Case 4 -

Necrotizing Granulomatous Inflammation with Rare AFB Consistent with MAC Andras Khoor Mayo Clinic Jacksonville, FL

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Clinical History: A 32-year-old woman presented with a 4-month history of progressively worsening nonproductive cough. Her history was notable for frequent use of her neighbors' outdoor hot tub. A chest radiograph (CXR) was suspicious for a cavitary lesion in the left base. Due to worsening cough and dyspnea, she was hospitalized for further evaluation. A CT scan of the chest confirmed a cavitary lesion in the left lower lobe (LLL). Sputum cultures and bronchial washings revealed Mycobacterium avium intracellulare complex (MAC). She was initially treated with ethambutol and azithromycin. Over the course of a week, fevers with temperatures up to 102.4°F, night sweats, progressive dyspnea, and a worsening, now productive cough developed. A repeat chest CT scan revealed the development of bilateral lower lobe infiltrates and a persistent LLL cavity. Therapy with ciprofloxacin was added without noticeable benefit. After 23 days of hospitalization, she was transferred to our facility for further evaluation. On presentation, she was febrile. The physical examination revealed a very toxic-appearing, tachypneic, thin white female. She became dyspneic after walking < 20 feet. Her CXR revealed ill-defined, multifocal airspace consolidation in both the mid and lower lung zones. On admission to our institution, therapy with ethambutol, azithromycin, and ciprofloxacin was discontinued. Further evaluation included a chest CT scan, which revealed dense areas of consolidation in the lingula and bilateral lower lobes. A 2.8 X 2.9 cm cavitary lesion was present in the LLL. There were scattered small centrilobular nodular opacities in the upper lobes that were consistent with bronchiolitis. A new sputum smear revealed 4+ acid-fast bacilli (AFB), and the culture grew 4+ MAC identified by DNA probe. A BAL from the LLL produced seven colonies of MAC; no other organisms were identified. Transbronchial biopsy specimens revealed a single vaguely formed granuloma. An open lung biopsy specimen was obtained to exclude other etiologies and to confirm the diagnosis of MAC infection. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: Biopsy specimens obtained from the right middle and lower lobes revealed granulomatous inflammation with well-formed, necrotizing granulomas. Ziehl-Neelsen stain revealed rare AFB. GMS stain was negative for fungal organisms. MAC was isolated from cultures of the lung tissue. Fungal culture and bacterial cultures for both aerobic and anaerobic bacteria from the lung tissue were negative. Cultures of the hot tub water failed to grow MAC. Case 4 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 4 - Figure 1 Panoramic view of the biopsy showing large consolidated areas (x0.5). Case 4 - Figure 2 Bronchiolocentric granulomas (x5.1) Case 4 - Figure 3 Extensive granulomatous inflammation with necrosis (x1.8). Case 4 - Figure 4 Same area as Fig 3 at medium power showing granulomatous inflammation with necrosis (x3.9). Case 4 - Figure 5 Granulomatous inflammation with necrosis and giant cells (x8.4) Case 4 - Figure 6 High power view showing granulomatous inflammation with necrosis, epithelioid histiocytes and multinucleated giant cell (x20). Differential Diagnoses: Differential diagnoses for necrotizing granulomas Infections Tuberculosis Non-tuberculous mycobacteria Fungi Histoplasma Cryptococcus Blastomyces Coccidioidomyces Miscellaneous Granulomatous bacterial infections Dirofilaria Other Wegener's granulomatosis Churg-Strauss syndrome Necrotizing sarcoid granulomatosis Bronchocentric granulomatosis Rheumatoid nodules Differential diagnoses for MAC lung disease Fibrocavitary MAC MAC in association with immunodeficiency Reticulonodular MAC with cylindrical bronchiectasis (Lady Windermere syndrome) Hot tub lung Final Diagnosis: Necrotizing granulomatous inflammation with rare AFB consistent with MAC. Comment: The clinical and pathologic features do not conveniently fit into any of the known categories of MAC lung disease. Case Discussion: The biopsy showed granulomatous inflammation with well formed necrotizing granulomas. Differential diagnoses for necrotizing granulomas are included in the "Differential Diagnoses" section. Most necrotizing granulomas are caused by infection, usually mycobacterial or fungal. In our case, Ziehl-Neelsen stain revealed rare AFB, and MAC was isolated from cultures of the lung tissue. Therefore, we had convincing evidence that the patient's granulomatous lung disease was caused by MAC. The real question was: What kind of MAC associated lung disease does this patient have? Four distinct clinicopathologic forms of MAC lung disease have been reported in the literature: 1) Fibrocavitary MAC: Fibrocavitary MAC has been described in older patients with a history of smoking and underlying structural lung disease, most commonly COPD. Other associated conditions include pulmonary fibrosis, rheumatoid lung, healed tuberculosis, silicosis and other pneumoconioses, previous chest surgery, and lung cancer. Children and young adults with cystic fibrosis represent a special subgroup of this presentation. Symptoms of fibrocavitary MAC are usually insidious. Radiographic findings include bilateral thin walled cavities and fibrocavitary disease. Histologic examination reveals necrotizing granulomas, which can be indistinguishable from tuberculosis. The course is usually slowly progressive. Antimycobacterial therapy is often beneficial, but recurrence is common and resection is required in some cases. The treatment of underlying lung disease is critical to the long-term management. 2) MAC in association with immunodeficiency: The second form of MAC lung disease was first described in patients with AIDS. It has also been reported in patients with immune deficiency due to steroids, organ transplants, leukemia, lymphoma, and severe combined immunodeficiency. These patients often present with severe disseminated MAC and the pulmonary manifestation is frequently destructive and cavitary. Histologic examination often reveals necrotizing granulomatous inflammation and accumulation of foamy macrophages filled with AFB. There is considerable mortality even with treatment, but prophylaxis can be effective. 3) Reticulonodular MAC with cylindrical bronchiectasis (Lady Windermere syndrome): This form of pulmonary MAC is characterized by slowly progressive nodular opacities and cylindrical bronchiectasis with a predilection for the right middle lobe, lingula, and dependent areas of the lung. Typical patients are thin, immunocompetent elderly females with no history of smoking or pre-existing lung disease. Prince et al have hypothesized that fastidiousness among these women contributes to disease development and dubbed this form of pulmonary MAC as Lady Windermere syndrome. Histologically, granulomatous inflammation, with or without necrosis, is present. Antimycobacterial therapy, in conjunction with bronchial hygiene, often leads to clinical and radiographic improvement, but the disease is chronic with a course that is characterized by frequent relapses. 4) Hot tub lung: Lung disease secondary to aerosolized MAC from hot tubs has more recently been described as a new form of MAC lung disease. Patients are typically young and immunocompetent. Most cases occur with indoor hot tubs since they are believed to allow maximal concentration of the aerosolized water in a confined space. Typical signs and symptoms at presentation include cough, dyspnea, chest tightness, fatigue, and hypoxia that progresses over the course of several weeks to months prior to diagnosis. Diffuse interstitial or nodular infiltrates are noted on the CXRs of virtually all of the documented cases. A high resolution CT scan of the chest typically demonstrates ground-glass opacities and scattered nodules with upper lobe predominance. Cavitary disease has not been described in this population. Sputum cultures from patients with hot tub lung are consistently positive for MAC. It is also helpful to grow MAC from the implicated hot tub water to confirm the diagnosis. Histologic examination most commonly reveals discrete nonnecrotizing granulomas. Other reported histopathologic findings include organizing pneumonia, patchy interstitial pneumonia, and occasional necrotizing granulomas. The histologic findings of hot tub lung are in distinct contrast to those found in patients with hypersensitivity pneumonia, which generally demonstrate vaguely formed granulomas with prominent interstitial infiltrates. Some authorities have postulated that hot tub lung is a hypersensitivity pneumonia reaction; others have argued that it is an infectious process. Proponents of hypersensitivity pneumonia cite several salient points including the rapid onset of symptoms, temporal relationship to hot tub exposure, and rapid clinical improvement after removal of the exposure. Our patient's clinicopathologic characteristics are not fully consistent with any of the previously described categories of MAC lung disease: 1) Fibrocavitary MAC: The patient had no preexisting clinical or radiographic evidence of chronic lung disease. 2) MAC in association with immunodeficiency: She was immunocompetent without a history of recurrent infections and had negative HIV test findings. 3) Reticulonodular MAC with cylindrical bronchiectasis (Lady Windermere syndrome): Our patient was female and a life-long nonsmoker, and had evidence of nodular infiltrates that are similar to those found in patients with Lady Windermere syndrome, but she was much younger than is typical for patients with this syndrome. More importantly, the severe, rapidly progressive nature of her disease, her toxic appearance at presentation, as well as the radiographic appearance of early cavitary disease, diffuse consolidation, and absence of bronchiectasis would be most atypical for patients with this form of MAC disease. 4) Hot tub lung: Our patient's demographics and clinical history would be appropriate for hot tub lung. The inability to grow MAC from water from her neighbor's hot tub does not exclude this diagnosis; other water sources could have been origin of the infection. Her radiologic manifestation of cavitary disease, however, has not been described in patients with hot tub lung. The diffuse necrotizing granulomatous inflammation found on her lung biopsy specimen is not characteristic of hot tub lung and is more characteristic of an infectious process rather than a hypersensitivity reaction. The patient's condition did not improve with simple removal from the source and continued to worsen during her hospital course prior to effective treatment. Review of the Literature/Treatment Options : The initiation of treatment with appropriate antimycobacterial agents combined with a 1-month course of steroids led to rapid and dramatic improvement in both symptoms and gas exchange, as well as to improvement in radiographic findings. Complete radiographic improvement did not occur within the typical period of 2 to 3 months as described with most cases of hot tub lung. Conclusion(s): This case may represent a more severe, fulminant form of hot tub lung or an entirely new form of MAC associated lung disease. Either way, the possibility of MAC should be considered in young, otherwise healthy individuals with fulminant cavitary lung disease. References: Marchevsky A, Damsker B, Gribetz B, et al. The spectrum of pathology of nontuberculous mycobacterial infections on open-lung biopsy specimens. Am J Clin Pathol 1982; 78:695-700 Farhi DC, Mason UG, Horsburgh CR. Pathologic findings in disseminated Mycobacterium avium-intracellulare infection. Am J Clin Pathol 1986; 85:67-72 Prince DS, Peterson DD, Steiner RM. Infection with Mycobacterium avium complex in patients without predisposing conditions. N Engl J Med 1989; 321:863-868 Reich J, Johnson R. Mycobacterium avium complex pulmonary disease presenting as an isolated lingular or middle lobe pattern: the Lady Windermere syndrome. Chest 1992; 101:1605-1609 Kahana LM, Kay M, Yakrus MA, et al. Mycobacterium avium complex infection in an immunocompetent young adult related to hot tub exposure. Chest 1997; 111:242-245 Embil J, Warren P, Yakrus M, et al. Pulmonary illness associated with exposure to Mycobacterium-avium complex in hot tube water: hypersensitivity pneumonitis or infection. Chest 1997; 111:813-816 Khoor A, Leslie KO, Tazelaar HD, et al. Diffuse pulmonary disease caused by nontuberculous mycobacteria in immunocompetent people (hot tub lung). Am J Clin Pathol 2001; 115:755-762 Aksamit TR. Hot tube lung: infection inflammation, or both? Semin Respir Infect 2003; 18:33-39 Cheung OY, Muhm JR, Helmers RA, Aubry MC, Tazelaar HD, Khoor A, Leslie KO, Colby TV. Surgical pathology of granulomatous interstitial pneumonia. Ann Diagn Pathol. 2003; 7:127-38 Waller EA, Roy A, Brumble L, Khoor A, Johnson MM, Garland JL. The expanding spectrum of Mycobacterium avium complex-associated pulmonary disease. Chest. 2006; 130:1234-41 El-Zammar OA, Katzenstein AL. Pathological diagnosis of granulomatous lung disease: a review. Histopathology. 2007; 50:289-310