Pathology_Robbins

Pathology_Robbins. About 80% of the population in certain Asian and African countries is tuberculin-positive. In contrast, in 2012, approximately, 5% to 10% of the U.S. population was positive, indicating the marked difference in rates of exposure to the tubercle bacillus. In general, 3% to 4% of previously unexposed individuals acquire active tuberculosis during the first year after “tuberculin conversion,” and no more than 15% do so thereafter. Thus, only a small fraction of those who contract an infection develop active disease.


Pathology_Robbins

Pathology_Robbins. Mycobacteria are slender rods that are acid-fast (i.e., they have a high content of complex lipids that readily bind the Ziehl-Neelsen [carbol fuchsin] stain and subsequently stubbornly resist decolorization). M. tuberculosis hominis is responsible for most cases of tuberculosis; the reservoir of infection typically is found in individuals with active pulmonary disease. Transmission usually is direct, by inhalation of airborne organisms in aerosols generated by expectoration or by exposure to contaminated secretions of infected individuals. Oropharyngeal and intestinal tuberculosis contracted by drinking milk contaminated with Mycobacterium bovis infection is now rare except in those countries with tuberculous dairy cows and sales of unpasteurized milk. Other mycobacteria, particularly Mycobacterium avium complex, are much less virulent than M. tuberculosis and rarely cause disease in immunocompetent individuals. However, they cause disease in 10% to 30% of patients with AIDS.


Pathology_Robbins

Pathology_Robbins. The pathogenesis of tuberculosis in the previously unexposed immunocompetent individual is centered on the development of cell-mediated immunity, which confers resistance to the organism and results in development of tissue hypersensitivity to tubercular antigens. The pathologic features of tuberculosis, such as caseating granulomas and cavitation, are the result of the destructive tissue hypersensitivity that is part and parcel of the host immune response. Because the effector cells for both protective http://ebooksmedicine.net Mycobacterium Mannose, C3b, others Mannose receptor, CR3, others Lack of acid pH Bacteremia with seeding of multiple sites TNF, ˜-IFN chemokines Production of nitric oxide Production of reactive oxygen species


Pathology_Robbins

Pathology_Robbins. Lack of acid pH Bacteremia with seeding of multiple sites TNF, ˜-IFN chemokines Production of nitric oxide Production of reactive oxygen species Fig. 13.33 Sequence of events in the natural history of primary pulmonary tuberculosis. This sequence commences with inhalation of virulent strains of Mycobacterium and culminates in the development of immunity and delayed hypersensitivity to the organism. (A) Events occurring in the first 3 weeks after exposure. (B) Events thereafter. The development of resistance to the organism is accompanied by conversion to a positive result on tuberculin skin testing. Cells and bacteria are not drawn to scale. IFN-γ, Interferon γ; iNOS, inducible nitric oxide synthase; MHC, major histocompatibility complex; MTb, Mycobacterium tuberculosis; TNF, tumor necrosis factor.


Pathology_Robbins

Pathology_Robbins. immunity and damaging hypersensitivity are the same, the appearance of tissue hypersensitivity also signals the acquisition of immunity to the organism. The sequence of events from inhalation of the infectious inoculum to containment of the primary focus is illustrated in Fig. 13.33 and can be outlined as follows: Entry into macrophages. A virulent strain of mycobacteria gains entry to macrophage endosomes, a process mediated by several macrophage receptors, including the macrophage mannose receptor and complement receptors that recognize several components of the mycobacterial cell walls.


Pathology_Robbins

Pathology_Robbins. Replication in macrophages. Once internalized, the organisms inhibit normal microbicidal responses by preventing the fusion of the lysosomes with the phagocytic vacuole, allowing the mycobacterium to persist and proliferate. Thus, the earliest phase of primary tuberculosis (the first 3 weeks) in the nonsensitized patient is characterized by bacillary proliferation within the pulmonary alveolar macrophages and air spaces, eventually resulting in bacteremia and seeding of the organisms to multiple sites. Despite the bacteremia, most individuals at this stage are asymptomatic or have a mild flulike illness. Development of cell-mediated immunity. This occurs approximately 3 weeks after exposure. Processed mycobacterial antigens reach the draining lymph nodes and are presented to CD4 T cells by dendritic cells and macrophages. Under the influence of macrophage-secreted IL-12, CD4+ T cells of the TH1 subset are generated that are capable of secreting IFN-γ.


Pathology_Robbins

Pathology_Robbins. T cell–mediated macrophage activation and killing of bacteria. IFN-γ released by the CD4+ T cells of the TH1 subset is crucial in activating macrophages. Activated macrophages, in turn, release a variety of mediators and upregulate expression of genes with important downstream effects, including: (1) TNF, which is responsible for recruitment of monocytes, which in turn undergo activation and differentiation into the “epithelioid histiocytes” that characterize the granulomatous response; (2) inducible nitric oxide synthase (iNOS), which raises nitric oxide (NO) levels, helping to create reactive nitrogen intermediates that appear to be particularly important in killing of mycobacteria; and (3) anti-microbial peptides (defensins) that are also toxic to mycobacterial organisms.


Pathology_Robbins

Pathology_Robbins. • Granulomatous inflammation and tissue damage. In addition to stimulating macrophages to kill mycobacteria, the TH1 response orchestrates the formation of granulomas and caseous necrosis. Macrophages activated by IFN-γ differentiate into the “epithelioid histiocytes” that aggregate to form granulomas; some epithelioid cells may fuse to form giant cells. In many individuals, this response halts the infection before significant tissue destruction or illness occur. In other individuals with immune deficits due to age or immunosuppression, the infection progresses and the ongoing immune response results in caseation necrosis. Activated macrophages also secrete TNF and chemokines, which promote recruitment of more monocytes. The importance of TNF is underscored by the fact that patients with rheumatoid arthritis who are treated with a TNF antagonist have an increased risk for tuberculosis reactivation.


Pathology_Robbins

Pathology_Robbins. In summary, immunity to a tubercular infection is primarily mediated by TH1 cells, which stimulate macrophages to kill mycobacteria. This immune response, while largely effective, comes at the cost of hypersensitivity and the accompanying tissue destruction. Defects in any of the steps of a TH1 T cell response (including IL-12, IFN-γ, TNF, or nitric oxide production) result in poorly formed granulomas, absence of resistance, and disease progression. Individuals with inherited mutations in any component of the TH1 pathway are extremely susceptible to infections with mycobacteria. Reactivation of the infection or reexposure to the bacilli in a previously sensitized host results in rapid mobilization of a defensive reaction but also increased tissue necrosis. Just as hypersensitivity and resistance appear in parallel, so, too, the loss of hypersensitivity (indicated by tuberculin negativity in a M. tuberculosis-infected patient) is an ominous sign of fading resistance to the organism.


Pathology_Robbins

Pathology_Robbins. Primary tuberculosis is the form of disease that develops in a previously unexposed and therefore unsensitized patient. About 5% of those newly infected acquire significant disease.


Pathology_Robbins

Pathology_Robbins. In the large majority of otherwise healthy individuals, the only consequence of primary tuberculosis are the foci of scarring discussed earlier. However, these foci may harbor viable bacilli and thus serve as a nidus for disease reactivation at a later time if host defenses wane. Uncommonly, new infection leads to progressive primary tuberculosis. This complication occurs in patients who are overtly immunocompromised or who have more subtle defects in host defenses, as is characteristic of malnourished individuals. Certain racial groups, such as the Inuit, also are more prone to the development of progressive primary tuberculosis. The incidence of progressive primary tuberculosis is particularly high in HIV-positive patients with significant immunosuppression (i.e., CD4+ T cell counts below 200 cells/µL). Immunosuppression results in an inability to mount a CD4+ T cell–mediated response that would contain the primary focus; because hypersensitivity and resistance are most often


Pathology_Robbins

Pathology_Robbins. below 200 cells/µL). Immunosuppression results in an inability to mount a CD4+ T cell–mediated response that would contain the primary focus; because hypersensitivity and resistance are most often concomitant factors, the lack of a tissue hypersensitivity reaction results in the absence of the characteristic caseating granulomas (nonreactive tuberculosis) (see


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Secondary tuberculosis is the pattern of disease that arises in a previously sensitized host. It may appear shortly after primary tuberculosis, but more commonly arises from reactivation of dormant primary lesions many decades after initial infection, particularly when host resistance is weakened. It also may result from reinfection, which may occur either because the protection afforded by the primary disease has waned or because of exposure to a large inoculum of virulent bacilli. Whatever the source of the organism, only a few patients (<5%) with primary disease subsequently develop secondary tuberculosis. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Secondary pulmonary tuberculosis is classically localized to the apex of one or both upper lobes. The reason is obscure but may relate to high oxygen tension in the apices. Because of the preexistence of hypersensitivity, the bacilli excite a prompt and marked tissue response that tends to wall off the focus. As a result of this localization, the regional lymph nodes are less prominently involved early in the disease than they are in primary tuberculosis. On the other hand, cavitation occurs readily in the secondary form, leading to erosion into and dissemination along airways. Such changes become an important source of infectivity, because the patient now produces sputum containing bacilli.


Pathology_Robbins

Pathology_Robbins. Secondary tuberculosis should always be an important consideration in HIV-positive patients who present with pulmonary disease. Of note, although an increased risk for tuberculosis exists at all stages of HIV disease, the manifestations differ depending on the degree of immunosuppression. For example, patients with less severe immunosuppression (CD4+ T cell counts >300 cells/µL) present with “usual” secondary tuberculosis (apical disease with cavitation) while those with more advanced immunosuppression (CD4+ T cell counts below 200 cells/µL) present with a clinical picture that resembles progressive primary tuberculosis (lower and middle lobe consolidation, hilar lymphadenopathy, and noncavitary disease). The extent of immunosuppression also determines the frequency of extrapulmonary involvement, rising from 10% to 15% in mildly immunosuppressed patients to greater than 50% in those with severe immune deficiency.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 13.36 Secondarypulmonarytuberculosis.Theupperpartsofbothlungsareriddledwithgray-whiteareasofcaseationandmultipleareasofsofteningandcavitation. Localized,apical,secondarypulmonarytuberculosismayhealwithfibrosiseitherspontaneouslyoraftertherapy,orthediseasemayprogressandextendalongseveraldifferentpathways.Inprogressive pulmonary tuberculosis, theapicallesionenlargesandtheareaofcaseationexpands.Erosionintoabronchusevacuatesthecaseouscenter,creatingaragged,irregular cavity lined by caseous material thatispoorlywalledoffbyfibroustissue(


Pathology_Robbins

Pathology_Robbins. Fig.13.38 Localized secondary tuberculosis may be asymptomatic. When manifestations appear, they are usually insidious in onset, with gradual development of both systemic and localizing symptoms and signs. Systemic manifestations, probably related to the release of cytokines by activated macrophages (e.g., TNF and IL-1), often appear early in the disease course and include malaise, anorexia, weight loss, and fever. Commonly, the fever is low grade and remittent (appearing late each afternoon and then subsiding), and night sweats occur. With progressive pulmonary involvement, increasing amounts of sputum, at first mucoid and later purulent, appear. When cavitation is present, the sputum contains tubercle bacilli. Some degree of hemoptysis Fig. 13.37 Miliarytuberculosisofthespleen.Thecutsurfaceshowsnumer-ousgray-whitegranulomas. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 13.37 Miliarytuberculosisofthespleen.Thecutsurfaceshowsnumer-ousgray-whitegranulomas. http://ebooksmedicine.net INCREASING IMMUNITY Primary infection Spreading lesions,little caseation Localized lesions,more caseation (localized caseation) Caseation Caseation in lymph node PRIMARY COMPLEX Massive hematogenous dissemination Liver Spleen Reactivation Reinfection Scar Caseation CaseationCavity (organisms dormant; pulmonary or extrapulmonary) PROGRESSIVE PRIMARY TB MILIARY TB SECONDARY TUBERCULOSIS LATENT LESIONS (organisms not viable) Scar Scar HEALED LESIONS Massive hematogenous dissemination PROGRESSIVE SECONDARY TB MILIARY TB LOCALIZED CASEATING DESTRUCTIVE LESIONS (pulmonary or extrapulmonary)


Pathology_Robbins

Pathology_Robbins. Fig. 13.38 Thenaturalhistoryandspectrumoftuberculosis.(Adapted from a sketch provided by Dr. R.K. Kumar,The University of New South Wales, School of Pathology, Sydney, Australia.) is present in about half of all cases of pulmonary tuberculosis. Pleuritic pain may result from extension of the infection to the pleural surfaces. Extrapulmonary manifestations of tuberculosis are legion and depend on the organ system involved (e.g., tuberculous salpingitis may present as infertility, tuberculous meningitis with headache and neurologic deficits, Pott disease with back pain and paraplegia). The diagnosis of pulmonary disease is based in part on the history and on physical and radiographic findings of consolidation or cavitation in the apices of the lungs. Ultimately, however, tubercle bacilli must be identified.


Pathology_Robbins

Pathology_Robbins. The most common methodology for diagnosis of tuberculosis remains demonstration of acid-fast organisms in sputum by staining or by use of fluorescent auramine rhodamine. Conventional cultures for mycobacteria require up to 10 weeks, but liquid media–based radiometric assays that detect mycobacterial metabolism are able to provide an answer within 2 weeks. PCR amplification can be performed on liquid media with growth, as well as on tissue sections, to identify the mycobacterium. However, culture remains the standard diagnostic modality because it can identify the occasional PCR-negative case and also allows testing of drug susceptibility. Of concern, multidrug resistance (MDR), defined as resistance of mycobacteria to two or more of the primary drugs used for treatment of tuberculosis, is becoming more common, and the WHO estimated that 500,000 individuals were newly infected with multidrug-resistant tuberculosis in 2014. This represents approximately 3% of new cases and 20% of


Pathology_Robbins

Pathology_Robbins. is becoming more common, and the WHO estimated that 500,000 individuals were newly infected with multidrug-resistant tuberculosis in 2014. This represents approximately 3% of new cases and 20% of previously treated cases. The epicenter of this troubling epidemic lies in Eastern Europe and Russia, where in some locales up to 20% of new infections are with multidrug-resistant strains. Of even greater concern, approximately 5% to 10% of such cases exhibit extensive multidrug resistance, defined by resistance to a broad spectrum of antibiotics in current use against tuberculosis.


Pathology_Robbins

Pathology_Robbins. The prognosis is determined by the extent of the infection (localized versus widespread), the immune status of the host, and the antibiotic sensitivity of the organism. Understandably, the prognosis is guarded in those with multidrug-resistant tuberculosis. Amyloidosis may develop in persistent cases. TuberculosisisachronicgranulomatousdiseasecausedbyM. tuberculosis, usuallyaffectingthelungs,butvirtuallyanyextra-pulmonaryorgancanbeinvolved. Initialexposuretomycobacteriaresultsindevelopmentofacellularimmuneresponsethatconfersresistanceandleadstohypersensitivity(asdeterminedbyapositiveresultonthetuberculinskintest). http://ebooksmedicine.net TheTH1subsetofCD4+ Tcellshasacrucialroleincell-mediatedimmunityagainstmycobacteria;mediatorsofinflammationandbacterialcontainmentincludeIFN-γ,TNF,andnitricoxide. Thehistopathologichallmarkofhostreactiontotuberculosisinimmunocompetentindividualsisthepresenceofgranulomas,usuallywithcaseousnecrosis.


Pathology_Robbins

Pathology_Robbins. HIV-seropositivestatusisanimportantriskfactorfordevelopmentorrecrudescenceofactivetuberculosis. Nontuberculous mycobacteria most commonly cause chronic, localized pulmonary disease in immunocompetent individuals. In the United States, strains implicated most frequently include Mycobacterium avium-intracellulare (also called M. avium complex), Mycobacterium kansasii, and Mycobacterium abscessus. It is not uncommon for nontuberculous mycobacterial infection to manifest as upper-lobe cavitary disease, mimicking tuberculosis, especially in patients with a long history of smoking or alcohol abuse. Concomitant chronic pulmonary disease (COPD, cystic fibrosis, pneumoconiosis) is often present.


Pathology_Robbins

Pathology_Robbins. In immunosuppressed individuals (primarily HIVseropositive patients), M. avium complex infection manifests as a disseminated disease associated with systemic signs and symptoms (fever, night sweats, weight loss). Hepatosplenomegaly and lymphadenopathy, signifying involvement of the mononuclear phagocyte system by the opportunistic pathogen, is common, as are gastrointestinal symptoms such as diarrhea and malabsorption. Pulmonary involvement is often indistinguishable from tuberculosis in patients with AIDS. Disseminated M. avium complex infection in patients with AIDS tends to occur late in the clinical course, when CD4+ T cell counts have fallen below 100 cells/µL. Hence, tissue examination usually does not reveal granulomas; instead, foamy macrophages “stuffed” with atypical mycobacteria typically are seen. Histoplasmosis,Coccidioidomycosis,andBlastomycosis


Pathology_Robbins

Pathology_Robbins. Histoplasmosis,Coccidioidomycosis,andBlastomycosis Infections caused by dimorphic fungi, which include Histoplasma capsulatum, Coccidioides immitis, and Blastomyces dermatitidis, manifest either with isolated pulmonary involvement, as commonly seen in infected immunocompetent individuals, or with disseminated disease in immunocompromised individuals. T cell–mediated immune responses are critical for containing the infection, so individuals with compromised cell-mediated immunity, such as those with HIV, are prone to systemic disease. In part because of the overlap in clinical presentations, infectious diseases due to all three dimorphic fungi are considered together in this section. Each of the dimorphic fungi has a typical geographic distribution, as follows:


Pathology_Robbins

Pathology_Robbins. Each of the dimorphic fungi has a typical geographic distribution, as follows: H. capsulatum is endemic in the Ohio and central Mississippi River valleys and along the Appalachian Mountains in the southeastern United States. Warm, moist soil containing droppings from bats and birds provides an ideal medium for the growth of the mycelial form, which produces infectious spores. C. immitis is endemic in the southwestern and far western regions of the United States, particularly in California’s San Joaquin Valley, where coccidial infection is known as “valley fever.” B. dermatitidis has a distribution in the United States that overlaps with those in which histoplasmosis is found. MORPHOLOGYTheyeastformsarefairlydistinctive,whichhelpsintheidenti ficationofindividualfungiintissuesections: H. capsulatum: roundtooval,smallyeastformsmeasuring2to5µmindiameter( Fig.13.39A C. immitis: thick-walled,nonbuddingspherules,20to60µmindiameter,oftenfilledwithsmallendospores(see Fig.13.39B


Pathology_Robbins

Pathology_Robbins. H. capsulatum: roundtooval,smallyeastformsmeasuring2to5µmindiameter( Fig.13.39A C. immitis: thick-walled,nonbuddingspherules,20to60µmindiameter,oftenfilledwithsmallendospores(see Fig.13.39B B. dermatitidis: roundtoovalandlargeryeastformsthanHistoplasma (5to25µmindiameter)thatreproducebycharacteristicbroad-basedbudding(see Fig.13.39CandD


Pathology_Robbins

Pathology_Robbins. Clinical manifestations may take the form of (1) acute (primary) pulmonary infection, (2) chronic (granulomatous) pulmonary disease, or (3) disseminated miliary disease. The primary pulmonary nodules, composed of aggregates of macrophages filled with organisms, are associated with similar lesions in the regional lymph nodes. These lesions evolve into small granulomas complete with giant cells and may develop central necrosis and later fibrosis and calcification. The similarity to primary tuberculosis is striking, and differentiation requires identification of the yeast forms (best seen with silver stains). The clinical symptoms and signs resemble those of a “flulike” syndrome and are most often self-limited. In the vulnerable host, chronic cavitary pulmonary disease develops, with a predilection for the upper lobe, resembling the secondary form of tuberculosis. It is not uncommon for these fungi to give rise to perihilar mass lesions that resemble bronchogenic carcinoma


Pathology_Robbins

Pathology_Robbins. with a predilection for the upper lobe, resembling the secondary form of tuberculosis. It is not uncommon for these fungi to give rise to perihilar mass lesions that resemble bronchogenic carcinoma radiologically. At this stage, manifestations may include cough, hemoptysis, and even dyspnea and chest pain.


Pathology_Robbins

Pathology_Robbins. In infants or immunocompromised adults, particularly those with HIV infection, disseminated disease (analogous to miliary tuberculosis) may develop. Under these circumstances, there are no well-formed granulomas. Instead, focal collections of phagocytes containing yeast forms are seen within the liver, spleen, lymph nodes, lymphoid tissue of the gastrointestinal tract, and bone marrow. The adrenal glands and meninges also may be involved, and in a minority of cases, ulcers form in the nose and mouth, on the tongue, or in the larynx. Disseminated disease produces a febrile illness marked by hepatosplenomegaly, anemia, leukopenia, and thrombocytopenia. Cutaneous infections with disseminated Blastomyces organisms frequently induce striking epithelial hyperplasia, which may be mistaken for squamous cell carcinoma. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 13.39 (A)Histoplasma capsulatum yeastformsfillphagocytesinalymphnodeofapatientwithdisseminatedhistoplasmosis(silverstain).(B)Coccidioidomycosiswithintactspheruleswithinmultinucleatedgiantcells.(C)Blastomycosis,withroundedbuddingyeasts,largerthanneutrophils.Notethecharacteristicthickwallandnuclei(notseeninotherfungi).(D)Silverstainhighlightsthebroad-basedbuddingseeninBlastomyces immitis organisms.


Pathology_Robbins

Pathology_Robbins. The appearance of a pulmonary infiltrate and signs of infection (e.g., fever) are some of the most common and serious complications in individuals with immune systems that are suppressed by disease, immunosuppressive drugs, or therapeutic irradiation. A wide variety of “opportunistic” pathogens, many of which rarely cause infection in normal individuals, can cause infections in these settings, and often more than one agent is involved. The more common pulmonary pathogens include (1) bacteria (P. aeruginosa, Mycobacterium spp., L. pneumophila, and Listeria monocytogenes); (2) viruses (cytomegalovirus and herpesvirus); and (3) fungi (P. jiroveci, Candida spp., Aspergillus spp., and Cryptococcus neoformans).


Pathology_Robbins

Pathology_Robbins. Infection by cytomegalovirus (CMV), a member of the herpesvirus family, may manifest in various forms, depending partly on the age and the immune status of the host. Cells infected by the virus exhibit gigantism of both the cytoplasm and the nucleus. The nucleus typically contains a large inclusion surrounded by a clear halo (“owl’s eye”), which gives the name to the classic form of symptomatic disease that occurs in neonates—cytomegalic inclusion disease. Although classic cytomegalic inclusion disease involves many organs, CMV infections are discussed here because in immunosuppressed adults, particularly patients with AIDS and recipients of allogeneic hematopoietic stem cell transplants, CMV pneumonitis is a serious problem. Transmission of CMV can occur by several mechanisms, depending on the age group: A fetus can be infected transplacentally from a newly acquired or reactivated infection in the mother (congenital CMV infection).


Pathology_Robbins

Pathology_Robbins. A fetus can be infected transplacentally from a newly acquired or reactivated infection in the mother (congenital CMV infection). The virus can be transmitted to the infant through cervical or vaginal secretions at birth, or later through the breast milk of a mother with an active infection (perinatal CMV infection). Preschool children, especially in day care centers, can acquire it through saliva. Toddlers so infected readily transmit the virus to their parents. In patients older than 15 years of age, the venereal route is the dominant mode of transmission, but spread also may occur through contact with respiratory secretions and by the fecal-oral route. Iatrogenic transmission can occur at any age through organ transplantation or blood transfusion. http://ebooksmedicine.net Fig. 13.40 Cytomegalovirusinfectionofthelung.Adistinctnuclearinclu-sionandmultiplecytoplasmicinclusionsareseeninanenlargedcell.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 13.40 Cytomegalovirusinfectionofthelung.Adistinctnuclearinclu-sionandmultiplecytoplasmicinclusionsareseeninanenlargedcell. MORPHOLOGYHistologically,thecharacteristicenlargementofCMV-infectedcellsisreadilyappreciated.Intheglandularorgans,theparenchymalepithelialcellsareaffected;inthebrain,theneurons;inthelungs,thealveolarmacrophagesandepithelialandendothelialcells;andinthekidneys,thetubularepithelialandglomerularendothelialcells.Infected cells are strikingly enlarged, often to a diameter of 40 µm, and exhibit cellular and nuclear pleiomorphism. Prominentintranuclearbasophilicinclusionsspanninghalfthenucleardiameterareusuallysetofffromthenuclearmembranebyaclearhalo( Fig.13.40).Within thecytoplasmofthesecells,smallerbasophilicinclusionsalsomaybeseen.


Pathology_Robbins

Pathology_Robbins. Fig.13.40).Within thecytoplasmofthesecells,smallerbasophilicinclusionsalsomaybeseen. In healthy young children and adults, the disease is nearly always asymptomatic. In surveys around the world, 50% to 100% of adults demonstrate anti-CMV antibodies in the serum, indicating previous exposure. The most common clinical manifestation of CMV infection in immunocompetent hosts beyond the neonatal period is an infectious mononucleosis–like illness marked by fever, atypical lymphocytosis, lymphadenopathy, and hepatomegaly accompanied by abnormal liver function test results, suggesting mild hepatitis. Most patients recover from CMV mononucleosis without any sequelae, although excretion of the virus may occur in body fluids for months to years. Irrespective of the presence or absence of symptoms after infection, an individual who is once infected becomes seropositive for life. The virus remains latent within leukocytes, which are the major reservoirs.


Pathology_Robbins

Pathology_Robbins. Immunosuppression-related CMV infection occurs most commonly in recipients of transplants (such as heart, liver, kidney, lung, or hematopoietic stem cell) and in patients with AIDS. This can be either primary infection or reactivation of a latent infection. CMV is the most common opportunistic viral pathogen in AIDS.


Pathology_Robbins

Pathology_Robbins. In all of these settings, serious disseminated CMV infections primarily affect the lungs (pneumonitis), gastrointestinal tract (colitis), and retina (retinitis); the central nervous system usually is spared. In the lung, infection is associated with typical cytomegalic changes, mononculear infiltrates, and foci of necrosis, which may progress to acute respiratory distress syndrome. Intestinal necrosis and ulceration can develop and may be extensive, leading to the formation of “pseudomembranes” (Chapter 15) and debilitating diarrhea. CMV retinitis, by far the most common form of opportunistic CMV disease, can occur either alone or in combination with involvement of the lungs and intestinal tract. Diagnosis of CMV infection is made by demonstration of characteristic viral inclusions in tissue sections, successful viral culture, rising anti-viral antibody titer, and qualitative or quantitative PCR assay–based detection of CMV DNA. The latter has revolutionized the approach to monitoring


Pathology_Robbins

Pathology_Robbins. sections, successful viral culture, rising anti-viral antibody titer, and qualitative or quantitative PCR assay–based detection of CMV DNA. The latter has revolutionized the approach to monitoring patients after transplantation.


Pathology_Robbins

Pathology_Robbins. P. jiroveci (previously P. carinii), an opportunistic infectious agent formerly considered to be a protozoan, is now classified as a fungus. Serologic evidence indicates that virtually all individuals are exposed to Pneumocystis during the first few years of life, but in most the infection remains latent. Reactivation with development of clinical disease occurs almost exclusively in immunocompromised individuals. Indeed, patients with AIDS are extremely susceptible to infection with P. jiroveci, and it also may infect severely malnourished infants and immunosuppressed individuals (especially after organ transplantation or in individuals receiving cytotoxic chemotherapy or corticosteroids). In patients with AIDS, the risk for acquiring P. jiroveci infections increases in inverse proportion to the CD4+ T cell count, with counts less than 200 cells/µL having a strong predictive value. Pneumocystis infection is largely confined to the lung, where it produces an interstitial pneumonitis.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYInvolvedareasofthelungcontainacharacteristicintraalveolar foamy, pink-staining exudate withhematoxylin-eosin(H&E)stain(“cottoncandy”exudate)( Fig.13.41A ).Theseptaarethickenedbyedemaandaminimalmononuclearinfiltrate.Specialstainsarerequiredtovisualizetheorganism.Silverstainoftissuesectionsrevealsroundto cup-shaped cysts (4to10µmindiameter)withinthealveolarexudates(see Fig.13.41B The diagnosis of Pneumocystis pneumonia should be considered in any immunocompromised patient with respiratory symptoms and abnormal findings on chest radiograph. Fever, dry cough, and dyspnea occur in 90% to 95% of patients, in whom radiographic evidence of bilateral perihilar and basilar infiltrates is typical. Hypoxia is frequent; pulmonary function studies show a restrictive lung defect. The most sensitive and effective method of diagnosis is to identify the organism in induced sputum or bronchoalveolar lavage fluid using immunofluorescence. If http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 13.41 Pneumocystispneumonia.(A)Thealveoliarefilledwithacharacteristicfoamyacellularexudate.(B)Silverstaindemonstratescup-shapedand roundcystswithintheexudate. treatment is initiated before widespread involvement, the outlook for recovery is good; however, because residual organisms are likely to persist, particularly in patients with AIDS, relapses are common unless the underlying immunodeficiency is corrected or prophylactic therapy is given. Candida albicans is the most common disease-causing fungus. It is a normal inhabitant of the oral cavity, gastrointestinal tract, and vagina in many individuals. Systemic candidiasis (with associated pneumonia) is a disease restricted to immunocompromised patients that has protean manifestations. MORPHOLOGYIntissuesections,C. albicans demonstratesyeastlikeforms(blastoconidia),pseudohyphae,andtruehyphae(


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Candidiasis can involve the mucous membranes, skin, and deep organs (invasive candidiasis). Among these varied presentations, the following merit brief mention: • Superficial infection on mucosal surfaces of the oral cavity (thrush). This is the most common presentation. Florid proliferation of the fungi creates gray-white, dirty-looking pseudomembranes composed of matted organisms and inflammatory cells and tissue debris. Deep to the surface, there is mucosal hyperemia and inflammation. Thrush is seen in newborns, debilitated patients, and children receiving oral corticosteroids for asthma, and after a course of broad-spectrum antibiotics that destroy competing normal bacterial flora. The other major risk group includes HIV-positive patients; patients with oral thrush not associated with an obvious underlying condition should be evaluated for HIV infection. Vaginitis is extremely common in women, especially those who are diabetic or pregnant or on oral contraceptive pills.


Pathology_Robbins

Pathology_Robbins. Vaginitis is extremely common in women, especially those who are diabetic or pregnant or on oral contraceptive pills. Esophagitis is common in patients with AIDS and in those with hematolymphoid malignancies. These patients present with dysphagia (painful swallowing) and retrosternal pain; endoscopy demonstrates white plaques and pseudomembranes resembling those found on other mucosal surfaces. Skin infection can manifest in many different forms, including infection of the nail (onychomycosis), nail folds (paronychia), hair follicles (folliculitis), moist, intertriginous skin such as armpits or webs of the fingers and toes (intertrigo), and penile skin (balanitis). Diaper rash is a cutaneous candidal infection seen in the perineum of infants, in the region of contact with wet diapers.


Pathology_Robbins

Pathology_Robbins. Chronic mucocutaneous candidiasis is a chronic refractory disease afflicting the mucous membranes, skin, hair, and nails; it is associated with a variety of underlying T cell defects. These in include Job syndrome, an inherited condition with a variety of abnormalitles including an defect in Th17 T cell responses, which are important in controlling fungal infections (Chapter 5). Invasive candidiasis implies blood-borne dissemination of organisms to various tissues or organs. Common patterns include (1) renal abscess, (2) myocardial abscess and endocarditis, (3) brain involvement (most commonly meningitis, but parenchymal microabscesses occur), (4) endophthalmitis (virtually any eye structure can be involved), (5) hepatic abscesses, and (6) Candida pneumonia, usually presenting with bilateral nodular infiltrates, resembling Pneumocystis pneumonia (see http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 13.42 Themorphologyoffungalinfections.(A)Candidaorganismhaspseudohyphaeandbuddingyeasts(silverstain).(B)Invasiveaspergillosis(grossappearance)ofthelunginahematopoieticstemcelltransplantrecipient.(C)Gomorimethenamine-silver(GMS)stainshowsseptatehyphaewithacute-anglebranching,consistentwithAspergillus.(D)CryptococcosisofthelunginapatientwithAIDS.Theorganismsaresomewhatvariableinsize.(B,Courtesy of Dr. Dominick Cavuoti,Department of Pathology,University of Texas Southwestern Medical School,Dallas,Texas.) earlier). Patients with acute leukemias who are profoundly neutropenic after chemotherapy are particularly prone to the development of systemic disease. Candida endocarditis is the most common fungal endocarditis, usually occurring in patients with prosthetic heart valves or in intravenous drug abusers.


Pathology_Robbins

Pathology_Robbins. Cryptococcosis, caused by C. neoformans, almost exclusively manifests as an opportunistic infection in immunocompromised hosts, particularly patients with AIDS or hematolymphoid malignancies. MORPHOLOGYThefungus,a5-to10-µmyeast,hasathick,gelatinouscapsuleandreproducesbybudding(see Fig.13.42D ).UnlikeinCandida infections,however,pseudohyphalortruehyphalformsarenotseen.Identificationofthecapsuleisakeydiagnosticclue.InroutineH&Estains,thecapsuleisnotdirectlyvisible,butoftenaclear“halo”representingtheareaoccupiedbythecapsulecanbeseensurroundingtheindividualfungi.Indiainkorperiodicacid–Schiffstainingeffectivelyhighlightsthefungus.Thecapsularpolysaccharideantigenisthesubstrateforthecryptococcallatexagglutinationassay,whichispositiveinmorethan95%ofpatientsinfectedwiththeorganism.


Pathology_Robbins

Pathology_Robbins. Cryptococcosis usually manifests as pulmonary, central nervous system, or disseminated disease. Cryptococcus is most likely to be acquired by inhalation of aerosolized contaminated soil or bird droppings. The fungus initially localizes in the lungs and then disseminates to other sites, particularly the meninges. Sites of involvement are marked by a variable tissue response, which ranges from florid proliferation of gelatinous organisms with a minimal or absent inflammatory cell infiltrate (in immunodeficient hosts) to a granulomatous reaction (in the more reactive host). In the central nervous system these fungi grow in gelatinous masses within the meninges or expand the perivascular Virchow-Robin spaces, producing so-called “soap-bubble lesions.” http://ebooksmedicine.net The Opportunistic Molds


Pathology_Robbins

Pathology_Robbins. The Opportunistic Molds Mucormycosis and invasive aspergillosis are uncommon infections that are almost always limited to immunocompromised hosts, particularly those with hematolymphoid malignancies and profound neutropenia, those undergoing corticosteroid therapy, or following hematopoietic stem cell transplant recipients. MORPHOLOGYMucormycosisiscausedbytheclassoffungiknownasZygomycetes.Rhizopus andMucor arethetwofungiofmedicalimportancewithintheZygomycetesclass.Theirhyphaearenonseptate andbranchatrightangles;bycontrast,thehyphaeofAspergillus organismsareseptate andbranchatmoreacuteangles(see Fig.13.42C ).BothzygomycetesandAspergillus causeanondistinctive,suppurative,sometimesgranulomatousreactionwithapredilection for invading blood vessel walls, causing hemorrahage, vascular necrosis and infarction (see Fig.13.42B


Pathology_Robbins

Pathology_Robbins. Fig.13.42B In rhinocerebral and pulmonary mucormycosis, zygomycetes have a propensity to colonize the nasal cavity or sinuses and then spread by direct extension into the brain, orbit, and other head and neck structures. Patients with diabetic ketoacidosis are most likely to develop a fulminant invasive form of rhinocerebral mucormycosis. Pulmonary disease can be localized (e.g., cavitary lesions) or may manifest radiologically with diffuse “miliary” involvement. Invasive aspergillosis preferentially localizes to the lungs, and infection most often manifests as a necrotizing pneumonia (see Fig. 13.42B ). Systemic dissemination, especially to the brain, is a complication that is often fatal. Allergic bronchopulmonary aspergillosis occurs in patients with asthma who develop an exacerbation of symptoms caused by a type I hypersensitivity against the fungus growing in the bronchi. Such patients often have circulating IgE antibodies against Aspergillus and peripheral eosinophilia.


Pathology_Robbins

Pathology_Robbins. Aspergilloma (“fungus ball”) formation occurs by fungal colonization of preexisting pulmonary cavities (e.g., dilated bronchi or lung cysts, posttuberculosis cavitary lesions). These masses may act as ball valves to occlude the cavity, thereby predisposing the patient to infection and hemoptysis. Pulmonary disease continues to be the leading contributor to morbidity and mortality in HIV-infected individuals. Although the use of potent anti-retroviral agents and effective chemoprophylaxis has markedly decreased the incidence and has improved outcomes, the plethora of entities involved makes diagnosis and treatment a distinct challenge.


Pathology_Robbins

Pathology_Robbins. Despite the emphasis on “opportunistic” infections, it should be recognized that bacterial lower-respiratory tract infection caused by the “usual” pathogens is exceedingly common in HIV infection. The implicated organisms include S. pneumoniae, S. aureus, H. influenzae, and gram-negative rods. Bacterial pneumonias in HIV-infected individuals are more common, more severe, and more often associated with bacteremia than in those without HIV infection. Not all pulmonary infiltrates in HIV-infected individuals are infectious. A host of noninfectious diseases, including Kaposi sarcoma (Chapters 5 and 10), pulmonary non-Hodgkin lymphoma (Chapter 12), and primary lung cancer, occur with increased frequency and must be excluded.


Pathology_Robbins

Pathology_Robbins. The CD4+ T cell count often is useful in narrowing the differential diagnosis. As a rule of thumb, bacterial and tubercular infections occur with mildly suppressed CD4+ counts (more than 200 cells/µL); Pneumocystis pneumonia usually occurs at CD4+ T cell counts below 200 cells/µL, while CMV and M. avium complex infections are uncommon until the very late stages of the disease (CD4+ T cell counts below 50 cells/µL). Finally, an important point is that pulmonary disease in HIV-infected individuals may result from more than one cause, and that even common pathogens may be responsible for disease with atypical manifestations.


Pathology_Robbins

Pathology_Robbins. Roughly 95% of primary lung tumors are carcinomas; the remaining 5% span a miscellaneous group that includes carcinoids, mesenchymal malignancies (e.g., fibrosarcomas, leiomyomas), lymphomas, and a few benign lesions. The most common benign tumor is a spherical, small (1 to 4 cm), discrete “hamartoma” that often shows up as a so-called “coin lesion” on chest imaging. It consists mainly of mature cartilage admixed with fat, fibrous tissue, and blood vessels in various proportions. Clonal cytogenetic abnormalities have been demonstrated, indicating that it is actually a benign neoplasm and that the name hamartoma (which implies a developmental anomaly) is a misnomer.


Pathology_Robbins

Pathology_Robbins. Carcinoma of the lung is the most important cause of cancer-related deaths in industrialized countries. It has long held this position among males in the United States, accounting for about one-third of cancer deaths in men, and has become the leading cause of cancer deaths in women as well. American Cancer Society estimates for 2016 include approximately 221,200 new cases of lung cancer and 158,040 deaths. The incidence among males is gradually decreasing, but it continues to increase among females, with more women dying each year from lung cancer than from breast cancers since 1987. These sobering http://ebooksmedicine.net Table 13.6 Histologic Classification of Malignant Epithelial Lung Tumors (2015 WHO Classification, Simplified Version)


Pathology_Robbins

Pathology_Robbins. Table 13.6 Histologic Classification of Malignant Epithelial Lung Tumors (2015 WHO Classification, Simplified Version) AdenocarcinomaAcinar,papillary,micropapillary,solid,lepidicpredominant,mucinous statistics reflect the fact that the incidence of smoking in women increased markedly over the past half century. The peak incidence of lung cancer is in individuals in their fifties and sixties. At diagnosis, more than 50% of patients already have distant metastases, while an additional one-fourth have disease in the regional lymph nodes. The prognosis remains dismal: the 5-year survival rate for all stages of lung cancer combined is about 16%, a figure that has not changed much over the last 35 years; even with disease localized to the lung, the 5-year survival rate is only 45%. The four major histologic types of carcinomas of the lung are adenocarcinoma, squamous cell carcinoma, small cell carcinoma (a subtype of neuroendocrine carcinoma), and large cell carcinoma (


Pathology_Robbins

Pathology_Robbins. The four major histologic types of carcinomas of the lung are adenocarcinoma, squamous cell carcinoma, small cell carcinoma (a subtype of neuroendocrine carcinoma), and large cell carcinoma ( Table 13.6 ). In some cases, there is a combination of histologic patterns (e.g., small cell carcinoma and adenocarcinoma). Squamous cell and small cell carcinomas have the strongest association with smoking, but there is also an association with adenocarcinoma. In fact, possibly because of changes in smoking patterns in the United States, adenocarcinoma has replaced squamous cell carcinoma as the most common primary lung tumor in recent years. Adenocarcinomas also are by far the most common primary tumors arising in women, in never-smokers, and in individuals younger than 45 years of age.


Pathology_Robbins

Pathology_Robbins. Until recently, carcinomas of the lung were classified into two broad groups: small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC), the latter including adenocarcinoma, squamous and large cell carcinoma, and large cell neuroendocrine carcinomas. This classification has been recently replaced by a 2015 World Health Organization classification (a simplified version of which is shown in Table 13.6). The reason for this historic division is that virtually all SCLCs have metastasized by the time of diagnosis. Therefore, they are best treated with systemic chemotherapy, with or without radiation therapy. By contrast, NSCLCs are more likely to be resectable and usually respond poorly to conventional chemotherapy. However, therapies are now available that target specific oncoproteins that are found in a subset of NSCLC, mainly adenocarcinomas but also squamous cell carcinomas. Thus, if adequate tissue is available, NSCLC is subjected to molecular analysis to determine if


Pathology_Robbins

Pathology_Robbins. that are found in a subset of NSCLC, mainly adenocarcinomas but also squamous cell carcinomas. Thus, if adequate tissue is available, NSCLC is subjected to molecular analysis to determine if targeted therapy is warranted. In addition, new immunotherapy approaches (checkpoint blockade, discussed in Chapter 6) are now approved for a subset of NSCLC and are being tested in SCLC.


Pathology_Robbins

Pathology_Robbins. Like other cancers, smoking-related carcinomas of the lung arise by a stepwise accumulation of driver mutations that result in transformation of benign progenitor cells in the lung into neoplastic cells possessing all of the hallmarks of cancer. The sequence of molecular changes is not random but tends to follow a sequence that parallels the histologic progression toward cancer. Thus, inactivation of the putative tumor suppressor genes located on the short arm of chromosome 3 (3p) is a very common early event, whereas mutations in the TP53 tumor suppressor gene and the KRAS oncogene occur relatively late. Certain genetic changes, such as loss of chromosomal material on 3p, are found even in benign bronchial epithelium of smokers without lung cancer, suggesting that large areas of the respiratory mucosa are mutagenized by exposure to carcinogens (“field effect”). On this fertile soil, those cells that accumulate additional mutations ultimately develop into cancer.


Pathology_Robbins

Pathology_Robbins. A subset of adenocarcinomas (about 10% in whites and 30% in Asians), particularly those arising in nonsmoking women, harbor mutations that activate the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase that stimulates downstream pro-growth pathways involving RAS, PI3K, and other signaling molecules. Of note, these tumors are sensitive to drugs that inhibit EGFR signaling, although the response is often short-lived. EGFR and KRAS mutations (in 30% of adenocarcinomas) are mutually exclusive, as might be expected since KRAS lies downstream of EGFR. Other “targetable” mutations have been described in a low frequency of adenocarcinomas (4% to 6% overall), including mutations that activate other tyrosine kinases, including ALK, ROS1, HER2, or c-MET. Each of these kinases is optimally targeted by a different drug, which has spurred a new era of “personalized” lung cancer treatment, in which the genetics of the tumor guide therapy.


Pathology_Robbins

Pathology_Robbins. With regard to carcinogenic influences, there is strong evidence that cigarette smoking and, to a much lesser extent, other environmental carcinogens are the main culprits responsible for the mutations that give rise to lung cancers. About 90% of lung cancers occur in active smokers or those who stopped recently. Moreover, there is a nearly linear correlation between the frequency of lung cancer and pack-years of cigarette smoking. The increased risk is 60 times greater among habitual heavy smokers (two packs a day for 20 years) than among nonsmokers. For unclear reasons, women are more susceptibile to carcinogens in tobacco smoke than men. Although cessation of smoking decreases the risk for developing lung cancer over time, it never returns to baseline levels, and genetic changes that predate the full development of lung cancer can persist for many years in the bronchial epithelium of former smokers. Passive smoking (proximity to cigarette smokers) also increases the risk for


Pathology_Robbins

Pathology_Robbins. that predate the full development of lung cancer can persist for many years in the bronchial epithelium of former smokers. Passive smoking (proximity to cigarette smokers) also increases the risk for developing lung cancer, as does smoking of pipes and cigars, albeit only modestly.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Other carcinogenic influences associated with occupational exposures act in concert with smoking and may sometimes be responsible for lung cancer all by themselves; examples include work in uranium mines, work with asbestos, and inhalation of dusts containing arsenic, chromium, nickel, or vinyl chloride. A cardinal example of a synergistic interaction between two carcinogens is found in asbestos and tobacco smoking. Exposure to asbestos in nonsmokers increases the risk for developing lung cancer 5-fold, whereas in heavy smokers exposed to asbestos the risk is elevated approximately 55-fold.


Pathology_Robbins

Pathology_Robbins. Even though smoking and other environmental influences are paramount in the causation of lung cancer, not all individuals exposed to tobacco smoke develop cancer (about 11% of heavy smokers do). It is very likely that the mutagenic effect of carcinogens is modified by hereditary (genetic) factors. Recall that many chemicals require metabolic activation via the P-450 monooxygenase enzyme system for conversion into ultimate carcinogens (Chapter 6). Individuals with certain polymorphisms involving the P-450 genes have an increased capacity to activate procarcinogens found cigarette smoke, and are thus exposed to larger doses of carcinogens and incur a greater risk of developing lung cancer. Similarly, individuals whose peripheral blood lymphocytes undergo chromosomal breakages after exposure to tobacco-related carcinogens (mutagen sensitive genotype) have a greater than 10-fold increased risk for developing lung cancer over control subjects.


Pathology_Robbins

Pathology_Robbins. By analogy to the adenoma–carcinoma sequence in the colon, it is proposed that some invasive adenocarcinomas of the lung arise through an atypical adenomatous hyperplasia–adenocarcinoma in situ–invasive adenocarcinoma sequence. Studies of lung injury models in mice have identified a population of multipotent cells at the bronchioloalveolar duct junction, termed bronchioalveolar stem cells (BASCs). After lung injury, multipotent BASCs proliferate and replenish the normal cell types (bronchiolar Clara cells and alveolar cells) found in this location, thereby facilitating epithelial regeneration. It is postulated that BASCs incur the initiating hit (for example, a somatic KRAS mutation) that enables these cells to escape normal “checkpoint” mechanisms and results in pulmonary adenocarcinomas.


Pathology_Robbins

Pathology_Robbins. The sequential changes leading development of squamous cell carcinomas are well documented; there is a linear correlation between the intensity of exposure to cigarette smoke and the appearance of ever more worrisome epithelial changes that begin with rather innocuous basal cell hyperplasia and squamous metaplasia and progress to squamous dysplasia and carcinoma in situ, before culminating in invasive cancer.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Fig.13.43B ).Thetumorcells,whichmaybenonmucinous,mucinous,ormixed,growinamonolayeralongthealveolarsepta,whichserveasascaffold.Bydefinition,AISdoesnotdemonstratedestructionofalveolararchitectureorstromalinvasionwithdesmoplasia,featuresthatwouldmeritthediagnosisofinvasiveadenocarcinoma. Squamous cell carcinomas aremorecommoninmenthaninwomenandarecloselycorrelatedwithasmokinghistory;theytendtoarise centrally in major bronchi andeventuallyspreadtolocalhilarnodes,buttheydisseminateoutsidethethoraxlaterthandootherhistologictypes.Largelesionsmayundergocentralnecrosis,givingrisetocavitation. Thepreneoplasticlesionsthatantedate,andusuallyaccompany,invasivesquamouscellcarcinomaarewellcharacterized.Squamouscellcarcinomasoftenareprecededbythedevelopment,overyears,ofsquamous metaplasia or dysplasia inthebronchialepithelium,whichthentransformstocarcinoma in situ, aphasethatmaylastforseveralyears(


Pathology_Robbins

Pathology_Robbins. Carcinomas of the lung are insidious lesions that in many cases have spread so as to be unresectable before they produce symptoms. In some instances chronic cough and http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 13.44 Precursorlesionsofsquamouscellcarcinomas.(AtoC)Someoftheearliest(and“mild”)changesinsmoking-damagedrespiratoryepitheliumincludegobletcellhyperplasia(A),basalcell(orreservecell)hyperplasia(B),andsquamousmetaplasia(C).(D)Moreominouschangesincludetheappearanceofsquamousdysplasia,characterizedbythepresenceofdisorderedsquamousepithelium,withlossofnuclearpolarity,nuclearhyperchromasia,pleomorphism,andmitoticfigures.(EandF)Squamousdysplasiamay,inturn,progressthroughthestagesofmild,moderate,andseveredysplasia.Carcinomainsitu(CIS) (E)isthestagethatimmediatelyprecedesinvasivesquamouscellcarcinoma(F).ApartfromthelackofbasementmembranedisruptioninCIS,thecytologicfeaturesofCISaresimilartothoseinfrankcarcinoma.(AtoE,Courtesy of Dr. Adi Gazdar, Department of Pathology, University of Texas Southwestern Medical School, Dallas,Texas. F,Reproduced with permission from Travis WD,Colby TV,Corrin B,et al,editors: WorldHealthOrganizationhistologicaltypingoflungandpleuraltumors,Heidelberg, 1999,


Pathology_Robbins

Pathology_Robbins. Medical School, Dallas,Texas. F,Reproduced with permission from Travis WD,Colby TV,Corrin B,et al,editors: WorldHealthOrganizationhistologicaltypingoflungandpleuraltumors,Heidelberg, 1999, Springer.)


Pathology_Robbins

Pathology_Robbins. Fig. 13.45 Squamouscellcarcinoma.(A)Squamouscellcarcinomaappearingasacentral(hilar)massthatisinvadingcontiguousparenchyma.(B)Well-differentiatedsquamouscellcarcinoma,showingkeratinizationandpearls. http://ebooksmedicine.net Fig. 13.46 Smallcellcarcinomawithsmalldeeplybasophiliccellsandareasofnecrosis(top left). Notebasophilicstainingofvascularwallsduetoencrus-tationbyDNAfromnecrotictumorcells(Azzopardieffect).


Pathology_Robbins

Pathology_Robbins. Fig. 13.46 Smallcellcarcinomawithsmalldeeplybasophiliccellsandareasofnecrosis(top left). Notebasophilicstainingofvascularwallsduetoencrus-tationbyDNAfromnecrotictumorcells(Azzopardieffect). expectoration call attention to localized, resectable disease. By the time other symptoms, such as hoarseness, chest pain, superior vena cava syndrome, pericardial or pleural effusion, or persistent segmental atelectasis or pneumonitis make their appearance, the prognosis is poor. Too often, the tumor presents with symptoms caused by metastatic spread to sites such as the brain (mental or neurologic changes), liver (hepatomegaly), or bones (pain). Although the adrenal glands may be nearly obliterated by metastatic disease, adrenal insufficiency (Addison disease) is uncommon, because islands of cortical cells sufficient to maintain adrenal function usually persist.


Pathology_Robbins

Pathology_Robbins. Overall, squamous cell carcinoma and adenocarcinoma carry a more favorable prognosis than SCLC. When squamous cell carcinomas or adenocarcinomas are detected before metastasis or local spread (as in high-risk patients undergoing surveillance imaging), cure is possible by lobectomy or pneumonectomy. Unresectable adenocarcinomas associated with targetable mutations in tyrosine kinases such as EGFR may show remarkable responses to specific inhibitors. A few of these patients have long-term remissions on the order of years, but relapse within months to a year or so is typical. Inevitably, resistant tumors are found to have new mutations that either alter the drug target themselves (e.g., an additional mutation in EGFR that prevents drug binding) or circumvent tumor dependence on the drug target. Much effort is currently being devoted to understanding the mechanisms of targeted drug resistance in order to develop strategies that prevent it from occurring. Immune checkpoint inhibitors


Pathology_Robbins

Pathology_Robbins. target. Much effort is currently being devoted to understanding the mechanisms of targeted drug resistance in order to develop strategies that prevent it from occurring. Immune checkpoint inhibitors produce responses in a subset of tumors, particularly those that are smoking related (perhaps because of a high burden of tumor


Pathology_Robbins

Pathology_Robbins. Table 13.7 Comparison of Small Cell Lung Carcinoma and Non–Small Cell Lung Carcinoma (Adenocarcinoma and Squamous Cell Carcinoma) Forexample,densecoregranulesonelectronPresentAbsentmicroscopy;expressionofchromogranin,synaptophysin,andCD56 Epithelialmembraneantigen,carcinoembryonicantigen,PresentPresentandcytokeratinintermediatefilaments EGFR mutationsAbsent~20%(adenocarcinomas,nonsmokers,women) ALK rearrangementsAbsent4%–6%adenocarcinomas,nonsmokers,oftenhavesignetringmorphology http://ebooksmedicine.net neoantigens), and represent a hopeful new avenue for therapy.


Pathology_Robbins

Pathology_Robbins. ALK rearrangementsAbsent4%–6%adenocarcinomas,nonsmokers,oftenhavesignetringmorphology http://ebooksmedicine.net neoantigens), and represent a hopeful new avenue for therapy. By contrast, the picture for SCLC unfortunately has changed little. SCLCs have invariably spread by the time they are detected, even if the primary tumor appears to be small and localized; thus, surgical resection is not a viable option. SCLCs are very sensitive to chemotherapy but invariably recur, and as of yet targeted therapies are unavailable. The median survival even with treatment remains only 1 year, and only 5% are alive at 10 years. Because these tumors have a very high mutation burden, they are likely to be immunogenic. Accordingly, immune checkpoint therapies have produced encouraging responses in patients with advanced SCLC.


Pathology_Robbins

Pathology_Robbins. In addition to the direct effects of the tumor cells, it is estimated that 3% to 10% of patients with lung cancer develop paraneoplastic syndromes (Chapter 6). These include hypercalcemia caused by secretion of a parathyroid hormone–related peptide; (2) Cushing syndrome (from increased production of adrenocorticotropic hormone); syndrome of inappropriate secretion of anti-diuretic hormone; (4) neuromuscular syndromes, including a myasthenic syndrome, peripheral neuropathy, and polymyositis; clubbing of the fingers and hypertrophic pulmonary osteoarthropathy; and (6) coagulation abnormalities, including migratory thrombophlebitis, nonbacterial endocarditis, and disseminated intravascular coagulation. Hypercalcemia most often is encountered with squamous cell neoplasms, the hematologic syndromes with adenocarcinomas, and the neurologic syndromes with small cell neoplasms, but exceptions abound.


Pathology_Robbins

Pathology_Robbins. Lungcancerscommonlycauseavarietyofparaneoplasticsyndromes. Carcinoid tumors are malignant tumors composed of cells that contain dense-core neurosecretory granules in their cytoplasm and, rarely, may secrete hormonally active polypeptides. They are best thought of a low-grade neuroendocrine carcinomas and are subclassified as typical or atypical; both are often resectable and curable. They occasionally occur as part of the multiple endocrine neoplasia syndrome (Chapter 20). Bronchial carcinoids occur in young adults (mean 40 years) and represent about 5% of all pulmonary neoplasms. MORPHOLOGYMostcarcinoidsoriginateinmainbronchiandgrowinoneoftwopatterns:(1)anobstructingpolypoid,spherical,intraluminalmass(


Pathology_Robbins

Pathology_Robbins. Fig.13.47B ).Atypical carcinoid tumorsdisplayahighermitoticrateandsmallfociofnecrosis.Thesetumorshaveahigherincidenceoflymphnodeanddistantmetastasisthantypicalcarcinoids.Unliketypicalcarcinoids,theatypicaltumorshaveTP53 mutationsin20%to40%ofcases.Typicalcarcinoid,atypicalcarcinoid,andlargecellneuroendocrineandsmallcellcarcinomacanbeviewedasacontinuumofincreasinghistologicaggressivenessandmalignantpotentialwithinthespectrumofpulmonaryneuroendocrineneoplasms. Fig. 13.47 Bronchialcarcinoid.(A)Carcinoidgrowingasaspherical,palemass(arrow) protrudingintothelumenofthebronchus.(B)Histologicappearancedemonstratingsmall,rounded,uniformnucleiandmoderatecytoplasm. (Courtesy of Dr. Thomas Krausz, Department of Pathology, University of Chicago Pritzker School of Medicine, Chicago, Illinois.) http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Most carcinoid tumors manifest with signs and symptoms related to their intraluminal growth, including cough, hemoptysis, and recurrent bronchial and pulmonary infections. Peripheral tumors are often asymptomatic and are discovered incidentally on chest radiographs. Only rarely do pulmonary carcinoids induce the carcinoid syndrome, characterized by intermittent attacks of diarrhea, flushing, and cyanosis. The reported 5and 10-year survival rates for typical carcinoids are above 85%, while these rates drop to 56% and 35%, respectively, for atypical carcinoids. Disease of the pleura usually is a complication of an underlying pulmonary disease. Secondary infections and pleural adhesions are common findings at autopsy. Important primary disorders are (1) primary intrapleural bacterial infections and (2) malignant mesothelioma, a primary neoplasm of the pleura.


Pathology_Robbins

Pathology_Robbins. Pleural effusions (fluids in the pleural space) can be either transudates or exudates. When the effusion is a transudate, the condition is termed hydrothorax. Congestive heart failure is the most common cause of bilateral hydrothorax. An exudate, characterized by protein content greater than 30 g/L and, often, inflammatory cells, suggests pleuritis. The four principal causes of pleural exudate formation are microbial invasion through either direct extension of a pulmonary infection or blood-borne seeding (suppurative pleuritis or empyema); (2) cancer (lung carcinoma, metastatic neoplasms to the lung or pleural surface, mesothelioma); pulmonary infarction; and (4) viral pleuritis. Other, less common causes of exudative pleural effusions are systemic lupus erythematosus, rheumatoid arthritis, and uremia, as well as previous thoracic surgery. Malignant effusions characteristically are large and frequently bloody (hemorrhagic pleuritis). Cytologic examination may reveal the malignant


Pathology_Robbins

Pathology_Robbins. and uremia, as well as previous thoracic surgery. Malignant effusions characteristically are large and frequently bloody (hemorrhagic pleuritis). Cytologic examination may reveal the malignant cells.


Pathology_Robbins

Pathology_Robbins. Whatever the cause, transudates and serous exudates usually are resorbed without residual effects if the inciting cause is controlled or remits. By contrast, fibrinous, hemorrhagic, and suppurative exudates may lead to fibrous organization, yielding adhesions or fibrous pleural thickenings that sometimes undergo calcification. Pneumothorax,Hemothorax,andChylothorax


Pathology_Robbins

Pathology_Robbins. Pneumothorax,Hemothorax,andChylothorax Pneumothorax refers to presence of air or other gas in the pleural sac. It may occur in young, apparently healthy adults, usually men without any known pulmonary disease (simple or spontaneous pneumothorax), or as a result of some thoracic or lung disorder (secondary pneumothorax), such as emphysema or a fractured rib. Secondary pneumothorax is the consequence of rupture of any pulmonary lesion situated close to the pleural surface that allows inspired air to gain access to the pleural cavity. Responsible pulmonary lesions include emphysema, lung abscess, tuberculosis, carcinoma, and many other, less common processes. Mechanical ventilatory support with high pressure also may trigger secondary pneumothorax.


Pathology_Robbins

Pathology_Robbins. There are several possible complications of pneumothorax. A ball-valve leak may create a tension pneumothorax that shifts the mediastinum. Compromise of the pulmonary circulation may follow and may even be fatal. If the leak seals and the lung is not reexpanded within a few weeks (either spontaneously or through medical or surgical intervention), so much scarring may occur that it can never be fully reexpanded. In these cases, serous fluid collects in the pleural cavity, creating hydropneumothorax. With prolonged collapse, the lung becomes vulnerable to infection, as does the pleural cavity when communication between it and the lung persists. Empyema is thus an important complication of pneumothorax (pyopneumothorax).


Pathology_Robbins

Pathology_Robbins. Hemothorax, the collection of whole blood (in contrast with bloody effusion) in the pleural cavity, may be a complication of a ruptured intrathoracic aortic aneurysm, an event that is almost always fatal. With hemothorax, in contrast with bloody pleural effusions, the blood clots within the pleural cavity. Chylothorax is a pleural collection of a milky lymphatic fluid containing microglobules of lipid. The total volume of fluid may not be large, but chylothorax is always significant because it implies obstruction of the major lymph ducts, usually by an intrathoracic cancer (e.g., a primary or secondary mediastinal neoplasm, such as a lymphoma).


Pathology_Robbins

Pathology_Robbins. Malignant mesothelioma has assumed great importance because it is highly related to exposure to airborne asbestos. It is a rare cancer of mesothelial cells, usually arising in the parietal or visceral pleura; it also occurs much less commonly in the peritoneum and pericardium. Approximately 80% to 90% of individuals with this cancer have a history of exposure to asbestos. Those who work directly with asbestos (shipyard workers, miners, insulators) are at greatest risk, but malignant mesotheliomas have appeared in individuals whose only exposure was living in proximity to an asbestos factory or being a relative of an asbestos worker. The latent period for developing malignant mesothelioma after the initial exposure is long, often 25 to 40 years, suggesting that causative driver mutations are acquired slowly, over a long period of time. As stated earlier, the combination of cigarette smoking and asbestos exposure greatly increases the risk for developing lung carcinoma, but it does not


Pathology_Robbins

Pathology_Robbins. acquired slowly, over a long period of time. As stated earlier, the combination of cigarette smoking and asbestos exposure greatly increases the risk for developing lung carcinoma, but it does not increase the risk for developing malignant mesothelioma.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Once inhaled, asbestos fibers remain in the body for life. Thus, the lifetime risk after exposure does not diminish over time (unlike with smoking, in which the risk decreases after cessation). It has been hypothesized that asbestos fibers preferentially gather near the mesothelial cell layer, where they generate reactive oxygen species that cause DNA damage and mutations. Sequencing of mesothelioma genomes has revealed multiple driver mutations, many of which cluster in pathways involved in DNA repair, cell cycle control, and growth factor signaling. Of interest, one of the most commonly mutated genes in sporadic mesothelioma, BAP1, encodes a tumor suppressor involved in DNA repair that also is affected by germ line mutations in families showing a high incidence of mesothelioma.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYMalignantmesotheliomasareoftenprecededbyextensivepleural fibrosis and plaque formation, readilyseenoncomputedtomographyscans.Thesetumorsbegininalocalizedareaandovertimespreadwidely,eitherbycontiguousgrowthorbydiffuseseedingofpleuralsurfaces.Atautopsy,theaffectedlung typically is ensheathed by a layer of yellow-white, firm, variably gelatinous tumor thatobliteratesthepleuralspace(


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Acute infections of the upper respiratory tract are among the most common afflictions of humans, most frequently manifesting as the “common cold.” The clinical features are well known: nasal congestion accompanied by watery discharge; sneezing; scratchy, dry sore throat; and a slight increase in temperature that is more pronounced in young children. The most common pathogens are rhinoviruses, but coronaviruses, respiratory syncytial viruses, parainfluenza and influenza viruses, adenoviruses, enteroviruses, and sometimes even group A β-hemolytic streptococci have been implicated. In a significant number of cases (around 40%), the cause cannot be determined; perhaps new viruses will be discovered. Most of these infections occur in the fall and winter and are self-limiting (usually lasting for 1 week or less). In a minority of cases, colds may be complicated by the development of bacterial otitis media or sinusitis.


Pathology_Robbins

Pathology_Robbins. In addition to the common cold, infections of the upper-respiratory tract may produce signs and symptoms localized to the pharynx, epiglottis, or larynx. Acute pharyngitis, manifesting as a sore throat, may be caused by a host of agents. Mild pharyngitis with minimal physical findings frequently accompanies a cold and is the most common form of pharyngitis. More severe forms with tonsillitis, associated with marked hyperemia and exudates, occur with β-hemolytic streptococcal and adenovirus infections. Streptococcal tonsillitis is important to recognize and treat early, because of the associated potential for development of peritonsillar abscesses (“quinsy”) or for progression to poststreptococcal glomerulonephritis and acute rheumatic fever. Coxsackievirus A infection may produce pharyngeal vesicles and ulcers (herpangina). Infectious mononucleosis, caused by Epstein-Barr virus (EBV), is an important cause of pharyngitis and bears the moniker of “kissing disease”—reflecting a common


Pathology_Robbins

Pathology_Robbins. vesicles and ulcers (herpangina). Infectious mononucleosis, caused by Epstein-Barr virus (EBV), is an important cause of pharyngitis and bears the moniker of “kissing disease”—reflecting a common mode of transmission in previously nonexposed individuals.


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Pathology_Robbins. Acute bacterial epiglottitis is a syndrome predominantly affecting young children who have an infection of the epiglottis caused by H. influenzae, in which pain and airway obstruction are the major findings. The onset is abrupt. Failure to appreciate the need to maintain an open airway for a child with this condition can have fatal consequences. The advent of vaccination against H. influenzae has greatly decreased the incidence of this disease.


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Pathology_Robbins. Acute laryngitis can result from inhalation of irritants or may be caused by allergic reactions. It also may be caused by agents that produce the common cold and usually involve the pharynx and nasal passages as well as the larynx. Brief mention should be made of two uncommon but important forms of laryngitis: tuberculous and diphtheritic. The former is almost always a consequence of protracted active tuberculosis, during which infected sputum is coughed up. Diphtheritic laryngitis has fortunately become uncommon because of the widespread immunization of young children against diphtheria toxin. After it is inhaled, Corynebacterium diphtheriae implants on the mucosa of the upper airways, where it elaborates a powerful exotoxin that causes necrosis of the mucosal epithelium, accompanied by a dense fibrinopurulent exudate, to create the classic superficial, dirty-gray pseudomembrane of diphtheria. The major hazards of this infection are sloughing and aspiration of the pseudomembrane


Pathology_Robbins

Pathology_Robbins. by a dense fibrinopurulent exudate, to create the classic superficial, dirty-gray pseudomembrane of diphtheria. The major hazards of this infection are sloughing and aspiration of the pseudomembrane (causing obstruction of major airways) and absorption of bacterial exotoxins (producing myocarditis, peripheral neuropathy, or other tissue injury).


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net In children, parainfluenza virus is the most common cause of laryngotracheobronchitis, more commonly known as croup, but other agents such as respiratory syncytial virus also may precipitate this condition. Although self-limited, croup may cause frightening inspiratory stridor and harsh, persistent cough. In occasional cases, the laryngeal inflammatory reaction may narrow the airway sufficiently to result in respiratory failure. Viral infections in the upper-respiratory tract predispose the patient to secondary bacterial infection, particularly by staphylococci, streptococci, and H. influenzae.


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Pathology_Robbins. Nasopharyngeal carcinoma is a rare neoplasm that merits comment because of (1) the strong epidemiologic links to EBV and (2) the high frequency of this cancer among the Chinese, which raises the possibility of viral oncogenesis on a background of genetic susceptibility. It is thought that EBV infects the host by first replicating in the nasopharyngeal epithelium and then infecting nearby tonsillar B lymphocytes. In some individuals, this leads to transformation of the epithelial cells. Unlike the case with Burkitt lymphoma (Chapter 12), another EBV-associated tumor, the EBV genome is found in virtually all nasopharyngeal carcinomas, including those that occur outside the endemic areas in Asia.


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Pathology_Robbins. The three histologic variants are keratinizing squamous cell carcinoma, nonkeratinizing squamous cell carcinoma, and undifferentiated carcinoma; the last-mentioned is the most common and the one most closely linked with EBV. The undifferentiated neoplasm is characterized by large epithelial cells with indistinct cell borders (reflecting “syncytial” growth) and prominent eosinophilic nucleoli. In nasopharyngeal carcinomas, the tumor cells are often accompanied by a striking influx of T cells, which are believed to be responding to viral antigens. Nasopharyngeal carcinomas invade locally, spread to cervical lymph nodes, and then metastasize to distant sites. They tend to be radiosensitive, and 5-year survival rates of 50% are reported, even for patients with advanced cancers. Responses to immune checkpoint inhibitors also have been reported, providing a new therapeutic strategy for tumors that do not respond to conventional therapy.


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Pathology_Robbins. A variety of nonneoplastic, benign, and malignant neoplasms of epithelial and mesenchymal origin may arise in the larynx, but only vocal cord nodules, papillomas, and squamous cell carcinomas are sufficiently common to merit comment. In all of these conditions, the most common presenting feature is hoarseness. Vocal cord nodules (“polyps”) are smooth, hemispherical protrusions (usually <0.5 cm in diameter) located, most often, on the true vocal cords. The nodules are composed of fibrous tissue and covered by stratified squamous mucosa that usually is intact but can be ulcerated from contact trauma with the other vocal cord. These lesions occur chiefly in heavy smokers or singers (singer’s nodes), suggesting that they are the result of chronic irritation or over use.


Pathology_Robbins

Pathology_Robbins. Laryngeal papilloma or squamous papilloma of the larynx is a benign neoplasm, usually located on the true vocal cords, that forms a soft, raspberry like excrescence rarely more than 1 cm in diameter. Histologically, it consists of multiple slender, fingerlike projections supported by central fibrovascular cores and covered by an orderly, typical, stratified squamous epithelium. When the papilloma is on the free edge of the vocal cord, trauma may lead to ulceration that can be accompanied by hemoptysis.


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Pathology_Robbins. Papillomas usually are single in adults but often are multiple in children, in whom the condition is referred to as recurrent respiratory papillomatosis (RRP), since they typically tend to recur after excision. These lesions are caused by human papillomavirus (HPV) types 6 and 11 and often spontaneously regress at puberty. Cancerous transformation is rare. The most likely cause for their occurrence in children is vertical transmission from an infected mother during delivery. Therefore, the recent availability of an HPV vaccine that can protect women of reproductive age against infection with types 6 and 11 provides an opportunity for prevention of RRP in children. Carcinoma of the Larynx


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Pathology_Robbins. Carcinoma of the Larynx Carcinoma of the larynx represents only 2% of all cancers. It most commonly occurs after 40 years of age and is more common in men than in women (with a gender ratio of 7:1). Environmental influences are very important in its causation; nearly all cases occur in smokers, and alcohol and asbestos exposure also may play roles. Human papillomavirus sequences have been detected in about 15% of tumors, which tend to have a better prognosis than other carcinomas. About 95% of laryngeal cancers are typical squamous cell carcinomas. Rarely, adenocarcinomas are seen, presumably arising from mucous glands. The tumor develops directly on the vocal cords (glottic tumors) in 60% to 75% of cases, but it also may arise above the cords (supraglottic; 25% to 40%) or below the cords (subglottic; <5%). Squamous cell carcinomas of the larynx begin as in situ lesions that later appear as pearly gray, wrinkled plaques on the mucosal surface, ultimately ulcerating and fungating (


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Pathology_Robbins. Fig. 13.49 ). The glottic tumors are usually keratinizing, well to moderately differentiated squamous cell carcinomas. As expected with lesions arising from recurrent exposure to environmental carcinogens, adjacent mucosa may demonstrate squamous cell hyperplasia with foci of dysplasia, or even carcinoma in situ. http://ebooksmedicine.net Fig. 13.49 Laryngealsquamouscellcarcinoma(arrow) arisinginasupraglotticlocation(abovethetruevocalcord).


Pathology_Robbins

Pathology_Robbins. Carcinoma of the larynx manifests clinically with persistent hoarseness. The location of the tumor within the larynx has a significant bearing on prognosis. For example, about 90% of glottic tumors are confined to the larynx at diagnosis. First, as a result of interference with vocal cord mobility, they develop symptoms early in the course of disease; second, the glottic region has a sparse lymphatic supply, and spread beyond the larynx is uncommon. By contrast, the supraglottic larynx is rich in lymphatic spaces, and nearly one-third of these tumors metastasize to regional (cervical) lymph nodes. The subglottic tumors tend to remain clinically quiescent, usually manifesting as advanced disease. With surgery, radiation therapy, or combination treatment, many patients can be cured, but about one-third die of the disease. The usual cause of death is widespread metastases and cachexia, sometimes complicated by pulmonary infection.


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Pathology_Robbins. Armanios M, Blackburn EH: The telomere syndromes, Nat Rev Genet 13:693, 2013. [A review of the role of telomere dysfunction in idiopathic pulmonary fibrosis and other diseases.] Ashley V, Harris CC: Biomarker development in the precision medicine era: lung cancer as a case study, Nat Rev Cancer 16:525, 2016. [A discussion of the impact of targeted therapy on the diagnosis and treatment of lung cancer.] Best DH, Austin ED, Chung WK, et al: Genetics of pulmonary hypertension, Curr Opin Cardiol 29:520, 2014. [A description of recent advances in genetic and molecular mechanisms in pulmonary hypertension.] Bittar HET, Yousem SA, Wenzel SE: Pathobiology of severe asthma, Annu Rev Pathol 10:511, 2015. [A review addressing the pathobiology of severe asthma, inflammatory cells and pathways, the structural and remodeling changes, and targeted therapy.]


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Pathology_Robbins. Boyton RJ, Altmann DM: Bronchiectasis: current concepts in pathogenesis, immunology, and microbiology, Annu Rev Pathol 11:523, 2016. [A review of bronchiectasis pathogenesis, focusing on interactions between host immunity and microorganisms.] Carmona EM, Kalra S, Ryu JH: Pulmonary sarcoidosis: diagnosis and treatment, Mayo Clin Proc 91:1946, 2016. [A concise current review of a still enigmatic disorder.] Hogg JC, Timens W: The pathology of chronic obstructive pulmonary disease, Annu Rev Pathol 4:435, 2009. [A still relevant review on the pathogenesis of COPD, stressing the roles of inflammation, tissue repair and remodeling, and small airway disease in COPD.] Lacasse Y, Girard M, Cormier Y: Recent advances in hypersensitivity pneumonitis, Chest 142:208, 2012. [This review summarizes clinical and pathophysiologic aspects of hypersensitivity pneumonitis.]


Pathology_Robbins

Pathology_Robbins. Lacasse Y, Girard M, Cormier Y: Recent advances in hypersensitivity pneumonitis, Chest 142:208, 2012. [This review summarizes clinical and pathophysiologic aspects of hypersensitivity pneumonitis.] Leung CC, Yu ITS, Chen W: Silicosis, Lancet 379:2008, 2012. [A review the pathogenesis of silicosis and its relationship to tuberculosis and lung cancer.] Meyers DA, Bleecker ER, Holloway JW, et al: Asthma genetics and personalized medicine, Lancet, Respir Med 2:405, 2014. [A review of genetic markers that reveal possible triggers and treatment strategies for asthma.] Orme IM, Robinson RT, Cooper AM: The balance between protective and pathogenic immune responses in the TB-infected lung, Nat Immunol 16:57, 2015. [A discussion of the delicate balance between host response, TB, immunity, and tissue damage.] Postma DS, Rabe KF: The asthma-COPD overlap syndrome, N Engl J Med 373:1241, 2015. [A review comparing and contrasting COPD and asthma, highlighting shared and distinctive features.]


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Pathology_Robbins. Postma DS, Rabe KF: The asthma-COPD overlap syndrome, N Engl J Med 373:1241, 2015. [A review comparing and contrasting COPD and asthma, highlighting shared and distinctive features.] Semenova EA, Nagel R, Berns A: Origins, genetic landscape, and emerging therapies of small cell lung cancer, Genes Dev 29:1447, 2015. [A review of the pathobiology and new treatment strategies in small cell lung cancer.] Simonneau G, Gatzoulis MA, Adatia I, et al: Updated clinical classification of pulmonary hypertension, J Am Coll Cardiol 62(SupplD):34, 2013. [A clinical classification based on pathologic and hemodynamic characteristics and therapeutic approaches.] Swanton C, Govinan R: Clinical implications of genomic discoveries in lung cancer, N Engl J Med 374:1864, 2016. [A review focused on how http://ebooksmedicine.net genomic insights into the pathogenesis of each major subtype of lung cancer have changed the clinical approach to patients with the disease.]


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Pathology_Robbins. Sweatt AJ, Levitt JE: Evolving epidemiology and definitions of the acute respiratory distress syndrome and early acute lung injury, Clin Chest Med 35:609, 2014. [A discussion of the impact of classification of ARDS into mild, moderate, and severe, with better definitions, prediction of mortality, and prevention and treatment strategies.] Travis WD, Brambilla E, Nicholson AG, et al: The 2015 World Health Organization Classification of Lung Tumors: impact of genetic, clinical and radiologic advances since the 2004 classification, J Thorac Oncol 6:244, 2011. [The latest classification of lung tumors that incorporates updated clinical, radiologic, histologic, molecular, and prognostic features.]


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Pathology_Robbins. Thorac Oncol 6:244, 2011. [The latest classification of lung tumors that incorporates updated clinical, radiologic, histologic, molecular, and prognostic features.] Travis WD, Costabel U, Hansell DM, et al: ATS/ERS Committee on Idiopathic Interstitial Pneumonias. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias, Am J Respir Crit Care Med 188:733, 2013. [An updated classification of interstitial lung diseases, which is used widely by clinicians, radiologists, and pathologists.] http://ebooksmedicine.net studentconsult.com Mechanisms of Glomerular Injury and ChronicKidneyDisease Neoplasms of the Kidney


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Pathology_Robbins. The kidney is a structurally complex organ that has evolved to carry out a number of important functions: excretion of the waste products of metabolism, regulation of body water and salt, maintenance of acid balance, and secretion of a variety of hormones and prostaglandins. Diseases of the kidney are as complex as its structure, but their study is facilitated by dividing them into those that affect its four components: glomeruli, tubules, interstitium, and blood vessels. This traditional approach is useful because the early manifestations of diseases that affect each of these compartments tend to be distinctive. Furthermore, some structures seem to be more vulnerable to specific forms of renal injury; for example, glomerular diseases are often immunologically mediated, whereas tubular and interstitial disorders are more likely to be caused by toxic or infectious agents. However, some disorders affect more than one structure, and functional interdependence of structures in the kidney


Pathology_Robbins

Pathology_Robbins. interstitial disorders are more likely to be caused by toxic or infectious agents. However, some disorders affect more than one structure, and functional interdependence of structures in the kidney means that damage to one component almost always affects the others. Thus, severe glomerular damage impairs blood flow through the peritubular vascular system; conversely, tubular destruction, by increasing intraglomerular pressure and inducing the production of cytokines and chemokines, may lead to glomerular sclerosis. When chronic kidney disease progresses to its most advanced stage, so-called end-stage renal disease, all four compartments of the kidney are usually damaged. Due to the large functional reserve capacity of the kidney, early signs of kidney disease are often missed, and much renal damage may occur before renal dysfunction becomes clinically apparent. Before discussing individual diseases of the kidney, we describe clinical manifestations of kidney diseases shared by several


Pathology_Robbins

Pathology_Robbins. damage may occur before renal dysfunction becomes clinically apparent. Before discussing individual diseases of the kidney, we describe clinical manifestations of kidney diseases shared by several disorders.


Pathology_Robbins

Pathology_Robbins. The clinical manifestations of renal disease can be grouped into reasonably well-defined syndromes. Some are peculiar to glomerular diseases, and others are shared by several renal disorders. Before we list the syndromes, a few terms must be defined. Azotemia is an elevation of blood urea nitrogen and creatinine levels and usually reflects a decreased glomerular filtration rate (GFR). GFR may be decreased as a consequence of intrinsic renal disease or extra-renal causes. Prerenal azotemia is encountered when there is hypoperfusion of the kidneys (usually due to reduced extracellular fluid volume). This decreases GFR in the absence of renal parenchymal damage and is usually reversible if the hypoperfusion is corrected in time. Postrenal azotemia results when urine outflow is obstructed. Relief of the obstruction is followed by correction of the azotemia.


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Pathology_Robbins. When azotemia gives rise to clinical manifestations and systemic biochemical abnormalities, it is termed uremia. Uremia is characterized not only by failure of renal excretory function but also by a host of metabolic and endocrine alterations incident to renal damage. In addition, there is secondary gastrointestinal (e.g., uremic gastroenteritis); neuromuscular (e.g., peripheral http://ebooksmedicine.net neuropathy); and cardiovascular (e.g., uremic fibrinous pericarditis) involvement. Below is a brief summary of the various clinical manifestations and syndromes of renal diseases with their defining features. The two most common syndromes associated with glomerular diseases, nephrotic and nephritic, are discussed in detail. Nephrotic syndrome is characterized by the following: Proteinuria, with daily protein loss in the urine of 3.5 g or more in adults (said to be in the “nephrotic range”) Hypoalbuminemia, with plasma albumin levels less than 3 g/dL


Pathology_Robbins

Pathology_Robbins. Proteinuria, with daily protein loss in the urine of 3.5 g or more in adults (said to be in the “nephrotic range”) Hypoalbuminemia, with plasma albumin levels less than 3 g/dL Generalized edema, the most obvious clinical manifestation


Pathology_Robbins

Pathology_Robbins. The nephrotic syndrome has diverse causes that share a common pathophysiology, a derangement in the capillary walls of the glomeruli that results in increased permeability to plasma proteins. Increased permeability of the glomerular basement membrane (GBM) may result from structural or physicochemical alterations in the GBM. With long-standing or heavy proteinuria, serum albumin is decreased, giving rise to hypoalbuminemia and a drop in plasma colloid osmotic pressure, which in turn leads to leakage of fluid from the blood into extravascular spaces. As discussed in Chapter 4, the resulting decrease in intravascular volume and renal blood flow triggers increased release of renin from renal juxtaglomerular cells. Renin in turn stimulates the angiotensin-aldosterone axis, which promotes the retention of salt and water by the kidney. This tendency is exacerbated by reductions in the cardiac secretion of natriuretic factors attributed to decreased intravascular volume. In the face of


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Pathology_Robbins. the retention of salt and water by the kidney. This tendency is exacerbated by reductions in the cardiac secretion of natriuretic factors attributed to decreased intravascular volume. In the face of continuing proteinuria, salt and water retention further aggravates the edema and if unchecked may lead to the development of generalized edema (termed anasarca). At the onset, there is little or no azotemia, hematuria, or hypertension.


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Pathology_Robbins. The genesis of the hyperlipidemia is more obscure. Presumably, hypoalbuminemia triggers increased synthesis of lipoproteins in the liver, or massive proteinuria causes loss of an inhibitor of their synthesis. There also is abnormal transport of circulating lipid particles and impairment of peripheral breakdown of lipoproteins. The associated lipiduria reflects the increased permeability of the GBM to lipoproteins. The most important of the primary glomerular lesions that characteristically lead to the nephrotic syndrome are focal segmental glomerulosclerosis and minimal-change disease. The latter is more important in children; the former is more important in adults. The nephrotic syndrome is also commonly seen in two other primary kidney diseases, membranous nephropathy and membranoproliferative glomerulonephritis, and as a complication of the systemic disease diabetes mellitus. By contrast, nephritic syndrome is characterized by the following:


Pathology_Robbins

Pathology_Robbins. By contrast, nephritic syndrome is characterized by the following: Proteinuria (usually in the subnephrotic range) with or without edema The nephritic syndrome usually has an acute onset and is caused by inflammatory lesions of glomeruli.


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Pathology_Robbins. Proteinuria (usually in the subnephrotic range) with or without edema The nephritic syndrome usually has an acute onset and is caused by inflammatory lesions of glomeruli. The lesions that cause the nephritic syndrome have in common proliferation of the cells within the glomeruli, often accompanied by an infiltrate of leukocytes. The inflammatory reaction injures the capillary walls, permitting blood to pass into the urine, and induces hemodynamic changes that lead to a reduction in the GFR. The reduced GFR is manifested clinically by oliguria, fluid retention, and azotemia. Hypertension probably is a result of both the fluid retention and augmented renin release from the ischemic kidneys. The acute nephritic syndrome may be caused by primary glomerular diseases, such as postinfectious glomerulonephritis (GN) and various forms of crescentic GN, or as a result of systemic disorders such as systemic lupus erythematosus.


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Pathology_Robbins. Asymptomatic hematuria or nonnephrotic proteinuria or a combination of the two is the typical clinical presentation of IgA nephropathy, Alport syndrome, or mild forms or early presentations of other glomerular diseases. Rapidly progressive glomerulonephritis (RPGN) results in rapid loss of renal function in a few days or weeks, typically in the setting of nephritic syndrome. The characteristic histologic finding associated with RPGN is the presence of crescents (crescentic GN). Rapidly progressive glomerulonephritis is a clinical syndrome and not a specific etiologic form of GN. If untreated, it leads to death from renal failure within a period of weeks to months.


Pathology_Robbins

Pathology_Robbins. Acute kidney injury refers to abrupt onset of renal dysfunction characterized by an acute increase in serum creatinine often associated with oliguria or anuria (decreased or no urine flow). It can result from glomerular injury (such as rapidly progressive GN), interstitial injury, vascular injury (such as thrombotic microangiopathy), or acute tubular epithelial cell injury. Chronic kidney disease results from progressive scarring in the kidney of any cause. It is characterized by various metabolic and electrolyte abnormalities such as hyperphosphatemia, dyslipidemia, and metabolic acidosis. However, it is often asymptomatic until the most advanced stages, when symptoms of uremia develop. End-stage renal disease (ESRD) is irreversible loss of renal function requiring dialysis or transplantation typically due to severe progressive scarring in the kidney from any cause.


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Pathology_Robbins. End-stage renal disease (ESRD) is irreversible loss of renal function requiring dialysis or transplantation typically due to severe progressive scarring in the kidney from any cause. Urinary tract infection (UTI) is characterized by bacteriuria and pyuria (bacteria and leukocytes in the urine). It may be symptomatic or asymptomatic, and may affect the kidney (pyelonephritis) or the bladder (cystitis) only. Nephrolithiasis refers to formation of stones in the collecting system and is manifested by renal colic and hematuria (without red cell casts). The glomerulus consists of an anastomosing network of capillaries invested by two layers of epithelium. The visceral epithelium (composed of podocytes) is part of the http://ebooksmedicine.net


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Pathology_Robbins. The glomerulus consists of an anastomosing network of capillaries invested by two layers of epithelium. The visceral epithelium (composed of podocytes) is part of the http://ebooksmedicine.net Complex of signaling and cytoskeletal proteins capillary wall, whereas the parietal epithelium encircles Bowman space (urinary space), the cavity in which filtrate of plasma collects. The glomerular capillary is the filtration unit and consists of the following components ( Figs. 14.1 14.2 Fenestrated endothelial cells, with each fenestra being 70 to 100 nm in diameter. The glomerular basement membrane (GBM), which has a thick, electron-dense central layer called the lamina densa, and two thinner, electron-lucent peripheral layers, the lamina rara interna and lamina rara externa. The GBM consists of collagen (mostly type IV), laminin, polyanionic proteoglycans, fibronectin, and several other glycoproteins.


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Pathology_Robbins. Podocytes, cells that possess interdigitating foot processes that are embedded in and adherent to the lamina rara externa. Adjacent foot processes are separated by 20to 30-nm–wide filtration slits, which are bridged by a thin slit diaphragm composed mainly of the protein nephrin (see later). Mesangial cells, which lie in a mesangial matrix between the capillaries that supports the glomerular tuft. These Fig. 14.2 Low-powerelectronmicrographofratglomerulus.B, Basementmembrane;CL, capillarylumen;End, endothelium;Ep, visceralepithelialcells(podocytes)withfootprocesses;Mes, mesangium;US, urinaryspace. cells, of mesenchymal origin, are contractile and are capable of proliferation, of laying down collagen and other matrix components, and of secreting a number of biologically active mediators in response to cytokines and other factors (described later).