Section 1 -

Atypical Manifestations of Pulmonary Infections Carol Farver Cleveland Clinic

Introduction Pulmonary pathologists commonly encounter cases of non-neoplastic lung pathology with unusual patterns of injury. When infection is suspected clinically, the pathologist is presented with the task of deciding which organisms can cause these histologic pictures. In general, unusual or 'atypical' infectious patterns of injury are the result of one of two scenarios: 1) Typical patterns of injury to uncommon (rarely encountered) organisms, or 2) Atypical patterns of injury to common organisms. Examples of the latter are presented as an overview of this extensive topic. As will become apparent in these examples, the unusual pathologic patterns usually arise as a result of defects in the host's lung defenses that either allow an otherwise benign organism to be a pathogen (the first scenario) or alter the usual host response to a pathogenic organism (the second scenario). Thus, the status of the host's lung defenses may provide a useful clue to whether or not an 'atypical' infectious pattern of injury is present. Atypical Patterns of Common Organisms Atypical variants of Non-tuberculous Mycobacteria Chronic Bronchiolitis with Bronchiectasis Prince et al described this form of MAC disease in 1989 and found it to be restricted to older non-smoking, HIV (-) Caucasian females. These patients present with an indolent productive cough, few constitutional symptoms and have no history of underlying lung disease (Prince, 1989). Radiographically, the appearance is distinct and consists of multiple small nodules (<5 mm) and branching linear structures combined with bronchiectasis in the same lobe of the lung (Patz, 1995) The pathology is predominantly that of chronic airway changes consisting of bronchiectasis with a chronic bronchiolitis, organizing pneumonia and granulomatous inflammation predominantly in the form of non-necrotizing granulomas and giant cells in the peribronchiolar area. The granulomas and giant cells consist of mononuclear cells and epithelioid histiocytes and are usually adjacent to areas of lymphocytic inflammation involving alveolar walls. In larger airways, there is destruction of bronchial cartilage and smooth muscles layers, ulceration of the bronchial mucosa and development of metaplastic squamous mucosa in the areas of repair. Also, other features of chronically inflamed airways, such as neuroendocrine cell hyperplasia and carcinoid tumorlets may be found. Organisms are not abundant and are rarely found in the sputum of these patients. Proximal Endobronchial Disease Isolated endobronchial lesions due to NTM are an unusual manifestation of the disease and can be seen in both adults and children (Nolt, 1995; Manali, 2005; Asano, 2002). The majority of the cases are due to MAC and present in the segmental airways in HIV patients as polyps (Kalayian). There is a single case report of endobronchial disease in an HIV negative adult with a long history of tracheal stenosis due to distortion of the carina by TB in his youth (Manali, 2005). Recent reports of isolated proximal airway polyps due to NTM have been reported in children. In those children with endobronchial disease, the usual clinical presentation was cough and wheezing with the initial clinical diagnosis of foreign body aspiration or asthma. Chest x-rays from both the adults and children revealed evidence of air-trapping and the majority had medastinal adenopathy consistent with involvement by NTM. Bronchoscopic images revealed white polyps occluding the proximal airways, some reported as fungating and ulcerating. Microscopic evaluation revealed necrotizing and non-necrotizing granulomas with ulceration and granulation tissue in the surrounding area. In both adults and children, the most common organisms cultured were MAC. Inflammatory Pseudotumor A marked spindle cell proliferation caused by NTM has been reported in the skin, lymph nodes and bone marrow. A similar lesion has been reported due to M. tuberculosis in the lungs (Sekosan, Cleto, et al. 1994). These inflammatory pseudotumors are found in immunocompromised patients including transplant patients and patients with AIDS (Baron, 1991; Sekosan et al. 1994; Logani et al. 1999; Umlas et al. 1991). Microscopically, there are whorls of spindle cells mixed with lymphocytes, plasma cells and dense collagen bands. In some areas the spindle cells can become more plump, resembling histiocytes, the probable cell of origin (Brandwein et al, 1990). Granulomas are usually not seen, though poorly-formed granulomata have been reported in lesions involving the skin (Brandwein et al. 1990). A Ziel-Neelsen stain reveals abundant intracellular acid fast organisms. Atypical histologic variants of Pneumocystis jiroveci In over half the cases of Pneumocystis jiroveci, atypical morphologic features are present (Weber, 1977). These include the following five histologic patterns. Diffuse alveolar damage Diffuse alveolar damage with prominent hyaline membranes has been in reported in 9 of 17 cases of Pneumocystis jiroveci by Askin and Katzenstein (Askin 1981). In this setting, cysts are incorporated in hyaline membranes, which may make them difficult to see by GMS staining. Diffuse interstitial fibrosis Diffuse interstitial fibrosis has been described (Gal 1989), however, this remains a controversial entity. The pathology is that of a diffuse fibrosis and may represent the fibrotic stages of a DAD from causes other than P. jiroveci. Necrotizing Pneumocystis jiroveci This histologic variant is found predominantly in patients with AIDS. The necrosis usually results from a dense intra-alveolar and interstitial infiltration of P. jiroveci, which proceeds to produce necrosis and cavitation (Saldana, 1989; Barrio, 1986). Infiltration of blood vessels by P. jiroveci may cause occlusion and ischemia and contribute to the necrosis. Travis et al report that ill-formed granulomas and calcification of the P. jiroveci exudate can be seen in this entity (Travis 1990). Upon healing, this form of P. jiroveci lung disease may produce thin-walled cysts that are predisposed toward spontaneous pneumothorax (Liu, 1989). Granulomatous Pneumocystis jiroveci A granulomatous response to P. jiroveci infection was increasingly reported during the 1980's AIDS epidemic. Previously, granulomas associated with this infection were described as ill-formed aggregates of histiocytes. However, in the AIDS population, the granulomas became well-formed, with central necrosis, similar to tuberculoid granulomas seen in miliary mycobacterial or fungal infections. (Cupples, 1989). More recently, this form of Pneumocystis infections has been seen in a variety of other settings of immunocompromised immunity, including transplantation (Cruickshank B, 1975), malignancy (Lauffer, 2004), and elderly patients (Travis, 1990). Unlike the other variants of PJ disease where the organisms are abundant, in this form, the PJ organisms are usually very sparse in the necrotic centers of the granulomas. Atypical Manifestations of Fungal Diseases Histoplasma Histoplasmosis capsulatum usually causes disease by inhalation of airborne spores manifesting as airway-based necrotizing and non-necrotizing granulomas that must be differentiated from other infectious causes. However, in the immunocompromised host, the response to this organism produces the following atypical patterns. Progressive disseminated histoplasmosis with diffuse alveolar damage This form usually follows massive fungal exposure of a normal person but occurs far more frequently in immunodeficient hosts. Diffuse alveolar damage with hyaline membrane formation is seen (Garrido, 2006). Foamy histiocytes in the alveolar spaces contain abundant yeast forms on Gomorri methenamine silver stain. Yeast forms may also be seen circulating within the alveolar capillaries if significant fungemia is present. Systemic invasion may result in hepatosplenomegaly, interstitial pneumonitis, and mediastinal lymphadenopathy. The most difficult distinction of this form is with Torulopsis glabrata, and Penicillium marneffei. T. glabrata is of similar size but is amphophilic and stains entirely with H & E stains. P. marneffei is also of similar size and shape but it does not bud though may form short hyphal or "sausage" forms that are up to 20 μ and contain septae. Capsule-deficient cryptococci may resemble H. capsulatum, however, should be more pleomorphic, ranging in size from 2 μ to 20 μ and will stain faintly for mucin by a mucicarmine stain. The amastigotes of Leishmania may be included in the differential if the patient has traveled to warmer parts of the globe such as Mediterranean , the Orient or Africa . However, these organisms have dot-like basal bodies or kinetoplasts. Similarly, Toxoplasma gondii may be confused with H. capsulati, but stain entirely with H&E, do not bud and, like Leishmania, do not stain with GMS. Cavitating histoplasmosis This form usually arises out of a chronic pulmonary histoplasmosis most commonly found in lungs with underlying chronic lung disease (Gallant, 1996) and in lungs of elderly patients (Loewen, 1960). This pathology is characterized by extensive, airway-based granulomas involving the entire lung. These granulomas undergo fibrosis, calcification and, rarely, cavitation (Loewen, 1960). In the largest series, cavitation is reported in approximately 2% of all cases of histoplasmosis (Connell, 1976) and approximately 20% of those of chronic pulmonary histoplasmosis (Goodwin, 1976). Upper lobe cavities are most common (Wheat, 1984, Goodwin, 1976) and many times this disease cannot be distinguished radiographically from tuberculosis. The pathology of the cavity shows a histiocytic infiltrate lining a thickened fibrous wall. Toward the center of the cavity, granular and caseous material is commonly seen containing degenerating macrophages. 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