A 47-Year-Old Woman With Progmsive Dyspnea and Recurrent Pneumotbmces*

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1 ' CHEST Postgraduate Education Corner -- CHEST IMAGING AND PATHOLOGY FOR CLINICIANS A 47-Year-Old Woman With Progmsive Dyspnea and Recurrent Pneumotbmces* Seth Brant, MD; Mark S. Parker, MD; Lisa K Brath, MD, FCCP; and Margaret M. Grimes, MD, FCCP (CHEST 2009; 135: ) 47-year-old woman was referred for evaluation Aof dyspnea and recurrent bilateral pneumothoraces, with the last episode requiring left apical resection and talc pleurodesis. The pathology from this procedure revealed only a scarred bleb lining. Dyspnea was described as insidious and gradually progressive since onset 5 years earlier. The medical history was notable for emphysema. The findings of a review of systems was otherwise negative, as was the family history. A social history revealed a 10 pack-year history of smoking with current use being described as sporadic. The physical examination findings were unremarkable with the exceptions of pulse oximetry values of 82% while breathing room air and a well-healed thoracotomy scar. The data available at the time of referral included normal serum chew levels, CBC, and a,-antibypsin levels, along with pulmonary function test (PFT) results that revealed an FEV, 74% of predicted, FVC 97% of predicted, and FEV,/FVC ratio 62% of predicted. The diffusing capacity of the lung for carbon monoxide ( DLCO) was also 27% of predicted. 'From the Divisions of Pulmonary and Critical Care (Drs. Brant and Brath), Thoracic Imaging (Dr. Parker), and Pathology (Dr. Grimes), Virginia Commonwealth University Health System, Richmond, VA. Dr. Parker receives royalties as a coauthor of the textbook Teaching Atlas of Chest Zmagin and functions as a paid consultant of Design Consultant Workvide Innovations and Technologies, Inc. Drs. Brant, Brath, and Grimes have re rted to the AccP that no significant conflicts of interest exist wigany com nies/organizations whose pcodud~ or services may be discusseck this article. Manuscript received May 5,2008; revision accepted October 13, Reproduction of this article is rohibited without written permission from the American college orchest Physicians ( org/sitdmidreprints.xhtml). Correspondence to: Seth Brant, MD, Pulmofia Critical Care Fellow, VCU Health System, 1200 Enst B J - 9, lolf West Hospital, Richmond, VA 23298; sbranthh-ocu.edu DOI: /chest After reviewing the chest imaging, the patient subsequently underwent video-assisted thoracoscopic lung biopsy. Radiologic Findings Posteroanterior (Fig 1, Zef, A) and lateral (Fig 1, right, B) chest radiographs demonstrate increased lung volumes and diffuse bilateral reticular opacities. Subtle cystic airspaces are seen to better advantage on the lateral view radiograph (Fig 1, right, B). A small left apical pneumothorax and an ipsilateral area of linear scarring in the upper lobe are also seen. A high-resolution CT (HRCT) scan (Fig 2) at the canna reveals the presence of diffuse, thinwalled cysts ranging between 0.2 and 2.0 cm throughout both lungs. The upper and lower lungs were equally affected. The apical pneumothorax is out of the field of view. A few indeterminate subcentimeter nodules were seen elsewhere in the chest (not illustrated). Pathology Findings The specimen consisted of an 8.4 X 3.2 X 2.0-cm wedge of lung parenchyma grossly remarkable for the presence of multiple cysts measuring from 0.3 to 0.8 cm in the greatest dimension. By histologic examination, the cyst walls comprised both normal septa as well as nodular and irregularly organized interstitial infiltrates consisting of spindle and epithelioid cells (Fig 3). These cells resembled smooth muscle cells, having bland nuclear features and eosinophilic cytoplasm with indistinct cell borders. No mitotic activity was evident. Occasional thinwalled vascular spaces were present within the cellular infiltrate. Alveolar spaces contained numerous hemosiderin-laden macrophages. Immunohistmhemisby using antibody HMBd demonstrated a patchy positive reaction in the interstitial cell population.' CHEST I 135 I5 I MAY,

2 FIGURE 1. Radiologic findings and legends. Posteroanterior (lej3, A) and lateral (right, B) chest radiographs demonstrate increased lung volumes and diffuse bilateral reticular opacities. Subtle cystic airspaces are seen to better advantage on the lateral examination. A small left apical pneumothorax and an ipsilateral area of linear scarring in the upper lobe are also seen. Postgraduate Educetion Comer

3 FIGURE 2. HRCT scan. A selected image at the carina reveals the presence of diffuse thin-walled cysts ranging between 0.2 and 2.0 cm in size throughout both lungs. The u per and lower lun s were equal affected. The apical neumotl!orax is out of the fie P d of view. A Ekw indeterminate su gc entimeter nodules were seen elsewhere in the chest (not illustrated). FIGURE 3. Walls of the c parenchymal lesions consist of aheohr septa infiltrated by spin r e and epithelioid cells (hematoxyheosin, original x 40). What is the diflerential diagnosis? Final diagnosis? CHEST I I MAY,

4 Diagnosis: Sporadic lymphungioleiomyornutosis CLINICAL DISCUSSION Lymphangioleiomyomatosis (LAM) is a rare disease characterized by the proliferation of abnormal smooth muscle cells within the lungs and lymphatic system, leading to diffuse cystic lung disease and progressive respiratory failure. Dyspnea or spontaneous pneumothorax is the typical presenting symp- Dyspnea typically becomes more prominent as LAM progresses, resulting from progressive airflow obstruction and parenchymal lung replacement by cysts. Pneumothorax is seen at some point in most cases and tends to be recurrent.1.2 Other manifestations include chylous pleural or peritoneal fluid collections, hemoptysis, and abdominal angiomyolipomas, occurring most commonly in the kidneys where they are seen in up to 50% of patients Traditionally, LAM has been described as occurring in premenopausal women. In the past few years, this belief has been challenged,2.57 with LAM having been detected in postmenopausal women and a male patient without tuberous sclerosis complex. In addition to the sporadic form of LAM, advanced cell biology techniques have demonstrated a tuberous sclerosis complex (TSC)-associated LAM that shares many of the same clinical and morphologic feat~res.7.~ Consequently, in all cases of suspected or confirmed LAM, patients should be carefully screened for the presence of TSC. A diagnosis of TSC is suggested by the presence of mental retardation, seizures, or dermatologic findings such as adenoma sebaceum or shagreen patches. These features were notably absent in our patient.9 While PFT results may reveal a variety of patterns, air-flow obstruction and a diminished DLCO occur in > 50% of patient^.^ The annual decline in FEV, has been found to be threefold to fourfold that of normal. lo Reported poor prognostic factors include the presence of air-flow obstruction and increased total lung capacity at the initial presentation, reversible aidlow demonstrated by positive bronchodilator response, and impairment of DLCO.~IJ~ Histologic factors may explain some of the different PFT result patterns wherein the proliferation of LAM cells around the airways may be associated with a decline in expiratory flow, but not DLCO; whereas, the presence of cystic lesions in the lung parenchyma may be associated with a decline in DLCO rather than expiratory flow.llj2 Similar to pulmonary Langerhans cell histiocytosis (PLCH) and sarcoidosis, a mixed pattern of obstruction and restriction may also be seen in patients with LAM. The differential diagnosis of cystic lung disease, in addition to LAM, includes emphysema, PLCH, lymphoid interstitial pneumonia (LIP) and Birt-Hogg- Dub6 (BHD) syndrome. The absence of distinct cystic walls enables the clinician to rapidly distinguish emphysema from true cystic lung disease. Although the clinical presentation of PLCH and LAM may be similar, important clinical and radiologic features differentiate them. While pneumothoraces may be seen in up to 25% of cases and PFTs initially demonstrate a reduced DLCO with preserved lung volumes, the majority of patients with PLCH are smokers in their 20s and 30s, with no gender ~redilection.l~-~~ Additionally, the combination of irregular cystic lesions and nodular opacities, seen predominately in the upper and middle zones, are more characteristic of PLCH.l4-I6 LIP refers to a rare clinical entity that is thought to represent a nonneoplastic, inflammatory pulmonary reaction to a variety of infectious stimuli and systemic diseases.17 It occurs most often in association with Sjogren syndrome and HN infection. Most individuals are women in the fourth through seventh decade, presenting with dyspnea and nonproductive cough. PFTs often reveal reduced lung volumes and DLCO. Approximately 80% of patients have serum dysproteinemias. Of note, pneumothorax is not usually associated with LIP.17 BHD syndrome is a rare disease that is associated with a mutation on chromosome 17 encoding the protein folliculin that is inherited in an autosomaldominant manner. Similar to patients with LAM, patients with BHD syndrome may present with a history of recurrent pneumothoraces (20%) and demonstrate diffuse cystic changes seen on an HRCT scan (90%). Important differences that may help to distinguish BHD syndrome from LAM include family history, occurrence in both genders, and the presence of extrapulmonary manifestations (fibrofolliculomas and renal tumors) Radiology Discussion Chest radiography may be normal in up to 20% of LAM patients. However, the more typical radiographic features include diffuse, bilateral, reticular opacities, cystic airspaces, hyperinflation, spon taneous and recurrent pneumothoraces, and/or pleural effusions. Reticular opacities are seen in 80% of affected individuals. Hyperinflation is a relatively late manifestation.13j5j6 Characteristic HRCT scan features include numerous diffusely distributed thinwalled cysts (diameter range, 0.2 to 2.0 cm) throughout both lungs. Such lesions may be seen on HRCT scans even in individuals with normal chest radb graph findings. 13~5~6.21 Nodules are typically absent Postgraduate Education Comr

5 This characteristic appearance on HRCT scans readily differentiates LAM from most other interstitial lung diseases in the vast majority of cases.13j5j691 On chest radiographs, PLCH manifests with symmetric, bilateral nodular or reticular nodular opacities diffusely throughout the upper and mid-lung zones, sparing the costophrenic angles. HRCT scanning is the most helpful imaging modality differentiating PLCH from LAM. Although both diseases are characterized by hyperinflation, PLCH is characterized by nodules and cysts with normal intervening lung, poorly defined centrilobular nodules (1 to 15 mm), solid or cavitating nodules, and cystic lesions of variable sizes (range, a few millimeters to 3.0 cm), often with bizarre shapes, with sparing of the extreme lower lobes.13j5j6 In the majority of cases, these characteristic features allow confident differentiation of PLCH from most other interstitial lung di~ease.~~j~j~.~~~ However, the primary differential diagnostic considerations often include sarcoidosis, silicosis, and hypersensitivity pneumonia, in addition to LAM.'5*25*26 Chest radiography findings are nonspecific in patients with LIP, most often revealing bilateral reticular and nodular opacities, as well as ground-glass opacities and consolidations predominantly in the lower lung zones. An HRCT scan often demonstrates ground-glass opacities and poorly defined centrilobular nodules 2 to 4 mm in size. Thickening of the bronchovascular interstitiurn and interlobular septa, cystic spaces, and lymphadenopathy are additional helpful imaging features HRCT features of BHD syndrome include randomly distributed, variably sized, round-to-ovalshaped cystic lesions throughout both lungs, with a predilection to involve the lung bases more extensively. These cystic changes tend to be more severe in those patients who smoke compared to nonsmokers.18-m CT scans may also reveal the presence of solid renal tumors Pathology Disnrsswn The pathologic changes in patients with symptomatic LAM mirror the clinical and radiologic findings. Obstructive pulmonary function, radiographic cysts, and pneumothorax correspond to the presence of cystic lesions as illustrated in this patient. The diagnostic feature seen on lung histology is the presence of LAM cells, which typically infiltrate blood vessels and lymphatic walls, distal airways, and the interstitium in nodular aggregates or irregular bundles.27.m Vessel disruption accounts for histologic evidence of hemosiderin deposition in alveolar macrophages.27.m Early cases can be difficult to diagnose because LAM cells may be inconspicuous and the histology findings confused with normal lung or emphysema.27 At the other end of the spectrum, advanced cases are characterized by diffuse interstitial involvement and the distortion of alveolar architecture. Nodular lesions seen on chest imaging in some cases may correspond to micronodular pneumocyte hyperplasia in patients with TSC or LAM While subcentimeter nodules were described in the HRCT scan, micronodular pneumocyte hyperplasia was not identified in this patient's biopsy specimen. Some patients present with chylothorax, resulting from LAM cell infiltration of lymphatic vessels. Similar cells may also be found involving mediastinal or abdominal lymph nodes.27 Matsui et a130 proposed a histologic scoring system based on the semiquantitative assessment of lung tissue involvement by cysts and LAM cells; in the study, higher scores correlated with poorer prognosis. LAM cells in the pulmonary interstitium differentiate this process from emphysema and BHD syndrome. In the latter, lung biopsy specimens demonstrate intraparenchymal collections of air. UP is characterized by dense interstitial lymphoid infiltrates, and PLCH is characterized by stellate interstitial fibrosis with CDlaand SloO-pOsitive Langerhans' cells. LAM cells exhibit cytologic and phenotypic heter- 0geneity.2~ They vary in shape ranging from spindle to epithelioid.27.m Both spindle and epithelioid cells are common in early cases, while spindle cells tend to predominate in advanced cases.27.m LAM cells, like smooth muscle cells, react with immunohistochemical stains for vimentin, smooth muscle actin, and desmin.27.m These cells, particularly the epithelioid type, variably react with HMB45, an antibady to a glycoprotein found in immature melanocytes.27.w In some cases, they also express estrogen and progesterone receptors, although hormone receptor expression does not always correlate with response to hormonal therapy and may be down-regulated after such therapy.31 Matrix metalloproteinases that likely contribute to connective tissue destruction and cyst formation in pulmonary LAM tend to be increased in the spindle LAM cells.32 The histologic appearances of lung lesions of pulmonary LAM are identical with those of tuberous sclerosis, and LAM cells resemble the cells of renal angiomyolipomas.s.s The latter are found in as many as 50% of patients with sporadic LAM.34 Some evidence33 has suggested a role for the somatic mutation of the TSC gene TSC2 in pulmonary LAM, although the origin of the mutated cell remains unknown. CONCLUSION This case illustrates the clinical, radiologic, and pathologic features of LAM. Although our level of

6 diagnostic confidence was high, the presence of a few scattered indeterminate subcentimeter nodules created some diagnostic concern for PLCH given the patient s history of tobacco abuse, ultimately leading to performance of an open lung biopsy to confirm the diagnosis. REFERENCES 1 Johnson SR. Lymphangioleiomyomatosis. Eur Respir J 2006; 27: Johson SR, Tattersfield AE. Clinical experience of lymphangioleiomyomatosis in the UK. Thorax 2000; %lo Johnson SR, Whale CI, Hubbard RB, et al. SuMval and disease progression in UK patients with lymphangioleiomyomatosis. Thorax 2004; 59: Ryu JH, Moss J, Beck GJ, et al. The NHLBI lymphangioleiomyomatosis registry. Am J Respir Crit Care Med 2006; 173:lOSlll 5 Cohen MM, Pollack-BarZiv S, Johnson SR. Emerging clinical picture of lymphangioleiomyomatosis. Thorax 2005; 60:87S Schiavina M, Di Scioscio V, Conti P, et al. Pulmonary lymphangioleiomyomatosis in a kayotypically normal man without tuberous sclerosis complex. 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