Section 4 -

Mimics of Lung Infection Anthony Gal

One of the greatest challenges for the pathologist is to classify non-neoplastic lung diseases into specific disorders. Pattern recognition is the mainstay of histo-pathological diagnosis and it is of great importance in the evaluation of lung biopsies. Since the lung responds to injury in a stereotypic fashion, irrespective of etiology, the various pathological findings can represent several different diagnoses under consideration. Not infrequently, the lung biopsy shows features that initially suggest an infection, but is subsequently proven to be some other type of pathological process. These mimics can be considered within the framework of three general categories: 1) those in which the pathological findings resemble an infection, 2) those in which the diagnosis of an infection necessitates a thorough clinicopathological correlation, and 3) those in which the clinical or pathological presentation suggests an infection, yet the pathological findings point to another diagnosis (TABLE 1). A. Pathological Mimics The pathological mimics of infection have histopathologcial features that overlap with other disorders. Certain non-infectious disorders associated with a granulomatous inflammatory infiltrate pose the greatest problems for the pathologist. A large number of entities can cause necrotizing and non-necrotizing granulomatous inflammation in the absence of infection. In terms of the former, Wegener's granulomatosis is a systemic vasculitic disorder that causes necrotizing granulomas in the lung, but also can affect the kidneys and head and neck. The necrotizing granulomas have a distinctive appearance with peripheral pallisading and central necrosis. These granulomas may somewhat resemble those seen in tuberculosis and in certain fungal disorders, such as blastomycosis and coccidioidomycosis. The presence of "tuberculoid-type" granulomas in this setting would be more worrisome for infection. Often, the broad areas of "geographic necrosis" bear some resemblance to the "caseous" necrosis seen in certain mycobacterial or fungal infections. The associated vasculitis seen in WG typically affects medium- to small-sized arteries and should be recognized in areas not associated with necrosis. This is an important consideration, since in certain infections or in infarction, the inflammatory cells can involve adjacent blood vessels and mimic a vasculitis. Sarcoidosis is a non-necrotizing granulomatous disorder that poses considerable diagnostic problems for the pathologist. Since certain infections may result in both necrotizing and non-necrotizing granulomas, the pathologist should be concerned that limited samples from transbronchial or needle biopsies may be misleading. In active sarcoidosis the characteristic well-delineated granulomas follow a bronchovascular and interstitial distribution. Small foci of fibrinoid, granular, or eosinophilic necrosis may be present in sarcoidosis; more extensive necrosis with or without vasculitis may be seen necrotizing sarcoid granulomatosis. Although histochemical stains for acid fast bacilli and fungi are useful in confirming the presence of an infection, the absence of organisms in these stains does not exclude this possibility. Certainly, additional correlations with microbiologcal cultures are needed to confirm or exclude an infectious diagnosis. Hamazaki-Wesenberg bodies which occur in various granulomatous disorders may mimic fungal organisms. These distinctive small (1-15μm) round, ovoid, or spindle-shaped yellow-brown structures may be seen in H&E stain. They stain black with GMS or Fontana stain and red with PAS stain. The location of these structures in the subcapsular sinus and lack of association with necrosis are key diagnostic features. Other non-infectious lung diseases evoke a prominent inflammatory response reminiscent of that seen in certain infections. Lymphocytic infiltrates are seen in non-infectious lung diseases, particularly for those disorders involving the airways or interstitum. Neutrophilic infiltrates are commonly associated with a number of acute infectious processes, but are a prominent feature in certain pulmonary alveolar hemorrhagic disorders. A neutrophilic capillaritis, which typically occurs in ANCA-associated disorders and other connective tissue diseases, can be difficult to separate from an early bronchopneumonia. Various types of pulmonary eosinophilic disorders can occur in the absence of infection, and consideration of certain fungal and parasitic disorders is always warranted. Hyperplastic alveolar lining cells that occur in the setting of acute lung injury such as in diffuse alveolar damage can resemble the changes seen in viral infections. The presence of many enlarged hob-nail shaped cells with clumped nuclear chromatin, eosinophilic nucleoli, and the absence of nuclear / cytoplasmic inclusions suggests a reactive process. However, since there can be some morphological overlap with viral infections, judicious use of immunohistochemical stains may be necessary in some cases. B. Clinicopathological Mimics Several disorders affecting the lungs show features that warrant a careful clinicopathological correlation to exclude an infection. In many of these disorders, the pathological findings are variable and overlap with other entities in the differential diagnosis. For example, lung biopsies from patients with acute interstitial pneumonia or with connective tissue disorders, such as systemic lupus erythematosus, may show diffuse alveolar damage. Special stains and correlation with microbiological cultures and serological tests are needed to exclude an infection or autoimmune process. Another example would be in the setting of pulmonary drug toxicity. A large number of drugs may cause direct and indirect injury and exhibit a wide spectrum of histopathological changes. It is only through careful correlation and exclusion of other disorders that this diagnosis can be substantiated. C. Radiological / Clinical Mimics In various clinical settings under which an infection is thought to be the main diagnosis, another pathological process is evident in the lung biopsy. These are the disorders in which there is considerable clinical overlap, yet the distinctive and often characteristic histopathological features make it relatively easy for the pathologist to render these diagnoses. Even as our radiologist colleagues become more confident in their ability to arrive at a specific diagnoses, it is not that uncommon for the pathologist to "surprise the clinician and radiologist" with an unsuspected diagnosis. For example, a multicentric bronchioloalveolar carcinoma or lymphangitic metastases may show radiographic resemblance to an infectious pneumonia. Several of the other disorders listed in TABLE 1 have unique pathological features which would exclude the possibility of infection. D. Conclusions Lung biopsies are preformed in the hopes of achieving useful information that would lead to appropriate clinical management. The separation of infectious lung diseases from its mimics may be straight-forward or more complex, necessitating clinicopathological correlation. As novel therapeutic modalities are implemented, there certainly will be many opportunities and challenges for the pathologist. Mimics of Infection 1. Pathological mimics Granulomas Disorders Wegener's granulomatosis Sarcoidosis Hamazaki-Weisenberg Bodies Lymphocytes Asthma / chronic bronchitis Chronic hypersensitivity pneumonitis Neutrophils Capillaritis Eosinophil-associated lung disease Pneumocyte hyperplasia in acute lung injury 2. Clinicopathological mimics Acute interstitial pneumonia Connective tissue disorders: systemic lupus erythematosus Bronchiolitis obliterans organizing pneumonia Drug toxicity Thromoembolic lung disease 3. Radiological / Clinical Mimics Bronchioloalveolar carcinoma Metastatic neoplasms Lymphoproliferative disorders & lymphoma Rejection in lung and heart-lung transplantation Obliterative bronchiolitis in bone marrow transplant patients Pulmonary alveolar proteinosis DAD / Pulmonary edema Acute & chronic aspiration pneumonia Lipoid pneumonia (exogenous / endogenous) Iatrogenic - Drugs - Radiation - Intravascular foreign body References Colby TV, Specks U. Wegener's granulomatosis in the 1990s--a pulmonary pathologist's perspective. Monogr Pathol. 1993;36:195-218. Flieder DB, Travis WD. Pathologic characteristics of drug-induced lung disease. Clin Chest Med. 2004;25:37-45. Gal AA. Use and abuse of lung biopsy. Adv Anat Pathol. 2005 Jul;12:195-202. Gal AA, Koss MN. The pathology of sarcoidosis. Curr Opin Pulm Med. 2002 ;8:445-51. Katzenstein ALA editor. Katzenstein and Askin's surgical pathology of non-neoplastic lung disease. 3rd Ed. Philadelphia: WB Saunders, 1997. Koss MN, Hochholzer L, Feigin DS, et al. Necrotizing sarcoid-like granulomatosis: clinical, pathologic, and immunopathologic findings. Hum Pathol. 1980;11:510-9. Ro JY, Luna MA, Mackay B, et al. Yellow-brown (Hamazaki-Wesenberg) bodies mimicking fungal yeasts. Arch Pathol Lab Med. 1987;111:555-9. Rosen Y, Vuletin JC, Pertschuk LP, et al. Sarcoidosis: from the pathologist's vantage point. Pathol Annu. 1979;14 Pt 1:405-39. Tomashefski JF Jr. Pulmonary pathology of acute respiratory distress syndrome. Clin Chest Med. 2000;21:435-66. Travis WD, Colby TV, Koss MN, et al, eds. Atlas of non-tumor pathology: non-neoplastic disorders of the lower respiratory tract. Washington : American Registry of Pathology: 2002. Travis WD, Hoffman GS, Leavitt RY, et al. Surgical pathology of the lung in Wegener's granulomatosis. Review of 87 open lung biopsies from 67 patients. Am J Surg Pathol. 1991;15:315-33. Travis WD, Garg K, Franklin WA, et al. Evolving concepts in the pathology and computed tomography imaging of lung adenocarcinoma and bronchioloalveolar carcinoma. J Clin Oncol. 2005;23:3279-87. Ulbright TM, Katzenstein AL.Solitary necrotizing granulomas of the lung: differentiating features and etiology. Am J Surg Pathol. 1980;4:13 -28.