[Robbins Pathology] Vinay Kumar, Abul K Abbas, Jo__250201_202051.PDF

426 CHAPTER 11 Lung pneumonia. An example of a highly pathogenic type is SARS-CoV-2 type 2 alveolar epithelium may cause damage through direct cyto- (severe acute respiratory syndrome coronavirus 2), a strain that is pathic effects of the virus as well as through the e...

426 CHAPTER 11 Lung pneumonia. An example of a highly pathogenic type is SARS-CoV-2 type 2 alveolar epithelium may cause damage through direct cyto- (severe acute respiratory syndrome coronavirus 2), a strain that is pathic effects of the virus as well as through the ensuing immune responsible for the first great pandemic of the 21st century, a viral response. Individuals who develop severe disease generally have higher disease called COVID-19. viral loads early in the course, indicating an inability to control the virus early on. In some individuals, this failure may be due to auto- Pathogenesis. Highly pathogenic coronaviruses like SARS-CoV-2 have antibodies or genetic variants that interfere with type I interferon viral spike proteins that bind the protein angiotensin-converting signaling, or to less well-defined alterations in the immune system that enzyme 2 (ACE2), which is found on the surface of nasopharyngeal occur with aging or in the presence of comorbid conditions such as epithelium and type 2 alveolar epithelial cells. Following exposure, obesity and diabetes. It is hypothesized that large numbers of SARS- the virus is taken up into ACE2-expressing cells and replicates CoV-2einfected cells elicit an excessive immune response marked rapidly, such that presymptomatic or newly symptomatic individuals by high levels of cytokines such as interferon-g, IL-6, and TNF, setting are most likely to spread the infection to others. Transmission is off an inflammatory cascade sometimes referred to as cytokine storm. mainly through respiratory droplets that are produced by coughing, This in turn produces dysfunction not only in the lung but in multiple sneezing, talking, or singing and is most likely to occur indoors in other organ systems, including the heart and kidneys, features that are poorly ventilated spaces. reminiscent of the systemic inflammatory response syndrome (SIRS, The outcome of SARS-CoV-2 infection is highly variable, ranging Chapter 2). In those who are severely affected, this pro-inflammatory from asymptomatic infection, particularly in children and younger state persists even after viral loads fall, perhaps because ongoing tissue adults, to severe disease that leads to rapid progressive pneumonia and damage causes more inflammation. A relatively unusual feature of pulmonary failure. The major risk factors for severe disease include the severe COVID-19 is a high propensity for venous and arterial following: thrombosis. The cause is incompletely understood, but it has been Age. Although COVID-19 can be lethal at any age, it is particularly noted that thrombosis often occurs in the setting of very high levels of deadly in the elderly, especially those older than 75 years. plasma fibrinogen and markedly elevated blood viscosity, a well- Comorbidities. These include obesity, smoking, diabetes, and known risk factor for thrombosis. chronic cardiac, pulmonary, and renal disease. Socioeconomic background, socially defined race, and gender. Males MORPHOLOGY are at higher risk for severe disease, as well as African Americans, In addition to features seen in other viral pneumonias (described previously), Hispanics, and South Asian Americans. Some studies that have severe cases of COVID-19 may show additional findings. The coagulopathy controlled for comorbidities suggest that the association with Afri- that accompanies the disease may cause venous thromboembolism and can and Hispanic descent is largely due to underlying health and arterial thrombosis, leading to limb ischemia and stroke, as well as the for- economic disparities, not genetic factors. mation of microthrombi in the inflamed lung that may exacerbate pulmonary Laboratory abnormalities. These include lymphopenia, thrombocy- dysfunction. Myocarditis and inflammatory infiltrates in the CNS have also topenia, and evidence of coagulopathy or hepatic, cardiac, or renal been reported, but whether these are direct or indirect effects of COVID-19 is damage. unclear. Genetic factors. Several studies have detected an association be- tween the type A blood group and severe disease, while others have identified germline mutations in genes encoding components of the type I interferon pathway in a subset of patients with severe Clinical Features. The onset of COVID-19 resembles that of other disease. causes of viral pneumonia, with the exception that it is likely to be associated with loss of smell and taste, apparently because of The pathogenesis of COVID-19 remains to be completely eluci- infection of olfactory epithelial cells. The diagnosis is readily made by dated, but a working model is shown in Fig. 11.33. Viral infection of PCR-based assays for the viral genome or by more rapid (but less Asymptomatic or Control of mild disease early infection Low viral ACE2 load Severe pulmonary Suboptimal disease and UPPER control of Nasopharynx multiorgan failure SARS-CoV-2 AND early infection respiratory LOWER droplets RESPIRATORY INFECTIONS High viral load Cytokine storm Systemic inflammatory response syndrome Alveolus FIG. 11.33 Pathogenesis of COVID-19. SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2. See text for details.  CHAPTER 11 Lung 427 sensitive) assays for viral proteins. Those with symptomatic pneumonia of abscesses. An abscess also may form within an excavated benefit from treatment with immunosuppressive steroids, in line with necrotic portion of a tumor. It may be preceded by bronchiectasis. the idea that severe disease involves an overexuberant immune Septic embolism, from infective endocarditis of the right side of the response. Low-dose anticoagulants also improve outcomes, heart presumably by countering the procoagulant state that is induced by In addition, lung abscesses may result from hematogenous spread of COVID-19. The availability of highly effective vaccines to SARS- bacteria in disseminated pyogenic infection. This occurs most char- CoV-2 is reducing the spread of this virus, but not before COVID-19 acteristically in staphylococcal bacteremia and often results in mul- took a terrible toll of millions of lives worldwide. The pandemic has tiple lung abscesses. also seen the emergence of new strains of SARS-CoV-2; some, such Finally, selected pathogens can generate or colonize cavitary lesions as the Omicron variant, are more easily spread, making it probable and radiographically mimic lung abscess. Culprit pathogens include that (like influenza) SARS-CoV-2 will persist and become an endemic fungi (e.g., Aspergillus spp., Cryptococcus spp., Histoplasma capsula- seasonal respiratory infection. tum, Blastomyces dermatitidis, Coccidioides spp., the agents of mucormycosis), Mycobacterium tuberculosis, nontuberculous Hospital-Acquired Pneumonias mycobacteria (e.g., M. avium, M. kansasii, M. abscessus), and par- Hospital-acquired, or nosocomial, pneumonias are defined as pul- asites (e.g., Entamoeba histolytica, Paragonimus westermani, Echi- monary infections acquired during a hospital stay. These infections nococcus [hydatid cyst]). Pyogenic bacteria can also superinfect not only have an adverse impact on the clinical course of ill patients cavities caused by mycobacterial, fungal, and parasitic infections, but also add considerably to the burgeoning cost of health care. leading to accumulation of liquid in an otherwise empty cavity. Hospital-acquired infections are common in patients with severe un- derlying disease and those who are immunosuppressed or are on Anaerobic bacteria are present in almost all lung abscesses, and they prolonged antibiotic regimens. Patients on mechanical ventilation are are the exclusive isolates in one-third to two-thirds of cases. The most a particularly high-risk group, and infections acquired in this setting frequently encountered anaerobes are commensals normally found in are given the designation ventilator-associated pneumonia. Gram- the oral cavity, principally species of Prevotella, Fusobacterium, Bac- negative rods (members of Enterobacteriaceae and Pseudomonas teroides, Peptostreptococcus, and microaerophilic streptococci. spp.) and S. aureus are the most common isolates; unlike community- acquired pneumonias, S. pneumoniae is not a common pathogen in MORPHOLOGY the hospital setting. Abscesses range in diameter from a few millimeters to large cavities 5 to 6 cm across. The location and number of abscesses in any particular case Aspiration Pneumonia depend on their mode of development. Pulmonary abscesses resulting from Aspiration pneumonia occurs in patients who are debilitated or aspiration of infective material are more common on the right side those who aspirate gastric contents while unconscious (e.g., after a (with its more vertical airways) than on the left and are usually single. They stroke) or during repeated vomiting. Those affected typically have tend to occur in the posterior segment of the right upper lobe and in the apical abnormal gag and swallowing reflexes. The resultant pneumonia is segments of the right lower lobe, locations that reflect the probable path of partly chemical, due to the irritating effects of the gastric acid, and aspirated material in a recumbent individual. Abscesses that develop in the partly bacterial. Typically, more than one organism is recovered on course of pneumonia or bronchiectasis are often multiple, basal, and scat- culture, aerobes being more common than anaerobes (Table 11.5). tered. Septic emboli and abscesses arising from hematogenous seeding are Aspiration pneumonia is often necrotizing, pursues a fulminant clin- commonly multiple and may affect any region of the lungs. ical course, and is a frequent cause of death in individuals predisposed As the focus of suppuration enlarges it almost inevitably ruptures into to aspiration. In those who survive, abscess formation is a common airways. The resulting partial drainage of the abscess cavity may produce an complication. By contrast, microaspiration occurs in many individuals, air-fluid level on radiographic examination. Occasionally, abscesses rupture especially those with gastroesophageal reflux, and may exacerbate into the pleural cavity, producing bronchopleural fistulas that may result in other lung diseases but does not lead to pneumonia. pneumothorax or empyema. Other complications arise from embo- lization of septic material to the brain, giving rise to meningitis or brain Lung Abscess abscess. On histologic examination, depending on the chronicity of the Lung abscess refers to a localized area of suppuration within the lesion, the suppurative focus is surrounded by mononuclear infiltrates pulmonary parenchyma that results in the formation of one or (lymphocytes, plasma cells, macrophages) and variable degrees of fibrous more large cavities. The causative organism may be introduced into scarring. the lung by any of the following mechanisms: Aspiration of infective material from carious teeth or infected si- nuses or tonsils. This may occur during oral surgery, anesthesia, coma, or alcoholic intoxication, or in debilitated patients with Clinical Features. The manifestations of a lung abscess are much like depressed cough reflexes. those of bronchiectasis and include a prominent cough that usually Aspiration of gastric contents, usually together with infectious or- yields copious amounts of foul-smelling, purulent, or sanguineous ganisms originating in the oropharynx sputum; occasionally, hemoptysis occurs. Spiking fever and malaise As a complication of necrotizing bacterial pneumonias, particularly are common. Clubbing of the fingers, weight loss, and anemia may those caused by S. aureus, Streptococcus pyogenes, K. pneumoniae, appear. Abscesses occur in 10% to 15% of patients with lung cancer; Pseudomonas spp., and, rarely, type 3 pneumococci. Mycotic infec- thus, when a lung abscess is found in an older adult, underlying tions and bronchiectasis also may lead to lung abscesses. carcinoma must be considered. Secondary amyloidosis (Chapter 5) Bronchial obstruction, particularly due to neoplasms, especially may develop in chronic cases. Treatment includes antibiotic therapy lung cancer. Impaired drainage, distal atelectasis, and aspiration and, if needed, surgical drainage or resection. Overall, the mortality of blood and tumor fragments all contribute to the development rate is in the range of 10%. 428 CHAPTER 11 Lung Tuberculosis positive reactions may result from infection by atypical Tuberculosis is a communicable chronic granulomatous disease mycobacteria. caused by Mycobacterium tuberculosis. It usually involves the lungs but About 80% of the population in certain Asian and African coun- may affect any organ or tissue in the body. tries is tuberculin positive; by contrast, in 2019 approximately 5% of Epidemiology. The World Health Organization (WHO) con- the U.S. population was positive. In general, 3% to 4% of individuals siders tuberculosis (TB) to be the most common cause of death acquire active TB during the first year after “tuberculin conversion” resulting from an endemic infectious agent. It is estimated in 2021 and no more than 15% do so thereafter. Thus, only a small fraction of that 1.3 million people died of TB worldwide and that there were 5.8 those who contract an infection develop active disease. million new cases. In the Western world, deaths from TB peaked in Etiology. Mycobacteria are slender rods that are acid fast (i.e., they 1800 and steadily declined throughout the 1800s and 1900s. However, have a high content of complex lipids that bind tightly to the Ziehl- in 1984 this decline reversed abruptly due to the increased incidence Neelsen [carbol fuchsin] stain). M. tuberculosis hominis is of TB in people infected with HIV. As a consequence of intensive responsible for most cases of TB, which is spread by individuals public health surveillance and TB prophylaxis among individuals who with active disease. Transmission is primarily through inhalation of are immunocompromised, the incidence of TB in U.S.-born airborne organisms in aerosols generated by expectoration or by individuals again started to decline in 1992. Nevertheless, as of exposure to contaminated secretions. Oropharyngeal and intestinal 2019 there were an estimated 13 million cases of latent tuberculosis TB contracted by drinking milk contaminated with Mycobacterium in the United States. bovis is now rare except in countries with tuberculous dairy cows TB flourishes in the settings of poverty, crowding, and chronic where unpasteurized milk is consumed. Other mycobacteria, debilitating illness. In the United States, TB is a disease of older particularly Mycobacterium avium complex, are much less virulent adults, the urban poor, the foreign-born, and patients with AIDS. than M. tuberculosis and rarely cause disease in immunocompetent African Americans, American Indians, the Inuit (from the Arctic), and individuals but may cause disseminated disease in patients with Hispanics have a higher incidence of tuberculosis than European AIDS and rare inherited deficiencies of cell-mediated immunity. Americans, most likely due to lack of access to care and socioeconomic factors such as multifamily housing. Certain diseases also increase the Pathogenesis. The course of TB in a newly exposed immunocompe- risk, such as diabetes, Hodgkin lymphoma, chronic lung disease tent individual is dictated by the development of cell-mediated (particularly silicosis), chronic renal failure, malnutrition, alcohol use immunity, which confers resistance to the organism and results in disorder, and immunosuppression. In areas of the world where HIV development of tissue hypersensitivity to tubercular antigens. The infection is prevalent, HIV infection is a dominant risk factor for the typical pathologic features such as caseating granulomas and development of TB. cavitation are the result of the destructive tissue hypersensitivity of It is important that infection be differentiated from disease. the host immune response. Because the effector cells for both Infection implies seeding of a focus with organisms, which may or protective immunity and damaging hypersensitivity are the same, may not cause clinically significant tissue damage (i.e., disease). the appearance of tissue hypersensitivity also signals the acquisition Infection is usually acquired by direct person-to-person transmission of immunity. The sequence of events from inhalation of the of organisms in airborne droplets from an individual with active infectious inoculum to containment of the primary focus is disease to a susceptible host. In most newly infected individuals, an illustrated in Fig. 11.34 and can be outlined as follows: asymptomatic focus of pulmonary infection appears that is self- Entry into macrophages. A virulent strain of mycobacteria gains en- limited and, upon resolution, leaves (if anything) a tiny, fibro- try to macrophage endosomes, a process mediated by several calcific nodule at the site. As discussed later, bacteria spread from the macrophage receptors, including the mannose receptor and com- primary focus to various other sites in the body but the infection plement receptors that recognize components of mycobacterial remains latent. Viable organisms may remain dormant in such foci cell walls. for decades and possibly for the life of the host. Such individuals are Replication in macrophages. Once internalized, the organisms infected but do not have active disease and therefore cannot transmit inhibit normal microbicidal responses by preventing the fusion of organisms to others. But if immune defenses are lowered, the infec- the lysosomes with the phagocytic vacuole, allowing the mycobac- tion may reactivate to produce communicable and potentially life- terium to persist in the vacuoles and proliferate. Thus, during the threatening disease. earliest phase of primary TB (the first 3 weeks) in a nonsensitized Infection with M. tuberculosis typically leads to the development patient, the bacilli proliferate unchecked within pulmonary alveolar of delayed hypersensitivity. This can be detected by either IFN-g macrophages and air spaces, eventually resulting in bacteremia and release assays (IGRAs) or the tuberculin (purified protein derivative seeding of the organisms to multiple sites. Despite the bacteremia, [PPD], or Mantoux) skin test. IGRAs are in vitro tests in which most individuals at this stage are asymptomatic or have a mild flu- T cells from the patient are stimulated with protein antigens from like illness. M. tuberculosis and production of IFN-g is measured to assess the Development of cell-mediated immunity. This occurs approximately level of T-cell immunity. The tuberculin skin test is performed by 3 weeks after exposure. Mycobacterial antigens reach the draining intracutaneous injection of a purified protein derivative of lymph nodes and are processed and presented to CD4þ T cells M. tuberculosis, which induces a visible and palpable induration in by dendritic cells and macrophages. Under the influence of infected individuals that peaks in 48 to 72 hours. A positive IGRA or macrophage-secreted IL-12, CD4þ T cells of the Th1 subset are tuberculin test signifies T cellemediated immunity to mycobacterial generated that secrete IFN-g. antigens but does not differentiate between infection and active T cellemediated macrophage activation and killing of bacteria. IFN-g disease. Recognized limitations of both tests are false-negative re- released by the Th1 cells is crucial for activating macrophages. Acti- actions (anergy) that may be produced by certain viral infections, vated macrophages, in turn, release a variety of mediators and upre- sarcoidosis, malnutrition, Hodgkin lymphoma, immunosuppression, gulate expression of genes with important anti-mycobacterial effects, and (notably) overwhelming active tuberculous disease. False- including (1) TNF, which is responsible for recruitment of  CHAPTER 11 Lung 429 A INFECTION BEFORE ACTIVATION OF B INITIATION AND CONSEQUENCES OF CELL MEDIATED IMMUNITY CELL MEDIATED IMMUNITY Mycobacterium Alveolar duct Alveolar macrophage presenting Lymph microbial antigen to CD4+ T-cell node Alveolus of draining lymph node Alveolar macrophage Alveolus IL-12 Mycobacterium T-cell Mannose, C3b, others Mannose receptor, Class II MTb T cell CR3, others Alveolar MHC antigen receptor macrophage Inadequate phagosome function: T-cell mediated macrophage activation Maturation arrest IFN-J Th1 Lack of acidification Lack of production of TNF, Alveolar reactive nitrogen and IFN-J macrophage chemokines oxygen species Activated Monocyte Epithelioid macrophage recruitment histiocyte Sensitized Unchecked bacillary Macrophage activation T cell proliferation Phagolysosome maturation and activation Caseous Production of nitric oxide necrosis Production of reactive Alveolar macrophage oxygen species Giant cell Bacteremia with seeding Mycobacterial Granuloma Tuberculin of multiple sites killing formation positivity FIG. 11.34 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 im- munity 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. CR3, Complement receptor 3; IFN-g, interferon g; MHC, major histocompatibility complex; MTb, Mycobacterium tuberculosis; TNF, tumor necrosis factor. monocytes, which are activated to develop into the macrophages that significant tissue destruction or illness occurs. In other individuals characterize the granulomatous response; (2) inducible nitric oxide with immune deficits due to age or immunosuppression, however, synthase (iNOS), which raises nitric oxide (NO) levels, helping to the immune response is insufficient to hold the infection at bay. create reactive nitrogen intermediates that appear to be particularly important in killing of mycobacteria; and (3) antimicrobial peptides In summary, immunity to a tubercular infection is primarily (defensins) that are also toxic to mycobacteria. mediated by Th1 cells, which stimulate macrophages to kill myco- Granulomatous inflammation and tissue damage. In addition to bacteria. This immune response, while largely effective, comes at the stimulating macrophages to kill mycobacteria, the Th1 response cost of hypersensitivity and accompanying tissue destruction. Defects orchestrates the formation of granulomas. Macrophages activated in any of the steps of a Th1 T-cell response (including IL-12, IFN-g, by IFN-g differentiate into the “epithelioid histiocytes” that aggre- TNF, or nitric oxide production) result in poorly formed granulomas, gate to form granulomas; some epithelioid cells may fuse to form absence of resistance, and disease progression. Individuals with giant cells. Activated macrophages also secrete TNF and chemo- inherited mutations in any component of the T-cell response are kines, which promote recruitment of more monocytes. The impor- extremely susceptible to infections with mycobacteria. Reactivation of tance of TNF is underscored by the fact that patients with the infection or reexposure to the bacilli in a previously sensitized host rheumatoid arthritis and inflammatory bowel disease being treated results in rapid mobilization of a defensive reaction but also increased with TNF antagonists are at increased risk for TB reactivation. In tissue necrosis. By contrast, the loss of hypersensitivity (indicated by many individuals, the T-cell response halts the infection before tuberculin negativity in an M. tuberculosiseinfected patient) is an 430 CHAPTER 11 Lung ominous sign of fading resistance to the organism and is a harbinger of severe disease. Primary Tuberculosis Primary TB is the form of disease that develops in a previously un- exposed and therefore unsensitized patient. About 5% of those newly infected develop significant disease. In the large majority of otherwise healthy individuals, the only short-term consequence of primary TB is a focus of pulmonary scarring, as discussed earlier. Uncommonly, however, this initial 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 individuals with severe acute malnutrition (Chapter 7). The incidence of pro- gressive primary TB is particularly high in patients who are HIV positive with significant immunosuppression (i.e., CD4þ T cell counts below 200 cells/mL). Immunosuppression blunts the ability to mount a CD4þ T cellemediated response and as a result the characteristic granulomatous reaction to TB is absent. MORPHOLOGY In countries in which bovine TB and infected milk have largely disappeared, primary TB almost always begins in the lungs. The inhaled bacilli usually implant in the distal air spaces of the lower part of the upper lobe or in the upper part of the lower lobe, typically close to the pleura. During the development of sensitization, a 1-cm to 1.5-cm area of gray-white consoli- dation appears that is called the Ghon focus. In the majority of cases, the FIG. 11.35 Primary pulmonary tuberculosis, Ghon complex. The gray- center of this focus undergoes caseous necrosis. Tubercle bacilli, either free or white parenchymal focus (arrow) is under the pleura in the lower part within phagocytes, travel via the lymphatic vessels to the regional lymph of the upper lobe. Hilar lymph nodes with caseation are seen (left). nodes, which also often caseate. This combination of parenchymal and nodal lesions is called the Ghon complex (Fig. 11.35). Lymphatic and hema- involved than in primary TB. On the other hand, the infection and togenous dissemination to other parts of the body also occurs during the first associated inflammation often undergo cavitation and erode into and few weeks. Development of cell-mediated immunity controls the infection in disseminate along airways. Such changes are an important source of approximately 95% of cases. Therefore, the Ghon complex undergoes pro- infectivity, as affected patients produce sputum containing the bacilli. gressive fibrosis, and calcification often follows (detectable as a Ranke Secondary TB should always be an important diagnostic consid- complex on radiograph). Despite seeding of other organs, no lesions eration in HIV-positive patients who present with pulmonary disease. develop. Histologically, sites of overt infection are involved by a characteristic Although an increased risk for TB exists at all stages of HIV disease, inflammatory reaction marked by the presence of caseating and noncaseating the manifestations differ depending on the degree to which the patient granulomas, which consist of epithelioid macrophages and multinucleate gi- is immunocompromised. For example, patients who are less severely ant cells (Fig. 11.36A to C). In those who do not mount an effective immune immunocompromised (CD4þ T cell counts >300 cells/mL) present response due to immunocompromise, progressive primary tuberculosis may with “usual” secondary TB (apical disease with cavitation), while those develop. Lesions in such individuals often lack granulomas and instead consist who are more significantly immunocompromised (CD4þ T cell of sheets of macrophages containing numerous bacilli (Fig. 11.36D). counts below 200 cells/mL) more often present with a clinical picture that resembles progressive primary TB (lower and middle lobe consolidation, hilar lymphadenopathy, and noncavitary disease). The extent to which the patient is immunocompromised also determines Secondary Tuberculosis (Reactivation Tuberculosis) the frequency of extrapulmonary involvement, rising from 10% to 15% Secondary TB is the pattern of disease that arises in a previously in patients who are mildly immunocompromised to greater than 50% sensitized host. It may appear shortly after primary TB but more in those with severe immune deficiency. commonly arises from reactivation of dormant primary lesions many decades after initial infection, particularly when host resistance is MORPHOLOGY weakened. It may also result from reinfection, which may occur either The initial lesion of secondary TB is usually a small focus of consolidation, because the protection afforded by the primary disease has waned or less than 2 cm in diameter, within 1 to 2 cm of the apical pleura. Such foci because of exposure to a large inoculum of virulent bacilli. Whatever are sharply circumscribed, firm, gray to yellow areas with a variable amount of the source of the organisms, only a few patients (90% >80% RB mutations w90% w20% p16/CDKN2A mutations w10% >50% TP53 mutations >90% >50% Dominant Oncogene Abnormalities KRAS mutations Rare w30% (adenocarcinomas) EGFR mutations Absent w20% (adenocarcinomas, nonsmokers, women) ALK rearrangements Absent 4%e6% adenocarcinomas, nonsmokers, often have signet ring morphology Response to Therapy Response to chemotherapy and radiotherapy Often complete response but Incomplete invariably recur Response to checkpoint inhibitor therapy Unresponsive Responsive particularly effective when combined with chemotherapy, a new nonbacterial endocarditis, and disseminated intravascular coagulation. therapeutic approach. Hypercalcemia is most often encountered with squamous cell carci- By contrast, the prognosis and treatment of small cell carcinoma noma, the hematologic syndromes with adenocarcinoma, and the have changed little. Small cell carcinoma has invariably spread by the neurologic syndromes with small cell carcinoma, but exceptions time it is detected, even when the primary tumor is small and appears abound. to be localized. Thus, surgical resection is not curative. Small cell carcinoma is very sensitive to radiotherapy and chemotherapy but Carcinoid Tumors invariably recurs, and as of yet targeted therapies are unavailable. The Carcinoid tumors are malignant tumors composed of cells that median survival with treatment is only 1 year and only 5% of patients contain dense-core neurosecretory granules in their cytoplasm and are alive at 10 years. Despite a very high mutation burden, these tu- occasionally secrete hormonally active polypeptides. They are best mors are less responsive to immune checkpoint inhibitors than non- thought of a low-grade neuroendocrine carcinoma and are sub- small cell lung cancers. Work is ongoing to understand and overcome classified as typical or atypical; both are often resectable and curable. resistance to immunotherapy. They may occur as part of the multiple endocrine neoplasia syndrome In addition to the direct effects of the tumor cells, it is estimated (Chapter 18). Bronchial carcinoids tend to occur in younger adults that 3% to 10% of patients with lung cancer develop a paraneoplastic (mean 40 years) and represent about 5% of all pulmonary neoplasms. syndrome (Chapter 6). The manifestations include (1) hypercalcemia caused by secretion of a parathyroid hormoneerelated peptide; (2) MORPHOLOGY Cushing syndrome (from increased production of adrenocorticotropic Most carcinoids originate in main bronchi and grow in one of two patterns: (1) hormone); (3) syndrome of inappropriate secretion of antidiuretic as a polypoid, spherical intraluminal mass (Fig. 11.45A); or (2) as a mucosal hormone; (4) neuromuscular syndromes, including a myasthenic plaque penetrating the bronchial wall to fan out in the peribronchial syndrome, peripheral neuropathy, and polymyositis; (5) clubbing of tissuedthe so-called collar-button lesion. Even penetrating lesions the fingers and hypertrophic pulmonary osteoarthropathy; and (6) push into the lung substance along a broad front and are well demarcated. coagulation abnormalities, including migratory thrombophlebitis, 442 CHAPTER 11 Lung B A C D E F FIG. 11.44 Pathology of lung carcinomas. (A) Lung adenocarcinoma. Note the central scarring associated with anthracotic pigments and pleural puckering (arrow). (B) Gland-forming adenocarcinoma; inset shows staining for thyroid transcription factor 1 (TTF-1), which is characteristic. (C) Well-differentiated squamous cell carcinoma, showing keratinization, pearls, and intercellular bridges (arrows). (D) Squamous cell carcinoma appearing as a central (hilar) mass that is invading contiguous parenchyma. (E) Large cell carcinoma, consisting of sheets of large cells without gland formation or squamous differentiation. (F) Small cell carcinoma with small deeply basophilic cells and areas of necrosis (top left). Note basophilic staining of vascular walls due to encrustation by DNA from necrotic tumor cells (Azzopardi effect). (A, From Diagnostic Pathology: Familial Cancer Syndromes and ExpertPath. Copyright Elsevier 2022.)  CHAPTER 11 Lung 443 Peripheral carcinoids are less common. Although 5% to 15% of carcinoids pleural exudate formation are (1) bacterial infection (suppurative have metastasized to the hilar nodes at presentation, distant metastases are pleuritis or empyema), either through direct extension of a pulmonary rare. Histologically, typical carcinoids, like their counterparts in the in- infection or bloodborne seeding; (2) cancer (lung carcinoma, meta- testinal tract, are composed of nests of uniform cells with regular round nuclei static neoplasms to the lung or pleural surface, mesothelioma); (3) and “salt-and-pepper” chromatin, absent or rare mitoses, and little pleo- pulmonary infarction; and (4) viral pleuritis. Other less common morphism (Fig. 11.45B). Atypical carcinoid tumors display a higher causes of pleural exudative effusions are systemic lupus erythematosus, mitotic rate and small foci of necrosis. These tumors have a higher incidence rheumatoid arthritis, and uremia, as well as previous thoracic surgery. of lymph node and distant metastasis than typical carcinoids. Unlike typical Malignant effusions are characteristically large and frequently bloody carcinoids, the atypical tumors have TP53 mutations in 20% to 40% of cases. (hemorrhagic pleuritis). Cytologic examination may reveal the malig- Typical carcinoid, atypical carcinoid, and large cell neuroendocrine and small nant cells. cell carcinoma can be viewed as a continuum of increasing histologic Whatever the cause, transudates and serous exudates are usually aggressiveness and malignant potential within the spectrum of pulmonary resorbed without residual effects if the inciting cause is controlled or neuroendocrine neoplasms. remits. By contrast, fibrinous, hemorrhagic and suppurative exudates may lead to fibrous organization, yielding adhesions or fibrous pleural thickenings that sometimes undergo calcification. Clinical Features. Most carcinoid tumors manifest with signs and Pneumothorax, Hemothorax, and Chylothorax symptoms related to their intraluminal growth, including cough, he- Pneumothorax refers to the presence of air or other gas in the pleural moptysis, and recurrent bronchial and pulmonary infections. Pe- sac. It may occur in young, apparently healthy adults, usually men ripheral tumors are often asymptomatic and are discovered without any known pulmonary disease (primary or spontaneous incidentally on chest radiographs. Only rarely do pulmonary carci- pneumothorax), or as a result of some thoracic or lung disorder noids induce the carcinoid syndrome, characterized by intermittent (secondary pneumothorax). Secondary pneumothorax occurs when a attacks of diarrhea, flushing, and cyanosis. The reported 5- and 10- pulmonary lesion situated close to the pleural surface ruptures, year survival rates for typical carcinoids are above 85%, while these allowing inspired air to gain access to the pleural cavity. Responsible rates drop to 56% and 35%, respectively, for atypical carcinoids. pulmonary lesions include emphysema, lung abscess, tuberculosis, carcinoma, and many other, less common processes. Mechanical ventilatory support with high pressure may also trigger secondary PLEURAL LESIONS pneumothorax. Disease of the pleura is usually a complication of underlying pulmo- There are several possible complications of pneumothorax. Some nary disease. Secondary infections and pleural adhesions are common air leaks only permit air to move into the pleural cavity, leading to an findings at autopsy. Important primary disorders are (1) intrapleural increase in intrapleural pressure (tension pneumothorax) that shifts bacterial infections and (2) malignant mesothelioma, a neoplasm of the the mediastinum (eFig. 11.7). Compromise of the pulmonary circu- pleura. lation may follow and may even be fatal. If the leak seals and the lung is not reexpanded within a few weeks (either spontaneously or Pleural Effusion and Pleuritis through medical or surgical intervention), scarring may occur that Pleural effusions (fluids in the pleural space) may be either transudates prevents the lung from ever fully reexpanding. In these cases, serous or exudates. When the effusion is a transudate, the condition is termed fluid collects in the pleural cavity, creating hydropneumothorax. With hydrothorax. Congestive heart failure (either right-sided or left-sided) prolonged collapse, the lung becomes vulnerable to infection, as does is the most common cause of bilateral hydrothorax. An exudate, the pleural cavity when communication between it and the lung characterized by protein content greater than 30 g/L and, often, in- persists. Empyema is thus an important complication of pneumo- flammatory cells, suggests pleuritis. The four principal causes of thorax (pyopneumothorax). A B FIG. 11.45 Bronchial carcinoid. (A) Carcinoid growing as a spherical, pale mass (arrow) protruding into the lumen of the bronchus. (B) Histologic appearance demonstrating small, rounded, uniform nuclei and moderate cytoplasm. (Courtesy of Dr. Thomas Krausz, Department of Pathology, University of Chicago Pritzker School of Medicine, Chicago, Illinois.)  CHAPTER 11 Lung 443.e1 eFIG. 11.7 Tension pneumothorax. The right lung is hyperlucent and the heart is shifted to the left side of the thoracic cavity due to a right lung tension pneumothorax. (From Klatt EC: Robbins and Cotran Atlas of Pathology, ed 4, Fig. 5.7, Philadelphia, 2021, Elsevier.) 444 CHAPTER 11 Lung 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. In contrast to bloody pleural effusions, with hemothorax, the blood clots within the pleural cavity. Chylothorax is a pleural collection of milky lymphatic fluid con- taining 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). Malignant Mesothelioma Despite its rarity, malignant mesothelioma has assumed great importance because it is highly related to exposure to airborne asbestos. It is a 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 in- dividuals with this cancer have a history of exposure to asbestos. Those who work directly with asbestos (e.g., shipyard workers, miners, insulators) are at greatest risk, but individuals whose only exposure is living in proximity to an asbestos factory or living with an asbestos worker are also at increased risk (due to particle contami- nation of the worker’s clothing). The latency period for development FIG. 11.46 Malignant mesothelioma. Note the thick, firm, white pleural of malignant mesothelioma after exposure to asbestos is long, often 25 tumor encasing the bisected lung. to 40 years, suggesting that causative driver mutations are acquired slowly over an extended period of time. As stated earlier, the com- bination of cigarette smoking and asbestos exposure greatly increases the risk for developing lung carcinoma, but it does not increase the Clinical Features. Malignant mesothelioma remains a nearly uni- risk for developing malignant mesothelioma, one of the many puzzles formly fatal disease. Most patients present with gradually worsening in cancer biology. nonspecific pulmonary symptoms such as cough and dyspnea. As the Once inhaled, asbestos fibers remain in the body for life. Thus, the disease advances, the tumor may impinge on local structures, leading lifetime risk after exposure does not diminish over time (unlike with to superior vena cava syndrome or heart failure. Imaging reveals smoking, in which the risk decreases after cessation). It has been hy- thickening of the pleura and often pleural effusion, sometimes pothesized that asbestos fibers preferentially gather near the meso- accompanied by a shift of the mediastinum toward the affected lung thelial cell layer, where they generate reactive oxygen species that cause due to its underinflation. Even with extrapleural pneumonectomy and DNA damage and mutations. Sequencing of mesothelioma genomes chemotherapy, most patients succumb due to respiratory failure or has revealed multiple driver mutations, many of which cluster in invasion of heart and pericardium in 12 to 18 months. pathways involved in DNA repair, cell cycle control, and growth factor signaling. Of interest, one of the most commonly mutated genes in LESIONS OF THE UPPER RESPIRATORY TRACT sporadic mesothelioma, BAP1, encodes a tumor suppressor involved in DNA repair that is also the target of germline mutations in families Acute Infections showing a high incidence of mesothelioma. Acute infections of the upper respiratory tract are among the most common afflictions of humans, most frequently manifesting as the MORPHOLOGY “common cold.” The clinical features are well known: nasal conges- Malignant mesotheliomas are often preceded by extensive pleural tion accompanied by watery discharge; sneezing; scratchy, dry, sore fibrosis and plaque formation, readily seen on computed tomography throat; and a slight increase in temperature that is more pronounced scans. These tumors begin in a localized area and over time spread widely, in young children. The most common pathogens are rhinoviruses, but either by contiguous growth or by diffuse seeding of pleural surfaces. At coronaviruses, respiratory syncytial viruses, parainfluenza and influ- autopsy, the affected lung is typically ensheathed by a layer of enza viruses, adenoviruses, enteroviruses, and sometimes even group yellow-white, firm, variably gelatinous tumor that obliterates A b-hemolytic streptococci have been implicated. In a significant the pleural space (Fig. 11.46). The neoplasm may directly invade the thoracic number of cases (around 40%), the organism cannot be identified. wall or the subpleural lung tissue, but distant metastases are uncommon. Most of these infections occur in the fall and winter and are self- Normal mesothelial cells are biphasic, giving rise to pleural lining cells as well limited (usually lasting for 1 week or less). In a minority of cases, as the underlying fibrous tissue. In line with this potential, mesotheliomas colds are complicated by the development of bacterial otitis media or conform to one of three morphologic appearances: (1) epithelial, in which sinusitis. cuboidal cells forming small papillary buds line tubular and microcystic spaces In addition to the common cold, infections of the upper respiratory (this is the most common pattern and also the one most likely to be confused tract may produce signs and symptoms localized to the pharynx, with a pulmonary adenocarcinoma); (2) sarcomatous, in which spindled, epiglottis, or larynx. Acute pharyngitis, manifesting as a sore throat, fibroblastic-appearing cells grow in sheets; and (3) biphasic, having both may be caused by a host of agents. Mild pharyngitis with minimal sarcomatous and epithelial areas. physical findings frequently accompanies a cold and is the most  CHAPTER 11 Lung 445 common form of pharyngitis. More severe forms with tonsillitis, oncogenic signals that active the NF-kB pathway. The undifferentiated associated with marked hyperemia and exudates, occur with b-he- tumors are composed of large epithelial cells with indistinct cell borders molytic streptococcal and adenovirus infections. Streptococcal tonsil- (“syncytial” growth) and prominent eosinophilic nucleoli and are often litis is important to recognize and treat early because of the associated heavily infiltrated by T cells, which are believed to be responding to potential for development of peritonsillar abscesses or for progression viral antigens. Nasopharyngeal carcinomas invade locally, spread to to poststreptococcal glomerulonephritis (Chapter 12) and acute cervical lymph nodes, and then metastasize to distant sites. They tend rheumatic fever (Chapter 9). Coxsackievirus A infection may produce to be radiosensitive, and 5-year survival rates of 50% are reported, even pharyngeal vesicles and ulcers (herpangina). Infectious mononucleosis, for patients with advanced disease. Responses to immune checkpoint caused by Epstein-Barr virus (EBV), is an important cause of inhibitors also have been reported, providing a new therapeutic strategy pharyngitis. for tumors that do not respond to conventional therapy. Acute bacterial epiglottitis is a syndrome predominantly affecting young children who have an infection of the epiglottis caused by Laryngeal Tumors H. influenzae, in which pain and airway obstruction are the major A variety of nonneoplastic, benign and malignant neoplasms of findings. The onset is abrupt. Failure to appreciate the need to maintain epithelial and mesenchymal origin may arise in the larynx, but only an open airway for a child with this condition can have fatal conse- vocal cord nodules, papillomas, and squamous cell carcinomas are quences. The advent of vaccination against H. influenzae has greatly sufficiently common to merit comment. In all these conditions, the decreased the incidence of this disease in resource-rich parts of the world. most common presenting feature is hoarseness. Acute laryngitis may result from inhalation of irritants, allergic reactions, and agents that produce the common cold. Brief mention Nonmalignant Lesions should be made of two uncommon but important forms of laryngitis: Vocal cord nodules (“polyps”) are smooth, hemispherical protrusions tuberculous and diphtheritic. The former is almost always a conse- (usually