The Pathology of Fungal Disease in the Lung

Transcription

1 The Pathology of Fungal Disease in the Lung HE PATHOLOGIST, like the radiologist, T generates a differential diagnosis based on pattern recognition. However, it is unfortunately true that the lung responds to injury in a limited number of ways and, therefore, a particular pattern of injury is rarely pathognomonic for a specific disease entity. This generalization is especially true for the pathology associated with fungal infections in the lung. Not only is there a significant degree of overlap in the gross and histological features among the various mycoses, but other infectious agents such as mycobacteria can present with identical pathological findings. The broad spectrum of clinicopathological entities encompassed by pulmonary fungal infections is related in part to host factors such as immunosuppression and underlying structural lung disease. Other articles in this issue will cover specific pulmonary mycoses, such as aspergillosis, in depth. There are also several excellent general references available on the pulmonary pathology of fungal diseases. 1-6 The purpose of this article is to briefly review the basic pathology associated with fungal diseases of the lung and the pathologist's approach to diagnosis. Here the focus will be on describing general patterns of injury and the usual pathogens associated with these types of inflammation. The site and manifestations of morphological injury are reflected at a macroscopic level by radiographic imaging and, therefore, this approach should provide further interpretative insight for the practicing radiologist. Fungal terminology, appropriate specimen processing, and current ancillary diagnostic techniques will also be discussed. From the Division of Anatomic Pathology, Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA. Address reprint requests to Leslie A. Litzky, MD, Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, 3400 Spruce St, Philadelphia, PA Copyright 1996 by W.B. Saunders Company X/96/ /0 By Leslie A. Litzky BACKGROUND AND GENERAL APPROACH TO DIAGNOSIS The diagnosis of many pulmonary diseases may rely solely on clinical symptoms, physical findings, and the appearance of the chest radiograph. When a fungal infection such as histoplasmosis occurs in a healthy host in an endemic area and the patient has an uncomplicated course, this may be the extent of the work-up. However, an invasive procedure for tissue examination is often required for the diagnosis of pulmonary fungal infection. The identification of fungal organisms and disease has become a routine practice for pathologists where the population of immunosuppressed patients has been so markedly increased because of human immunodeficiency virus-related illness, organ transplantation, cancer chemotherapy, and prolonged steroid use for a variety of disorders. With the exception of the superficial and cutaneous mycoses, the lung is usually the initial and primary site of systemic mycotic infection through inhalation of aerosolized fungal forms from the environment. Once in the lungs, a fungal infection may be effectively localized by host defenses or can disseminate hematogenously or by lymphatics. It is also not uncommon for an extrapulmonic focus of infection with a fungal species such as Candida albicans to result in fungemia and to secondarily involve the lung. Once established, regardless of the route of infection, fungal infections often cause severe and frequently fatal respiratory disease. The fungi that cause invasive pulmonary infection can be divided into the primary or true pathogens and the opportunistic pathogens. ~ Primary pathogens are those that can cause disease in healthy, immunologically intact patients. Examples include histoplasmosis and coccidiomycosis. By comparison, opportunistic fungi, which are normally ubiquitous in the environment and can be saprophytic, become pathogenic when the host's immune defenses are compromised. A good example of this would be mucormycosis. Considerable overlap exists in this conceptual framework and the type of 4 Seminars in Roentgenology, Vol XXXI, No 1 (January), 1996: pp 4-13

2 THE PATHOLOGY OF FUNGAL DISEASE IN THE LUNG 5 disease that a particular fungal organism can cause can be quite diverse; aspergillosis is a classic example. For the pathologist, it is probably more useful to think in terms of patterns of inflammation, factoring into the differential diagnosis what is known about the patient's travel history, environmental exposure, underlying medical illnesses, medications, and immunologic status. SAMPLING FOR ANATOMIC PATHOLOGY AND SPECIALIZED TECHNIQUES Although, as previously emphasized, histological identification of fungi in tissue sections is often central to the diagnosis, the isolation of the fungus by culture is a complimentary procedure. Rare or fragmented fungal hyphae and pleomorphic yeast forms may be difficult to classify based on histological appearance alone and, therefore, whenever pulmonary mycotic disease is suspected, appropriate samples should be specifically sent for mycotic isolation and culture. Specimens such as sputum, pleural fluid, bronchial washings, or tissue are all suitable for culture confirmation. For radiologists who perform or who assist in fine-needle aspirations, additional material should be set aside for culture if the clinical history, radiographic findings, or the preliminary on-site cytological evaluation of the aspirate suggests infection. Definitive speciation by culture can nonetheless have important epidemiological and prognostic implications, despite the present limited number of therapeutic options. Standard mycologic culture requires up to 6 weeks for completion and ultimately cannot distinguish an environmental contaminant or saprophytic infection from an invasive pathogen. The information obtained from culture cannot be incorporated into clinical decisions when a rapid turnaround time is required for critically ill patients. For these reasons, or when fungal infection was not clinically suspected or could not be cultured, the morphological identification of fungi within cytological preparations or fixed sections continues to play a prominent role in the diagnosis of pulmonary mycoses. Cytology involves the examination of fluids or cell fragments and includes samples such as sputum, bronchial washings, bronchial brushings, pleural fluid and fine needle aspirates of lung tissue. The advantages of cytological specimens for the diagnosis of fungal disease include rapid slide preparation and excellent morphological preservation. The main disadvantage is similar to that of culture in that it is not always possible to confidently exclude saprophytic infection or contamination. Clinical correlation is therefore essential. Tissue sampling in the form of a transbronchial biopsy,, wedge biopsy, or resection of the lesion is usually obtained when it is necessary to histologically document invasion for diagnostic and therapeutic purposes. Excisional biopsy may be pursued as a means of excluding other diagnoses, such as malignancy in a pulmonary nodule, or to optimize diagnostic yield by submitting the entire lesion for histological examination and concomitant culture. In general, the diagnosis of lung disease can be limited by the technique used to obtain cells or tissue and by sampling error. Concomitant bronchoalveolar lavage increases the diagnostic yield of transbronchial biopsy for infections. When smaller samples of tissue are obtained by procedures such as fine-needle aspiration or transbronchial biopsy, it is critically important to correlate the histological findings with the clinical history and the radiographic report. The correct pathological interpretation is more likely when the pathologist actively questions whether the pathological and radiographic findings are consistent. Does the histology account for the diffuse infiltrate noted on chest radiograph? Does the pathological material actually represent the cavitary lesion targeted with computed tomography guidance? Fungi are eukaryotic and unicellular organisms that have cell walls. Because of their size and chemical composition, many fungi can be identified by routine light microscopy. Fortunately, the pathologist must be familiar with the diverse morphology of only a few fungi that are known to be pathogenic and not with the more than 100,000 fungal species that exist in the environment. Fungi can be classified as dimorphic or monomorphic. The term dimorphic indicates that the fungus grows as budding yeast forms (Fig 1) or spherules (Fig 1) in infected tissues or at 37 C on special media but as hyphae in vitro at 25 C. 1 Examples of dimorphic fungi include Histoplasma capsulatum variety capsulatum, Blastomyces derrnatitidis, and

3 6 LESLIE A. LITZKY

4 THE PATHOLOGY OF FUNGAL DISEASE IN THE LUNG 7 Coccidiodes immitis. Other fungi are monomorphic, growing only as yeasts (Cryptococcus neoformans) or hyphae (Aspergillus spp, Mucor spp). Examples of some common forms are illustrated in Fig 1. A yeast is a round to oval unicellular fungus that reproduces by budding or fission. A hypha is a filament that forms the body of most fungi (Fig 1). A pseudohypha is a short hyphal-like filament produced by successive yeast buds that elongate but fail to separate (Fig lg). When there are sufficient numbers of fungi, a genus identification, eg, Aspergillus or Candida, can be assigned with reasonable certainty but precise speciation is not usually possible. Routine hematoxylin and eosin (H&E) staining allows the pathologist to characterize the pattern of injury and, perhaps, to favor one etiologic agent over another. For example, the identification of granulomas typically prompts special histochemical stains to exclude infectious disease. Fungi can occasionally be clearly noted, particularly if numerous, by routine hematoxylin and eosin sections. However, the standard approach to histological analysis in tissue includes the use of special histochemical stains to show fungal morphology and to more precisely assess tissue invasion. These stains include silver stains (such as Gomori's methenamine silver) and the periodic acid-schiff reaction. Silver stains have the added advantage of staining organisms such as Pneumocystis carinii, most mycobacteria and bacteria, so that multiple infectious agents can be excluded with one Fig 1. (A) Histoplasma capsulatum. Small (2 to 4 i~m) budding yeast foims (silver stain, original magnification x 1000). (B) Blastomyces dermatitidis. Larger (up to 25 tzm) yeast forms with broad-based budding (silver stain, original magnification x400). (C) Coccidioides immitis, Large (20 to 40 i~m) spherules with endospores. Arrow at ruptured endospore releasing spherules (silver stain, original magnification 1000). (D) Cryptococcus neoformans. Small, variably sized (5 to 10 I~m) budding yeast, usually with thick capsule. Arrow indicating intracellular yeasts within a multinucleated giant cell (H&E, original magnification x400). (E) Aspergillus spp. True hyphae with septations (3 to 6 ilm wide), 45 branching indicated at arrow, and showing invasion into ulcerated bronchial mucosa (silver stain, original magnification x400). (F) Fungi in the Order Mucorales, Class Zygomycetes (genera Rhizopus, Absidia, Mucor, etc) Broad, nonseptate hyphae, with wide 90 branching (10 to 20 ilm wide) indicated at arrow (silver stain, original magnification x400). (G) Candida spp. Yeast (2 to 4 i~m wide) with pseudohyphae indicated at arrow (silver stain, original magnification 400). stain? Mucicarmine stains are also used to highlight the thickly encapsulated forms of cryptococcus. Poor tissue preservation may distort the fungal hyphae and make the distinction between genera such as Aspergillus and Mucormycosis more difficult] Although misidentification may not practically influence the clinical outcome, subtle differences between genera such as aspergillus and pseudoallescheria should be considered when tissue is received for diagnostic evaluation. Recent advances in the morphological identification of fungi by light microscopy include the use of in situ hybridization for the rapid diagnosis of fungal disease. 8 The technique is based on genus-specific biotinylated oligonucleotide probes that are complementary to highly conserved ribosomal RNA sequences. This method extends the utility of histopathological analysis to more precise fungal classification if fungal forms are present in the tissue. Negative stains do not exclude a diagnosis of fungal infection and it must be stressed that material for culture should always be sent to the microbiology laboratory. PATTERNS OF INFLAMMATION It is critical for the pathologist to recognize that well-characterized patterns of inflammation may be profoundly influenced by the host's immune status. Granulomas may not be well formed or there may be little or no tissue reaction to large numbers of fungi. Organisms may be relatively few in number in more immunologically intact patients and, therefore, more difficult to identify. The practical implication of these differences is that a broader work-up is required beyond standard histology with H&E staining. This work-up should include multiple sections and special stains. Conscious attention to the possibility of multiple infections must also be considered in severely immunocompromised patients. Although each fungal genera is associated with several distinct clinical syndromes, there are enough similarities among the mycoses to permit a general description of pathologic features. What follows is a summary of some of the more significant or characteristic patterns of inflammation with their associated clinicopathological entities. These descriptions are summarized from references that provide a detailed discussion of individual fungal organ-

5 8 LESLIE A. LITZKY isms and the reader is directed to these sources for additional information. 9-3 Acute Pulmonary Histoplasmosis, Acute Pulmonary Blastomycosis, Acute Pulmonary Coccidiomycosis, Pulmonary Cryptococcosis (Immunocompetent HosO, and Candidal Bronchopneumonia Although it is not all that common for radiologists (or for that matter, pathologists) to see patients in the initial phase of a fungal infection, bronchopneumonia is often the initial pattern of fungal infection and may be indistinguishable from a bacterial bronchopneumonia without tissue examination. The infectious organisms that are usually inhaled incite an acute inflammatory response in which neutrophils and fibrin fill alveolar spaces causing the gross appearance of consolidation. At this stage, the fungi can be seen microscopically and special stains can be used to highlight the organisms (Fig 2). The fungal spores proliferate and enter lymphatics that drain into hilar nodes. In the course of a few days to a week or two, the host defenses of most immunocompetent patients will tend to localize the infection by cellmediated immunity. As with mycobacterial infections, fungal antigens are processed by macrophages, presented to B and T lymphocytes, which in turn attract more macrophages that are now activated. The recruited macrophages become "epithelioid"--a term that refers to the histological appearance of macrophages that acquire increased amounts of eosinophilic cytoplasm and, therefore, resemble epithelial cells. Fig 3. Acute pulmonary histoplasmosis. At low power, it is apparent that the granulomatous inflammation obliterates the normal airspaces and the lung parenchyma appears consolidated (H&E, original magnification 40). Accumulated lymphocytes, macrophages and multinucleated giant cells surround and kill the organisms (and the tissue) resulting in granulomas with central necrosis (Figs 3 and 4). This type of necrotizing granuloma cannot be distinguished from mycobacterial disease without special stains. The draining lymph nodes in this region usually show a similar granulomatous response. Certain fungal infections, such as histoplasmosis, have more of a tendency to produce a regional lymphadenopathy but this is not a specific and reproducible finding. Occasionally, massive lymphadenopathy may lead to bronchial obstruction with atelectasis or obstructive pneumonia. The majority of patients with this type of acute infection are asymptomatic and the disease is self limited. In the active inflammatory phase, many of the Fig 2. Acute pulmonary blastomycosis. Large numbers of extracellular yeasts (indicated at small arrows) within intraalveolar exudate of fibrin and neutrophils {H&E, original magnification x 200). Fig 4. Acute pulmonary histoplasmosis. Necrotizing granu- Ioma. Thick arrow indicating multinucleated giant cell. Central necrosis (at star) with a rim of epithelioid histiocytes (thin arrow) and lymphocytes (small arrows) (H&E, original magnification 200).

6 THE PATHOLOGY OF FUNGAL DISEASE IN THE LUNG 9 fungal infections will show a mixed pattern of inflammation that is partially granulomatous and partially suppurative. Suppurative inflammation is characterized by intra-alveolar fibrinous exudates associated with variable numbers of neutrophils and the formation of microabscesses. Certain infections such as histoplasmosis and coccidiomycosis tend to produce more circumscribed caseating granulomas rather than suppurative inflammation. Blastomycosis and cryptococcosis tend to show more microabscesses in association with granulomatous inflammation. The inflammatory response in candidal bronchopneumonia is predominantly neutrophilic but granulomatous inflammation has been described. These characterizations are not sufficiently predictable to permit a definitive etiologic diagnosis without the identification of the microorganism. Either pattern will grossly consolidate the lung and give the radiographic pattern of segmental or nonsegmental opacification. Diffuse alveolar damage may also be seen with overwhelming infections, particularly in immunosuppressed patients. Progressive Disseminated Coccidiomycosis, Disseminated Blastomycosis, Disseminated Cryptococcosis With Mild Immunosuppression, and Embolic Candidiasis Disseminated fungal infections may form miliary nodules, which by definition are small loci of inflammation like millet seeds (typically 1 to 4 mm), distributed randomly throughout the lung (Fig 5). The apparent random distribution, which can be seen grossly and appreciated radiographically, reflects hematogenous spread that may be from an intrapulmonic or extrapulmonic focus. Microscopically, these nodules may be composed of clustered granulomas or Fig 5, Disseminated cryptococcosis. Necrotizing miliary nodules in a patient receiving corticosteroids who was otherwise immunologically competent, Fig 6. Embolic candidiasis. Necrotizing inflammation centered on a small blood vessel (which is starred). A pseudohyphal form is indicated by an arrow (H&E, original magnification 200). neutrophilic microabscesses may predominate. Although the neutrophilic response may be more limited in cytopenic patients, these small nodules are typically necrotic and may be centered around small vessels (Fig 6). There may be some acute exudate and hemorrhage. Mycotic, mycobacterial, and bacterial infections can all be associated with a miliary pattern of spread and therefore special histochemical stains should be incorporated in the work-up. Histoplasmoma, Coccidiomycoma, and Cryptococcoma The most common outcome in immunologically intact individuals is a localized infection that consists of a single large nodule formed by coalescent granulomas or a cluster of smaller nodules. The location of these nodules is typically subpleural and there are often some residual nodules in the hilar or mediastinal lymph nodes. In earlier stages of healing, or with reactivation, the center of the granuloma may be necrotic. In time, these lesions usually fibrose and can calcify leading to the radiographic appearance of a solitary pulmonary nodule (Fig 7). The pathologist encounters these nodules incidentally at autopsy or when they are excised in the usual surgical context of excluding a malignancy. The average size of these nodules ranges anywhere from 0.5 cm to several centimeters in diameter. The incidence of a particular organism will reflect regional endemics and the individual's travel history. Silver stains may, but often do not, reveal

7 10 LESLIE A. LITZKY mycobacterial disease or to determine the etiologic agent. Sclerosing mediastinitis has been epidemiologically linked with histoplasmosis.11 Fig 7. Solitary, subpleural granuloma incidentally discovered at autopsy. residual microorganisms. Solitary residual nodules are reported to be rare with blastomyces. Chronic Pulmonary Histoplasmosis, Chronic Progressive Coccidiomycosis, Chronic Pulmonary Blastomycosis, Chronic Progressive Pulmonary Cryptococcosis Unresolved mycotic infection may result in a chronic progressive form of disease that can be indistinguishable from postprimary tuberculosis. Persistent infection leads to parenchymal destruction with a variable degree of interstitial fibrosis, granulomatous inflammation, cavitation, irregular emphysema, and bronchiectasis (Fig 8). Some differences in distribution, ie, predilection for upper lobe versus lower lobe or tendency to cavitation, do exist among the various mycoses and may suggest a diagnosis other than tuberculosis, but again histological sampling is required to confidently exclude Fig 8. Upper lobe resection from a patient with a chronic granulomatous infection showing cavitation, bronchiectasjs, and fibrosis. The gross appearance would be consistent with postprimary tuberculosis or a chronic progressive mycosis. Invasive Pulmonary Aspergillosis, Invasive Fungi of the Order Mucorales, Class Zygomycetes Aspergillus and mucormycetes are associated with a fulminant invasive form of infection in immunocompromised patients that begins with inhalation and hyphal proliferation within the traeheobronchial tree and results in a necrotizing tracheobronchitis. These hyphae then penetrate through bronchial walls and invade adjacent arterial branches to cause vascular thrombosis and parenchymal infarction. Grossly, these infarcts are nodular, producing a characteristic "target lesion" that appears as a central necrotic zone (in which a thrombosed vessel may be apparent) surrounded by hemorrhage (Fig 9). Microscopically, hyphal forms are easily identified within vessel walls. In severely cytopenic patients, hemorrhage and fibrinous exudates predominate but in less neutropenic patients, the infarcts are septic with large numbers of neutrophils. These infarcts may necrose and cavitate. Invasion of lobar or segmental arteries results in larger hemorrhagic infarcts (Fig 10). PATTERNS OF INFLAMMATION ASSOCIATED WITH SPECIFIC PATHOGENS AND OTHER RARE FUNGAL PATHOGENS Diffuse interstitial inflammation is usually noted in severely immunocompromised patients who cannot mount a more vigorous inflammatory response. Crytococcus can cause a minimal to more marked chronic interstitial inflammatory infiltrate (Fig 11). Numerous organisms may fill alveolar septal capillaries. As the infection progresses, masses of cryptococcal organisms may accumulate--again without eliciting a more exuberant inflammatory response. The alveolar spaces are distended with extracellular microorganisms (Fig 12) and the thickly encapsulated strains of cryptoeoccus create the gross appearance of a "mucoid" pneumonia. Histiocytic inflammation, ie, intracellular accumulations of microorganisms within aggregations of macrophages but no true granuloma formation, can be seen as well. In very young or immunosuppressed patients, disseminated histoplasmosis

8 THE PATHOLOGY OF FUNGAL DISEASE IN THE LUNG Fig 9. Nodular infarcts in a patient who died of invasive pulmonary aspergillosis. can also present as diffuse interstitial inflammation and large numbers of intracellular organisms within histiocytes. Although infrequently biopsied, the syndrome of allergic bronchopulmonary aspergillosis is characterized by a broad spectrum of pathological findings including mucoid impaction, proximal bronchiectasis, bronchocentric granulomatosis, exudative bronehiolitis, and eosinophilic pneumonia. Eosinophilic pneumonia shows abundant eosinophils and some macrophages within alveolar spaces and is accompanied by peripheral eosinophilia. Sections of mucoid impaction show dilated bronchi that are distended by mucus and contain numerous eosinophils, eosinophilic debris, and fragmented Aspergillus hyphae. The mucus has a characteristic laminated appearance. As its name implies, 11 Fig 10, Extensive hemorrhagic infarction in a diabetic with invasion of the left main pulmonary artery by mucormycosis, The patient survived with aggressive surgical resection and antifungal therapy, Fig 11. Early cryptococcosis in a patient with AIDS. There is diffuse chronic interstitial inflammation. Rare organisms confined to the alveolar capillaries were identified on this transbronchial biopsy (H&E, original magnification x200).

9 12 LESLIE A. LITZKY Fig 12. Cryptococcal pneumonia in patient with AIDS. Same patient as fig 11. Sections taken at autopsy showed massive numbers of extracellular organisms distending alveolar spaces (Mucicarmine stain, original magnification x2og). bronchocentric granulomatosis is an inflammatory process that is centered on the airways. The respiratory epithelium is replaced by a necrotizing granulomatous reaction. Adjacent or distal bronchioles may show an acute and chronic inflammatory infiltrate, along with mucostasis and eosinophilic luminal debris. It should be emphasized that bronchocentric granulomatous represents a nonspecific reaction pattern to injury. Other infectious agents besides Aspergillus and noninfectious causes such as Wegener's granulomatosis, have been reported in association with bronchocentric granulomatosis. Surface colonization of the tracheobronchial tree is typical of Aspergillus and can be seen in patients with bronchiectasis, chronic bronchitis, asthma, and cystic fibrosis. An aspergilloma results from the saprophytic colonization of a preexisting pulmonary cavity caused by any number of diseases including tuberculosis and sarcoidosis. The radiographic findings reflect the gross appearance of friable tan-red/brown material within a cavitary lesion. Histologically, the cavity is lined by highly vascularized connective tissue and there is an inflammatory infiltrate within the wall that is mostly chronic in nature. The fungus ball itself is composed of tangles of hyphae and necrotic debris but there is no tissue invasion. In some patients with underlying chronic lung disease (and particularly in association with corticosteroid use), Aspergillus may lead to a locally destructive lesion known as chronic necrotizing (or "semiinvasive") aspergillosis. Cavities that are noted to enlarge radiographically and are excised may show superficial invasion of the adjacent pulmonary parenchyma. As opposed to aspergillomas, chronic necrotizing aspergillosis will respond to antifungal therapy and, therefore, the pathologist is often specifically requested to exclude parenchymal invasion. It is clear that preexisting structural lung disease doesn't always precede this semi-invasive formy These clinical syndromes and histological findings are not specific for Aspergillus or the other more common mycoses. Geotrichum candidum has been isolated as a bronchial colonizer and in cavitary lung lesions. 31 PseudaIlescheria boydii has been shown to be a colonizer in chronic fibrotic or cavitary lung disease. 32 Sporothrix schenkii may involve the lungs secondarily or result in primary pulmonary disease. Primary pulmonary sporotrichosis is a locally progressive and cavitating mycosis that is characterized histologically by necrotizing and non-necrotizing granulomas that are often large and confluent Paracocciodes brasiliensis, which is largely confined to Latin America, causes disease similar to North American blastomycosis? 6 A recent series of adiaspiromycosis caused by the fungus Emmonsia crescens (now renamed Chrysosporium parvum variety crescens) describes both a localized and a disseminated form of disease similar to other mycoses such as Coccidiodes immitis. 37 SUMMARY The gross and histological appearance of pulmonary mycotic disease is rarely pathognomonic for a particular entity. Tissue obtained through an invasive procedure is usually necessary for a specific diagnosis. Pathological diagnosis is directed by the pattern of inflammation and based on the morphological identification of fungi. The interventional radiologist plays a critical role in the diagnosis of pulmonary mycoses by obtaining additional material for culture. An open and inquisitive collaboration between the radiologist and pathologist can improve diagnostic accuracy for both specialists.

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