample nature, monoclonal antibodies and immunophenotyping methods are essential to improve quality, reliability and reproducibility of the results and must be carefully controlled in and between laboratories.

Acute Disease↗
PubMed2026

SeqQC-former: A sequence-quality fusion framework for QC-aware review prioritization of candidate somatic SNVs in cancer genomics.

The accurate prioritization of candidate somatic single-nucleotide variants (SNVs) remains a challenge due to the substantial variability in sequencing quality across genomic loci. SeqQC-Former is a sequence-quality fusion framework that integrates the local nucleotide context with read-level quality-control (QC) covariates derived from matched tumor-normal sequencing data. This integration generates QC-aware prioritization scores for the downstream review of candidate variants. Unlike conventional variant callers, SeqQC-Former is designed not to infer biological truth but to support post-calling review and prioritization under heterogeneous sequencing conditions. The framework was trained and evaluated on a SEQC2-derived dataset comprising 89,447 candidate loci, including 1378 positive and 88,069 negative loci. In chromosome-held-out validation, which aims to reduce potential genomic-position leakage, SeqQC-Former demonstrated strong discrimination (AUROC = 0.9479; AUPRC = 0.9448), indicating good generalization to previously unseen chromosomes. Given that the SEQC2-derived labels contain QC-associated information; these results should be interpreted as an evaluation of QC-aware prioritization capability rather than an independent validation of biological variant correctness. Ablation analyses revealed that structured QC covariates provided the dominant predictive signal under the current SEQC2-derived labeling regime. SeqQC-Former achieved a significantly higher AUROC than classical machine-learning baselines, as determined by DeLong's test (p&#x202f;<&#x202f;0.01). Application to 53,164 glioblastoma variants demonstrated that external predictions were sensitive to QC scaling and threshold selection, underscoring that model outputs should be interpreted as QC-dependent prioritization scores rather than calibrated probabilities or definitive biological classifications. Overall, SeqQC-Former offers a reproducible post-calling QC-aware prioritization framework for large-scale somatic SNV review and underscores the importance of explicitly modeling sequencing-quality information when interpreting structured cancer genomics datasets.

Humans↗
PubMed1976

Breast adenomas.

True adenomas of the breast are cellular epithelial lesions, which may be confused with carcinoma and are difficult to classify. We have reviewed 28 adenomas of the breast and have developed specific diagnostic criteria, as well as a classification of breast adenomas based on histologic features. Electron microscopic studies confirm that adenomas have ultrastructural features similar to normal breast epithelium and are not variants of fibroadenomas. The association between lactating adenomas and pregnancy has been confirmed; however, clinicopathologic correlation does not suggest a relationship between adenomas and oral hormonal medication. Although adenomas are benign, this study includes the third reported case of an infiltrating carcinoma associated with a lactating adenoma.

Adenofibroma↗
PubMed2004

The CDKN2A database: Integrating allelic variants with evolution, structure, function, and disease association.

In this report, we introduce the CDKN2A Database, an online database of germline and somatic variants of the CDKN2A tumor suppressor gene recorded in human disease through the year 2002, annotated with evolutionary, structural, and functional information. The CDKN2A Database improves upon existing resources by: 1) including both somatic mutations and germline variants, thereby adding the perspective of somatic cell carcinogenesis to that of hereditary cancer predisposition; 2) including information that assists with the interpretation of allelic variants, such as other primary data (sequences, structures, alignments, functional measurements, and literature references) and annotations (extensive text, figures, and a tree-based phylogenetic classification); and 3) providing the information in a format that allows a user to either download the database or to easily manipulate it online. We describe the database structure, content, current uses, and potential implications (http://biodesktop.uvm.edu/perl/p16).

Alleles↗