Soft TissueTumours of Uncertain Differentiation
Gastrointestinal Stromal Tumour
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Systemic amyloidosis: Systemic amyloidosis is associated with the following conditions: 1. Primary amyloidosis (B-cell dyscrasias): This is the most common form and composed of AL-type amyloid. (i) AL-type systemic amyloidosis occurs in 5 to 15% of patients with multiple myeloma. (ii) Tumour-plasma cells synthesize abnormal quantities of a single immunoglobulin. The patients show M spike on serum protein-electrophoresis or Bence Jones protein (immunoglobulin light chain). By virtue of their smaller size, Bence Jones proteins are frequently excreted in the urine. (iii) The vast majority of cases of AL-type systemic amyloidosis are not associated with overt B-cell neoplasms. Nevertheless, they have monoclonal immuno-globulins, light chains, or both. (iv) Typically (but not always), this type involves the heart, gastrointestinal tract, peripheral nerves, skin, and tongue more than other organs. 2. Secondary or Reactive amyloidosis: Composed of AA type amyloid. (i) Secondary amyloidosis is associated with chronic inflammatory states (infectious and noninfectious) producing protracted cell breakdown (e.g., rheumatoid arthritis, scleroderma, dermatomyositis, bronchiectasis, chronic osteomyelitis). (ii) Typically, involves kidneys, liver, spleen, lymph nodes, adrenals, and thyroid. 3. Hemodialysis related: It affects up to 70% of patients on chronic hemodialysis. This is due to deposition (in joints, synovium, and tendon sheaths) of Beta2-microglobulin which is not filtered by normal dialysis membranes. 4. Hereditary forms: Include many rare entities, often confined to specific geographic locations. (i) Most common and best characterized is familial Mediterranean fever: a recurrent febrile illness typically in Sephardic Jews, Armenians, and Arabs, characterized by bouts of serosal inflammation. The systemic amyloid is of AA type, suggesting that chronic inflammation plays a key role. ii) Familial amyloidotic poly-neuropathies: have autosomal dominant transmission and show deposition of varient transthyrectins principally in peripheral and autonomic nerves. Localized amyloidosis: Localized amyloidosis is confined to amyloid in a single organ or tissue without involvement of any other site of the body. The following conditions are associated: (i) Nodular (tumor-forming) deposits: Often AL protein with associated plasma cell infiltrates. It occurs most frequently in lung, larynx, skin, bladder, tongue and periorbitally. Often there are infiltrates of lymphocytes and plasma cells in the periphery of the amyloid mass. It may represent localized forms of B-cell dyscrasias. (ii) Endocrine amyloid -microscopic deposits of localized amyloid found in some endocrine tumours. Eg. medullary carcinoma of thyroid, islet cell tumors of pancreas, pheochromocytoma and undifferentiated carcinoma of stomach and in the islets of Langerhans (in patients with type II diabetes mellitus). |
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Amyloidosis is associated with: - advanced aging and - a variety of chronic diseases, specially those accompanied by chronic infection and inflammation, - disturbances of immune and autoimmune reactions, - excessive tissue breakdown and wasting, and - certain neoplasms. The lesions include chronic tuberculosis , osteomyelitis , lupus erythematosus , rheumatoid arthritis, Hodgkin's disease , multiple myeloma , and medullary carcinoma of the thyroid . More rarely amyloidosis is encountered as a primary disease that in some cases appears to have a genetic background and is familial. The most common form of this disease is the secondary type, which is systemic with involvement of multiple organs including the kidney, liver, spleen, adrenals, pancreas, and lymph nodes. Occasionally more widespread involvement including the heart , gastrointestinal tract, and blood vessels is encountered. Amyloid accumulation may in some cases be limited to one organ such as the heart, tongue, brain, or, in association with diabetes mellitus , the islets of Langerhans in the pancreas. Amyloid is an amorphous, insoluble, pink-staining material deposited between cells. Involved organs are pale and enlarged and have the consistency of hard rubber. Rarely, the kidney may be smaller than normal because of atrophy resulting from vascular narrowing by intramural deposits of amyloid. In the kidney, amyloid is present as homogeneous eosinophilic deposits in the mesangium of the glomerulus, the basement membrane of interstitial arteries and arterioles, and, in advanced cases the basement membrane and peritubular tissue of renal tubules. In the liver deposits begin in the space of Disse between the endothelium of the sinusoids and the hepatocytes and ultimately extend to involve the entire liver lobule. Deposits in spleen are localized either to the splenic follicles where amyloid accumulates between and around individual or small groups of lymphoid cells or in the pulp where it is deposited along the basement membrane of the sinuses and between the connective tissue cells and fibers that surround them. In other organs there is the same general pattern of extracellular deposits. As the condition worsens, the deposits enlarge to the point that entrapped cells become atrophic and ultimately die. When cell loss is excessive and the vascular supply to an organ is severely diminished, its function is compromised. Thus renal or cardiac failure is not uncommon in patients with advanced amyloidosis. Amyloid can be further identified in tissue sections by its staining reaction with the metachromatic dyes crystal violet and toluidine blue, which gives a rose-pink coloration to the deposits, and its binding to Congo red dye, which stains it orange and has an intense green birefringence when viewed with polarized light. Congo red has been used clinically for the diagnosis of amyloidosis in living patients by virtue of its rapid disappearance from the blood after injection, presumably because it is bound by amyloid deposits. High-resolution electron microscopy has established that the homogeneous-appearing deposits in tissues actually consist of a meshwork of nonbranching fibrils each measuring 7.5 nm in diameter, each fiber in turn appears to be composed of a pentagonal array of protofibrils that measure 2.5 to 3.5 nm in diameter and are twisted in a plait-like fashion so that they impart periodicity to the fibril. A second component contained in such deposits consists of short, ring-like structures with a pentagonal profile (P component), which appears to be identical to a 9.5S alfa-glycoprotein normally present in serum. P component constitutes about 10% of the protein in all amyloid proteins and is periodic acid-Schiff positive. The third component, a glycosaminoglycan usually heparan sulfate, is responsible for the intense staining of these deposits by iodine. After its initial description in 1842 by Rokitansky and subsequent studies by Virchow that led to its naming a few years later, the nature of amyloid until recent years was a matter of considerable controversy. On the basis of its mahogany-brown staining reaction with an aqueous solution of iodine and violet coloration after subsequent exposure to dilute sulfuric acid, Virchow was convinced that such deposits consist of a starch-like carbohydrate, hence the name. The clinical association of amyloid with diseases characterized by chronic antigenic stimulation, plasma cell proliferation, and frequently the presence of abnormal immunoglobulins in the blood and urine has long indicated that the condition may be related to a protracted immune response. Amyloid is frequently encountered in horses that have been used for 20 years or so for the commercial production of antitoxin by the pharmaceutical industry. An immune mechanism for the formation of some cases of amyloid was supported by experimental studies showing that splenectomy prevented the development of amyloid in mice after the injection of casein and that it could be induced in normal syngeneic hosts by transfer of splenic cells from animals with amyloidosis. A major feature of amyloid that proved to be a hurdle to its definitive chemical characterization was its insolubility. The finding that amyloid could be readily solubilized in a 6 M solution of guanidine hydrochloride allowed a detailed analysis of its amino acid sequence. Solubilized amyloid fibrils have an amino acid sequence identical to that found in the amino terminal variable segment of the light chains of immunoglobulin. Later it was established that amyloid is a fibrillar protein with a beta-pleated structure and molecular weight ranging from 5000 to 18,000 daltons. A feature of plasma cell myeloma that has been of assistance in increasing our knowledge of the nature of amyloid is the synthesis and secretion of immunoglobulins and their light chain subunits (Bence Jones proteins) by this tumour. On proteolytic digestion the fraction of Bence Jones protein that contains the variable portion of the light-chain molecule forms fibrils with properties similar to those of amyloid. On the basis of detailed studies of the sequence of amino acids in solubilized amyloid "protein", it has become clear that amyloid is a heterogeneous spectrum of proteins.
The following distinct types have been identified: 1. AL type: Its major protein component is derived from immunoglobulin. 2. AA type: This type is encountered in patients with recurrent and protracted inflammatory diseases such as rheumatoid arthritis, tuberculosis , malaria , familial Mediterranean fever, and a variety of malignancies including those of the kidney, Hodgkin’s disease, and multiple myeloma. Its major protein component is that of the amino terminal, two thirds of acute phase protein, and differs from that of the AL type. 3. AE type: The major protein is polypeptide with an amino acid sequence identical to part of the hormone thyrocalcitonin and believed to represent calcitonin precursor protein. 4. A type: The major protein in this type of amyloid is prealbumin (transthyretin), a protein that migrates ahead of albumin in electrophoresis, binds vitamin and thyroid hormones, and carries them to the blood. This type of amyloid accumulates in the heart of patients in the eighth and ninth decades of life, giving rise to so-called senile amyloid heart disease. 5. AP type: Its protein component present in all types of amyloid is derived from a normal serum protein called serum amyloid p (SAP) substance. 6. Beta2-amyloid protein (ABeta2): A peptide found in Alzheimer disease that forms the core of cerebral plaques and deposits within cerebral vessel walls. It derives from a transmembrane glycoprotein precursor (APP). Some less common forms of amyloid in particular clinical settings include: 1. Transthyretin (TTR): A normal serum protein that binds and transports thyroxine and retinal. A mutant form is deposited as amyloid in a group of hereditary diseases called familial amyloid polyneuropathy. 2. Beta2-microglobulin: The smaller nonpolymorphic peptide component of class I MHC molecules and a normal serum protein; deposited in amyloidosis complicating long-term hemodialysis. Although the pathogenesis of amyloid is not clear, it appears that one facet involves the proteolytic alteration of protein to beta-pleated fibrils.
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Amyloidosis of Aging:
Amyloidosis of aging occurs in the 8th and 9th decades of life, and is most commonly due to deposition of transthyretin. Although amyloid distribution is systemic, the dominant involve-ment is of the heart and it presents with cardiomyopathy or arrhythmias. In addition to the sporadic senile systemic amyloidosis, there is another form, affecting predominantly the heart, in which mutant transthyretin is deposited. This condition is more common in blacks. Senile cerebral amyloidosis is due to the deposition of amyloid causing Alzheimer disease.
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Introduction of Pathology An outline of Diagnostic Techniques available in Pathology Diagram showing Structural Changes in Reversible and Irreversible Cell Injury Coagulation (Coagulative) necrosis Circulatory Anatomy, Physiology and Regulation Diagram showing Capillary System and Mechanisms of Edema Formation |
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Myxoid
Tumours of Soft Tissue Classification of Soft Tissue Tumour Gross examination of soft tissue specimen A practical approach to histopathological reporting of soft tissue tumours Grading of soft tissue tumours |