感染性肉芽肿（英文）

IDENTIFICATION OF ORGANISMS 306 GENERAL FEATURES OF INFECTIOUS GRANULOMAS 307 HISTOPLASMOSIS 308 Clinical features 309 Pathologic features 310 Staining techniques 311 COCCIDIOIDOMYCOSIS 312 Clinical features 312 Histopathologic features 312 CRYPTOCOCCOSIS 313 Clinical and radiographic features 313 Histologic features 314 NORTH AMERICAN BLASTOMYCOSIS 317 Clinical features 317 Histologic features 317 Differential diagnosis 318 MISCELLANEOUS FUNGAL INFECTIONS 319 TUBERCULOSIS 319 Clinical features 319 Pathologic features 320 NONTUBERCULOUS MYCOBACTERIAL INFECTIONS 320 Hot tub lung 321 M. bovis infection 322 DIROFILARIASIS 322 Clinical features 323 Pathologic features 323 The evaluation of granulomatous lung inflammation is a common task for the surgical pathologist. Most necrotizing granulomas are caused by infection, usually fungal or mycobacterial, and the responsible organism is usually demonstrable in the tissue. A number of important noninfectious lesions, however, especially various pulmonary vasculitides and sarcoidosis, can also cause pulmonary granulomas. Although ideally all specimens should be cultured, in practice this procedure is not always possible, since the tissue may be immersed in formalin before being received by the pathology laboratory. Furthermore, in acutely ill patients, a diagnosis may be needed before the results of cultures are available. The pathologist, therefore, rather than the microbiologist, must assume primary responsibility for identifying infectious organisms in lung granulomas.6 Helpful guidelines for evaluating necrotizing granu- lomas are summarized in Table 11–1. Not only can the pathologist be expected to document the presence or absence of organisms in granulomas, but also he or she 11 INFECTION II. GRANULOMATOUS INFECTIONS 305 Table 11–1 Guidelines for Identifying Organisms in Necrotizing Granulomas • Use the H and E in addition to special stains to identify fungi (both the tissue reaction and organism morphology are important). • Begin the search for organisms in the center of necrotic zones rather than in the surrounding viable inflammatory areas. • Perform special stains (AFB, GMS) on at least two blocks that contain active, necrotic granulomatous areas. • Remember that organisms may not be identifiable in up to one-third of solitary necrotizing granulomas. Absence of organisms does not by itself imply a noninfectious condition. W0041-Ch11.qxd 2/4/06 12:14 PM Page 305 can, with good accuracy, specifically identify many fungi (Table 11–2). IDENTIFICATION OF ORGANISMS Special stains for acid-fast bacilli and fungi should be examined in all cases.2,3,5,6 We prefer the Ziehl–Neelsen (AFB) stain for mycobacteria and Grocott–Gomori methenamine silver (GMS) stain for fungi, although the auramine–rhodamine and PAS–Gridley stains are also satisfactory. Use of the periodic acid–Schiff (PAS) stain without a counterstain is not recommended when searching for fungi in necrotizing granulomas, because it fails to adequately differentiate the organisms from the background necrosis and debris. However, it can be helpful in delineating the internal structural detail of a fungus that already has been located by other staining methods. Other stains that are useful include the Fontana–Masson (FM) stain and the combined FM–alcian blue, FM–mucicarmine, and alcian blue–PAS stains, especially for identifying cryptococci.35,36,40 Rarely, ordinary bacteria have been reported to cause necrotizing, usually suppurative, granulomatous reactions.1,4 Examples include Burkholderia pseudomallei (melioidosis), Brucella suis (tularemia), and other rare organisms (Burkholderia cepacia, Pseudomonas andersonii). Gram stains or silver impregnation techniques (Warthin Starry stain) can sometimes outline the organisms, but more often the diagnosis depends on cultures. The importance of an ordinary hematoxylin and eosin (H and E) stain cannot be overemphasized in evaluating necrotizing granulomas. Several fungi, including blastomyces, cryptococcus, and coccidioides, for example, are easily visualized with H and E and show distinct morphologic features in this stain. The combination of the H and E appearance and the special stain findings can greatly facilitate identification. The appearance of the tissue reaction can provide addi- tional clues to the organism. For example, suppurative granulomas are characteristic of blastomycosis and coccidioidomycosis, non-necrotizing granulomas are common in cryptococcosis, and eosinophilia may be prominent in coccidioidomycosis. In some cases, immunofluorescence or immunoperoxidase techniques using specific antibodies can help in identifying the organism. More sophisticated methods utilizing the polymerase chain reaction (PCR) have been utilized in tuberculosis cases.73,81,83,87,89 It should be remembered that organisms are almost always located in the central necrotic zones of caseating granulomas rather than in surrounding viable tissue or non-necrotizing granulomas.6,92 In the study by Ulbright and Katzenstein,6 acid-fast bacilli and histoplasma were 306 INFECTION II. GRANULOMATOUS INFECTIONS Table 11–2 Contrasting Morphologic Features of Common Fungi Causing Granulomatous Inflammation in the Lung Histoplasma Coccidioides Cryptococcus Blastomyces Average size 3 μm (range, 1 to 5 μm) 30 to 60 μm (spherules); 4 to 7 μm (range, 8 to 15 μm 2 to 5 μm (endospores) 2 to 15 μm) (range, 2 to 30 μm) Morphology Oval, budding yeast; Spherules, endospores; Round, budding yeast; Round, budding uniform in size, buds no budding forms variation in size, yeast; uniform uncommon fragmentation common in size Distinguishing Single nucleus, perinuclear Thick wall, central Pale, thin cell wall; Thick cell wall, structural features clear zone (intracellular basophilic endospores extracellular clear zone basophilic (H and E) organisms only)* (spherule only) (halo) protoplasm, multiple nuclei Mucicarmine staining Negative Negative Usually positive Negative Type of granulomas Necrotizing Necrotizing; early lesions Necrotizing, Necrotizing with suppurative; eosinophils non-necrotizing suppuration common *Intracellular organisms are seen only in disseminated histoplasmosis. Histoplasma cannot be visualized within caseous necrosis in lung granulomas without special stains. W0041-Ch11.qxd 2/4/06 12:14 PM Page 306 found almost exclusively within such an area. Although cryptococcus and coccidioides occasionally were found in surrounding viable histiocytes, they were mainly present in necrotic zones. To conserve time and energy, therefore, the pathologist should begin his or her search for organisms in the central, most necrotic portion of the granuloma. In most cases, the examination of sections from two tissue blocks is sufficient to identify an infectious agent, provided that the blocks include areas containing the most active and preferably most necrotic granulo- matous inflammation. With this technique, an infec- tious agent will be identifiable in most necrotizing granulomas. It should be remembered, however, that a small but significant proportion of otherwise typical necrotizing granulomas (one-third in Ulbright and Katzenstein’s study6 of radiographically solitary lesions) will be negative for organisms by special stains and sometimes cultures. These cases likely represent infectious granulomas in which organisms have been removed by the inflammatory process, and the diagnosis of other diseases, especially pulmonary vasculitides, should not be considered unless specific diagnostic features are present (see Chapter 8). GENERAL FEATURES OF INFECTIOUS GRANULOMAS Infectious granulomas share some features with the pulmonary vasculitides (see Chapter 8), which may make diagnosis difficult.5,6 Irregular, ‘geographic’-shaped necrosis, a characteristic finding in Wegener’s granulo- matosis, occasionally occurs in infections (Fig. 11–1a). Remnants of inflamed blood vessels and ghosts of alveolar septa are sometimes seen in the necrotic zones (so-called infarct-like necrosis, Fig. 11–1b). Vasculitis, which is a hallmark of Wegener’s granulomatosis and other vasculitides, is common in both fungal and mycobacterial infections (Fig. 11–2). The vasculitis of infection is not necrotizing, however, and is generally characterized by a mural infiltrate of lymphocytes and 307GENERAL FEATURES OF INFECTIOUS GRANULOMAS Figure 11–1 Infectious granulomas. (a) Irregular, geographic-shaped necrosis is seen in this example of tuberculosis. Inflammation in blood vessels is also prominent. (b) Infarct-like necrosis is prominent in this example of histoplasmosis. Note the remnants of alveolar septa in the necrotic zone. An adjacent artery is also inflamed (left). (a) (b) W0041-Ch11.qxd 2/4/06 12:14 PM Page 307 plasma cells. The intima may be expanded by the cellular infiltrate, and, sometimes, epithelioid histiocytes, and even non-necrotizing granulomas, accompany the other chronic inflammatory cells. A transmural neutro- phil infiltrate with necrosis that is characteristic of Wegener’s granulomatosis, however, is not a feature of infection-related vasculitis. Bronchocentric granulomas, the characteristic finding in bronchocentric granulo- matosis (see Chapter 6), are common in infections. In these lesions, bronchiolar mucosa is partially or completely replaced by palisading epithelioid histiocytes (Fig. 11–3). The former instance is easy to recognize because the necrotizing granuloma is partly surrounded by bronchiolar epithelium. When there is no residual epithelium, the bronchocentric location of the granulo- matous inflammation is inferred by the presence of a nearby pulmonary artery (see Fig. 6–20). These observations underscore the need to carefully exclude an infectious etiology by means of special stains and cultures before considering a diagnosis of noninfectious granulomatous diseases. The differential diagnosis of granulomatous infections and the noninfectious pulmonary vasculitides is discussed in more detail in Chapter 8. The following sections concentrate mainly on fungal organisms that are common in the United States. Histologic features that aid in their recognition and differentiation are summarized in Table 11–2. Dirofilarial infections are also discussed, since they are an impor- tant cause of solitary lung nodules in certain areas of the United States, and aspects of tuberculosis and nontuberculous mycobacteria that are relevant to the surgical pathologist are briefly reviewed. HISTOPLASMOSIS Histoplasma capsulatum is a widespread fungus whose natural habitat is the soil. It exists in the mycelial form in nature but assumes the yeast phase at body temperature. The organism is endemic primarily in the central United States, but cases of histoplasmosis may occur well outside of this area. 308 INFECTION II. GRANULOMATOUS INFECTIONS Figure 11–2 Vasculitis in infectious granulomas. (a) A dense chronic inflammatory cell infiltrate is present in the wall of this artery and narrows the lumen. The artery is located on the edge of a necrotizing granuloma (right), in which histoplasma were identified. (b) This artery from a case of tuberculosis shows granulomatous inflammation in its wall. The necrotic center of the granuloma is on the right. (a) (b) W0041-Ch11.qxd 2/4/06 12:14 PM Page 308 Clinical Features The vast majority of histoplasma infections in humans do not produce symptoms. Their existence is docu- mented by the subsequent development of skin or serologic reactivity to histoplasma-related antigens or by the presence of characteristic radiographic calcifi- cations. Several clinical syndromes occur, however, including acute pulmonary histoplasmosis, disseminated histoplasmosis, and chronic histoplasmosis.7,8 Histo- plasmoma is an important complication of acute pulmo- nary histoplasmosis which may be encountered by the surgical pathologist. Acute Pulmonary Histoplasmosis Acute pulmonary histoplasmosis encompasses the forms of the disease previously termed primary histoplasmosis and acute histoplasmosis.7,8 Primary histoplasmosis is considered a misnomer since, unlike primary tuber- culosis, which is followed by life-long tuberculin hypersensitivity, histoplasmosis is not necessarily associated with lasting histoplasmin sensitivity, and, therefore, infection and reinfection are common in endemic areas. Clinically, most patients are asympto- matic. The uncommon symptomatic form of the disease occurs predominantly in infants or children, and fever and cough are the usual clinical manifestations. Hilar and mediastinal lymph node enlargement and a patchy parenchymal infiltrate are seen radiographically. The course is usually self-limited, although sometimes dissemination occurs (see text following). Occasionally, inhalation of a large number of spores causes sympto- matic disease, a form of infection previously termed acute histoplasmosis. These patients present with influenza-like symptoms accompanied by patchy, soft infiltrates or nodules that can be seen on chest radio- graphs. This form of the disease can represent a type of primary infection, or it can occur in previously infected individuals (reinfection type). It is usually self-limited, and the diagnosis is based on clinical, laboratory, and radiographic findings. Occasionally, in acutely ill patients in whom the diagnosis is unsuspected clinically, a lung biopsy will be performed. Disseminated Histoplasmosis This entity usually occurs in patients with abnormal immune systems, although otherwise apparently healthy individuals can be affected as well.7,10,12 Approximately a third of the cases involve infants younger than 1 year old. This form of the disease is characterized by wide- spread parasitization of macrophages by the organisms, and multiple organs, especially reticuloendothelial, are affected. Interstitial lung infiltrates are often seen radiographically. The diagnosis is usually established from urine or blood cultures or by liver or bone marrow biopsy. Bronchoalveolar lavage specimens and lung biopsy specimens may be used in some cases. Chronic Histoplasmosis This type of histoplasmosis usually occurs in patients with emphysema or other chronic lung disease.9 White males are affected more frequently than women or blacks, and the symptoms resemble those of tuber- culosis. Pneumonic infiltrates and cavitary lesions are seen radiographically. The diagnosis is usually based on recovery of the organisms from sputum cultures, although lung biopsy occasionally may be necessary. Elevated complement-fixation titers can also help to establish the diagnosis in some cases. Skin tests are not useful, because false-negative results can occur, and positive results are found in the majority of healthy persons in endemic areas.7 Histoplasmomas Histoplasmomas are thought to develop around a healing or healed focus of acute pulmonary histoplasmosis.7 They appear radiographically as well-circumscribed 309HISTOPLASMOSIS Figure 11–3 Bronchocentric granuloma in tuberculosis. A necrotizing granuloma partially replaces the bronchiole in the center. W0041-Ch11.qxd 2/4/06 12:14 PM Page 309 masses, and they may slowly enlarge. Patients are usually asymptomatic, the lesions being found on a routine chest radiograph. This is the form of histo- plasmosis most frequently encountered by the surgical pathologist, since the nodules are often excised. Pathologic Features The gross appearance of most forms of pulmonary histoplasmosis resembles that of any other necrotizing granulomatous process. Pulmonary histoplasmomas tend to be distinct, however, because their caseous central portion is often composed of multiple concentric lamellae, resembling the growth rings of a tree (Fig. 11–4). Although this lamellated appearance is characteristic of a histoplasmoma, it is not patho- gnomonic and may also be produced by other organisms. Disseminated histoplasmosis differs grossly in that necrotizing granulomas are usually not seen. Microscopically, histoplasmomas and other forms of histoplasmosis (except disseminated histoplasmosis, see text following) are indistinguishable from necrotizing granulomas caused by other fungi and mycobacteria.6 Usually, the granulomas are well circumscribed and often contain a layer of laminated acellular collagen that is external to a rim of active granulomatous inflam- mation (Fig. 11–4b). Central calcification is common. In occasional cases, the granulomas are poorly circum- scribed, and the inflammatory process may invade and destroy the pulmonary parenchyma in an irregular pattern. The frequent occurrence of infarct-like necrosis and vasculitis (see Fig. 11–1b) in such cases initially may suggest Wegener’s granulomatosis. The correct diagnosis is established, however, when organisms are demonstrated in special stains or cultures. GMS is the most useful stain for identifying histoplasma in lung granulomas. Numerous organisms can usually be found within the central necrotic zones, although they may be sparse in the poorly circumscribed lesions (Fig. 11–5).6 They appear as small, uniform, oval-shaped yeasts ranging in size from 1 to 5 μm (average, 3 μm). Budding forms can be found but usually are not numerous. The organisms cannot be seen in routine H and E stains unless they are present within histiocytes, a finding usually observed only in disseminated histoplasmosis (see text following). Rarely, hyphae have been described 310 INFECTION II. GRANULOMATOUS INFECTIONS Figure 11–4 Histoplasmoma. (a) Gross appearance of a necrotizing granuloma due to histoplasma. Note the lamellated, tree- ring appearance of the necrotic zone. This appearance, although characteristic of histoplasmoma, is not specific and can be seen in other fungal as well as mycobacterial granulomas. (b) Microscopic appearance of necrotizing granuloma, showing the characteristic epithelioid histiocytes surrounding central necrosis. (a) (b) W0041-Ch11.qxd 2/4/06 12:14 PM Page 310 in tissue, most commonly in cases of endocarditis with intravascular growth.11 In one case of acute histoplasmosis biopsied early in its course, granulomas were said to be absent, and the main finding was an intraalveolar mononuclear inflam- matory cell exudate, containing organisms.14 That patient, however, was an intravenous drug user and may have had underlying immune compromise (AIDS) that altered the inflammatory response. In our experi- ence, active granulomatous inflammation is seen even in early acute histoplasmosis, although the granulomas may have purulent centers. Disseminated histoplasmosis differs microscopically from other forms of histoplasmosis in that well-formed, necrotizing granulomas are usually absent, and the organisms are present extensively within histiocytes.10,13 In the lung, the interstitium is the main site of involve- ment, although histiocytes accumulate within alveolar spaces as well (Fig. 11–6). At low magnification, the alveolar septa and peribronchiolar tissue appear expanded by sheets of plump histiocytes with granular cytoplasm, and organism-filled macrophages may pack alveolar spaces. The typical morphology of the intra- cellular organisms is readily appreciated when the slides are examined under higher magnification. In contrast to the granulomatous forms of the disease, in which the organism usually cannot be visualized in H and E stains, the intracellular yeasts in disseminated histo- plasmosis are readily visible in routine H and E stains. They appear as small, ovoid bodies with a single, often eccentric nucleus and a characteristic perinuclear clear zone resulting from shrinkage of protoplasm from the cell walls (Fig. 11–6, inset). Staining Techniques Sometimes, histoplasma stains only faintly with GMS, even when a control slide using another fungus (usually candida or aspergillus) stains strongly.6 For this reason, a control slide conta