Proposed criteria for mixed-dust pneumoconiosis: Definition, descriptions, and guidelines for pathologic diagnosis and clinical correlation

We defined mixed-dust pneumoconiosis (MDP) pathologically as a pneumoconiosis showing dust macules or mixed-dust fibrotic nodules (MDF), with or without silicotic nodules (SN), in an individual with a history of exposure to mixed dust. We defined the latter arbitrarily as a mixture of crystalline silica and nonfibrous silicates. According to our definition of MDP, therefore, MDF should outnumber SN in the lung to make a pathologic diagnosis of MDP. In the absence of confirmation of exposure, mineralogic analyses can be used to support the pathologic diagnosis. The clinical diagnosis of MDP requires the exclusion of other well-defined pneumoconioses, including asbestosis, coal workers' pneumoconiosis, silicosis, hematite miners' pneumoconiosis, welders' pneumoconiosis, berylliosis, hard metal disease, silicate pneumoconiosis, diatomaceous earth pneumoconiosis, carborundum pneumoconiosis, and corundum pneumoconiosis. Typical occupations associated with the diagnosis of MDP include metal miners, quarry workers, foundry workers, pottery and ceramics workers, and stonemasons. Irregular opacities are the major radiographic findings in MDP (ILO 1980), in contrast to silicosis, in which small rounded opacities predominate. Clinical symptoms of MDP are nonspecific. MDP must be distinguished from a variety of nonoccupational interstitial pulmonary disorders.     

Talc pneumoconiosis: A pathologic and mineralogic study

Seventeen cases of "talc pneumoconiosis" were examined pathologically and mineralogically to ascertain whether a true talc pneumoconiosis existed and also to compare these results in primary, secondary, and tertiary exposures. Mineralogic analyses were performed on wet tissue or tissue blocks by a variety of techniques, including analytical transmission electron microscopy and x-ray diffraction. Overall, the pathologic appearance of the tissues was similar in primary, secondary, and tertiary exposures, although ferruginous bodies and foreign body giant cells were not always present in cases caused by secondary exposures. Mixed dust fibrotic lesions were found in two cases in which there were substantial quantities of quartz present. There was great variation in the minerals found within the lung tissues. Several cases showed significant quantities of mica and kaolin in addition to talc. One case consisted predominantly of mica and in fact could be regarded as "mica pneumoconiosis"; this diagnosis was correctly attributed because of the mineralogic findings. Tremolite fibers were found in only two cases. Substantial quantities of crocidolite and amosite fibers were found in one case. This study shows that "talcosis" frequently represents disease associated with a variety of minerals and that talc is a common denominator. It shows also the usefulness of lung dust mineral analysis, particularly in secondary industries, for evaluating the cause of a pathologic reaction when exposures are especially complex.     

Meckel-Gruber syndrome: pathologic manifestations, minimal diagnostic criteria, and differential diagnosis

This article provides an overview of the major pathologic manifestations of Meckel-Gruber syndrome, current knowledge about its pathogenesis, minimal diagnostic criteria, and differential diagnosis. Typical sonographic findings (occipital encephalocele, postaxial polydactyly, and cystic enlargement of the kidneys) allow for diagnosis of most cases before the 14th week of gestation, but the pathologist may encounter clinically unsuspected or atypical cases that require morphologic confirmation. In these cases, a meticulous autopsy is necessary to establish the diagnosis of Meckel-Gruber syndrome.     

Pfeiffer syndrome update,clinical subtypes,and guidelines for differential diagnosis

Seven Pfeiffer syndrome pedigrees (three 3 generation and four 2 generation) have been recorded to date in addition to at least a dozen sporadic cases. Autosomal dominant inheritance with complete penetrance is characteristic of the 7 familial instances. Variable expressivity has involved mostly the presence or absence of syndactyly and the degree of syndactyly when present. Classic Pfeiffer syndrome is designated type I. Type 2 consists of cloverleaf skull with Pfeiffer hands and feet together with ankylosis of the elbows. Such patients do poorly with an early death. All reported instances to date have been sporadic. Type 3 is similar to type 2 but without cloverleaf skull. Ocular proptosis is severe in degree and the anterior cranial base is markedly short. These patients also do poorly and tend to have an early death. To date all cases have occurred sporadically. Although these 3 clinical subtypes do not have status as separate entities, their diagnostic and prognostic implications are important. Type 1 is commonly associated with normal intelligence, generally good outcome, and can be found dominantly inherited in some families. Types 2 and 3 generally have severe neurological compromise, poor prognosis, early death, and sporadic occurrence. Recognition of type 3 is particularly important because extreme ocular proptosis in the absence of cloverleaf skull but with various visceral anomalies can result in failure to diagnose Pfeiffer syndrome and labeling the patient as an “unknown” or as a “newly recognized entity.” The major diagnostic clues in type 3, as well as in the other clinical subtypes, remain classic Pfeiffer hands and feet in association with craniosynostosis, regardless of craniofacial variability or the presence or absence of visceral anomalies. A ratio of hallucal width to second toe width is developed to provide guidelines for what constitutes a broad great toe in Pfeiffer syndrome. Cases that do not qualify as examples of Pfeiffer syndrome are then reviewed. © 1993 Wiley-Liss, Inc.     

Myeloid sarcoma: clinical and morphologic criteria useful for diagnosis

Extramedullary accumulation of myeloblasts or immature myeloid cells form tumors called myeloid sarcoma in the WHO classification. Such tumors develop in lymphoid organs, bone (skull, orbit, etc.), skin, soft tissue, various mucosae and organs, and the CNS. They may precede or occur concurrently with acute myeloid leukemia, or reveal blastic transformation of chronic myeloproliferative disorders or myelodysplastic syndromes. They may also reveal relapses in treated patients. They are constituted by a diffuse infiltrate made up of medium-to-large cells. The cells are difficult to identify. Imprints are very useful. Immunohistochemistry can help diagnose and distinguish four variants: granulocytic myeloperoxidase (MPO+, CD 68+ [KP1+/-, PGM1-] lysozyme+, CD 34+/-), monoblastic (MPO-, CD 68+, [KP1+, PGM1+] lysozyme+, CD 34-), myelomonoblastic (MPO-, CD 68+, [KP1+, PGM1+] lysozyme+, CD 34-), or megakaryoblastic (positivity for factor VIII, CD 61, CD 31). Immunohistochemistry sometimes demonstrates expression of CD 43, CD 7, CD 79a, and CD 56 (particularly the monoblastic variant with t[8;21]). Recently the demonstration of CD 99 and CD 117, which can now be done on paraffin sections, may be useful to identify blasts of granulocytic origin. The diagnosis is missed in about 50% of cases when immunohistochemistry is not used. Patients with myeloid sarcomas should be treated in the same way as patients with acute myeloblastic leukemia. Disease progression and prognosis are similar for the two conditions.     

pT1 urothelial carcinoma of the bladder: criteria for diagnosis, pitfalls, and clinical implications

One of the challenging areas in genitourinary pathology is the recognition of early invasion in urothelial neoplasia. Not uncommon, the patterns of invasion into lamina propria are subtle because a desmoplastic response is absent. Tangential sectioning due to inability to orient transurethral resection of bladder tumor specimens, crush and cautery artifacts further compound this problem. This review is presented to familiarize surgical pathologists with the criteria and different patterns of lamina propria invasion by urothelial carcinoma. Problems and pitfalls associated with the recognition of invasion and the clinicopathologic significance of lamina propria invasive urothelial cancer are also discussed.     

Indeterminate colitis: definition, diagnosis, implications and a plea for nosological sanity

In 1978, Price introduced the concept of indeterminate colitis to describe cases in which colonic resections had been undertaken for chronic inflammatory bowel disease (CIBD), but a definitive diagnosis of either of the classical types of CIBD, ulcerative colitis and Crohn's disease, was not possible. This was especially apposite in cases of acute fulminant disease of the colorectum. More recently, the term indeterminate colitis has been applied to biopsy material, when it has not been possible to differentiate between ulcerative colitis and Crohn's disease. In our opinion, and in those of other workers in this field, the term should be restricted to that originally suggested by Price. This then provides a relatively well-defined group of patients in whom the implications and management of the disease are becoming much clearer. Cases where there are only biopsies with CIBD, but equivocal features for ulcerative colitis and Crohn's disease, should be termed 'CIBD, unclassified', 'equivocal/non-specific CIBD' or IBD unclassified (IBDU), in line with recent recommendations. When the diagnosis is correctly restricted to colectomy specimens, there is now good evidence that the majority of cases will behave like ulcerative colitis. Furthermore, the diagnosis should not be a contraindication to subsequent pouch surgery. When the latter is undertaken, surgeons and patients can expect an increased complication rate, compared with classical ulcerative colitis, especially of pelvic sepsis, but most patients fare well. Only very occasional patients, around 10%, will eventually be shown to have Crohn's disease. This review describes the pathology of cases appropriately classified as indeterminate colitis and the implications of that diagnosis. It also highlights recent advances in its pathological features, clinical management and its immunological and genetic associations.     

Generalized anxiety disorder: clinical presentation, diagnostic features, and guidelines for clinical practice

Generalized anxiety disorder (GAD) is a prevalent and disabling disorder characterised by persistent worrying, anxiety symptoms, and tension. General practitioners and mental healthcare professionals frequently misdiagnose the presenting symptoms. This article addresses the clinical presentation of GAD and provides guidelines for discriminating GAD from other disorders, based on theoretical considerations and clinical experience. Debate relating to the validity of the definition of GAD is discussed, and suggestions are made for improving the criteria for GAD, which may guide future versions of classification systems such as the Diagnostic and Statistical Manual.     

Primary appendiceal lymphoma presenting as suspected perforated acute appendicitis: clinical,sonography and CT findings with pathologic correlation

The gastrointestinal tract is the most common site for extranodal involvement by non-Hodgkin’s lymphoma. However, primary appendiceal lymphomas presenting as perforated acute appendicitis are very rare: they occur in only 0.015% of all gastrointestinal lymphoma cases. The management of this condition is still controversial, and a multimodality approach (e.g., surgery, radiation therapy, and chemotherapy) is the optimal treatment. In these cases, appendiceal non-Hodgkin’s lymphomas typically manifest with acute symptoms in patients with no prior lymphoma history. Additionally, we treated our patient with a right hemicolectomy and postoperative multiagent chemotherapy.     

Sinonasal undifferentiated carcinoma: clinical and pathologic features and a discussion on classification, cellular differentiation, and differential diagnosis

Sinonasal undifferentiated carcinoma (SNUC) is an uncommon, highly aggressive, and clinicopathologically distinctive carcinoma of uncertain histogenesis. SNUC typically presents as a rapidly enlarging tumor mass involving multiple (sinonasal tract) sites, often with evidence of extension beyond the anatomic confines of the sinonasal tract. The light microscopic features include the presence of a hypercellular proliferation with varied growth patterns, including trabecular, sheet-like, ribbon, lobular, and organoid patterns. The tumor cells are medium to large sized and round to oval and have pleomorphic and hyperchromatic nuclei, inconspicuous to prominent nucleoli, varying amount of eosinophilic cytoplasm, high nuclear-to-cytoplasmic ratio, marked increase in mitotic activity frequently with atypical mitoses, tumor necrosis, and apoptosis. Adjunct analyses (eg, immunohistochemistry, electron microscopy, and molecular biologic studies) are often required in the diagnosis of SNUC and in differentiating it from other undifferentiated malignant neoplasms. The treatment of SNUC includes aggressive multimodality therapy, including surgical resection and adjuvant therapy (ie, radiotherapy, chemotherapy). The prognosis associated with SNUC is poor, and death due to disease often occurs within short periods following the diagnosis. We believe that the histologic definition of SNUC can be expanded to include tumors with limited differentiated foci (ie, squamous cell differentiation) predicated on the caveats that the clinical parameters (ie, rapidly enlarging and destructive sinonasal lesions) and the majority of the histologic findings (ie, undifferentiated pleomorphic cell population) match those features that have heretofore defined SNUC. The presence of squamous cell differentiation would correlate to origin in the Schneiderian epithelium, thereby conferring an ectodermal derivation to these tumors. Irrespective of its cell of origin and perhaps even in the face of differentiated foci in limited parts of the tumor, given its rather unique clinicopathologic characteristics, this tumor should be identified and classified as SNUC, thereby differentiating it from the other specific types of sinonasal carcinomas and nonepithelial malignant tumors.     

Proteus syndrome review: molecular,clinical, and pathologic features

Proteus syndrome is caused by an activating AKT1 mutation (c.49G>A, p.Glu17Lys). Many variable features are possible in this mosaic disorder, including: (i) disproportionate, asymmetric, and distorting overgrowth; (ii) bone abnormalities different from those observed in other disorders; (iii) a characteristic cerebriform connective tissue nevus made up of highly collagenized connective tissue; (iv) epidermal nevi in early life, consisting of acanthosis and hyperkeratosis; (v) vascular malformations of the capillary, venous, or lymphatic types; (vi) dysregulated adipose tissue including lipomas, lipohypoplasia, fatty overgrowth, and localized fat deposits; (vii) other unusual features, including bullous lung alterations; specific neoplasms; a facial phenotype associated with intellectual disability and/or seizures, and/or brain malformations; and (viii) deep vein thrombosis, resulting in premature death. Concluding remarks address diagnostic criteria, natural history, management, psychosocial issues, and differential diagnosis.     

Evaluation of a point-of-care test, BVBlue, and clinical and laboratory criteria for diagnosis of bacterial vaginosis

Bacterial vaginosis (BV) remains the most common cause of abnormal vaginal discharge in women of reproductive age and is associated with increased susceptibility to human immunodeficiency virus and sexually transmitted infections and preterm delivery. Present diagnostic methods require access to microscopy and laboratory expertise; however, the majority of women, particularly those in populations with a high prevalence of BV, do not have access to clinical services with on-site microscopy capabilities. We evaluated a point-of-care test for the diagnosis of BV, the BVBlue test, with 288 women attending a sexual health service with symptoms of abnormal vaginal discharge and/or odor. The BVBlue test performed well compared with conventional diagnostic methods for the assessment of women with symptoms suggestive of BV at the bedside and significantly better than other simple tests, such as vaginal pH determination and the amine test, that do not require microscopy. The BVBlue test was sensitive (88%; 95% confidence interval [CI], 81 to 93%) and specific (95%; 95% CI, 91 to 98%) compared to the method of Nugent et al. (R. P. Nugent, M. A. Krohn, and S. L. Hillier, J. Clin. Microbiol. 29:297-301, 1991) and performed well compared with the method of Amsel et al. (R. Amsel, P. A. Totten, C. A. Spiegel, K. C. Chen, D. Eschenbach, and K. K. Holmes, Am. J. Med. 74:14-22, 1983), with a sensitivity of 88% (95% CI, 81 to 93%) and a specificity of 91% (95% CI, 85 to 94%). The BVBlue test is a simple, rapid, and objective test for the diagnosis of BV and has the potential to facilitate prompt diagnosis and appropriate treatment of BV in the absence of microscopy. The majority of women at the greatest risk for the sequelae of BV are not in settings where the conventional diagnostic methods are either practical or possible, and they would greatly benefit from access to rapid and reliable point-of-care tests to improve the diagnosis and management of BV.     

ERN GENTURIS clinical practice guidelines for the diagnosis,treatment, management and surveillance of people with schwannomatosis

A Guideline Group (GG) was convened from multiple specialties and patients to develop the first comprehensive schwannomatosis guideline. The GG undertook thorough literature review and wrote recommendations for treatment and surveillance. A modified Delphi process was used to gain approval for recommendations which were further altered for maximal consensus. Schwannomatosis is a tumour predisposition syndrome leading to development of multiple benign nerve-sheath non-intra-cutaneous schwannomas that infrequently affect the vestibulocochlear nerves. Two definitive genes (SMARCB1/LZTR1) have been identified on chromosome 22q centromeric to NF2 that cause schwannoma development by a 3-event, 4-hit mechanism leading to complete inactivation of each gene plus NF2. These genes together account for 70–85% of familial schwannomatosis and 30–40% of isolated cases in which there is considerable overlap with mosaic NF2. Craniospinal MRI is generally recommended from symptomatic diagnosis or from age 12–14 if molecularly confirmed in asymptomatic individuals whose relative has schwannomas. Whole-body MRI may also be deployed and can alternate with craniospinal MRI. Ultrasound scans are useful in limbs where typical pain is not associated with palpable lumps. Malignant-Peripheral-Nerve-Sheath-Tumour-MPNST should be suspected in anyone with rapidly growing tumours and/or functional loss especially with SMARCB1-related schwannomatosis. Pain (often intractable to medication) is the most frequent symptom. Surgical removal, the most effective treatment, must be balanced against potential loss of function of adjacent nerves. Assessment of patients’ psychosocial needs should be assessed annually as well as review of pain/pain medication. Genetic diagnosis and counselling should be guided ideally by both blood and tumour molecular testing.Subject terms: Cancer genomics, Whole body imaging     

Randomized clinical trials,developmental theory,and antisocial youth: guidelines for research

The design of effective interventions for antisocial adolescents has been greatly influenced by research-based developmental theories. However, randomized clinical trials (RCTs) demonstrating effectiveness of these treatments have contributed minimally to alterations and refinements of these theories. In this article, nine guidelines for research that may enhance the contributions of RCTs to developmental theory are proposed: (1) use mediational analyses to test and refine theories of change; (2) use moderator analyses to test differential pathways to change; (3) assess change processes separately for different types of antisocial behavior; (4) use constructive and dismantling designs to isolate effects of intervention components on targeted mediators and outcomes; (5) assess the time-sensitive nature of change mechanisms with theoretically relevant spacing of multiple assessments and long-term follow-ups; (6) expand the nomological net of developmental theories by assessing intervention effects on nontargeted constructs; (7) use RCTs to disentangle direction of effects questions in developmental theories; (8) conduct secondary analyses of RCTs to assess extra-treatment influences on antisocial behavior; and (9) assess the generalizability of mediator and moderator effects. Use of these guidelines may promote a recursive and iterative relationship between RCTs and theory building. Improved developmental theories may yield more effective interventions, and theory-testing interventions may engender more comprehensive and better informed theories.     

Role of IS6110-targeted PCR, culture, biochemical, clinical, and immunological criteria for diagnosis of tuberculous meningitis

An open prospective clinical, microbiological, and molecular analysis of a national molecular diagnostic service for tuberculous meningitis (TBM) using an in-house IS6110-targeted PCR for molecular "Fastrack" diagnosis was carried out. Between April 1997 and June 1998. Consecutive cerebrospinal fluid (CSF) samples from 131 patients were assessed. Against a culture on the same sample, PCR had a sensitivity of 75% and a specificity of 94%. Of samples from patients classified as definite or probable TBM cases based on clinical criteria, 81% had raised CSF protein levels and 73% had a lymphocytosis, although 57% of all submitted samples showed a raised lymphocyte count. While only 46% had a CSF glucose level below the normal range, the CSF glucose level was significantly lower (P = 0. 0281) than in cases of meningitis of other etiologies. Levels of tumor necrosis factor alpha were also found to be significantly raised in definite or probable TBM cases (P = 0.028), while adenosine deaminase levels were not. The study showed IS6110-targeted PCR to be a rapid, sensitive, and specific test in routine use for the diagnosis of TBM.     

Diffuse axonal injury in head injury: definition, diagnosis and grading

Diffuse axonal injury is one of the most important types of brain damage that can occur as a result of non-missile head injury, and it may be very difficult to diagnose post mortem unless the pathologist knows precisely what he is looking for. Increasing experience with fatal non-missile head injury in man has allowed the identification of three grades of diffuse axonal injury. In grade 1 there is histological evidence of axonal injury in the white matter of the cerebral hemispheres, the corpus callosum, the brain stem and, less commonly, the cerebellum; in grade 2 there is also a focal lesion in the corpus callosum; and in grade 3 there is in addition a focal lesion in the dorsolateral quadrant or quadrants of the rostral brain stem. The focal lesions can often only be identified microscopically. Diffuse axonal injury was identified in 122 of a series of 434 fatal non-missile head injuries--10 grade 1, 29 grade 2 and 83 grade 3. In 24 of these cases the diagnosis could not have been made without microscopical examination, while in a further 31 microscopical examination was required to establish its severity.     

Proteus syndrome: Diagnostic criteria,differential diagnosis,and patient evaluation

Proteus syndrome is a complex disorder comprising malformations and overgrowth of multiple tissues. The disorder is highly variable and appears to affect patients in a mosaic manner. This intrinsic variability has led to diagnostic confusion associated with a dearth of longitudinal data on the natural history of Proteus syndrome. To clarify some of these issues, a workshop on Proteus syndrome was held in March 1998 at the National Institutes of Health, and participants developed recommendations for diagnostic criteria, differential diagnosis, and guidelines for the evaluation of patients. This is a review of those recommendations. Am. J. Med. Genet. 84:389–395, 1999. © 1999 Wiley-Liss, Inc.     

Somatic mutation databases as tools for molecular epidemiology and molecular pathology of cancer: Proposed guidelines for improving data collection,distribution, and integration

There are currently less than 40 locus‐specific databases (LSDBs) and one large general database that curate data on somatic mutations in human cancer genes. These databases have different scope and use different annotation standards and database systems, resulting in duplicated efforts in data curation, and making it difficult for users to find clear and consistent information. As data related to somatic mutations are generated at an increasing pace it is urgent to create a framework for improving the collecting of this information and making it more accessible to clinicians, scientists, and epidemiologists to facilitate research on biomarkers. Here we propose a data flow for improving the connectivity between existing databases and we provide practical guidelines for data reporting, database contents, and annotation standards. These proposals are based on common standards recommended by the Human Genome Variation Society (HGVS) with additions related to specific requirements of somatic mutations in cancer. Indeed, somatic mutations may be used in molecular pathology and clinical studies to characterize tumor types, help treatment choice, predict response to treatment and patient outcome, or in epidemiological studies as markers for tumor etiology or exposure assessment. Thus, specific annotations are required to cover these diverse research topics. This initiative is meant to promote collaboration and discussion on these issues and the development of adequate resources that would avoid the loss of extremely valuable information generated by years of basic and clinical research. Hum Mutat 0,1–8, 2008. © 2008 Wiley‐Liss, Inc.     

Adenoid cystic carcinoma of the uterine cervix: ultrastructure, immunofluorescence, and criteria for diagnosis

An example of adenoid cystic carcinoma of the cervix was recently encountered in our laboratory and studied by histochemistry, electron microscopy, and immunofluorescence in order to compare the neoplasm with adenoid cystic tumors at other sites and to establish criteria for diagnosis. Histochemically, cervical adenoid cystic carcinoma showed the two types of mucin, epithelial and stromal, as expected in adenoid cystic carcinomas of other organs. Ultrastructurally, this tumor was characterized by redundant basal lamina forming pseudocysts, intercellular spaces, and occasional true lumens with microvilli. Immunofluorescence studies showed that the cells contain at least two antigenically different types of filaments, actin and keratin, and that the cells produce true basement membrane (collagen IV). The presence of actin suggests myoepithelial differentiation even though the tumor probably originated from the cervical reserve cells, and myoepithelium is not a known component of normal cervix. This study shows that cervical adenoid cystic carcinoma is a distinct entity which can be identified and separated from other types of cervical adenocarcinomas.