Pathology_Robbins

Pathology_Robbins. The onset of CML is insidious, as the initial symptoms usually are nonspecific (e.g., easy fatigability, weakness, weight loss). Sometimes the first symptom is a dragging sensation in the abdomen caused by splenomegaly. On occasion it may be necessary to distinguish CML from a lekemoid reaction a dramatic elevation of the granulocyte count in response to infection, stress, chronic inflammation, and certain neoplasms. This distinction can be achieved definitively by testing for the presence of the BCR-ABL fusion gene, which can be done by karyotyping, fluorescence in situ hybridization, or PCR assay. Fig. 12.28 CML—peripheralbloodsmear.Granulocyticformsatvariousstagesofdifferentiationarepresent.(Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas,Texas.)


Pathology_Robbins

Pathology_Robbins. The natural history of CML initially is one of slow progression. Even without treatment, the median survival is 3 years. After a variable (and unpredictable) period, approximately half of CML cases enter an accelerated phase marked by increasing anemia and new thrombocytopenia, the appearance of additional cytogenetic abnormalities, and finally transformation into a picture resembling acute leukemia (blast crisis). In the remaining 50% of cases, blast crisis occurs abruptly, without an accelerated phase. Of note, in 30% of cases the blast crisis resembles precursor-B cell ALL, further attesting to the origin of CML from hematopoietic stem cells. In the remaining 70% of cases, the blast crisis resembles AML. Less commonly, CML progresses to a phase of extensive bone marrow fibrosis resembling primary myelofibrosis.


Pathology_Robbins

Pathology_Robbins. Fortunately for those affected, the natural history of CML has been altered dramatically by the emergence of targeted therapy. Treatment with tyrosine kinase inhibitors, particularly in patients with early disease, induces sustained remissions with manageable toxicity and prevents progression to blast crisis, apparently by suppressing the proliferative drive that leads to the acquisition of additional mutations. When patients on tyrosine kinase inhibitors relapse, their tumors frequently are found to have acquired mutations in the kinase domain of BCR-ABL that prevent the drugs from binding. The selective outgrowth of these cells is explained by the powerful anti-tumor effects of BCR-ABL inhibitors, and indicates that many resistant tumors are still “addicted” to the progrowth signals created by BCR-ABL. In some instances resistant tumors can be treated with “third-generation” BCR-ABL inhibitors. For others, hematopoietic stem cell transplantation offers a chance of cure, but carries


Pathology_Robbins

Pathology_Robbins. by BCR-ABL. In some instances resistant tumors can be treated with “third-generation” BCR-ABL inhibitors. For others, hematopoietic stem cell transplantation offers a chance of cure, but carries with it substantial risks, particularly in the aged.


Pathology_Robbins

Pathology_Robbins. Polycythemia vera is strongly associated with activating point mutations in the tyrosine kinase JAK2. JAK2 normally acts in the signaling pathways downstream of the erythropoietin receptor and other growth factor receptors. The most common JAK2 mutation, sharply lowers the dependence of hematopoietic cells on growth factors for growth and survival. This produces excessive proliferation of erythroid, granulocytic, and megakaryocytic elements (panmyelosis), but most clinical signs and symptoms are related to an absolute increase in red cell mass. Polycythemia vera must be distinguished from relative polycythemia, which results from hemoconcentration. Unlike reactive forms of absolute polycythemia, polycythemia vera is associated with low levels of serum erythropoietin, which is a reflection of the growth factor–independent growth of the neoplastic clone. http://ebooksmedicine.net


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Thebonemarrowishypercellularowingtoincreasednumbersoferythroid,myeloid,andmegakaryocyticforms.Inaddition,somedegreeofmarrowfibrosisispresentin10%ofpatientsatthetimeofdiagnosis.Inasubsetofpatients,thisprogressestoaspentphasewherethemarrowislargelyreplacedbyfibroblastsandcollagen. Polycythemia vera appears insidiously, usually in late middle age. Patients are plethoric and often somewhat cyanotic. Histamine released from the neoplastic basophils may contribute to pruritus and also may account for the increased incidence of peptic ulceration. Other complaints are referable to the thrombotic and hemorrhagic tendencies and to hypertension. Headache, dizziness, gastrointestinal symptoms, hematemesis, and melena are common. Because of the high rate of cell turnover, symptomatic gout is seen in 5% to 10% of cases.


Pathology_Robbins

Pathology_Robbins. The diagnosis usually is made in the laboratory. Red cell counts range from 6 to 10 million/µL, and the hematocrit is often 60% or greater. The granulocyte count can be as high as 50,000 cells/µL, and the platelet count is often more than 400,000/µL. Basophilia is common. The platelets are functionally abnormal in most cases, and giant platelets and megakaryocyte fragments are often seen in the blood. About 30% of patients develop thrombotic complications, usually affecting the brain or heart. Hepatic vein thrombosis giving rise to Budd-Chiari syndrome (Chapter 15) is an uncommon but grave complication. Minor hemorrhages (e.g., epistaxis and bleeding from gums) are common and life-threatening hemorrhages that occur in 5% to 10% of patients. In those receiving no treatment, death occurs from vascular complications within months; however, the median survival is increased to about 10 years by lowering the red cell count to near normal through repeated phlebotomy.


Pathology_Robbins

Pathology_Robbins. Unfortunately, prolonged survival has shown a propensity for polycythemia vera to evolve to a “spent phase” resembling primary myelofibrosis. After an average interval of 10 years, 15% to 20% of cases undergo such a transformation. Owing to the extensive marrow fibrosis, hematopoiesis shifts to the spleen, which enlarges markedly. Inhibitors that target JAK2 have been approved for treatment of the spent phase of polycythemia vera and lead to some improvement in most patients. Transformation to a “blast crisis” identical to AML also occurs, but much less frequently than in CML. The hallmark of primary myelofibrosis is the development ofobliterativemarrowfibrosis,whichreducesbonemarrow hematopoiesis and leads to cytopenias and extensive extramedullary hematopoiesis. Histologically, the appearance is identical to the spent phase that occurs occasionally late in the course of other myeloproliferative disorders. This similarity also extends to the underlying pathogenesis.


Pathology_Robbins

Pathology_Robbins. JAK-STAT signaling seems to be the underlying driver in almost all cases. Thus, JAK2 mutations are present in 50% to 60% of cases and activating mutations in MPL, the thrombopoietin receptor, are seen in an additional 1% to 5% of cases. Most of the remaining cases have other mutations, which also are hypothesized to stimulate increased JAK-STAT signaling. Why JAK2 mutations are associated with polycythemia vera in some patients and primary myelofibrosis in others is not understood; differences in the cell of origin and the genetic backgrounds that give rise to these two disorders are suspected.


Pathology_Robbins

Pathology_Robbins. It is believed that the characteristic marrow fibrosis is caused by the inappropriate release of fibrogenic factors from neoplastic megakaryocytes. Two factors synthesized by megakaryocytes have been implicated: platelet-derived growth factor and TGF-β. As you recall, platelet-derived growth factor and TGF-β are fibroblast mitogens. In addition, TGF-β promotes collagen deposition and causes angiogenesis, both of which are observed in myelofibrosis. As marrow fibrosis progresses, displaced hematopoietic stem cells take up residence in niches in secondary hematopoietic organs, such as the spleen, the liver, and the lymph nodes, leading to the appearance of extramedullary hematopoiesis. For incompletely understood reasons, red cell production at extramedullary sites is disordered. This factor and the concomitant suppression of marrow function result in moderate to severe anemia.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 12.29 Primarymyelofibrosis—peripheralbloodsmear.Twonucleatederythroidprecursorsandseveralteardrop-shapedredcells(dacryocytes)areevident.Immaturemyeloidcellswerepresentinotherfields.Anidenticalhistologicpicturecanbeseeninotherdiseasesproducingmarrowdistortionandfibrosis. Primary myelofibrosis usually occurs in individuals older than 60 years who come to attention because of progressive anemia and splenomegaly. Nonspecific symptoms such as fatigue, weight loss, and night sweats are common. Hyperuricemia and secondary gout resulting from a high rate of cell turnover also are frequently seen.


Pathology_Robbins

Pathology_Robbins. Laboratory studies typically show a moderate to severe normochromic normocytic anemia accompanied by leukoerythroblastosis. The white cell count is usually normal or mildly reduced, but can be elevated early in the course. The platelet count is usually normal or elevated at diagnosis, but thrombocytopenia often supervenes as the disease progresses. These blood findings are not specific, and bone marrow biopsy is essential for diagnosis.


Pathology_Robbins

Pathology_Robbins. Primary myelofibrosis is more difficult to treat than polycythemia vera and CML. The median survival is in the range of 4 to 5 years. Threats to life include infection, thrombosis and bleeding related to platelet abnormalities, and transformation to AML, which occurs in 5% to 20% of cases. JAK2 inhibitors are effective at decreasing the splenomegaly and constitutional symptoms, even in those without JAK2 mutations, presumably because increased JAK/STAT signaling is common to all molecular subtypes. Hematopoietic stem cell transplantation may be curative in those young and fit enough to withstand the procedure. Myeloidtumorsoccurmainlyinadultsandfallintothreemajorgroups: •Aggressivetumorscomprisedofimmaturemyeloidlineageblasts,whichreplacethemarrowandsuppressnormalhematopoiesis •Associatedwithdiverseacquiredmutationsthatleadtoexpressionofabnormaltranscriptionfactors,whichinterferewithmyeloiddifferentiation


Pathology_Robbins

Pathology_Robbins. Allcantransformtoacuteleukemiaandtoaspentphaseofmarrowfibrosisassociatedwithanemia,thrombocytopenia,andsplenomegaly. The term histiocytosis is an “umbrella” designation for a variety of proliferative disorders of dendritic cells or macrophages. Some, such as very rare histiocytic lymphomas, are highly malignant neoplasms. Others, such as most histiocytic proliferations in lymph nodes, are completely benign and reactive. Between these two extremes lie a group of relatively rare tumors comprised of Langerhans cells, the Langerhans cell histiocytoses. As described in Chapter 5, Langerhans cells are immature dendritic cells found in the epidermis; similar cells are found in many other organs, and they function to capture antigens and display them to T cells.


Pathology_Robbins

Pathology_Robbins. Langerhans cell proliferations take on different clinical forms, but all are believed to be variations of the same basic disorder. The proliferating Langerhans cells express MHC class II antigens, CD1a, and langerin. Langerin is a trans-membrane protein found in Birbeck granules, cytoplasmic pentalaminar rodlike tubular structures that in electron micrographs have a characteristic periodicity and sometimes a dilated terminal end (“tennis racket” appearance). Under the light microscope, the proliferating Langerhans cells do not resemble their normal dendritic counterparts. Instead, they have abundant, often vacuolated cytoplasm and vesicular nuclei, an appearance more akin to that of tissue macrophages (called histiocytes by morphologists)— hence the term Langerhans cell histiocytosis. Langerhans cell histiocytoses can be grouped into two major relatively distinctive clinicopathologic entities.


Pathology_Robbins

Pathology_Robbins. Langerhans cell histiocytoses can be grouped into two major relatively distinctive clinicopathologic entities. • Multisystem Langerhans cell histiocytosis (Letterer-Siwe disease) usually occurs in children younger than 2 years of age. It typically manifests with multifocal cutaneous lesions that grossly resemble seborrheic skin eruptions and are composed of Langerhans cells. Most affected patients have hepatosplenomegaly, lymphadenopathy, pulmonary lesions, and (later in the course) destructive osteolytic bone lesions. Extensive marrow infiltration often leads to pancytopenia and predisposes the patient to recurrent bacterial infections. The disease is rapidly fatal if untreated. With intensive chemotherapy, 50% of patients survive 5 years.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net • Unisystem Langerhans cell histiocytosis (eosinophilic granuloma) may be unifocal or multifocal. It is characterized by expanding accumulations of Langerhans cells, usually within the medullary cavities of bones or less commonly in the skin, lungs, or stomach. The Langerhans cells are admixed with variable numbers of lymphocytes, plasma cells, neutrophils, and eosinophils, which are usually prominent. Virtually any bone may be involved; the calvaria, ribs, and femur are most commonly affected. Unifocal disease most often involves a single bone. It may be asymptomatic or cause pain, tenderness, and pathologic fracture. It is an indolent disorder that may heal spontaneously or be cured by local excision or irradiation. Multifocal unisystem disease usually affects children and typically manifests with multiple erosive bony masses that sometimes extend into soft tissues. In about 50% of cases, involvement of the posterior pituitary stalk of the hypothalamus


Pathology_Robbins

Pathology_Robbins. children and typically manifests with multiple erosive bony masses that sometimes extend into soft tissues. In about 50% of cases, involvement of the posterior pituitary stalk of the hypothalamus leads to diabetes insipidus. The combination of calvarial bone defects, diabetes insipidus, and exophthalmos is referred to as the Hand-Schüller-Christian triad. Many patients experience spontaneous regressions; others are treated effectively with chemotherapy.


Pathology_Robbins

Pathology_Robbins. A clue to the pathogenesis of Langerhans cell tumors lies in the discovery that the different clinical forms are frequently associated with an acquired mutation in the serine/threonine kinase BRAF, that leads to hyperactivity of the kinase. This same mutation is found in a variety of other tumors, including hairy cell leukemia (described earlier), benign nevi, malignant melanoma, papillary thyroid carcinoma, and some colon cancers (Chapter 6). BRAF is a component of the RAS signaling pathway that drives cellular proliferation and survival, effects that likely contribute to the growth of neoplastic Langerhans cells.


Pathology_Robbins

Pathology_Robbins. Bleeding disorders are characterized clinically by abnormal bleeding, which can appear spontaneously or follow some inciting event (e.g., trauma or surgery). As described in Chapter 4, normal clotting involves the vessel wall, the platelets, and the clotting factors. It follows that abnormalities in any of these components can lead to clinically significant bleeding. A review of the laboratory tests used in the evaluation of patients with a suspected bleeding disorder, along with the principles involved, is presented next, followed by consideration of specific disorders of coagulation. We finish with a discussion of a few clinically important complications of blood product transfusion. The most important tests for investigation of suspected coagulopathies include the following:


Pathology_Robbins

Pathology_Robbins. The most important tests for investigation of suspected coagulopathies include the following: Prothrombin time (PT). This test assesses the extrinsic and common coagulation pathways. It measures the time (in seconds) needed for plasma to clot after addition of tissue thromboplastin (e.g., brain extract) and Ca2+ ions. A prolonged PT can result from a deficiency of factor V, VII, or X; prothrombin; or fibrinogen or the presence of an acquired inhibitor (typically an antibody) that interferes with the extrinsic pathway.


Pathology_Robbins

Pathology_Robbins. Partial thromboplastin time (PTT). This test assesses the intrinsic and common coagulation pathways. It measures the time (in seconds) needed for the plasma to clot after the addition of kaolin, cephalin, and Ca2+ . Kaolin activates the contact-dependent factor XII and cephalin substitutes for platelet phospholipids. Prolongation of PTT can be caused by a deficiency of factor V, VIII, IX, X, XI, or XII; prothrombin; or fibrinogen or the presence of an acquired inhibitor that interferes with the intrinsic pathway. Platelet count. This is obtained on anti-coagulated blood using an electronic particle counter. The reference range is 150,000 to 450,000/µL. Counts outside this range must be confirmed by a visual inspection of a peripheral blood smear.


Pathology_Robbins

Pathology_Robbins. • Tests of platelet function. At present no single test provides an adequate assessment of the complex functions of platelets. Aggregation tests that measure the response of platelets to certain agonists and qualitative and quantitative tests of von Willebrand factor (vWF) (which you will recall is required for platelet adherence to subvascular collagen) are both commonly used in clinical practice. An old test, the bleeding time, has some value but is time-consuming and difficult to standardize and is therefore performed only rarely. Newer instrument-based assays that provide quantitative measures of platelet function are being evaluated but are not yet available for routine use in the clinic. In addition, more specialized tests are available that measure the levels of specific clotting factors and fibrin split products or assess the presence of circulating anti-coagulants.


Pathology_Robbins

Pathology_Robbins. In addition, more specialized tests are available that measure the levels of specific clotting factors and fibrin split products or assess the presence of circulating anti-coagulants. Bleeding disorders may stem from abnormalities of vessels, platelets, or coagulation factors, alone or in combination. Bleeding resulting from vascular fragility is seen with vitamin C deficiency (scurvy) (Chapter 8), systemic amyloidosis (Chapter 5), chronic glucocorticoid use, rare inherited conditions affecting the connective tissues, and a large number of infectious and hypersensitivity vasculitides. Some of these conditions are discussed in other chapters; others are beyond the scope of this book. Bleeding that results purely from vascular fragility is characterized by the “spontaneous” appearance of petechiae and ecchymoses in the skin and mucous membranes (probably resulting from minor trauma). In most instances laboratory tests of coagulation are normal.


Pathology_Robbins

Pathology_Robbins. Bleeding also can be triggered by systemic conditions that inflame or damage endothelial cells. If severe http://ebooksmedicine.net enough, such insults convert the vascular lining to a pro-thrombotic surface that activates coagulation throughout the circulatory system, a condition known as disseminated intravascular coagulation (DIC) (discussed in the next section). Paradoxically, in DIC, platelets and coagulation factors often are used up faster than they can be replaced, resulting in deficiencies that may lead to severe bleeding (a condition referred to as consumptive coagulopathy).


Pathology_Robbins

Pathology_Robbins. Deficiencies of platelets (thrombocytopenia) also are an important cause of bleeding. These occur in a variety of clinical settings that are discussed later. Other bleeding disorders stem from qualitative defects in platelet function. Such defects may be acquired, as in uremia and certain myeloproliferative disorders and after aspirin ingestion; or inherited, as in von Willebrand disease and other rare congenital disorders. The clinical signs of inadequate platelet function include easy bruising, nosebleeds, excessive bleeding from minor trauma, and menorrhagia.


Pathology_Robbins

Pathology_Robbins. In bleeding disorders stemming from defects in one or more coagulation factors, the PT, PTT, or both are prolonged. Unlike platelet defects, petechiae and mucosal bleeding are usually absent. Instead, hemorrhages tend to occur in parts of the body that are subject to trauma, such as the joints of the lower extremities. Massive hemorrhage may occur after surgery, dental procedures, or severe trauma. This category includes the hemophilias, an important group of inherited coagulation disorders. It is not uncommon for bleeding to occur as a consequence of a mixture of defects. This is the case in DIC, in which both thrombocytopenia and coagulation factor deficiencies contribute to bleeding, and in von Willebrand disease, a fairly common inherited disorder in which both platelet function and (to a lesser degree) coagulation factor function are abnormal. With the foregoing overview as background, we now turn to specific bleeding disorders.


Pathology_Robbins

Pathology_Robbins. With the foregoing overview as background, we now turn to specific bleeding disorders. DIC occurs as a complication of a wide variety of disorders; it is caused by the systemic activation of coagulation and results in the formation of thrombi throughout the microcirculation. As a consequence, platelets and coagulation factors are consumed and, secondarily, fibrinolysis is activated. Thus, DIC can give rise either to tissue hypoxia and microinfarcts caused by myriad microthrombi or to a bleeding disorder related to pathologic activation of fibrinolysis and the depletion of the elements required for hemostasis (hence the term consumptive coagulopathy). This entity probably causes bleeding more commonly than all of the congenital coagulation disorders combined.


Pathology_Robbins

Pathology_Robbins. Before discussing specific disorders associated with DIC, we must first consider in a general way the pathogenic mechanisms by which intravascular clotting occurs. Reference to earlier comments on normal blood coagulation (Chapter 4) may be helpful at this point. It suffices to recall that clotting can be initiated by either the extrinsic pathway, which is triggered by the release of tissue factor (tissue thromboplastin); or the intrinsic pathway, which involves the activation of factor XII by surface contact, collagen, or other negatively charged substances. Both pathways lead to the generation of thrombin. Clotting normally is limited by the rapid clearance of activated clotting factors by the macrophages and the liver, endogenous anticoagulants (e.g., protein C), and the concomitant activation of fibrinolysis. DIC usually is triggered by either (1) the release of tissue factor or thromboplastic substances into the circulation or (2) widespread endothelial cell damage ( Fig.


Pathology_Robbins

Pathology_Robbins. Fig. 12.30 ). Thromboplastic substances can be released into the circulation from a variety of sources—for example, the placenta in obstetric complications or certain types of cancer cells, particularly those of acute promyelocytic leukemia and adenocarcinomas. Cancer cells may also provoke coagulation in other ways, such as by releasing proteolytic enzymes and by expressing tissue factor. In gram-negative and gram-positive sepsis (important causes of DIC), endotoxins or exotoxins stimulate the release of tissue factor from monocytes. Activated monocytes also release IL-1 and tumor necrosis factor, both of which stimulate the expression of tissue factor on endothelial cells and simultaneously decrease the expression of thrombomodulin. The latter, as discussed, activates protein C, an anticoagulant (Chapter 4). The net result of these alterations is the enhanced generation of thrombin and the blunting of inhibitory pathways that limit coagulation.


Pathology_Robbins

Pathology_Robbins. Severe endothelial cell injury can initiate DIC by causing the release of tissue factor and by exposing subendothelial collagen and vWF. However, even subtle forms of endothelial damage can unleash procoagulant activity by stimulating tissue factor expression on endothelial cell surfaces. Widespread endothelial injury can be produced by the deposition of antigen-antibody complexes (e.g., in systemic lupus erythematosus), by temperature extremes (e.g., after heat stroke or burn injury), or by infections (e.g., resulting from meningococci or rickettsiae). As discussed in Chapter 4, endothelial injury is an important consequence of systemic inflammatory response syndrome (SIRS) triggered by sepsis and other systemic insults, and, not surprisingly, DIC is a frequent complication of SIRS. Disorders associated with DIC are listed in


Pathology_Robbins

Pathology_Robbins. Disorders associated with DIC are listed in Table 12.12 . Of these, DIC is most often associated with sepsis, obstetric complications, malignancy, and major trauma (especially to the brain). The initiating events in these conditions are multiple and often interrelated. For example, in obstetric conditions, tissue factor derived from the placenta, retained dead fetus, or amniotic fluid enters the circulation; however, shock, hypoxia, and acidosis often coexist and can lead to widespread endothelial injury. Trauma to the brain releases fat and phospholipids, which act as contact factors and thereby activate the intrinsic arm of the coagulation cascade.


Pathology_Robbins

Pathology_Robbins. Whatever the pathogenic mechanism, DIC has two consequences. First, there is widespread fibrin deposition within the microcirculation. The associated obstruction leads to ischemia in the more severely affected or vulnerable organs and hemolysis as red cells are traumatized while passing through vessels narrowed by fibrin thrombi (microangiopathic hemolytic anemia). Second, because of the depletion of platelets and clotting factors and the secondary release of plasminogen activators, there is a superimposed bleeding tendency. Plasmin cleaves not only to fibrin (fibrinolysis) but also to factors V and VIII, thereby reducing their concentration further. In addition, fibrinolysis creates fibrin degradation products. These inhibit platelet aggregation, have anti-thrombin activity, and impair fibrin polymerization, all of which contribute to the hemostatic failure ( Fig. 12.30 http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 12.30 http://ebooksmedicine.net Fig. 12.30 Pathophysiologyofdisseminatedintravascularcoagulation.Massive tissue destruction Activation of plasmin Microangiopathic hemolytic anemia Proteolysis of clotting factors Fibrin split products Inhibition of thrombin, platelet aggregation, and fibrin polymerization Endothelial injury Platelet aggregation Consumption of clotting factors and platelets Sepsis Fibrinolysis Bleeding Ischemic tissue damage Vascular occlusion Widespread microvascular thrombosis Table 12.12 Major Disorders Associated With Disseminated Intravascular Coagulation Carcinomasofpancreas,prostate,lung,andstomachAcutepromyelocyticleukemia Acuteintravascularhemolysis,snakebite,gianthemangioma,shock,heatstroke,vasculitis,aorticaneurysm,liverdisease Release of tissue factor


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. As might be imagined, depending on the balance between clotting and bleeding tendencies, the range of possible clinical manifestations is enormous. In general, acute DIC (e.g., that associated with obstetric complications) is dominated by bleeding, whereas chronic DIC (e.g., as occurs in those with cancer) tends to manifest with signs and symptoms related to thrombosis. The abnormal clotting usually is confined to the microcirculation, but large vessels are involved on occasion. The manifestations may be minimal, or there may be shock, acute renal failure, dyspnea, cyanosis, convulsions, and coma. Most often, the onset of DIC is announced by prolonged and copious postpartum bleeding or the presence of petechiae and ecchymoses on the skin. These may be the only manifestations, or there may be severe hemorrhage into the gut or urinary tract. Laboratory evaluation shows thrombocytopenia and prolongation of the PT and the PTT (from depletion of platelets, clotting factors, and


Pathology_Robbins

Pathology_Robbins. there may be severe hemorrhage into the gut or urinary tract. Laboratory evaluation shows thrombocytopenia and prolongation of the PT and the PTT (from depletion of platelets, clotting factors, and fibrinogen). Fibrin split products are increased in the plasma.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net The prognosis varies widely depending on the nature of the underlying disorder and the severity of the intra-vascular clotting and fibrinolysis. Acute DIC can be life threatening and must be treated aggressively with anticoagulants such as heparin or the coagulants contained in fresh frozen plasma. Conversely, chronic DIC is sometimes identified unexpectedly by laboratory testing. In either circumstance, definitive treatment must be directed at the underlying cause.


Pathology_Robbins

Pathology_Robbins. Isolated thrombocytopenia is associated with a bleeding tendency and normal coagulation tests. A count less than 150,000 platelets/µL generally is considered thrombocytopenia. However, only when platelet counts fall to 20,000 to 50,000 platelets/µL is there an increased risk of posttraumatic bleeding, and spontaneous bleeding is unlikely until counts fall below 5000 platelets/µL. Most bleeding occurs from small, superficial blood vessels and produces petechiae or large ecchymoses in the skin, the mucous membranes of the gastrointestinal and urinary tracts, and other sites. Larger hemorrhages into the central nervous system are a major hazard in those with markedly depressed platelet counts. The major causes of thrombocytopenia are listed in


Pathology_Robbins

Pathology_Robbins. The major causes of thrombocytopenia are listed in Table 12.13 . Clinically important thrombocytopenia is confined to disorders with reduced production or increased destruction of platelets. When the cause is the accelerated destruction of platelets, the bone marrow usually shows a compensatory increase in the number of megakaryocytes. Also of note, thrombocytopenia is one of the most common hematologic manifestations of AIDS. It can occur early in the course of HIV infection and has a multifactorial basis, including immune complex–mediated platelet destruction, anti-platelet autoantibodies, and HIV-mediated suppression of megakaryocyte development and survival. Immune thrombocytopenic purpura (ITP) includes two clinical subtypes. Chronic ITP is a relatively common disorder that tends to affect women between the ages of 20 and 40 years. Acute ITP is a self-limited form seen mostly in children after viral infections.


Pathology_Robbins

Pathology_Robbins. Antibodies directed against platelet membrane glycoproteins IIb/IIIa or Ib/IX complexes can be detected in roughly 80% of cases of chronic ITP. The spleen is an important site of anti-platelet antibody production and the major site of destruction of the IgG-coated platelets. Although splenomegaly is not a feature of uncomplicated chronic ITP, the importance of the spleen in the premature Table 12.13 Causes of Thrombocytopenia Aplasticanemia:congenitalandacquiredMarrowinfiltration:leukemia,disseminatedcancer Drug-induced:alcohol,thiazides,cytotoxicdrugsInfections:measles,HIVinfection Autoimmune:ITP,systemiclupuserythematosus Isoimmune:posttransfusionandneonatal Drug-associated:quinidine,heparin,sulfacompounds Infections:infectiousmononucleosis,HIVinfection,cytomegalovirusinfection Multipletransfusions(e.g.,formassivebloodloss) DIC, Disseminatedintravascularcoagulation;HIV, humanimmunodeficiencyvirus;ITP, immunethrombocytopenicpurpura;TTP, thromboticthrombocytopenicpurpura.


Pathology_Robbins

Pathology_Robbins. Multipletransfusions(e.g.,formassivebloodloss) DIC, Disseminatedintravascularcoagulation;HIV, humanimmunodeficiencyvirus;ITP, immunethrombocytopenicpurpura;TTP, thromboticthrombocytopenicpurpura. destruction of platelets is proved by the benefits of splenectomy, which normalizes the platelet count and induces a complete remission in more than two-thirds of patients. The bone marrow usually contains increased numbers of megakaryocytes, a finding common to all forms of thrombocytopenia caused by accelerated platelet destruction.


Pathology_Robbins

Pathology_Robbins. The onset of chronic ITP is insidious. Common findings include petechiae, easy bruising, epistaxis, gum bleeding, and hemorrhages after minor trauma. Fortunately, more serious intracerebral or subarachnoid hemorrhages are uncommon. The diagnosis rests on the clinical features, the presence of thrombocytopenia, examination of the marrow, and the exclusion of secondary ITP. Reliable clinical tests for anti-platelet antibodies are not available. Treatment usually involves the use of immunosuppressive agents and, in some cases, splenectomy.


Pathology_Robbins

Pathology_Robbins. This special type of drug-induced thrombocytopenia (discussed in more detail in Chapter 4) merits brief mention because of its clinical importance. Moderate to severe thrombocytopenia develops in 3% to 5% of patients after 1 to 2 weeks of treatment with unfractionated heparin. The disorder is caused by IgG antibodies that bind to platelet factor 4 on platelet membranes in a heparin-dependent fashion. Resultant activation of the platelets induces their aggregation, thereby exacerbating the condition that heparin is used to treat—thrombosis. Both venous and arterial thromboses occur, even in the setting of marked thrombocytopenia, and may cause severe morbidity (e.g., loss of limbs) and death. Cessation of heparin therapy breaks the cycle of platelet activation and consumption. The risk of this complication is lowered (but not prevented entirely) by use of low-molecular-weight heparin preparations. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net ThromboticMicroangiopathies:ThromboticThrombocytopenicPurpuraandHemolyticUremicSyndrome


Pathology_Robbins

Pathology_Robbins. The term thrombotic microangiopathies encompasses a spectrum of clinical syndromes that include thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). As originally defined, TTP is associated with the pentad of fever, thrombocytopenia, microangiopathic hemolytic anemia, transient neurologic deficits, and renal failure. HUS also is associated with microangiopathic hemolytic anemia and thrombocytopenia but is distinguished from TTP by the absence of neurologic symptoms, the dominance of acute renal failure, and frequent occurrence in children (Chapter 14). Clinical experience has blurred these distinctions, as many adults with TTP lack one or more of the five criteria, and some patients with HUS have fever and neurologic dysfunction. Fundamental to both conditions is the widespread formation of platelet-rich thrombi in the microcirculation. The consumption of platelets leads to thrombocytopenia, and the narrowing of blood vessels by the platelet-rich thrombi


Pathology_Robbins

Pathology_Robbins. is the widespread formation of platelet-rich thrombi in the microcirculation. The consumption of platelets leads to thrombocytopenia, and the narrowing of blood vessels by the platelet-rich thrombi results in a microangiopathic hemolytic anemia. All of the thrombotic microangiopathies produce renal damage of variable severity, and their pathogenesis is discussed in greater detail in Chapter 14.


Pathology_Robbins

Pathology_Robbins. It is important to note that although DIC and the thrombotic microangiopathies share features such as microvascular occlusion and microangiopathic hemolytic anemia, they are pathogenically distinct. Furthermore, unlike in DIC, in TTP and HUS activation of the coagulation cascade is not of primary importance, and so the results of laboratory tests of coagulation (e.g., the PT and PTT tests) usually are normal.


Pathology_Robbins

Pathology_Robbins. Coagulation disorders result from either congenital or acquired deficiencies of clotting factors. Acquired deficiencies are most common and often involve several factors simultaneously. As discussed in Chapter 8, vitamin K is required for the synthesis of prothrombin and clotting factors VII, IX, and X, and its deficiency causes a severe coagulation defect. The liver synthesizes several coagulation factors and also removes many activated coagulation factors from the circulation; thus, hepatic parenchymal diseases are common causes of complex hemorrhagic diatheses. As already discussed, DIC also may lead to multiple concomitant factor deficiencies. Rarely, autoantibodies may cause acquired deficiencies limited to a single factor. Hereditary deficiencies of many coagulation factors also have been identified. Hemophilia A (a deficiency of factor


Pathology_Robbins

Pathology_Robbins. Hereditary deficiencies of many coagulation factors also have been identified. Hemophilia A (a deficiency of factor VIII) and hemophilia B (Christmas disease, a deficiency of factor IX) are X-linked traits, whereas other deficiencies are autosomal recessive disorders. Of the inherited deficiencies, only von Willebrand disease, hemophilia A, and hemophilia B are sufficiently common to warrant further consideration. Hemophilia A and von Willebrand disease are caused by qualitative or quantitative defects involving the factor VIII–vWF complex. As background for subsequent discussion of these disorders, it is useful to review the structure and function of these two proteins ( Fig. 12.31 As described earlier, factor VIII is an essential cofactor for factor IX, which activates factor X in the intrinsic coagulation pathway. Circulating factor VIII binds noncovalently to vWF, which exists as large multimers of up to


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Pathology_Robbins. Fig. 12.31 StructureandfunctionoffactorVIII–vonWillebrandfactor(vWF)complex.FactorVIIIandvWFcirculateasacomplex.vWFalsoispresentinthesubendothelialmatrixofnormalbloodvessels.FactorVIIItakespartinthecoagulationcascadebyactivatingfactorXbymeansoffactorIX(not shown).vWFcausesadhesionofplateletstosubendothelialcollagen,primarilythroughtheglycoproteinIb(GpIb)plateletreceptor.Factor VIII Clotting cascade Activated, aggregated platelets X XavWF GpIb GpIIb/IIIa Fibrinogen Circulating vWF with Factor VIII Subendothelial vWF Platelet Endothelial defect Platelet n 20 Megadaltons in weight. Endothelial cells are the major source of plasma vWF, whereas most factor VIII is synthesized in the liver. vWF is found in the plasma (in association with factor VIII), in platelet granules, in endothelial cells within cytoplasmic vesicles called Weibel-Palade bodies, and in the subendothelium, where it binds to collagen.


Pathology_Robbins

Pathology_Robbins. When endothelial cells are stripped away by trauma or injury, subendothelial vWF is exposed and binds platelets, mainly through glycoprotein Ib and to a lesser degree through glycoprotein IIb/IIIa ( Fig. 12.31 ). The most important function of vWF is to facilitate the adhesion of platelets to damaged blood vessel walls, a crucial early event in the formation of a hemostatic plug. Inadequate platelet adhesion is believed to underlie the bleeding tendency in von Willebrand disease. In addition to its role in platelet adhesion, vWF also stabilizes factor VIII; thus, vWF deficiency leads to a secondary deficiency of factor VIII.


Pathology_Robbins

Pathology_Robbins. The various forms of von Willebrand disease are diagnosed by measuring the quantity, size, and function of vWF. vWF function is assessed using the ristocetin platelet agglutination test. Ristocetin somehow “activates” the bivalent binding of vWF and platelet membrane glycoprotein Ib, creating interplatelet “bridges” that cause platelets to clump (agglutination), an event that can be measured easily. Thus, ristocetin-dependent platelet agglutination serves as a useful bioassay for vWF. With this background we now turn to the discussion of diseases resulting from deficiencies of factor VIII–vWF complex.


Pathology_Robbins

Pathology_Robbins. With this background we now turn to the discussion of diseases resulting from deficiencies of factor VIII–vWF complex. von Willebrand disease is transmitted as an autosomal dominant disorder. It usually presents as spontaneous bleeding from mucous membranes, excessive bleeding from wounds, and menorrhagia. It is underrecognized, as the diagnosis requires sophisticated tests and the clinical manifestations often are quite mild. Actually, this disease is surprisingly prevalent, particularly in persons of European descent. It is estimated that approximately 1% of people in the United States have von Willebrand disease, making it the most common inherited bleeding disorder.


Pathology_Robbins

Pathology_Robbins. People with von Willebrand disease have compound defects in platelet function and coagulation, but in most cases only the platelet defect produces clinical findings. The exceptions are rare in patients with homozygous von Willebrand disease, in whom there is a concomitant deficiency of factor VIII severe enough to produce features resembling those of hemophilia (described later). The effects of the causative mutations vary, allowing von Willebrand disease to be divided into several subtypes Type 1 is the classic and most common variant of von Willebrand disease. It is an autosomal dominant disorder in which the quantity of circulating vWF is reduced. There is also a measurable but clinically insignificant decrease in factor VIII levels.


Pathology_Robbins

Pathology_Robbins. Type II is divided into several subtypes characterized by the selective loss of high–molecular-weight multimers of vWF. Because these large multimers are the most active form, there is a functional deficiency of vWF. In type IIA, the high-molecular-weight multimers are not synthesized, leading to a true deficiency. In type IIB, abnormal “hyperfunctional” high-molecular-weight multimers are synthesized that are rapidly removed from the circulation. These high-molecular-weight multimers cause spontaneous platelet aggregation (a situation reminiscent of the very-high–molecular-weight multimer aggregates seen in TTP); indeed, some people with type IIB von Willebrand disease have mild chronic thrombocytopenia, presumably resulting from platelet consumption.


Pathology_Robbins

Pathology_Robbins. Hemophilia A is the most common hereditary cause of serious bleeding. It is an X-linked recessive disorder caused by reduced factor VIII activity. It primarily affects males. Much less commonly, excessive bleeding occurs in heterozygous females, presumably due to preferential inactivation of the X chromosome carrying the normal factor VIII gene (unfavorable lyonization). Approximately 30% of cases are caused by new mutations; in the remainder, there is a positive family history. Severe hemophilia A is observed in people with marked deficiencies of factor VIII (activity levels < 1% of normal). Milder deficiencies may only become apparent in the face of trauma or other hemostatic stressses. The varying degrees of factor VIII deficiency are explained by the existence of many different causative mutations, including deletions, inversions, and splice junction mutations. In about 10% of patients, the factor VIII concentration is normal by immunoassay, but the coagulant activity is low


Pathology_Robbins

Pathology_Robbins. mutations, including deletions, inversions, and splice junction mutations. In about 10% of patients, the factor VIII concentration is normal by immunoassay, but the coagulant activity is low because of a mutation in factor VIII that causes a loss of function.


Pathology_Robbins

Pathology_Robbins. In symptomatic cases there is a tendency toward easy bruising and massive hemorrhage after trauma or operative procedures. In addition, “spontaneous” hemorrhages frequently are encountered in tissues that normally are subject to mechanical stress, particularly the joints, where recurrent bleeds (hemarthroses) lead to progressive deformities that can be crippling. Petechiae are characteristically absent. Specific assays for factor VIII are used to confirm the diagnosis of hemophilia A. Typically, patients with hemophilia A have a prolonged PTT that is corrected by mixing the patient’s plasma with normal plasma. Specific factor assays are then used to confirm the deficiency of factor VIII. In approximately 15% of those with severe hemophilia A, replacement therapy is complicated by the development of neutralizing antibodies against factor VIII, probably because factor VIII is seen by the immune system as a “foreign” antigen. In these persons, the PTT fails to correct in mixing studies.


Pathology_Robbins

Pathology_Robbins. Hemophilia A is treated with factor VIII infusions. Historically, factor VIII was prepared from human plasma, carrying with it the risk of transmission of viral diseases. As mentioned in Chapter 5, before 1985 thousands of hemophiliacs received factor VIII preparations contaminated with HIV and subsequently developed AIDS. The availability and widespread use of recombinant factor VIII and more highly purified factor VIII concentrates have now eliminated the infectious risk of factor VIII replacement therapy. Severe factor IX deficiency is an X-linked disorder that is indistinguishable clinically from hemophilia A but is much less common. The PTT is prolonged. The diagnosis is made using specific assays of factor IX. It is treated by infusion of recombinant factor IX. http://ebooksmedicine.net Canbedominatedbybleeding,vascularocclusionandtissuehypoxemia,orboth Commontriggers:sepsis,majortrauma,certaincancers,obstetriccomplications


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Canbedominatedbybleeding,vascularocclusionandtissuehypoxemia,orboth Commontriggers:sepsis,majortrauma,certaincancers,obstetriccomplications Maybetriggeredbydrugs,infections,orlymphomas,ormaybeidiopathic Bothmanifestwiththrombocytopenia,microangiopathichemolyticanemia,andrenalfailure;feverandCNSinvolvementaremoretypicalofTTP. TTP: CausedbyacquiredorinheriteddeficienciesofADAMTS13,aplasmametalloproteasethatcleavesvery-high-molecular- Complications of Transfusion weightmultimersofvWF.DeficiencyofADAMTS13resultsinabnormallylargevWFmultimersthatactivateplatelets. •Hemolytic uremic syndrome: Causedbydeficienciesofcomplementregulatoryproteinsoragentsthatdamageendothelialcells,suchasaShiga-liketoxinelaboratedbyE. coli strainO157:H7.Theendothelialinjuryinitiatesplateletactivation,plateletaggregation,andmicrovascularthrombosis. AutosomaldominantdisordercausedbymutationsinvWF,alargeproteinthatpromotestheadhesionofplateletstosubendothelialcollagen.


Pathology_Robbins

Pathology_Robbins. AutosomaldominantdisordercausedbymutationsinvWF,alargeproteinthatpromotestheadhesionofplateletstosubendothelialcollagen. Typicallycausesamildtomoderatebleedingdisorderresemblingthatassociatedwiththrombocytopenia. Hemophilia A: X-linkeddisordercausedbymutationsinfactorVIII.AffectedmalestypicallypresentwithseverebleedingintosofttissuesandjointsandhaveaPTT. Hemophilia B: X-linkeddisordercausedbymutationsincoagulationfactorIX.ItisclinicallyidenticaltohemophiliaA. Blood products often are rightly called “the gift of life,” permitting people to survive traumatic injuries and procedures such as hematopoietic stem cell transplantation and complex surgical procedures that would otherwise prove fatal. Over 5 million red cell transfusions are given in U.S. hospitals each year. Thanks to improved screening of donors, blood products (packed red blood cells, platelets, and fresh-frozen plasma) are safer than ever before.


Pathology_Robbins

Pathology_Robbins. U.S. hospitals each year. Thanks to improved screening of donors, blood products (packed red blood cells, platelets, and fresh-frozen plasma) are safer than ever before. Nevertheless, complications still occur. Most are minor and transient. The most common is referred to as a febrile nonhemolytic reaction, which takes the form of fever and chills, sometimes with mild dyspnea, within 6 hours of a transfusion of red cells or platelets. It is thought that these reactions are caused by inflammatory mediators derived from donor leukocytes. The frequency of these reactions increases with the storage age of the product and is decreased by measures that limit donor leukocyte contamination. Symptoms respond to anti-pyretics and are short-lived. Other transfusion reactions are uncommon or rare, but can have severe and sometimes fatal consequences, and therefore merit brief discussion.


Pathology_Robbins

Pathology_Robbins. Other transfusion reactions are uncommon or rare, but can have severe and sometimes fatal consequences, and therefore merit brief discussion. Severe, potentially fatal allergic reactions may occur when blood products containing certain antigens are given to previously sensitized recipients. These are most likely to occur in patients with IgA deficiency, which has a frequency of 1:300 to 1:500 people. The reaction is triggered by IgG antibodies that recognize IgA in the infused blood product. Fortunately, most patients with IgA deficiency do not develop such antibodies, and these severe reactions are rare, occurring in 1 in 20,000 to 1 in 50,000 transfusions. Urticarial allergic reactions may be triggered by the presence of an allergen in the donated blood product that is recognized by IgE antibodies in the recipient. These are more common, occurring in 1% to 3% of transfusions, but they are generally mild.


Pathology_Robbins

Pathology_Robbins. Acute hemolytic reactions usually are caused by preformed IgM antibodies against donor red cells that fix complement. They most commonly stem from an error in patient identification or tube labeling that allows a patient to receive an ABO incompatible unit of blood. Preexisting “natural” IgM antibodies, usually against blood group antigens A or B, bind to red cells and rapidly induce complement-mediated lysis, intravascular hemolysis, and hemoglobinuria associated with fever, shaking chills, and flank pain. The direct Coombs test is positive unless all of the donor red cells have lysed. The signs and symptoms are due to complement activation rather than hemolysis per se, as osmotic lysis of red cells (e.g., by mistakenly infusing red cells and 5% dextrose in water simultaneously) produces hemoglobinuria without any other symptoms. In severe cases the process may rapidly progress to DIC, shock, renal failure, and death.


Pathology_Robbins

Pathology_Robbins. Delayed hemolytic reactions are caused by antibodies that recognize red cell antigens that the recipient was sensitized to previously, for example, through a http://ebooksmedicine.net previous blood transfusion. These are typically caused by IgG antibodies and are associated with a positive direct Coombs test and laboratory features of hemolysis (e.g., low haptoglobin and elevated LDH). Antibodies to antigens such as Rh, Kell, and Kidd sometimes fix complement, resulting in severe and potentially fatal reactions identical to those seen with ABO mismatches. Other antibodies that do not fix complement typically result in extravascular hemolysis and relatively minor signs and symptoms.


Pathology_Robbins

Pathology_Robbins. Transfusion-related acute lung injury (TRALI) is a severe, frequently fatal complication in which factors in a transfused blood product trigger the activation of neutrophils in the lung microvasculature. The incidence is low, probably less than 1 per 10,000 transfusions. Current thinking about TRALI favors a “two hit” hypothesis. The first hit is an exposure that activates endothelial cells in pulmonary capillaries. This “priming” event has diverse causes, including smoking, sepsis, and shock, and leads to sequestration of neutrophils. The primed neutrophils are then activated by a factor present in the transfused blood product, which constitutes the second hit.


Pathology_Robbins

Pathology_Robbins. The leading “second hit” candidate is an antibody in the transfused blood product that recognizes antigens expressed on neutrophils. By far the most common antibodies associated with TRALI are those that bind major histocompatibility complex (MHC) class I antigens. These antibodies are often found in multiparous women, in whom they are generated in response to foreign MHC antigens expressed by the fetus. Indeed, measures to exclude multiparous women from plasma donation have resulted in the incidence of TRALI being cut in half. The presentation is dramatic, with sudden onset of respiratory failure associated with diffuse bilateral pulmonary infiltrates during or soon after a transfusion. The treatment is largely supportive and the outcome is guarded; mortality is 5% in uncomplicated cases and up to 67% in those who are severely ill.


Pathology_Robbins

Pathology_Robbins. Virtually any infectious agent can be transmitted through blood products, but bacterial and viral infections are most likely to be so. Significant bacterial contamination (sufficient to produce symptoms) is much more common in platelet preparations than red cell preparations, because of the fact that platelets (unlike red cells) must be stored at room temperature, which favors growth of bacterial contaminants. Rates of bacterial infection secondary to platelet transfusion can be as high as 1 in 5000. Many of the symptoms (fever, chills, hypotension) resemble those of transfusion reactions, and it may be necessary to start broad-spectrum antibiotics prospectively in symptomatic patients while awaiting laboratory results.


Pathology_Robbins

Pathology_Robbins. Advances in donor selection, donor screening, and infectious disease testing have dramatically decreased the incidence of viral transmission by blood products. However on rare occasions when the donor is acutely infected, there can still be transfusion-related transmission of viruses. Rates of transmission of HIV, hepatitis C, and hepatitis B are estimated to be 1 in 2 million, 1 in 1 million, and 1 in 500,000, respectively. There also remains a low risk of “exotic” infectious agents such as West Nile virus, trypanosomiasis, and babesiosis. Disorders of the Spleen and Thymus


Pathology_Robbins

Pathology_Robbins. Disorders of the Spleen and Thymus The spleen is frequently involved in a wide variety of systemic diseases. In virtually all instances the spleen responds by enlarging (splenomegaly), an alteration that produces a set of stereotypical signs and symptoms. Evaluation of splenic enlargement is aided by recognition of the usual limits of splenomegaly produced by specific disorders. It would be erroneous to attribute an enlarged spleen pushing into the pelvis to vitamin B12 deficiency, or to entertain a diagnosis of CML in the absence of splenomegaly. Disorders may be grouped according to the degree of splenomegaly that they characteristically produce: Myeloproliferative neoplasms (CML, primary myelofibrosis); certain indolent leukemias (CLL and hairy cell leukemia); many lymphomas; infectious diseases (e.g., malaria); Gaucher disease


Pathology_Robbins

Pathology_Robbins. Myeloproliferative neoplasms (CML, primary myelofibrosis); certain indolent leukemias (CLL and hairy cell leukemia); many lymphomas; infectious diseases (e.g., malaria); Gaucher disease Chronic congestive splenomegaly (portal hypertension or splenic vein obstruction); acute leukemias; disorders with extravascular hemolysis (hereditary spherocytosis, thalassemia major, autoimmune hemolytic anemia; amyloidosis; Niemann-Pick disease; many infections, including infective endocarditis, tuberculosis, and typhoid; sarcoidosis; metastatic carcinoma or sarcoma Acute splenitis; acute splenic congestion; infectious mononucleosis; miscellaneous disorders, including septicemia, systemic lupus erythematosus, and intraabdominal infections The microscopic changes associated with these diseases are discussed in the relevant sections of this and other chapters.


Pathology_Robbins

Pathology_Robbins. The microscopic changes associated with these diseases are discussed in the relevant sections of this and other chapters. A chronically enlarged spleen often removes excessive numbers of one or more of the formed elements of blood, resulting in anemia, leukopenia, or thrombocytopenia. This is referred to as hypersplenism, a state that can be associated with many of the diseases listed previously. In addition, platelets are particularly susceptible to sequestration in the interstices of the red pulp; as a result, thrombocytopenia is more prevalent and severe in persons with splenomegaly than is anemia or neutropenia. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net As is well known, the thymus has a crucial role in T cell differentiation. It is not surprising, therefore, that the thymus can be involved by lymphomas, particularly those of T cell lineage (discussed earlier in this chapter). The focus here is on the two most frequent (albeit still uncommon) disorders of the thymus: thymic hyperplasia and thymoma. Thymic enlargement often is associated with the presence of lymphoid follicles, or germinal centers, within the medulla. These germinal centers contain reactive B cells, which are only present in small numbers in normal thymuses. Thymic follicular hyperplasia is found in most patients with myasthenia gravis and sometimes also occurs in other autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis. The relationship between the thymus and myasthenia gravis is discussed in Chapter 22. Of significance, removal of the hyperplastic thymus is often beneficial early in the disease.


Pathology_Robbins

Pathology_Robbins. Thymomas are tumors of thymic epithelial cells. Several classification systems for thymoma based on cytologic and biologic criteria have been proposed. One simple and clinically useful classification is as follows: Benign or encapsulated thymoma: cytologically and biologically benign Type I: cytologically benign but infiltrative and locally aggressive Type II (thymic carcinoma): cytologically and biologically malignant


Pathology_Robbins

Pathology_Robbins. Type I: cytologically benign but infiltrative and locally aggressive Type II (thymic carcinoma): cytologically and biologically malignant MORPHOLOGYMacroscopically,thymomasarelobulated,firm,gray-whitemassesupto15to20cmindimension.Mostappearencapsulated,but20%to25%penetratethecapsuleandinfiltrateperithymictissues.Microscopically,virtuallyallthymomasarecomposedofamixtureofepithelialtumorcellsandnonneoplasticthymocytes(immatureTcells).Inbenign thymomas, theepithelialcellsarespindledorelongatedandresemblethosethatnormallypopulatethemedulla.Asaresult,thesearesometimesreferredtoasmedullary thymomas. Inothertumors,thereisanadmixtureoftheplumper,rounder,cortical-typeepithelialcells;thispatternissometimesreferredtoasamixedthymoma.Themedullaryandmixedpatternsaccountfor60%to70%ofallthymomas.


Pathology_Robbins


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Pathology_Robbins. Thymomas are rare. They may arise at any age, but most occur in middle-aged adults. In a large series about 30% were asymptomatic; 30% to 40% produced local manifestations such as cough, dyspnea, and superior vena cava syndrome; and the remainder were associated with a systemic disease, most commonly myasthenia gravis, in which a concomitant thymoma is discovered in 15% to 20% of patients. Removal of the tumor often leads to improvement of the neuromuscular disorder. In addition to myasthenia gravis , thymomas may be associated with several other pareneoplastic syndromes. These include in rough order of frequency , pure red cell aplasia, hypogammaglobulinemia, and multi organ autoimmunity. The latter bears resemblance with graft versus host disease. Brodsky RA: Paroxysmal nocturnal hemoglobinuria, Blood 124:2804, 2014. [A concise current review.]


Pathology_Robbins

Pathology_Robbins. Brodsky RA: Paroxysmal nocturnal hemoglobinuria, Blood 124:2804, 2014. [A concise current review.] Da Cost L, Galimand J, Fenneteau O, et al: Hereditary spherocytosis, elliptocytosis, and other red cell membrane disorders, Blood Rev 27:167, 2013. [An excellent overview of inherited red cell membrane defects.] Ganz T: Systemic iron homeostasis, Physiol Rev 93:1721, 2013. [A review of iron metabolism in health and disease.] Platt OS: Hydroxyurea for the treatment of sickle cell disease, N Engl J Med 358:1362, 2008. [A review focused on the beneficial effects of hydroxyurea in sickle cell disease.] Wassmer SC, Taylor TE, Rathod PK, et al: Investigating the pathogenesis of severe malaria: a multidisciplinary and cross-geographical approach, Am J Trop Med Hyg 93(Suppl):42, 2015. [A review of the proposed pathophysiology of severe forms of malaria.]


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Pathology_Robbins. Wong TE, Brandow AM, Lim W, et al: Update on the use of hydroxy-urea therapy in sickle cell disease, Blood 124:3850, 2014. [A review focused on the beneficial effects of hydroxyurea in sickle cell disease.] Young NS, Bacigalupo A, Marsh JC: Aplastic anemia: pathophysiology and treatment, Biol Blood Marrow Transplant 16:S119, 2010. [Discussion of the role of the immune system and telomerase mutations in aplastic anemia.] Anderson KC, Carrasco RD: Pathogenesis of myeloma, Annu Rev Pathol 6:249, 2011. [A review of advances in understanding the molecular pathogenesis of multiple myeloma.] Arber DA, Orazi A, Hasserjian R, et al: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia, Blood 127:2391, 2016. [A report providing the rationale for revision of the WHO classification of myeloid neoplasms.] http://ebooksmedicine.net


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Pathology_Robbins. Inaba H, Greaves M, Mullighan CG: Acute lymphoblastic leukemia, Lancet 381:1943, 2013. [A review of the pathogenesis, diagnosis, and treatment of ALL.] Mathas S, Hartmann S, Kuppers R: Hodgkin lymphoma: Pathology and biology, Semin Hematol 53:139, 2016. [A concise review of Hodgkin lymphoma pathogenesis.] Swerdlow SH, Campo E, Pileri SA, et al: The 2016 revision of the World Health Organization classification of lymphoid neoplasms, Blood 127:2375, 2016. [An overview of the most recent WHO classification of lymphoid neoplasms.] The Cancer Genome Atlas Research Network: Genomic and epigenomic networks landscapes in adult de novo acute myeloid leukemia, N Engl J Med 368:2059, 2013. [Landmark paper that uses next-generation sequencing and other genome-wide approaches to systematically describe genomic alterations in AML.]


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Pathology_Robbins. Young RM, Staudt LM: Targeting pathological B cell receptor signaling in lymphoid malignancies, Nat Rev Drug Discov 12:229, 2013. [An excellent review of the role of B cell receptor signaling in non-Hodgkin lymphoma and its potential as a therapeutic target.] Arepally GM, Ortel TL: Heparin-induced thrombocytopenia, Annu Rev Med 61:77, 2010. [A discussion of pathogenesis, clinical features, diagnostic criteria, and therapeutic approaches in HIT.] Ng C, Motto DG, Di Paola J: Diagnostic approach to von Willebrand disease, Blood 125:2029, 2015. [A review on the molecular pathogenesis and diagnosis of vWD.] Noris M, Mescia F, Remuzzi G: STEC-HUS, atypical HUS and TTP are all diseases of complement activation, Nat Rev Nephrol 8:622, 2013. [An article focused on the possible role of excessive activation of the alternative complement pathway in HUS and TTP.]


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Pathology_Robbins. Pawlinski R, Mackman N: Cellular sources of tissue factor in endotoxemia and sepsis, Thromb Res 125(S1):S70, 2010. [An overview of the role of cellular procoagulants in DIC associated with bacterial infection.] Zhou Z, Nguyen TC, Guchhait P, et al: Von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenia purpura, Semin Thromb Hemost 36:71, 2010. [A review focused on the role of vWF deregulation and ADAMTS 13 deficiency in TTP.] Disorders That Affect the Spleen and Thymus Choi SS, Kim KD, Chung KY: Prognostic and clinical relevance of the World Health Organization schema for the classification of thymic epithelial tumors: a clinicopathologic study of 108 patients and literature review, Chest 127:755, 2005. [A large clinicopathologic series that shows that stage is the best predictor of outcome in thymoma.] http://ebooksmedicine.net studentconsult.com ChronicInterstitial(Restrictive,Infiltrative)LungDiseases


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Pathology_Robbins. ChronicInterstitial(Restrictive,Infiltrative)LungDiseases Pulmonary Disease in Human Immunodeficiency Pulmonary Embolism, Hemorrhage, and Virus Infection Pneumothorax, Hemothorax, and Hospital-Acquired Pneumonias Histoplasmosis, Coccidioidomycosis, and Nasopharyngeal Carcinoma Pneumonia in the Immunocompromised


Pathology_Robbins

Pathology_Robbins. The major function of the lung is to replenish oxygen and remove carbon dioxide from blood. Developmentally, the respiratory system is an outgrowth from the ventral wall of the foregut. The midline trachea develops two lateral outpouchings, the lung buds. The right lung bud eventually divides into three main bronchi, and the left into two main bronchi, thus giving rise to three lobes on the right and two on the left. The main bronchi branch dichotomously, giving rise to progressively smaller airways, termed bronchioles, which are distinguished from bronchi by the lack of cartilage and submucosal glands within their walls. Additional branching of bronchioles leads to terminal bronchioles; the part of the lung distal to the terminal bronchiole is called an acinus. Pulmonary acini are composed of respiratory bronchioles (emanating from the terminal bronchiole) that proceed into alveolar ducts, which immediately branch into alveolar sacs, the blind ends of the respiratory passages, whose


Pathology_Robbins

Pathology_Robbins. of respiratory bronchioles (emanating from the terminal bronchiole) that proceed into alveolar ducts, which immediately branch into alveolar sacs, the blind ends of the respiratory passages, whose walls are formed entirely of alveoli, the ultimate site of gas exchange. The alveolar walls (or alveolar septa) consist of the following components, proceeding from blood to air (


Pathology_Robbins

Pathology_Robbins. Fig. 13.1 The capillary endothelium and basement membrane. The pulmonary interstitium, composed of fine elastic fibers, small bundles of collagen, a few fibroblast-like cells, smooth muscle cells, mast cells, and rare mononuclear cells. • Alveolar epithelium, consisting of a continuous layer of two principal cell types: flattened, plate-like type I pneumocytes covering 95% of the alveolar surface; and rounded type II pneumocytes. The latter synthesize pulmonary surfactant and are the main cell type involved in repair of alveolar epithelium after damage to type I pneumocytes. A few alveolar macrophages usually lie free within the alveolar space. In the city dwellers, these macrophages often contain phagocytosed carbon particles.


Pathology_Robbins

Pathology_Robbins. A few alveolar macrophages usually lie free within the alveolar space. In the city dwellers, these macrophages often contain phagocytosed carbon particles. Lung diseases can broadly be divided into those affecting (1) the airways, (2) the interstitium, and (3) the pulmonary vascular system. This division into discrete compartments is, of course, deceptively simple. In reality, disease in one compartment often causes secondary alterations of morphology and function in others. Atelectasis, also known as collapse, is loss of lung volume caused by inadequate expansion of air spaces. It results in shunting of inadequately oxygenated blood from pulmonary arteries into veins, thus giving rise to a ventilation-perfusion imbalance and hypoxia. On the basis of the http://ebooksmedicine.net Fig.13.1 Microscopicstructureofthealveolarwall.Notethatthebasementmembrane(yellow) isthinononesideandwidenedwhereitiscontinuouswiththeinterstitialspace.


Pathology_Robbins

Pathology_Robbins. Fig.13.1 Microscopicstructureofthealveolarwall.Notethatthebasementmembrane(yellow) isthinononesideandwidenedwhereitiscontinuouswiththeinterstitialspace. underlying mechanism and the distribution of alveolar collapse, atelectasis is classified into three forms Resorption atelectasis occurs when an obstruction prevents air from reaching distal airways. Any air present gradually becomes absorbed, and alveolar collapse follows. The most common cause of resorption collapse is obstruction of a bronchus. Resorption atelectasis most frequently occurs postoperatively due to intrabronchial mucous or mucopurulent plugs, but also may result from foreign body aspiration (particularly in children), bronchial asthma, bronchiectasis, chronic bronchitis, or intrabronchial tumor, in which it may be the first sign of malignancy.


Pathology_Robbins

Pathology_Robbins. Compression atelectasis is usually associated with accumulation of fluid, blood, or air within the pleural cavity. A frequent cause is pleural effusions occurring in the setting of congestive heart failure. Leakage of air into the pleural cavity (pneumothorax) also leads to compression atelectasis. Basal atelectasis resulting from a failure to breath deeply commonly occurs in bedridden patients, in patients with ascites, and during and after surgery. Contraction atelectasis (or cicatrization atelectasis) occurs when local or diffuse fibrosis affecting the lung or the pleura hamper lung expansion. Atelectasis (except when caused by contraction) is potentially reversible and should be treated promptly to prevent hypoxemia and superimposed infection of the collapsed lung.


Pathology_Robbins

Pathology_Robbins. Atelectasis (except when caused by contraction) is potentially reversible and should be treated promptly to prevent hypoxemia and superimposed infection of the collapsed lung. The epidemiology and definition of acute respiratory distress syndrome (ARDS) are evolving. Formerly considered to be the severe end of a spectrum of acute lung injury, it is now defined as respiratory failure occurring within 1 week of a known clinical insult with bilateral opacities on chest imaging, not fully explained by effusions, atelectasis, cardiac failure, or fluid overload. It is graded based on the severity of the changes in arterial blood oxygenation. Causes are diverse; the shared feature is that all lead to extensive bilateral injury to alveoli.


Pathology_Robbins

Pathology_Robbins. Severe ARDS is characterized by rapid onset of life-threatening respiratory insufficiency, cyanosis, and severe arterial hypoxemia that is refractory to oxygen therapy. The histologic manifestation of ARDS in the lungs is known as diffuse alveolar damage (DAD). ARDS may occur in a multitude of clinical settings and is associated with primary pulmonary diseases and severe systemic inflammatory disorders such as sepsis. The most frequent triggers of ARDS are pneumonia (35%–45%) and sepsis (30%–35%), followed by aspiration, trauma (including brain injury, abdominal surgery, and multiple fractures), pancreatitis, and transfusion reactions. ARDS should not be confused with respiratory distress syndrome of the newborn; the latter is caused by a deficiency of surfactant caused by prematurity.


Pathology_Robbins

Pathology_Robbins. In ARDS, the integrity of the alveolar-capillary membrane is compromised by endothelial and epithelial injury. Most work suggests that ARDS stems from an inflammatory reaction initiated by a variety of pro-inflammatory mediators (


Pathology_Robbins

Pathology_Robbins. Fig. 13.2 ). As early as 30 minutes after an acute insult, there is increased synthesis of interleukin 8 (IL-8), a potent neutrophil chemotactic and activating agent, by pulmonary macrophages. Release of IL-8 and other factors, such as IL-1 and tumor necrosis factor (TNF), leads to endothelial activation and sequestration and activation of neutrophils in pulmonary capillaries. Neutrophils are thought to have an important role in the pathogenesis of ARDS. Histologic examination of lungs early in the disease process shows increased numbers of neutrophils within the vascular space, the interstitium, and the alveoli. Activated neutrophils release a variety of products (e.g., reactive oxygen species, proteases) that damage the alveolar epithelium and endothelium. The assault on the endothelium and epithelium causes vascular leakiness and loss of surfactant that render the alveolar unit unable to expand. Of note, the destructive forces unleashed by neutrophils can be counteracted by an


Pathology_Robbins

Pathology_Robbins. and epithelium causes vascular leakiness and loss of surfactant that render the alveolar unit unable to expand. Of note, the destructive forces unleashed by neutrophils can be counteracted by an array of endogenous anti-proteases and anti-oxidants that are upregulated by proinflammatory cytokines. In the end, it is the balance between the destructive and protective factors that determines the degree of tissue injury and clinical severity of the ARDS.


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Pathology_Robbins. MORPHOLOGYIntheacute phase of ARDS, thelungsaredarkred,firm,airless,andheavy.Microscopicexaminationrevealscapillarycongestion,necrosisofalveolarepithelialcells,interstitialandintra-alveolaredemaandhemorrhage,and(particularlywithsepsis)collectionsofneutrophilsincapillaries.Themostcharacteristicfindingisthepresenceofhyaline membranes, particularly http://ebooksmedicine.net NORMAL ALVEOLUS Type I cell Surfactant layer Type II cell Interstitium Alveolar macrophage Bronchial epithelium Basement membrane Sloughed bronchial epithelium Necrotic type I cell Edema fluid Hyaline membrane Fibroblast Procollagen Fibrin Neutrophil sequestration and migration into alveolus Alveolus Leukotrienes Inactivated surfactant PAF Proteases TNF IL-1 TNF Chemokines ACUTE LUNG INJURY Capillary Endothelial cell Injured, swollen endothelial cells Cellular debris Edema


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Pathology_Robbins. Fig. 13.2 Thenormalalveolus(left) andtheinjuredalveolusintheearlyphaseofacutelunginjuryandtheacuterespiratorydistresssyndrome.UndertheinfluenceofproinflammatorycytokinessuchasinterleukinsIL-8andIL-1andtumornecrosisfactor(TNF)(releasedbymacrophages),neutrophilsaresequesteredinthepulmonarymicrovasculatureandthenegressintothealveolarspace,wheretheyundergoactivation.Activatedneutrophilsreleaseleukotrienes,oxidants,proteases,andplatelet-activatingfactor(PAF),whichcontributetolocaltissuedamage,accumulationofedemafluid,surfactantinactivation,andhyalinemembraneformation.Subsequently,thereleaseofmacrophage-derivedfibrogeniccytokinessuchastransforminggrowthfactor-β (TGF-β)andplatelet-derivedgrowthfactor(PGDF)stimulatefibroblastgrowthandcollagendepositionassociatedwiththehealingphaseofinjury.(Modified from Ware LB: Pathophysiology of acute lung injury and the acute respiratory distress syndrome, SeminRespirCritCareMed27:337, 2006.)


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Pathology_Robbins. The clinical syndrome of acute lung injury or ARDS affects approximately 190,000 patients per year in the United States. In 85% of cases, it develops within 72 hours of the initial insult. The overall hospital mortality rate is 38.5% (27%, 32%, and 45% for mild, moderate, and severe ARDS, respectively). Predictors of poor prognosis include advanced age, bacteremia (sepsis), and the development of multiorgan failure. Most patients who survive the acute insult recover normal respiratory function within 6 to 12 months, but the rest develop diffuse interstitial fibrosis leading to chronic respiratory insufficiency. ARDSisaclinicalsyndromeofprogressiverespiratoryinsufficiencycausedbydiffusealveolardamageinthesettingofsepsis,severetrauma,ordiffusepulmonaryinfection. NeutrophilsandtheirproductshaveacrucialroleinthepathogenesisofARDSbycausingendothelialandepithelialinjury.


Pathology_Robbins

Pathology_Robbins. Diffuse pulmonary diseases can be classified into two categories: (1) obstructive (airway) disease, characterized by an increase in resistance to air flow caused by partial or complete obstruction at any level; and (2) restrictive disease, characterized by reduced expansion of lung parenchyma and decreased total lung capacity. The major diffuse obstructive disorders are emphysema, chronic bronchitis, bronchiectasis, and asthma. In patients with these diseases, forced vital capacity (FVC) is either normal or slightly decreased, while the expiratory flow rate, usually measured as the forced expiratory volume at 1 second (FEV1), is significantly decreased. Thus, the ratio of FEV to FVC is characteristically decreased. Expiratory obstruction may result from anatomic airway narrowing, classically observed in asthma, or from loss of elastic recoil, characteristic of emphysema.


Pathology_Robbins

Pathology_Robbins. By contrast, in diffuse restrictive diseases, FVC is reduced and the expiratory flow rate is normal or reduced proportionately. Hence, the ratio of FEV to FVC is near normal. Restrictive defects occur in two general conditions: (1) chest wall disorders in the presence of normal lungs (e.g., with severe obesity, diseases of the pleura, and neuromuscular disorders, such as the Guillain-Barré syndrome [Chapter 22], that affect the respiratory muscles) and (2) acute or chronic interstitial lung diseases. The classic acute restrictive disease is ARDS, discussed earlier. Chronic restrictive diseases (discussed later) include the pneumoconioses, interstitial fibrosis of unknown etiology, and infiltrative conditions such as sarcoidosis. In their prototypical forms, the four disorders in this group—emphysema, chronic bronchitis, asthma, and bronchiectasis—have distinct clinical and anatomic characteristics (


Pathology_Robbins

Pathology_Robbins. In their prototypical forms, the four disorders in this group—emphysema, chronic bronchitis, asthma, and bronchiectasis—have distinct clinical and anatomic characteristics ( Table 13.1 ), but overlaps between emphysema, chronic bronchitis, and asthma are common.


Pathology_Robbins

Pathology_Robbins. It should be noted that emphysema is defined on the basis of morphologic and radiologic features, whereas chronic bronchitis is defined on the basis of clinical features (described later). The anatomic distribution of these disorders also is somewhat different, as chronic bronchitis initially involves the large airways, whereas emphysema affects the acinus. In severe or advanced cases of both, small airway disease (chronic bronchiolitis) is also present. Although emphysema may exist without chronic bronchitis (particularly in inherited α1-anti-trypsin deficiency, discussed later) and vice versa, the two diseases usually coexist. This is almost certainly because cigarette smoking is the major underlying cause of both. In view of their propensity to coexist, emphysema and chronic bronchitis often are grouped together under the rubric of chronic obstructive pulmonary disease (COPD). COPD affects more than 10% of the U.S. adult population and is the fourth leading cause of death in this


Pathology_Robbins

Pathology_Robbins. often are grouped together under the rubric of chronic obstructive pulmonary disease (COPD). COPD affects more than 10% of the U.S. adult population and is the fourth leading cause of death in this country. The largely irreversible airflow obstruction of COPD distinguishes it from asthma, which, as discussed later, is characterized by reversible airflow obstruction (


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Pathology_Robbins. Fig. 13.4 Emphysema is characterized by permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls without significant fibrosis. It is classified according to its anatomic distribution. As discussed earlier, the acinus is the structure distal to terminal bronchioles, and a cluster of three to five acini is called a lobule ( Fig. 13.5A ). There are four major types of emphysema: (1) centriacinar, (2) panacinar, (3) distal acinar, and (4) irregular. Only the first two types cause significant airway obstruction, with centriacinar emphysema being about 20 times more common than panacinar disease. • Centriacinar (centrilobular) emphysema. The distinctive feature of centriacinar emphysema is that the central or proximal parts of the acini, formed by respiratory http://ebooksmedicine.net Table 13.1 Disorders Associated With Airflow Obstruction:The Spectrum of Chronic Obstructive Pulmonary Disease


Pathology_Robbins

Pathology_Robbins. Table 13.1 Disorders Associated With Airflow Obstruction:The Spectrum of Chronic Obstructive Pulmonary Disease ChronicbronchitisBronchusMucousglandhypertrophyandTobaccosmoke,airpollutantsCough,sputumproductionhyperplasia,hypersecretion BronchiectasisBronchusAirwaydilationandscarringPersistentorsevereinfectionsCough,purulentsputum,fever EmphysemaAcinusAirspaceenlargement,wallTobaccosmokeDyspneadestruction Smallairwaydisease,BronchioleInflammatoryscarring,partialTobaccosmoke,airpollutantsCough,dyspneabronchiolitis *Canbepresentinallformsofobstructivelungdiseaseorbyitself. bronchioles, are affected, while distal alveoli are spared. Thus, both emphysematous and normal air spaces exist within the same acinus and lobule (see Fig.


Pathology_Robbins

Pathology_Robbins. bronchioles, are affected, while distal alveoli are spared. Thus, both emphysematous and normal air spaces exist within the same acinus and lobule (see Fig. 13.5B ). The lesions are more common and severe in the upper lobes, particularly in the apical segments. In severe centriacinar emphysema, the distal acinus also becomes involved, and thus, the differentiation from panacinar emphysema becomes difficult. This type of emphysema is most common in cigarette smokers, often in association with chronic bronchitis. • Panacinar (panlobular) emphysema. In panacinar (panlobular) emphysema, the acini are uniformly enlarged, from the level of the respiratory bronchiole to the terminal blind alveoli (see Fig. 13.5C ). In contrast to centriacinar emphysema, panacinar emphysema occurs more commonly in the lower lung zones and is associated with α1-anti-trypsin deficiency.


Pathology_Robbins

Pathology_Robbins. Fig. 13.5C ). In contrast to centriacinar emphysema, panacinar emphysema occurs more commonly in the lower lung zones and is associated with α1-anti-trypsin deficiency. • Distal acinar (paraseptal) emphysema. In this form of emphysema, the proximal portion of the acinus is normal but the distal part is primarily involved. The emphysema is more striking adjacent to the pleura, along the lobular connective tissue septa, and at the Chronic injury (e.g., smoking) Fig. 13.4 Schematicrepresentationofoverlapbetweenchronicobstructivelungdiseases.Small airway disease EMPHYSEMA Alveolar wall destruction Overinflation CHRONIC BRONCHITIS Productive cough Airway inflammation ASTHMA Reversible obstruction Bronchial hyperresponsiveness triggered by allergens, infection, etc.


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Pathology_Robbins. margins of the lobules. It occurs adjacent to areas of fibrosis, scarring, or atelectasis and is usually more severe in the upper half of the lungs. The characteristic finding is the presence of multiple, contiguous, enlarged air spaces ranging in diameter from less than 0.5 mm to more than 2.0 cm, sometimes forming cystic structures that, with progressive enlargement, give rise to bullae. The cause of this type of emphysema is unknown; it comes to attention most often in young adults who present with spontaneous pneumothorax. Fig. 13.5 Majorpatternsofemphysema.(A)Diagramofnormalstructureoftheacinus,thefundamentalunitofthelung.(B)Centriacinaremphysemawithdilationthatinitiallyaffectstherespiratorybronchioles.(C)Panacinaremphysemawithinitialdistentionofalltheperipheralstructures(i.e.,thealveolusandalveolarduct);thediseaselaterextendstoaffecttherespiratorybronchioles. http://ebooksmedicine.net Oxidative stress, Inflammatory increased cells, release of


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Oxidative stress, Inflammatory increased cells, release of Fig. 13.6 Pathogenesisofemphysema.Seetextfordetails. • Irregular emphysema. Irregular emphysema, so named because the acinus is irregularly involved, is almost invariably associated with scarring, such as that resulting from healed inflammatory diseases. Although clinically asymptomatic, this may be the most common form of emphysema. Inhaled cigarette smoke and other noxious particles cause lung damage and inflammation, which, particularly in patients with a genetic predisposition, result in parenchymal destruction (emphysema) and airway disease (bronchiolitis and chronic bronchitis). Factors that influence the development of emphysema include the following ( Fig. 13.6


Pathology_Robbins

Pathology_Robbins. Fig. 13.6 Inflammatory cells and mediators: A wide variety of inflammatory mediators have been shown to be increased (including leukotriene B4, IL-8, TNF, and others) that attract more inflammatory cells from the circulation (chemotactic factors), amplify the inflammatory process (proinflammatory cytokines), and induce structural changes (growth factors). The inflammatory cells present in lesions include neutrophils, macrophages, and CD4+ and CD8+ T cells. It is not known if the T cells are specific for a particular antigen or are recruited as part of inflammation. Protease–anti-protease imbalance: Several proteases are released from the inflammatory cells and epithelial cells that break down connective tissues. In patients who develop emphysema, there is a relative deficiency of protective anti-proteases (further discussed below).


Pathology_Robbins

Pathology_Robbins. Oxidative stress: Reactive oxygen species are generated by cigarette smoke and other inhaled particles and released from activated inflammatory cells such as macrophages and neutrophils. These cause additional tissue damage and inflammation (Chapter 3). Airway infection: Although infection is not thought to play a role in the initiation of tissue destruction, bacterial and/or viral infections cause acute exacerbations.


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Pathology_Robbins. The idea that proteases are important is based in part on the observation that patients with a genetic deficiency of the anti-protease α1-anti-trypsin have a predisposition to develop pulmonary emphysema, which is compounded by smoking. About 1% of all patients with emphysema have this defect. α1-anti-trypsin, normally present in serum, tissue fluids, and macrophages, is a major inhibitor of proteases (particularly elastase) secreted by neutrophils during inflammation. α1-anti-trypsin is encoded by a gene in the proteinase inhibitor (Pi) locus on chromosome 14. The Pi locus is polymorphic, and approximately 0.012% of the U.S. population is homozygous for the Z allele, a genotype that is associated with markedly decreased serum levels of α1-anti-trypsin. More than 80% of these individuals develop symptomatic panacinar emphysema, which occurs at an earlier age and is of greater severity if the individual smokes.


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Pathology_Robbins. Protease-mediated damage of extracellular matrix has a central role in the airway obstruction seen in emphysema. Small airways are normally held open by the elastic recoil of the lung parenchyma, and the loss of elastic tissue in the walls of alveoli that surround respiratory bronchioles reduces radial traction and thus causes the respiratory bronchioles to collapse during expiration. This leads to functional airflow obstruction despite the absence of mechanical obstruction.


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Pathology_Robbins. MORPHOLOGYThediagnosisandclassificationofemphysemadependlargelyonthemacroscopicappearanceofthelung.Typicalpanacinar emphysema producespale,voluminouslungsthatoftenobscuretheheartwhentheanteriorchestwallisremovedatautopsy.Themacroscopicfeaturesofcentriacinar emphysema arelessimpressive.Untillatestages,thelungsareadeeperpinkthaninpanacinaremphysemaandlessvoluminous,andtheuppertwo-thirdsofthelungsaremoreseverelyaffectedthanthelowerlungs.Histologicexaminationrevealsdestruction of alveolar walls without fibrosis, leading to enlarged air spaces (


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Fig. 13.7 Pulmonaryemphysema.Thereismarkedenlargementoftheairspaces,withdestructionofalveolarseptabutwithoutfibrosis.Notethepresenceofblackanthracoticpigment. http://ebooksmedicine.net Dyspnea usually is the first symptom; it begins insidiously but is steadily progressive. In patients with underlying chronic bronchitis or chronic asthmatic bronchitis, cough and wheezing may be the initial complaints. Weight loss is common and may be severe enough to suggest an occult malignant tumor. Pulmonary function tests reveal reduced FEV1 with normal or near-normal FVC. Hence, the FEV1 to FVC ratio is reduced.


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Pathology_Robbins. The classic presentation of emphysema with no “bronchitic” component is one in which the patient is barrel-chested and dyspneic, with obviously prolonged expiration, sitting forward in a hunched-over position. In these patients, air space enlargement is severe and diffusing capacity is low. Dyspnea and hyperventilation are prominent, so that until very late in the disease, gas exchange is adequate and blood gas values are relatively normal. Because of prominent dyspnea and adequate oxygenation of hemoglobin, these patients sometimes are sometimes called “pink puffers.” At the other end of the clinical spectrum is a patient with emphysema who also has pronounced chronic bronchitis and a history of recurrent infections. Dyspnea usually is less prominent, and in the absence of increased respiratory drive the patient retains carbon dioxide, becoming hypoxic and often cyanotic. For unclear reasons, such patients tend to be obese—hence the designation “blue bloaters.”


Pathology_Robbins

Pathology_Robbins. In most patients with COPD the symptoms fall in between these two extremes. Hypoxia-induced pulmonary vascular spasm and loss of pulmonary capillary surface area from alveolar destruction causes the gradual development of secondary pulmonary hypertension, which in 20% to 30% of patients leads to right-sided congestive heart failure (cor pulmonale, Chapter 11). Death from emphysema is related to either respiratory failure or right-sided heart failure. Conditions Related to Emphysema Several conditions involving abnormal airspaces or accumulations of air within the lungs or other tissues also are recognized: Compensatory emphysema describes the dilation of residual alveoli in response to loss of lung substance elsewhere, such as occurs after surgical removal of a diseased lung or lobe.


Pathology_Robbins

Pathology_Robbins. Compensatory emphysema describes the dilation of residual alveoli in response to loss of lung substance elsewhere, such as occurs after surgical removal of a diseased lung or lobe. Obstructive overinflation refers to expansion of the lung due to air trapping. A common cause is subtotal obstruction of an airway by a tumor or foreign object. Obstructive overinflation can be life-threatening if expansion of the affected portion produces compression of the remaining normal lung. Bullous emphysema refers to any form of emphysema that produces large subpleural blebs or bullae (spaces >1 cm Fig. 13.8 Bullousemphysemawithlargeapicalandsubpleuralbullae.(From the Teaching Collection of the Department of Pathology, University of Texas South-western Medical School, Dallas,Texas.) in diameter in the distended state) (


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Pathology_Robbins. Fig. 13.8 ). Such blebs represent localized accentuations of one of the four forms of emphysema; most often the blebs are subpleural, and on occasion they may rupture, leading to pneumothorax.


Pathology_Robbins

Pathology_Robbins. • Mediastinal (interstitial) emphysema is caused by entry of air into the interstitium of the lung, from where it may track to the mediastinum and sometimes the subcutaneous tissue. It may occur spontaneously if a sudden increase in intraalveolar pressure (as with vomiting or violent coughing) produces alveolar rupture, which allows air to dissect into the interstitium. Sometimes it develops in children with whooping cough. It may also occur in patients on respirators who have partial bronchiolar obstruction or in individuals with a perforating injury (e.g., a fractured rib). When the interstitial air gets into the subcutaneous tissue, the patient may literally blow up like a balloon, with marked swelling of the head and neck and crackling crepitation over the chest (subcutaneous emphysema). In most instances the air is resorbed spontaneously after the site of entry seals. Emphysemaisachronicobstructiveairwaydiseasecharacterizedbyenlargementofairspacesdistaltoterminalbronchioles.


Pathology_Robbins

Pathology_Robbins. Mostpatientswithemphysemaalsohavesignsandsymptomsofconcurrentchronicbronchitis,sincecigarettesmokingisariskfactorforboth. http://ebooksmedicine.net Chronic bronchitis is diagnosed on clinical grounds: it is defined by the presence of a persistent productive cough for at least 3 consecutive months in at least 2 consecutive years. It is common among cigarette smokers and urban dwellers in smog-ridden cities; some studies indicate that 20% to 25% of men in the 40to 65-year-old age group have the disease. In early stages of the disease, the cough raises mucoid sputum, but airflow is not obstructed. Some patients with chronic bronchitis have evidence of hyperresponsive airways, with intermittent bronchospasm and wheezing (asthmatic bronchitis), while other bronchitic patients, especially heavy smokers, develop chronic outflow obstruction, usually with associated emphysema (COPD). The distinctive feature of chronic bronchitis is hypersecretion of mucus, beginning in the large airways.


Pathology_Robbins

Pathology_Robbins. Although the most important cause is cigarette smoking, other air pollutants, such as sulfur dioxide and nitrogen dioxide, may contribute. These environmental irritants induce hypertrophy of mucous glands in the trachea and bronchi as well as an increase in mucin-secreting goblet cells in the epithelial surfaces of smaller bronchi and bronchioles. These irritants also cause inflammation marked by the infiltration of macrophages, neutrophils, and lymphocytes. In contrast with asthma, eosinophils are not seen in chronic bronchitis. Whereas the defining mucus hypersecretion is primarily a reflection of involvement of large bronchi, the airflow obstruction in chronic bronchitis results from (1) small airway disease, induced by mucous plugging of the bronchiolar lumen, inflammation, and bronchiolar wall fibrosis, and (2) coexistent emphysema. In general, while small airway disease (chronic bronchiolitis) is an important component of early, mild airflow obstruction, chronic bronchitis with


Pathology_Robbins

Pathology_Robbins. wall fibrosis, and (2) coexistent emphysema. In general, while small airway disease (chronic bronchiolitis) is an important component of early, mild airflow obstruction, chronic bronchitis with significant airflow obstruction almost always is complicated by emphysema.


Pathology_Robbins

Pathology_Robbins. It is postulated that many of the effects of environmental irritants on respiratory epithelium are mediated by local release of cytokines such as IL-13 from T cells and innate lymphoid cells. The transcription of the mucin gene in bronchial epithelium and the production of neutrophil elastase are increased as a consequence of exposure to tobacco smoke. Microbial infection often is present but has a secondary role, chiefly by maintaining inflammation and exacerbating symptoms. MORPHOLOGYAsseeningrossspecimens,themucosalliningofthelargerairwaysusuallyishyperemic and swollen byedemafluidandiscoveredbyalayerofmucinousormucopurulentsecretions. Thesmallerbronchiandbronchiolesalsomaybefilledwithsecretions.Thediagnosticfeatureofchronicbronchitisinthetracheaandlargerbronchiisenlargement of the mucus-secreting glands (


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Pathology_Robbins. Fig.13.9 ).Themagnitudeoftheincreaseinsizeisassessedbytheratioofthethicknessofthesubmucosalglandlayertothatofthebronchialwall(theReidindex—normally0.4).Variablenumbersofinflammatorycells,largelylymphocytesandmacrophagesbutsometimesalsoadmixedneutrophils,arefrequentlyseeninthebronchialmucosa.Chronic bronchiolitis (smallairwaydisease),characterizedbygobletcellmetaplasia,mucousplugging,inflammation,andfibrosis,alsoisseen.Inseverecases,theremaybecompleteobliterationofthelumenasaconsequenceoffibrosis(bronchiolitis obliterans). Itisthesubmucosalfibrosisthatleadstoluminalnarrowingandairwayobstruction.Emphysematouschangesoftencoexist. Fig. 13.9 Chronicbronchitis.Thelumenofthebronchusisabove.Notethemarkedthickeningofthemucousglandlayer(approximatelytwice-normal)andsquamousmetaplasiaoflungepithelium.(From the Teaching Collection of the Department of Pathology, University of Texas, Southwestern Medical School, Dallas,Texas.)


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Pathology_Robbins. The course of chronic bronchitis is quite variable. In some patients, cough and sputum production persist indefinitely without ventilatory dysfunction, while others develop COPD with significant outflow obstruction marked by hypercapnia, hypoxemia, and cyanosis. Patients with chronic bronchitis and COPD have frequent exacerbations, more rapid disease progression, and poorer outcomes than those with emphysema alone. Progressive disease is marked by the development of pulmonary hypertension, sometimes leading to cardiac failure (Chapter 11); recurrent infections; and ultimately respiratory failure. Chronicbronchitisisdefinedaspersistentproductivecoughforatleast3consecutivemonthsinatleast2consecutiveyears. Cigarettesmokingisthemostimportantunderlyingriskfactor;airpollutantsalsocontribute. Chronicairwayobstructionlargelyresultsfromsmallairwaydisease(chronicbronchiolitis)andcoexistentemphysema.