Aubrey J. Hough

Cytokines in malignant lymphomas: Review and prospective evaluation

Cytokines play important roles in the pathogenesis of lymphomas. Cytokines either can be produced or exert effects on neoplastic or reactive cells. The secretion of cytokines can provide growth advantages for tumor cells in either an autocrine or a paracrine fashion. An elevated serum or tissue level of cytokines can contribute to the clinical and histopathologic alterations associated with malignant lymphomas. The effects of cytokines on the histopathologic changes are most noticeable in Hodgkins disease (HD). The malignant (Hodgkins-Reed-Sternberg) cells in HD have been shown to secrete interleukin-1 (IL-1), IL-5, IL-6, IL-9, tumor necrosis factor-alpha, macrophage colony-stimulating factor, transforming growth factor-beta, and, less frequently, IL-4 and granulocyte colony-stimulating factor. These cytokines may be responsible for the increased cellular reaction and fibrosis observed in tissues involved by HD and for the immunosuppression in patients with HD. In contrast to Hodgkins-Reed-Sternberg cells, most non-HD lymphoma cells do not produce cytokines in excess amounts. Exceptions include T-cell-rich B-cell lymphoma (IL-4), angioimmunoblastic lymphadenopathy-like T-cell lymphoma with plasmacytosis and hypergammaglobulinemia (IL-6), anaplastic large-cell lymphoma (IL-9), polymorphic immunocytoma (IL-6), and immunoblastic lymphoma (IBL) (IL-6). Some cytokines are involved in the unique cellular reactions in each of these types of lymphoma. For example, IL-4 is responsible for the T-cell reaction in T-cell-rich B-cell lymphoma, while IL-6 is accountable for the plasma cell reaction in angioimmunoblastic lymphadenopathy-type T-cell lymphoma. Others may be directly involved in the tumor cell growth or differentiation. For instance, IL-9 may be important for the autocrine proliferation of anaplastic large cell lymphoma, whereas IL-6 is essential for plasmacytoid differentiation in polymorphic immunocytoma. Further studies of the roles of cytokines in lymphomas may lead to major advances in the understanding of the molecular processes involved in the histopathogenesis of malignant lymphomas. Elucidation of the autocrine or paracrine function of cytokines also may lead to new approaches to a rational intervention in these disease processes.

Myeloma of the central nervous system: association with high-risk chromosomal abnormalities, plasmablastic morphology and extramedullary manifestations.

Summary.  Involvement of the central nervous system (CNS) by multiple myeloma, as defined by the detection of malignant plasma cells in the cerebrospinal fluid in the presence of suggestive symptoms, is considered extremely rare. We report on the characteristics of 18 such patients diagnosed and treated at the University of Arkansas over the last 10 years for an overall incidence of approximately 1%. Their evaluation revealed association of CNS involvement with unfavourable cytogenetic abnormalities (especially translocations and deletion of the chromosome 13), high tumour mass, plasmablastic morphology, additional extramedullary myeloma manifestations and circulating plasma cells. The presence of these features should alert clinicians to the possibility of CNS involvement. The outcome of these patients was extremely poor despite the use of aggressive local and systemic treatment including autologous stem cell transplants. Given this universally poor prognosis, the application of allogeneic transplants should be studied in this clinical setting.

Renal pathologic spectrum in an autopsy series of patients with plasma cell dyscrasia

CONTEXT Renal dysfunction in plasma cell dyscrasias is common. It is the second most common cause of death in patients with myeloma. OBJECTIVE We evaluated 77 sequential autopsies performed on patients dying from complications of plasma cell dyscrasias during an 11-year period at the University of Arkansas for Medical Sciences. These consisted of 15% of all the autopsies performed during this time. DESIGN The kidneys were evaluated by light microscopy using hematoxylin-eosin-stained sections as well as Congo red and thioflavin T stains when amyloidosis was in the differential diagnosis. Immunofluorescence was performed on selected cases. RESULTS The most common lesion identified was cast nephropathy (30%). Other findings included acute tubulopathy, AL-amyloidosis, light chain deposition disease, tubulointerstitial nephritis associated with monotypic light chain deposits, thrombotic microangiopathy, renal infarction, fungal infection, and plasma cell tumor nodules. Autolysis, an expected finding in autopsy evaluations, was significant in 25 cases. CONCLUSIONS Renal lesions are heterogeneous in these patients. In some cases, combined pathologic lesions were noted. Myeloma cast nephropathy predominated among all the renal lesions noted.

An organ culture model for assaying wound repair of the fibrocartilaginous knee joint meniscus

We describe an in vitro organ culture system that can be used to test the effect of various substances and compounds on the wound healing process in the fibro cartilaginous substance of the knee joint meniscus. Using culture medium containing either 10% fetal bo vine serum (FBS) or our recently developed serum-free, defined culture medium (DM), we have demonstrated the ability of meniscal fibrochondrocytes from intact rabbit menisci to extricate themselves from their sur rounding matrix and migrate into an exogenous, purified fibrin clot in vitro. After 4 weeks of culture in FBS containing medium, the cells which had invaded the clot had initiated the early aspects of a typical reparative response; the same response did not occur in DM alone. Morphologically, the cells on the surface of the clot resembled the original superficial fibrochondro cytes, whereas those cells within the substance of the clot more closely resembled the original deep fibro chondrocytes. After 10 weeks, the reparative response had progressed only to a certain point and then failed to progress further under these culture conditions. However, use of this culture system should now make it possible to rapidly identify and quantitate those fac tors which would most likely be useful in continuing the reparative response and in affecting meniscal wound repair. Elucidation of the mechanisms and requirements for meniscal healing will eventually allow the practicing orthopaedic surgeon to effect in situ meniscal repair and obviate the need for meniscectomy and its morbid sequelae.

Pathology of the meniscus

The pathologic description of the menisci is facilitated by grouping the various disorders into etiologic groups. These include congenital anomalies, traumatic conditions, inflammatory disorders, metabolic disorders, degenerative conditions, and neoplasms. In clinical practice, traumatic conditions, as exemplified by meniscal tears of the vertical-longitudinal or vertical-transverse type, are the most important pathologic disorders. Healing of meniscal tears occurs only when the tear involves the peripheral vascularized attachment of either the lateral or medial meniscus. Intensive clinical and animal experimentation suggests that serum-derived growth factors are necessary for meniscal healing. Chondrocalcinosis is extremely frequent in the menisci of older individuals and may or may not be associated with degenerative changes of the menisci, including fibrillation, loss of protein polysaccharide ground substance, and chondrocytic proliferation. The role of degenerative changes of the menisci, including tears of the horizontal type, in the development of osteoarthritis (OA) of the knee is a subject of intense interest, as is the relationship between chondrocalcinosis and OA. Neoplastic involvement of the menisci is essentially limited to invasion by tumors starting in or, more commonly, adjacent to the knee joints.

MDS-type abnormalities within myeloma signature karyotype (MM-MDS): only 13% 1-year survival despite tandem transplants

Summary. Cytogenetic abnormalities (CA), especially of chromosome 13, have been used to identify a subgroup of previously untreated multiple myeloma (MM) patients with very poor prognosis despite high‐dose therapy (HDT). We examined the prognostic implications of CA in 1000 MM patients receiving melphalan‐based tandem autotransplants (median follow‐up, 5 years). Negative consequences for both overall survival (OS) and event‐free survival (EFS) in the presence of any CA were confirmed, especially when detected within 3 months of HDT. In the context of standard prognostic factors (SPF), ‘MM‐MDS’ (MM karyotype that contains, in addition, CA typical of MDS) imparted a poor OS and EFS, after adjusting for any CA and all individual CA. One‐year mortality was also high, especially for the MM‐MDS subgroup with trisomy 8 within a MM signature karyotype (87%vs 34% in its absence, P < 0·001). No patient remained event free 5 years post transplant in the presence of these baseline high‐risk CA. However, certain trisomies (e.g. chromosomes 7 and 9) and del 20 had favourable clinical consequences. The higher risk that is associated with CA compared with SPF justifies routine cytogenetic studies in all patients with MM at diagnosis and whenever additional treatment decisions are considered, such as in planning HDT either for initial response consolidation, at the time of primary unresponsiveness to induction therapy, or at relapse.

Tissue Sampling as a Potential Source of Error in Experimental Studies of Cartilage

Although it might seem trite to point out that tissue sampling is a potential source of experimental error, this survey disclosed that even experienced investigators in fact often work with cartilage that is contaminated by non-cartilaginous tissue of which they were unaware. Twenty-two specimens ranging from chick embryo sternum to bovine nasal septum were studied by serial sectioning. Eighteen of the 22 contained extraneous tissue comprising from 3 to 50% of the cross-sectional area. The impact of the contamination depends on the use being made of the material and probably is greatest in cell culture studies because chondrocytes and fibroblasts have large differences in population doubling time. Several approaches for minimizing the error are suggested by the findings. Histological examination of specimen material is thus a desirable quality control procedure in the design and interpretation of experiments on cartilage as well as other tissues.

Nuclear magnetic resonance in pathology: I. Principles and general aspects

Nuclear magnetic resonance (NMR) has become established as a powerful diagnostic imaging technique in medicine. The power of NMR as a tool for characterizing molecular structure and for quantitative analysis of complex mixtures in the clinical laboratory or even in vivo is beginning to be exploited. In the clinical laboratory, NMR can analyze the complex mixtures of bodily fluids, intact cells, tissues, and their extracts. Phosphorus-31 or 1H NMR spectroscopy in vivo can provide a noninvasive probe of high-energy compounds, amino acids, and compounds of phospholipid metabolism. The basic principles of NMR spectroscopy are presented here, with emphasis on the various NMR parameters and the information they provide. A companion article presents a survey of applications in pathology.