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Notes: Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases Neoplasms of histiocytes and dendritic cells are rare, and their phenotypic and biological definition is incomplete. Seeking to identify antigens detectable in paraffin-embedded sections that might allow a more complete, rational immunophenotypic classification of histiocytic/dendritic cell neoplasms, the International Lymphoma Study Group (ILSG) stained 61 tumours of suspected histiocytic/dendritic cell type with a panel of 15 antibodies including those reactive with histiocytes (CD68, lysozyme (LYS)), Langerhans cells (CD1a), follicular dendritic cells (FDC: CD21, CD35) and S100 protein. This analysis revealed that 57 cases (93%) fit into four major immunophenotypic groups (one histiocytic and three dendritic cell types) utilizing six markers: CD68, LYS, CD1a, S100, CD21, and CD35. The four (7%) unclassified cases were further classifiable into the above four groups using additional morphological and ultrastructural features. The four groups then included: (i) histiocytic sarcoma (n=18) with the following phenotype: CD68 (100%), LYS (94%), CD1a (0%), S100 (33%), CD21/35 (0%). The median age was 46 years. Presentation was predominantly extranodal (72%) with high mortality (58% dead of disease (DOD)). Three had systemic involvement consistent with `malignant histiocytosis'; (ii) Langerhans cell tumour (LCT) (n=26) which expressed: CD68 (96%), LYS (42%), CD1a (100%), S100 (100%), CD21/35 (0%). There were two morphological variants: cytologically typical (n=17) designated LCT; and cytologically malignant (n=9) designated Langerhans cell sarcoma (LCS). The LCS were often not easily recognized morphologically as LC-derived, but were diagnosed based on CD1a staining. LCT and LCS differed in median age (33 versus 41 years), male:female ratio (3.7:1 versus 1:2), and death rate (31% versus 50% DOD). Four LCT patients had systemic involvement typical of Letterer–Siwe disease; (iii) follicular dendritic cell tumour/sarcoma (FDCT) (n=13) which expressed: CD68 (54%), LYS (8%), CD1a (0%), S100 (16%), FDC markers CD21/35 (100%), EMA (40%). These patients were adults (median age 65 years) with predominantly localized nodal disease (75%) and low mortality (9% DOD); (iv) interdigitating dendritic cell tumour/sarcoma (IDCT) (n=4) which expressed: CD68 (50%), LYS (25%), CD1a (0%), S100 (100%), CD21/35 (0%). The patients were adults (median 71 years) with localized nodal disease (75%) without mortality (0% DOD). In conclusion, definitive immunophenotypic classification of histiocytic and accessory cell neoplasms into four categories was possible in 93% of the cases using six antigens detected in paraffin-embedded sections. Exceptional cases (7%) were resolvable when added morphological and ultrastructural features were considered. We propose a classification combining immunophenotype and morphology with five categories, including Langerhans cell sarcoma. This simplified scheme is practical for everyday diagnostic use and should provide a framework for additional investigation of these unusual neoplasms.

Notes: Diffuse large B-cell lymphoma (DLBCL), the single largest category of lymphoma, is a clinically and biologically heterogeneous disease entity. Clinically, patients differ in their mode of presentation and respond variably to therapy. A combination of clinical parameters can be used to predict the patient's response to therapy and survival. The pathological variability of DLBCL is expressed in morphology, immunophenotype, cytogenetic and molecular genetic features. Numerous markers detectable by immunohistochemistry and linked to different aspects of tumour biology have been studied in DLBCL, including lineage-associated and immune markers, proliferation and apoptosis markers, cell adhesion molecules, and more recently stage-specific markers of B-cell differentiation. This review summarizes these studies in regard to their clinical significance and in the light of recent advances in our understanding of the molecular pathology and histogenesis of DLBCL.

Notes: Garnet-whole rock Sm-Nd data are presented for several samples from the Indian plate in the NW Himalaya. These dates, when combined with the P-T evolution of the Indian plate rocks, allow a thorough reconstruction of the prograde thermal evolution of this region (including the Nanga Parbat Haramosh Massif) during the early Cenozoic. Combining these data with Rb-Sr mineral separate ages, enables us to constrain the post-peak cooling history of this region of the Himalaya.The data presented here indicate that the upper structural levels of the cover rocks of the Nanga Parbat Haramosh Massif, and similar rocks in the Kaghan Valley to the south-west, were buried to pressures of c. 10 kbar and heated to temperatures of c. 650 °C at 46–41 Ma. The burial of the lower structural levels of the cover rocks of the Nanga Parbat Haramosh Massif, to similar depths but at higher temperatures of c. 700 °C, occurred slightly later at 40–36 Ma, synchronous with the imbrication and exhumation of the amphibolite- and eclogite-grade rocks of the Kaghan Valley. In contrast, the cover rocks of the Nanga Parbat Haramosh Massif were not imbricated or exhumed at this time, remaining buried beneath the Kohistan-Ladakh Island Arc until the syntaxis-forming event that occurred in the last 10 Myr. The timing of tectonic events in the north-western Himalaya differs from that experienced by the rocks of the Central Himalaya in that the earliest stage of burial in the NW Himalaya predates that of the Central Himalaya by c. 6 Myr. This difference may result from the diachronous nature of the Indo-Asian collision or may simply be a reflection of differing timing at different structural levels.

Notes: A combined metamorphic and isotopic study of lit-par-lit migmatites exposed in the hanging wall of the Main Central Thrust (MCT) from Sikkim has provided a unique insight into the pressure–temperature–time path of the High Himalayan Crystalline Series of the eastern Himalaya. The petrology and geochemistry of one such migmatite indicates that the leucosome comprises a crystallized peraluminous granite coexisting with sillimanite and alkali feldspar. Large garnet crystals (2–3 mm across) are strongly zoned and grew initially within the kyanite stability field. The melanosome is a biotite–garnet pelitic gneiss, with fibrolitic sillimanite resulting from polymorphic inversion of kyanite. By combining garnet zoning profiles with the NaCaMnKFMASHTO pseudosection appropriate to the bulk composition of a migmatite retrieved from c. 1 km above the thrust zone, it has been established that early garnet formed at pressures of 10–12 kbar, and that subsequent decompression caused the rock to enter the melt field at c. 8 kbar and c. 750 °C, generating peritectic sillimanite and alkali feldspar by the incongruent melting of muscovite. Continuing exhumation resulted in resorption of garnet. Sm–Nd growth ages of garnet cores and rim, indicate pre-decompression garnet growth at 23 ± 3 Ma and near-peak temperatures during melting at 16 ± 2 Ma. This provides a decompression rate of 2 ± 1 mm yr−1 that is consistent with exhumation rates inferred from mineral cooling ages from the eastern Himalaya. Simple 1D thermal modelling confirms that exhumation at this rate would result in a near-isothermal decompression path, a result that is supported by the phase relations in both the melanosome and leucosome components of the migmatite. Results from this study suggest that anatexis of Miocene granite protoliths from the Himalaya was a consequence of rapid decompression, probably in response to movement on the MCT and on the South Tibetan detachment to the north.

Notes: Mycobacterium avium ssp. paratuberculosis (M. paratuberculosis) causes Johne's disease, a chronic and fatal enteritis in ruminants. In the last stage of the disease, antibody titres rise and levels of interferon-γ decrease, suggesting that the host–immune response is switching from a T helper 1 (Th1) to a Th2 profile. In infected cattle, the membrane protein p34 elicits the predominant humoral response against M. paratuberculosis. To map the B-cell epitopes of this antigen, affinity-purified bovine antibodies against the carboxy-terminal region of p34 were used to screen a 12-mer phage display library. Several phage clones carrying peptides resembling fragments of p34 were affinity selected. Based on the predicted amino acid sequence, peptides were chemically synthesized, which demonstrated reactivity with serum from naturally infected and p34-vaccinated cattle. Immunization of mice with these peptides elicited an anti-p34 antibody response. Two B-cell epitopes were identified and characterized. Based on the reactivity and the type of immune response elicited, epitope A was determined to be conformational, whereas epitope B was demonstrated to be sequential. Both epitopes were shown to be present in p34 proteins from M. avium ssp. avium or M. paratuberculosis but absent from M. intracellulare, the other member of the M. avium complex. Furthermore, both epitopes were mapped to regions of p34 that display high variability when compared to homologous proteins from other mycobacterial species of public and animal health importance. We hypothesize that these variable regions of p34 may play a role in the immunobiology of M. paratuberculosis infections.

Notes: Abstract In today's business environment companies need to adapt and respond to new business challenges in a rapid but controlled manner, in keeping with their business model. Technology is a key enabler, allowing organisations to respond to changes in their business environment in a managed way. The corporate intranet is a key tool in allowing a company to communicate and operate efficiently. Intranet Advantage was developed as a way to provide a highly customised intranet solution to meet real business needs. It can be rapidly deployed on a customer's site by using preconfigured packages and a suite of optional applications, all of which combine to offer measurable business benefits.

Notes: Abstract Background:Controversy in lymphoma classification dates back tothe first attempts to formulate such classifications. Over the years, much ofthis controversy arose from the assumption that there had to be a singleguiding principle – a `gold standard' – for classification, andfrom the existence of multiple different classifications. Design:The International Lymphoma Study Group (I.L.S.G.)developed a consensus list of lymphoid neoplasms, which was published in 1994as the `Revised European–American Classification of Lymphoid Neoplasms'(R.E.A.L.). The classification is based on the principle that a classificationis a list of `real' disease entities, which are defined by a combination ofmorphology, immunophenotype, genetic features, and clinical features. Therelative importance of each of these features varies among diseases, and thereis no one `gold standard'. In some tumors morphology is paramount, in othersit is immunophenotype, a specific genetic abnormality, or clinical features.An international study of 1300 patients, supported by the San SalvatoreFoundation, was conducted to determine whether the R.E.A.L. Classificationcould be used by expert pathologists and had clinical relevance. Since 1995,the European Association of Pathologists (EAHP) and the Society forHematopathology (SH) have been developing a new World Health Organization(WHO) Classification of hematologic malignancies, using an updated R.E.A.L.Classification for lymphomas and applying the principles of the R.E.A.L.Classification to myeloid and histiocytic neoplasms. A Clinical AdvisoryCommittee (CAC) was formed to ensure that the WHO Classification will beuseful to clinicians. Results:The International Lymphoma Study showed that the R.E.A.L.Classification could be used by pathologists, with inter-observerreproducibility better than for other classifications (〉85%).Immunophenotyping was helpful in some diagnoses, but not required for manyothers. New entities not specifically recognized in the Working Formulationaccounted for 27% of the cases. Diseases that would have been lumpedtogether as `low grade' or `intermediate/high grade' in the WorkingFormulation showed marked differences in survival, confirming that they needto be treated as distinct entities. Clinical features such as theInternational Prognostic Index were also important in determining patientoutcome. The WHO Clinical Advisory Committee concluded that clinical groupingsof lymphoid neoplasms was neither necessary nor desirable. Patient treatmentis determined by the specific type of lymphoma, with the addition of gradewithin the tumor type, if applicable, and clinical prognostic factors such asthe International Prognostic Index (IPI). Conclusions:The experience of developing the WHO Classificationhas produced a new and exciting degree of cooperation and communicationbetween oncologists and pathologists from around the world, which shouldfacilitate progress in the understanding and treatment of hematologicmalignancies.