From the Archives of the AFIP

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1 AFIP ARCHIVES 803 CME FEATURE See accompanying test at /education /rg_cme.html LEARNING OBJECTIVES FOR TEST 6 After reading this article and taking the test, the reader will be able to: Describe the typical radiographic and cross-sectional imaging features of LAM. Correlate the imaging abnormalities with the underlying pathologic features of LAM. Discuss the imaging differential diagnosis of LAM. From the Archives of the AFIP Lymphangioleiomyomatosis: Radiologic-Pathologic Correlation 1 Gerald F. Abbott, MD Melissa L. Rosado-de-Christenson, MD Aletta Ann Frazier, MD Teri J. Franks, MD Robert D. Pugatch, MD Jeffrey R. Galvin, MD Lymphangioleiomyomatosis (LAM) is an uncommon interstitial lung disease that exclusively affects women, usually during their reproductive years. LAM is characterized pathologically by abnormal proliferation of LAM cells in the lungs and in thoracic and retroperitoneal lymphatics. Thirty-three cases of LAM were reviewed retrospectively for clinical and radiologic findings. Twenty-eight (85%) of 33 women (aged years; mean, 37.5 years) were symptomatic. Radiographs (n 32) demonstrated reticular opacities in 21 (66%) patients, large lung volumes in 17 (53%), pleural effusion in 14 (44%), and pneumothorax in 13 (41%). High-resolution CT (n 15) and conventional CT (n 3) showed 2 5-mm bilateral thin-walled cysts in all patients and cysts that were 6 12 mm or larger in patients with severe lung involvement. CT depicted diffuse lung involvement by cysts in nine (50%) patients, relative sparing of lung apices in seven (39%), and relative sparing of lung bases in two (11%). Pleural effusion and pneumothorax were seen at CT in four (22%) and three (17%) patients, respectively. Four cases of tuberous sclerosis complex associated LAM (TSC-LAM) (women aged years; mean, 35.7 years) were similarly reviewed. Three (75%) were symptomatic. Radiographs (n 4) demonstrated reticular opacities in three (75%) and large lung volumes in two (50%). All high-resolution CT (n 3) and conventional CT (n 1) studies showed 2 5-mm bilateral thin-walled cysts and cysts that were 6 12 mm or larger in two patients with severe lung involvement. Pleural effusion and pneumothorax were demonstrated at CT in three (75%) and two (50%) patients, respectively. LAM and TSC-LAM affect symptomatic women who often exhibit reticular opacities and large lung volumes at radiography and bilateral uniform small thin-walled cysts at CT. Large ( 12 mm) cysts occur in patients with severe cystic lung involvement. Pneumothorax and pleural effusion are common associated findings. Abbreviations: Dlco diffusing capacity of lung for carbon monoxide, FEV 1 forced expiratory volume in 1 second, H-E hematoxylin-eosin, HMB human melanin black, IPF idiopathic pulmonary fibrosis, LAM lymphangioleiomyomatosis, TSC tuberous sclerosis complex 2005; 25: Published online /rg Content Codes: 1 From the Dept of Diagnostic Imaging, Brown Medical School, Rhode Island Hospital, 593 Eddy St, Providence, RI (G.F.A.); Dept of Radiology, Ohio State Univ Medical Center, Columbus, Ohio (M.L.R.); Dept of Radiology and Nuclear Medicine, Uniformed Services Univ of the Health Sciences, Bethesda, Md (M.L.R.); Depts of Radiologic Pathology (A.A.F., J.R.G.) and Pulmonary and Mediastinal Pathology (T.J.F.), Armed Forces Institute of Pathology, Washington, DC; and Dept of Diagnostic Radiology, Univ of Maryland Medical System, Baltimore, Md (A.A.F., J.R.G., R.D.P.). Received January 20, 2005; revision requested January 27 and received February 23; accepted February 25. All authors have no financial relationships to disclose. Address correspondence to G.F.A. ( gabbott@lifespan.org). The opinions and assertions contained herein are the private views of the authors and are not to be construed as official nor as representing the views of the Uniformed Services University or the Department of Defense.

2 804 May-June 2005 RG f Volume 25 Number 3 Introduction Lymphangioleiomyomatosis (LAM) is a rare interstitial lung disease that affects women exclusively, typically during their reproductive years. A small percentage of patients, also typically women, have LAM in association with tuberous sclerosis complex (TSC). LAM is characterized by the abnormal proliferation of smooth muscle cells (LAM cells) in the lungs and in the thoracic and retroperitoneal lymphatics. Affected patients are at risk of developing renal hamartomas or angiomyolipomas. Patients with LAM characteristically present with chronic dyspnea and cough and less commonly with spontaneous pneumothorax. At radiography, LAM manifests with normalto-large lung volumes and interstitial reticular opacities that may be subtle. Unilateral pneumothorax and unilateral or bilateral pleural effusions are frequent radiographic findings. Computed tomography (CT) and high-resolution CT demonstrate bilateral diffuse thin-walled cysts surrounded by normal lung parenchyma. CT may also demonstrate associated pleural effusion or pneumothorax; thoracic or abdominal lymphadenopathy; and other abdominal abnormalities including angiomyolipomas, lymphangioleiomyomas, and ascites. Disease severity and progression are evaluated with pulmonary function and gas exchange testing (FEV 1 [forced expiratory volume in 1 second] and Dlco [diffusing capacity of lung for carbon monoxide]) as well as imaging findings. Treatment measures include pleural interventions (to control pneumothoraces and pleural effusions), hormone therapy, and lung transplantation. Demographic features, clinical presentation, imaging features, and lung function abnormalities are almost identical in patients with LAM and TSC-LAM. In this article, we review the clinical, pathologic, and imaging features of LAM and TSC-LAM, complemented by data from a retrospective review of case material contained in the Thompson Radiologic Pathology Archives of the Armed Forces Institute of Pathology. Materials and Methods The records of 33 patients with LAM referred to the Pulmonary and Mediastinal Section of the Department of Radiologic Pathology at the Armed Forces Institute of Pathology between 1960 and 2003 were reviewed retrospectively. Thirty-two patients were evaluated with chest radiography, and 18 with CT, including 15 who were evaluated with high-resolution CT (17 patients underwent both chest radiography and CT Clinical Data for Patients with LAM and TSC-LAM Sign or Symptom LAM (n 31)* TSC-LAM (n 4) Dyspnea 24 (77) 1 (25) Cough 6 (19) 0 (0) Chest pain 8 (26) 2 (50) Hemoptysis 3 (10) 1 (25) Weight loss 1 (3) 0 (0) Asymptomatic 5 (16) 3 (75) Note. Numbers in parentheses are percentages. *Clinical data were not available for two patients, and 10 patients had multiple signs or symptoms. Patients presented with pneumothorax. Two patients were asymptomatic before they presented with chest pain and spontaneous pneumothorax; a third patient had no pulmonary symptoms and cysts were found incidentally at abdominal CT. [either conventional or high-resolution]; 15 patients, chest radiography only; one, high-resolution CT only). Detailed clinical histories were available for 31 patients and were reviewed for age, gender, and clinical presentation. The results of pulmonary function testing were available for 11 patients. Surgical and pathology reports were also reviewed. The diagnosis of LAM was confirmed in each case through the microscopic evaluation of glass slides prepared from resected or biopsy tissue samples and examined by an experienced pulmonary pathologist (T.J.F.). Five thoracic radiologists (G.F.A., M.L.R., A.A.F., R.D.P., J.R.G.) reviewed all chest radiographic and CT studies. Findings were recorded by consensus. Chest radiographs were evaluated to determine the presence or absence of abnormalities, including increased lung volumes, interstitial opacities, ground-glass opacities or consolidations, pneumothorax, pleural effusion, and lymphadenopathy. CT studies were performed at multiple institutions with a variety of scanners and scanning techniques. Eighteen chest CT studies were performed without intravenous contrast material; 15, with high-resolution parameters (1 1.5-mm-section thickness); and three, with conventional parameters (5 10-mm-section thickness). Disease extent was assessed on CT scans by using a visual score to grade the extent of cystic abnormalities as mild ( 25% of the lung parenchyma replaced by cysts), moderate (25% 80% replaced), or severe ( 80% replaced). The visual score was modeled after the method used by Müller et al (1). Cyst size was measured and visually evaluated to estimate the range of cyst sizes observed in each patient.

3 RG f Volume 25 Number 3 Abbott et al 805 Figure 1. LAM in a 32-year-old woman with a 1-month of history of dyspnea. Posteroanterior chest radiograph demonstrates large lung volumes, diffuse bilateral interstitial linear and nodular opacities, and pulmonary artery enlargement suggestive of pulmonary arterial hypertension. Figure 2. LAM in a 23-year-old woman with dyspnea, cough, hemoptysis, and weight loss. Posteroanterior chest radiograph demonstrates normal-to-large lung volumes, bilateral increased interstitial opacities, and bilateral pleural effusions (left one larger than the right). The interstitial opacities are more pronounced in the lung bases, and distinct cystic structures are seen in the right lung base (arrow). Four cases of TSC-LAM were also reviewed. Clinical histories, chest radiographs, and chest CT studies were available for all four patients (three high-resolution CT; one conventional CT). Records and imaging findings for these patients were reviewed and coded by consensus by using the same chest radiologists and techniques previously outlined for the patients with LAM only. Results Patients and Clinical Presentation The 33 women with LAM ranged in age from 21 to 62 years (mean, 37.5 years). Clinical data (available in 31 of 33 patients) are presented in the Table. Pulmonary function testing (performed in 11 patients) revealed obstructive findings in all patients (100%) and decreased diffusing capacity in six (54%). The four patients with TSC-LAM ranged in age from 27 to 50 years (mean, 35.7 years). Clinical data (available in all four) are presented in the Table. Pulmonary function test results were not available for this group. Pathologic Findings Case descriptions of macroscopic analysis, available in five cases, noted hyperaerated lungs with extensive, diffuse cysts affecting both lungs and distorting the pleural surfaces. Histologic diagnosis of LAM was achieved by review of specimens obtained by the following methods: (a) open lung biopsy in 17 patients, (b) transbronchial biopsy in two patients, and (c) lymph node biopsy in one patient. Although tissue specimens were available in every case, the exact technique used to obtain the tissue was not recorded in 13 cases. The diagnosis of LAM was established based on the microscopic examination of every case. Chest Radiographic Findings Lymphangioleiomyomatosis. Thirty-two patients with LAM were imaged with chest radiography. Twenty-nine (91%) had abnormal findings. Lung volumes were increased in 17 (53%) patients (Fig 1) and reduced in one (3%). Interstitial reticular opacities were demonstrated in 21 (66%) patients (Fig 1), predominantly involving the lower lung zones in 20 (Fig 1) and affecting the lung diffusely in one. Cysts were seen in 12 (38%) cases (Fig 2) and were most frequently evident in patients who also had a lower lung zone predominance of interstitial abnormalities (11 of 12 patients). Focal consolidation was demonstrated in one patient, who presented with hemoptysis. No nodules were seen at chest radiography.

4 806 May-June 2005 RG f Volume 25 Number 3 Figure 3. LAM in a 55-year-old woman with cough and acute onset of dyspnea and chest pain. Posteroanterior (a) and collimated posteroanterior (b) chest radiographs demonstrate a moderate-sized left pneumothorax and the suggestion of cysts in the atelectatic left upper lobe. Figure 4. LAM in a 39-year-old woman with dyspnea. High-resolution CT scans (obtained at descending levels) demonstrate bilateral diffuse small thinwalled cysts with relative sparing of the lung apices (cf a with b and c). Note the moderate left pleural effusion.

5 RG f Volume 25 Number 3 Abbott et al 807 Figure 5. LAM in a 52-year-old woman with cough and dyspnea on exertion, who recently had undergone laser ablation and pleurectomy for treatment of recurrent spontaneous right pneumothorax. High-resolution CT scans demonstrate mild involvement by thin-walled cysts randomly distributed throughout both lungs with relative sparing of the lung bases (cf b with a). Pneumothorax was demonstrated in 13 (41%) patients at chest radiography and was associated with an ipsilateral pleural effusion in three. In 10 patients with pneumothorax, the underlying lung exhibited interstitial reticular opacities (Fig 3), and cysts were visible radiographically in five (Fig 3b). In the remaining three patients with pneumothorax, the lungs appeared normal. Pleural effusions were demonstrated in 14 (44%) patients; effusions were bilateral in seven (Fig 2), right-sided in five, and left-sided in two. Ten pleural effusions (71%) were documented as chylous. None of the chest radiographs in this series demonstrated mediastinal or hilar lymphadenopathy. Pulmonary artery enlargement suggestive of pulmonary arterial hypertension was noted in one case (Fig 1). TSC associated LAM. Of four patients with TSC-LAM imaged with chest radiography, three (75%) exhibited abnormalities. Lung volumes were increased in two patients (50%) and normal in two (50%). Interstitial reticular opacities were seen in three patients (75%), and cysts were visible in two of these. The interstitial markings predominantly involved the lower lung zones in two patients and affected the lung diffusely in one. Pneumothorax was seen in one patient and was associated with an ipsilateral pleural effusion. Pleural effusions were found in two patients, with bilateral effusions in one and a right-sided effusion in the other. One effusion was documented as chylous. There was no radiographic evidence of mediastinal or hilar lymphadenopathy or pulmonary arterial hypertension. CT Findings Lymphangioleiomyomatosis. Cysts were observed in all 18 (100%) patients imaged with chest CT and involved all lung zones in all cases. The cysts appeared diffusely distributed in nine (50%) patients, with relative sparing of the lung apices in seven (39%) (Fig 4) and of the lung bases in two (11%) (Fig 5). The majority of cysts measured 2 5 mm in diameter, but larger cysts measuring 6 30 mm were also seen. CT studies in 10 patients were scored as exhibiting moderate cystic lung disease (25% 80% of parenchyma replaced by cysts) (Fig 4), and four each were scored as exhibiting mild ( 25% of parenchyma replaced) (Fig 5) and severe ( 80% of parenchyma replaced) cystic lung disease (Fig 6). Cyst size correlated with

6 808 May-June 2005 RG f Volume 25 Number 3 Figure 6. LAM in a 34-year-old woman with progressive dyspnea. (a) Posteroanterior chest radiograph depicts large lung volumes and somewhat coarse bilateral diffuse reticular and linear opacities. (b d) High-resolution CT scans (obtained at descending levels) show diffuse severe pulmonary involvement by thin-walled cysts. Although several cysts are small (2 5 mm), the majority are much larger, measuring up to 12 mm. Note variable cyst shapes including polygonal (arrow in b). (e) Photograph of the resected right lung at the time of single lung transplantation demonstrates profuse involvement of every lung lobe by cysts of varying size.

7 RG f Volume 25 Number 3 Abbott et al 809 Figure 7. LAM in a 27-year-old woman with dyspnea who presented with a right spontaneous hydropneumothorax. (a c) High-resolution CT scans (obtained at descending levels) collimated to the left lung demonstrate diffuse but mild ( 25% of the lung parenchyma) lung involvement by small (2 5-mm) thin-walled cysts. Figure 8. LAM in a 29-year-old woman with dyspnea and chest pain who presented with a left spontaneous pneumothorax. (a c) High-resolution CT scans (obtained at descending levels) with targeted reconstructions of the right lung demonstrate moderate (between 25% and 80% of the lung parenchyma) lung involvement by numerous thinwalled cysts. Although many cysts are small (2 5 mm), some are larger (10 mm). radiologic severity of disease, measuring predominantly 2 5 mm in all four patients with mild disease (Fig 5) with occasional cysts measuring up to 8 mm in two (Fig 7). In the ten patients with moderate lung involvement, the majority of cysts measured 2 5 mm in all ten, with occasional cysts measuring up to 10 mm in seven and up to 8 mm in two (Fig 8). In the four patients with severe

8 810 May-June 2005 RG f Volume 25 Number 3 Figure 9. LAM in a 46-year-old woman who developed progressive dyspnea during pregnancy. (a) High-resolution CT scan shows severe lung involvement by numerous thinwalled cysts of various sizes, with a large cyst in the left upper lobe measuring 30 mm in its largest diameter. (b) Photograph of the resected left lung at the time of lung transplantation demonstrates profuse cysts with several dominant cysts. Figure 10. LAM in a 40-year-old woman with progressive dyspnea. High-resolution CT image (targeted reconstruction) of the right lung demonstrates severe cystic lung disease and a pseudo-beaded appearance of the major interlobar fissure. disease, the majority of cysts measured 6 12 mm in diameter with a scant amount of smaller cysts measuring 2 5 mm (Fig 6). In one of the four patients with severe disease, cysts measured up to 30 mm in diameter (Fig 9). In the majority of patients (n 14), cyst walls ranged from being barely perceptible to 2 mm in thickness (Figs 4, 5, 7, 8). In a few cases (n 4), thicker walls measuring up to 4 mm were demonstrated. The cysts were characteristically surrounded by normal lung parenchyma (Fig 7). In patients with severe cystic lung disease, the parenchyma was replaced completely by cysts (Fig 6). Cysts exhibited varied shapes, with round, polygonal, and ovoid shapes evident in decreasing order of frequency (Fig 6). In patients with mild cystic lung disease, cysts were predominantly round with minimal variation in shape (Fig 7). In patients with moderate cystic lung disease, round cysts were seen in combination with polygonal and ovoid cysts (Fig 8b, 8c). In patients with severe cystic lung disease, cysts appeared larger and more varied in shape, exhibiting round, polygonal, ovoid, and occasionally irregular shapes (Figs 6, 9). In nine cases (50%) four with moderate, three with severe, and two with mild cystic lung disease high-resolution CT demonstrated a nodular or beaded appearance of the major interlobar fissures (Figs 6, 8, 10). Small (1 2-mm) nodules (Fig 8b, 8c) were demonstrated by highresolution CT in two patients in whom the diagnosis of LAM was established from transbronchial biopsy results in one and open lung biopsy results in the other. Analysis of the tissue samples from these patients established the diagnosis of LAM but did not reveal the nature of the nodules seen at high-resolution CT.

9 RG f Volume 25 Number 3 Abbott et al 811 Figure 11. LAM in a 21-year-old woman who presented with a small subtle left spontaneous pneumothorax. (a) Posteroanterior chest radiograph demonstrates increased lung volumes. (b, c) High-resolution CT scans collimated to the left lung show the small left pneumothorax (arrow in b) and mild pulmonary involvement by thin-walled cysts. Some of the cysts have a subpleural distribution. (d) Low-power photomicrograph (original magnification, 200; hematoxylin-eosin [H-E] stain) demonstrates a subpleural cyst with marginal round and elongated clusters of LAM cells. Pleural effusions were seen at CT in four patients (bilateral effusions in two, left sided in one, and right sided in one) (Fig 4). Pneumothorax was demonstrated by CT in three patients (right sided in two and left sided in one) (Fig 11). In three other patients, a chest tube was demonstrated at high-resolution CT related to treatment of pneumothorax (right sided in two and left sided in one). In two of three patients with pneumothorax and normal lungs at chest radiography, CT scans demonstrated diffuse cystic lung disease graded as mild in one case (Fig 11) and moderate in the other; the third patient was not

10 812 May-June 2005 RG f Volume 25 Number 3 Figure 12. LAM in a 40-year-old woman with progressive dyspnea. (a) High-resolution CT scan demonstrates severe pulmonary involvement by cysts of variable sizes, some with thin, others with thick walls. (b) Contrast-enhanced abdominal CT scan shows extensive retroperitoneal lymphadenopathy. The diagnosis of LAM was established from the biopsy specimen from the retroperitoneal lymph nodes. Figure 13. TSC-LAM in a 29-year-old woman who presented with a right spontaneous hydropneumothorax and spontaneous right retroperitoneal hemorrhage. These findings led to the diagnosis of TSC. (a) Clinical photograph demonstrates the typical appearance of facial angiofibromas. (b) High-resolution CT scan reveals severe pulmonary involvement by thick- and thin-walled cysts of varying sizes and a right hydropneumothorax. (c, d) Abdominal CT scans (c at a higher level than d) show a left renal mass with fat attenuation and a right soft-tissue renal mass surrounded by perinephric hemorrhage.

11 RG f Volume 25 Number 3 Abbott et al 813 Figure 14. TSC-LAM in a 37-year-old woman with TSC that manifested with mental retardation and seizures who was evaluated for bilateral renal angiomyolipomas. (a) Contrast-enhanced brain CT scan shows numerous calcified periventricular nodules consistent with multifocal tubers. (b) Contrast-enhanced abdominal CT scan demonstrates bilateral renal enlargement by numerous cysts and large bilateral masses of mixed attenuation containing large vascular structures. Note fat-attenuation lesion in the mid pole of the left kidney. (c) Highresolution CT scan shows mild pulmonary involvement by scattered small thin-walled pulmonary cysts. The cysts were incidentally found at abdominal CT, and the patient had no pulmonary symptoms. imaged with CT. Only retrocrural lymphadenopathy was demonstrated at high-resolution CT in one patient. Retroperitoneal lymphadenopathy was demonstrated in two patients (Fig 12). Renal angiomyolipomas were seen on abdominal CT scans in two patients and involved the left kidney in one patient and both kidneys in the other. TSC associated LAM. In all four (100%) patients with TSC-LAM, high-resolution CT demonstrated cysts, which involved all lung zones in all cases. Similar to the high-resolution CT findings in patients with LAM, the majority of cysts measured 2 5 mm, but larger cysts measuring 6 30 mm were also observed. Two of the four patients had severe lung involvement ( 80% of parenchyma replaced by cysts) and exhibited a predominance of large cysts measuring 6 12 mm and 6 30 mm, respectively (Fig 13). Small (2 5- mm) cysts predominated in one patient with mild ( 25% of parenchyma replaced) disease (Fig 14) and in one patient with moderate (25% 80% of parenchyma replaced) cystic lung disease, but cysts measuring up to 8 mm in diameter were also demonstrated, and cyst walls appeared thin in both cases (Fig 14). Thick cyst walls measuring up to 4 mm were demonstrated in both patients with severe cystic lung disease (Fig 13). Normal lung parenchyma was demonstrated in between cysts in the patients with mild and moderate lung involvement (Fig 14) but was difficult to identify in both patients with severe cystic disease (Fig 13). Cyst shape also varied, with round cysts predominantly seen in patients with mild (Fig 14)

12 814 May-June 2005 RG f Volume 25 Number 3 and moderate lung involvement, and larger cysts with variable shapes observed in patients with severe lung disease (Fig 13). Pleural effusions were demonstrated by highresolution CT in three patients with TSC-LAM, including right-sided pleural effusions in two patients who had ipsilateral pneumothoraces and bilateral pleural effusions in one patient; the latter were documented as chylous. Abdominal CT demonstrated bilateral angiomyolipomas in two patients, one with mild (Fig 14) and one with severe cystic lung disease (Fig 13). Discussion Background In 1918, Lutembacher published what is considered the first report of cystic lung disease occurring in association with TSC in a 36-year-old woman with bilateral pneumothoraces who died. Lutembacher attributed the pulmonary nodules and cysts found in this patient to metastases from renal fibrosarcoma (2). In 1937, von Stössel published what is regarded as the first description of sporadic LAM in an adult woman who died of respiratory failure (3). Her autopsy revealed pulmonary cysts and dilated lymphatics, described by von Stössel as muscular cirrhosis of the lung (3). Also in 1937, Burrell and Ross described a 36-year-old woman with a unilateral chylous pleural effusion, smooth muscle proliferation in the lungs and lymph nodes, and honeycomb-like pulmonary abnormalities (4). In 1942, Rosendal (5) published a case report that described what he called myomatosis of the lung. Indeed, over the years a variety of terms have been used to designate LAM, including lymphangioma, lymphangiomyoma, lymphangiopericytoma, leiomyomatosis, lymphangiomatous malformation, and intrathoracic angiomatous hyperplasia (6). Cornog and Enterline (7) published a report of the first series of patients with LAM in They described six new cases, analyzed an additional 14 cases from the published medical literature (6,7), and presented a review that included many of the currently established features of LAM. All patients with symptoms had dyspnea, and all but two had chylous pleural effusions (6,7). At least nine patients had cystic pulmonary disease in addition to mediastinal or retroperitoneal masses (6,7). Microscopy revealed highly organized hamartomatous lesions without cellular atypia, mitoses, or distant metastases (6,7). The authors postulated a multifocal origin of the lesions in response to a single stimulus that was perhaps genetically mediated. These authors also recognized that the lymph node and pulmonary parenchymal lesions were identical to those reported in some cases of TSC (6,7). In recent decades, great strides have been made in further understanding LAM, although its causes and pathogenesis are still unclear and its relationship to TSC continues to be debated. Clinical Features Demographics. The prevalence of LAM in the United Kingdom, France, and United States is estimated as approximately one case per million. Although descriptions of LAM are also found in the Asian medical literature, prevalence data in this population are not available (8). Worldwide occurrence of LAM is estimated at more than 100 cases per year (4). In 2002, it was estimated that there were approximately 450 women with LAM in North America (9). LAM affects women exclusively, and most reported cases of the disease occur in white women of childbearing age with a mean age of 34 years (8,10). Hormonal factors may play a role in the pathogenesis and clinical course of LAM, and menstruation, pregnancy, and exogenous estrogen treatment (including use of oral contraceptives) may result in an exacerbation of symptoms (11,12). In one series, the onset of pulmonary symptoms occurred during pregnancy in 23% of 69 patients with LAM (13). There are also reports of LAM developing in postmenopausal women, many of whom had a history of estrogen therapy, although onset of LAM in postmenopausal women without oophorectomy or exogenous estrogen therapy has also been reported (8,13). There are a handful of reports of LAM affecting men. Few of these cases are well documented, and those with histologic proof occurred in the setting of TSC (14). In fact, it is recommended that men suspected of having LAM should have their karyotype confirmed and should be evaluated with chest CT and lung biopsy to exclude other diffuse pulmonary diseases (2). Clinical Presentation. The most common presenting symptom in patients with LAM is dyspnea, reported in up to 59% of affected women. Dyspnea is usually progressive and may be exacerbated by exertion (8,15). Acute onset of dyspnea and chest pain may occur in association with

13 RG f Volume 25 Number 3 Abbott et al 815 spontaneous pneumothorax, reported in approximately 39% 53% of patients with LAM at presentation and in up to 81% during the course of the disease (8,15,16). In fact, patients who present with a spontaneous pneumothorax may be diagnosed with LAM when chest CT is performed for further evaluation. Cough is probably the third most common presenting complaint, reported in approximately 39% of affected patients (8). Less frequent presenting symptoms include chest pain, hemoptysis, and wheezing. Hemoptysis likely relates to obstruction of pulmonary venules and resultant pulmonary hemorrhage and hemosiderosis (15). Chyloptysis may occur, and chylothorax is reported in up to 14% of patients with LAM at presentation and in 22% 39% during the course of the disease (8). Chylothorax may result from obstruction of the thoracic duct or its tributaries, leakage from pleural lymphatics, or transdiaphragmatic flow from associated chylous ascites (17). In rare cases, patients with LAM may develop a chylous pericardial effusion (15). Auscultation typically reveals crackles and occasional wheezing. Decreased breath sounds may be noted in patients with pleural effusion or pneumothorax (9). Patients with LAM may also exhibit clinical evidence of pulmonary hypertension related to chronic respiratory failure (9). Disease progression is variable, but patients usually experience progressive deterioration of pulmonary function from slowly advancing, cystic and obstructive lung disease. This deterioration invariably results in respiratory failure and cor pulmonale (8,11). The diagnosis of LAM is often delayed, with a reported average period of 44 months from onset of symptoms to diagnosis (4,18). For patients who present with a pneumothorax, LAM may be initially misdiagnosed as primary spontaneous pneumothorax (18). For those who present with exertional dyspnea, nearly normal chest radiographic findings, and obstructive pulmonary function, LAM may be misdiagnosed as asthma, emphysema, bronchitis, sarcoidosis, or bronchiolitis (18). Pulmonary Function. Although a small percentage of patients with LAM have normal lung function at presentation, functional deterioration as cystic lung disease progresses is typical (8). Pulmonary function studies usually demonstrate obstructive lung disease characterized by a reduction in FEV 1 and the FEV 1 -to-forced vital capacity (FEV 1 /FVC) ratio (3). These findings likely relate to LAM cell overgrowth, which produces airflow obstruction, alveolar disruption, and cyst formation (3,18). Another common abnormality in pulmonary function is reduced Dlco because of destruction of alveolar-capillary interfaces as well as ventilation perfusion abnormalities (4). Dlco is typically decreased out of proportion to spirometric abnormalities (9). The rate of decline of Dlco correlates directly with histologic disease burden and inversely with the time to lung transplantation (9). Lung volumes are typically normal to increased (3,16). Arterial blood gas analysis demonstrates hypoxemia (at rest or exercise) without hypercapnia (3,9). Although the predominant pulmonary function abnormalities in patients with LAM are airflow obstruction and impaired gas transfer, superimposed restrictive pulmonary function may be seen in 27% of affected individuals. The latter is usually encountered in patients with pleural effusion, prior pleurectomy, or thoracotomy (8,9). Taveira-DaSilva and colleagues (19) demonstrated that cardiopulmonary exercise testing may be an important measure of disease severity in patients with LAM. Such testing allows a measure of the severity of gas exchange abnormalities and reveals exercise-induced hypoxemia, which may occur in patients with only mildly impaired pulmonary function (19). CT Pulmonary Function Correlation. Aberle et al (20) showed a correlation between the visual assessment of extent of cystic replacement of the lung and the abnormalities of airflow obstruction and pulmonary diffusing capacity in eight patients with LAM. In addition, Müller and colleagues showed a correlation between extent of cystic lung disease seen at chest CT and reduction in Dlco (1). Avila et al (21) showed a positive correlation between the qualitative and quantitative grade of disease severity and the decrease in FEV 1. Paciocco and colleagues (22) used a highresolution CT related density mask evaluation in 25 patients with diffuse cystic lung disease (13 of whom had LAM) and found a good correlation between the density mask findings and functional parameters including FEV 1 and Dlco. Extrapulmonary Manifestations. Patients with LAM often exhibit extrapulmonary manifestations of the disease and in some rare cases may present because of symptoms related to extrapulmonary involvement. Approximately 15% 57%

14 816 May-June 2005 RG f Volume 25 Number 3 of patients with LAM have renal angiomyolipomas, which are often small and asymptomatic (8,15). Patients with large ( 4 cm) angiomyolipomas may present with symptoms related to the rapid growth of these lesions or hemorrhage including flank pain and severe hypotension (8). Other extrapulmonary manifestations of LAM include chylous ascites (in up to one-third of patients), uterine leiomyomas, and lymphaticoureteric and lymphaticovenous communications (23). LAM may also affect the liver and pancreas (15). Abdominal and pelvic lymphangioleiomyomas were described in 21% of patients with LAM in one study (24,25). These masses occur along the axial lymphatic system and may affect the posterior mediastinum and the retroperitoneum near the abdominal aorta, the mesentery, and the renal arteries (26). Large masses often contain chyle-filled cystic spaces and may exhibit diurnal variations in size with consequent worsening of symptoms over the course of the day (25,26). Affected patients may experience severe abdominal, flank, or pelvic pain; abdominal distention; incontinence; chyluria; hematuria; and lower-extremity lymphedema and paresthesias (9,25). Patients who present because of extrapulmonary LAM may be incidentally found to have asymptomatic pulmonary involvement at CT (9,27,28). Matsui and colleagues (26) described 22 patients who presented with symptoms of extrapulmonary LAM that preceded symptoms related to pulmonary LAM by 1 2 years. Tuberous Sclerosis Complex. Von Recklinghausen first described tuberous sclerosis in 1862 in a newborn with multiple cardiac and cortical brain tumors (29). Bourneville coined the term tuberous sclerosis in 1880 based on the gross appearance of the classic central nervous system lesions in this disease (6,30). TSC is an inheritable autosomal dominant disorder characterized by multifocal systemic hamartomas that may affect the central nervous system, skin, heart, kidneys, and other organs (31). The Vogt triad of epileptic seizures, mental retardation, and facial angiofibromas (formerly misnamed as adenoma sebaceum) is exhibited by only approximately 29% of affected patients (30,32). Although 25% 50% of patients with TSC have a family history of the disease (6), approximately 60% of cases are sporadic and likely are related to spontaneous mutations or incomplete penetrance (6,32). The incidence of TSC may be as high as one in 6,000 live births with an estimated prevalence of nearly one in 10,000 (11,12). Dermatologic manifestations of TSC include hypomelanotic macules, ungal fibromas, shagreen patches, and fibrous forehead plaques (30). Angiofibromas have a characteristic malar distribution (30) (Fig 13a). Neurologic manifestations include intractable seizures, severe mental retardation, and progressive hydrocephalus from subependymal giant cell tumor (30). Autism as well as behavioral, sleep, and psychiatric disorders may also occur (30). Retinal hamartomas are common. Cardiac rhabdomyomas are seen in children and typically are clinically silent (30). Renal angiomyolipomas are often bilateral and multiple (Figs 13c, 13d, 14b) and may be associated with renal cell carcinoma (6,29,30). Affected patients may also have renal cysts (30). The first accurate description of TSC pulmonary involvement was published in 1930 by Berg and Vejilens, who described a young woman with recurrent pneumothoraces and progressive respiratory insufficiency (2). Today, it is recognized that patients with TSC may develop gross, histologic, and functional lung abnormalities identical to those found in patients with LAM (11). Pulmonary involvement typically occurs in women in the 3rd through 5th decades of life, with the onset of respiratory symptoms typically in the middle of the 4th decade. In 1971, Dwyer reported that women accounted for 84% of patients with pulmonary TSC, but many cases reported in men did not include histologic descriptions of the pulmonary lesions (6). Pulmonary involvement in TSC is thought to be rare and is estimated to occur in approximately 2.3% of affected patients (32). Some investigators argue that this figure may grossly underestimate the prevalence of lung disease in patients with TSC, as morphologic changes of LAM probably occur in a much larger percentage of individuals with clinically silent lung involvement (11,32). Costello and colleagues (11) found a 26% frequency rate of cystic lung disease on chest CT scans of 78 women with TSC who had no respiratory symptoms. McCormack et al (33) described CT evidence of pulmonary cysts in 39% of 23 patients with TSC without pulmonary symptoms. Moss and colleagues (34) reported a high prevalence (34%) of CT findings of LAM in asymptomatic women with TSC and normal pulmonary

15 RG f Volume 25 Number 3 Abbott et al 817 Figure 15. LAM, gross features. Photograph of the cut surface of a lung specimen demonstrates numerous cysts evenly distributed throughout the parenchyma with little intervening normal lung tissue. function and no male patients with TSC and cystic lung disease. Interestingly, lung nodules were also found in affected men and women and were thought to represent multifocal micronodular pneumocyte hyperplasia (MMNPH) (34). Aubry et al (14) published a report documenting pulmonary LAM in a man with TSC in whom typical LAM lesions occurred in association with MMNPH. At the time of their report, there were previous reports of LAM in only six men with or without associated TSC; one of these patients was later identified as a woman, another had mediastinal disease without lung involvement, one had atypical histologic findings, and two had no histologic confirmation. The sixth patient was later excluded after a second review of his biopsy material (14). Genetics of TSC. The TSC phenotype is postulated to result from a germ line mutation in one of two genes, TSC-1 or TSC-2, occurring on chromosomes 9 and 16, respectively (8,29,31). A second somatic mutation may result in loss of the gene product in the affected cell and is referred to as loss of heterozygosity (8). As TSC genes are thought to represent tumor suppressor genes, loss of the gene product may result in the formation of the hamartomas that characterize this disease (8). Essentially, TSC exhibits genetic heterogeneity, and mutations of either TSC-1 or TSC-2 account for 100% of cases (30). Relationship between TSC and LAM. For many years, it has been debated whether LAM represents a forme fruste of TSC. The distinction between both conditions is made increasingly controversial by the diagnostic criteria proposed by the National Tuberous Sclerosis Association, in which the presence of LAM is considered as probable TSC and the combined presence of LAM and renal angiomyolipomas represents definite TSC (32). Although histologic and clinical features may be identical in women with LAM and patients with TSC-associated pulmonary involvement, there are reported differences. Patients with TSCassociated LAM, compared with patients with sporadic LAM, generally experience a longer delay between onset of symptoms and diagnosis of pulmonary disease, exhibit chylothoraces less frequently, and are more likely to present with gradual onset of dyspnea (12). Renal angiomyolipomas are found in 40% 80% of patients with TSC but occur in 8% 57% of patients with sporadic LAM (35). Interestingly, loss of heterozygosity for TSC-2 has been described in angiomyolipomas occurring in patients with both sporadic LAM and TSC (8). It is postulated that patients with LAM may carry the TSC-2 mutation in only a small population of cells or may have sequential somatic mutations of the TSC-2 gene (8). Identical loss-of-function TSC-2 mutations have been identified in lung lesions, lymph nodes, and angiomyolipomas of patients with LAM. This finding suggests that LAM cells may be capable of migrating to distant sites and forming new lesions (36). Pathologic Features Gross Findings. The gross pathologic characteristics of LAM are distinctive. The lungs are enlarged and the visceral pleura is covered with numerous cysts. Examination of the cut surface reveals air- or fluid-filled (chylous or serosanguinous) cysts distributed homogeneously throughout the parenchyma (Fig 15). Cysts typically range from 0.5 to 2.0 cm in diameter but have been reported to be over 10 cm (17,37). LAM may involve axillary, cervical, subclavian, mediastinal, retroperitoneal, and pelvic lymph nodes. Affected nodes are spongy and pale tan or white (38). Obliteration and dilatation of lymphatic channels secondary to involvement by

16 818 May-June 2005 RG f Volume 25 Number 3 Figures LAM, microscopic features. (16) Low-power photomicrograph (original magnification, 40; H-E stain) demonstrates a cystic pattern similar to that seen at gross examination. (17) Lowpower photomicrograph (original magnification, 40; H-E stain) shows a cyst with only a single, inconspicuous focus of LAM cells (arrowhead). (18) Low-power photomicrograph (original magnification, 40; H-E stain) demonstrates abundant LAM cell proliferation with loss of normal architectural features. LAM cells can lead to enlargement of the thoracic duct, distention of the mediastinal and retroperitoneal lymphatics, and chylous effusions. Microscopic Features. Two key microscopic features characterize LAM: cysts and proliferation of atypical smooth muscle cells (LAM cells). The cystic pattern seen at gross examination is readily apparent at scanning (low) magnification light microscopy (Fig 16). LAM cells are seen in the walls of cysts (Fig 11d) and along pulmonary lymphatics, the latter of which explains the clinical features of the disease. LAM cells infiltrate distal airways, which leads to airway narrowing, air trapping, formation of bullae, and pneumothoraces (37). Obstruction of lymphatics causes chylous effusions of the thorax and abdomen. Involvement of pulmonary vessels is associated with thickened arterial walls and venous occlusion, resulting in hemosiderosis and hemoptysis (38). Early in the disease process, LAM cells may be inconspicuous and readily overlooked (Fig 17). In advanced cases, LAM cells may be so abundant that they hinder identification of normal lung structures (Fig 18) (37). Proliferating LAM cells are morphologically heterogeneous, with a spectrum from small and round to large, spindle-shaped, and epithelioid (37). Cells have varying amounts of eosinophilic cytoplasm and fine or vesicular nuclear chromatin (Fig 19). Cytologically atypical cells and rare mitotic figures may be seen. LAM cells grow in a haphazard fashion in contradistinction to the orderly, parallel, or concentric growth pattern of normal smooth muscle cells around airways and blood vessels. In addition, LAM cells tend to be shorter and plumper, with a higher nuclear-tocytoplasmic ratio than normal smooth muscle cells (39). LAM cells appear to be of smooth muscle origin, demonstrating immunoreactivity for -smooth muscle actin, desmin, and vimentin (17). Myofilaments are evident at electron microscopy. In contrast to normal smooth muscle cells, LAM cells display indented nuclei, prominent endoplasmic reticulum, microfilament bundles with dense bodies, numerous electrondense membrane bound granules, and immunoreactivity with HMB-45 (40). HMB-45, human melanin black-45, is a monoclonal antibody generated against a melanoma extract. Immunoelectron microscopic studies have localized the reactivity of HMB-45 in LAM cells to structures with morphologic characteristics of immature melano-

17 RG f Volume 25 Number 3 Abbott et al 819 Figure 19. LAM, microscopic features. High-power photomicrograph (original magnification, 400; H-E stain) demonstrates the variable morphology of LAM cells. Figure 20. LAM, microscopic features. High-power photomicrograph (original magnification, 400; HMB-45 immunostain) demonstrates the characteristic granular cytoplasmic staining with HMB-45 in a small percentage of cells. Figure 21. LAM, microscopic features. High-power photomicrograph (original magnification, 200; H-E stain) of a transbronchial biopsy specimen demonstrates the presence of characteristic LAM cells, which were confirmed with HMB-45 staining. somes (4,37). Not all LAM cells react with HMB-45; strong immunoreactivity is said to be associated with epithelioid features, whereas spindle-shaped cells are less frequently reactive (Fig 20) (4). The histologic features of LAM in sporadic cases and in patients with TSC are identical. The only distinguishing feature is the lesion termed multifocal micronodular pneumocyte hyperplasia (MMNPH). When present, MMNPH is pathognomonic for TSC in patients with LAM (41). MMNPH is microscopically characterized by discrete nodules composed of cuboidal or hobnailshaped type 2 pneumocytes that proliferate along slightly thickened alveolar walls. Histologic Diagnosis. In open or thoracoscopic lung biopsy specimens, the histologic diagnosis of LAM is often apparent at scanning magnification of H-E stained sections when cysts and LAM cell proliferations are present. Although the diagnosis may be obvious in most cases, the presence of LAM cells is generally confirmed with HMB-45 staining. In some cases, the content of LAM cells may be inconspicuous, leading the unwary pathologist to an erroneous diagnosis of emphysema or normal lung (17). Although the histologic diagnosis of most diffuse lung diseases requires use of open lung biopsy with clinical correlation, diseases such as LAM with specific pathologic features can be diagnosed from transbronchial biopsy specimens. Thus, in the appropriate clinical setting, use of transbronchial biopsy in conjunction with HMB-45 staining can be sufficient to make a diagnosis of LAM (Fig 21) (42,43). Histologic Differential Diagnosis. Pulmonary LAM may be confused with benign metastasizing leiomyoma (BML), metastasizing leiomyosarcoma, lymphangiomatosis, and hyperplasia of interstitial smooth muscle cells in honeycomb fibrosing lesions of the lung such as those that occur in idiopathic pulmonary fibrosis (IPF). These diagnostic considerations, however, may be systematically excluded on the basis of features that are not characteristic of LAM. For example, BML and leiomyosarcoma typically form multiple nodules and usually lack diffuse cystic change. BML recapitulates the appearance of benign leiomyomas of the uterus and is HMB-45 negative. Although LAM cells are regarded as atypical smooth muscle cells, they lack the cytologic atypia of leiomyosarcoma. Lymphangioma-

18 820 May-June 2005 RG f Volume 25 Number 3 tosis is primarily a vascular lesion and lacks the distinctive HMB-45 positive cells of LAM. Reactive smooth muscle hyperplasia and cystic changes are common in IPF, but they are found in the presence of extensive interstitial dense fibrosis, remodeling of the lung architecture, and inflammation; these features are absent in LAM (17). Imaging Features Chest Radiography. Radiographic abnormalities in patients with LAM have been reported as reticular, reticulonodular, and miliary opacities or pulmonary cysts (1,44,45). These manifestations may precede, accompany, or postdate other thoracic manifestations of the disease, including pneumothorax and chylous pleural effusion (1). The most commonly described radiographic manifestation of LAM is a pattern of generalized, symmetric, reticular, or reticulonodular opacities (Fig 6a), seen in approximately 80% 90% of affected patients (1,44,45). It is postulated that these reticular and reticulonodular opacities may result from the visualization of numerous superimposed cyst walls (46). In some patients, the appearance of the chest radiograph may be normal initially, but reticular opacities and cystic changes develop with progressive clinical deterioration and correspond to increasing pulmonary involvement by cysts (1,8). In general, radiographic abnormalities have been reported as varying roughly according to disease severity, with more apparent reticulation and cystic changes described in patients with severe pulmonary involvement (Fig 6a) (1,38). In the largest reported radiographic series of 46 patients with LAM, Kitaichi and colleagues (47) noted that the distribution of interstitial opacities was typically diffuse and equal in all lung zones (Fig 6a). In another series by Lenoir et al (45), who provided more detailed descriptions of radiographic findings, interstitial opacities were described as affecting both lungs diffusely in 78% of 11 patients with LAM and TSC-LAM and less frequently as predominantly involving the upper (11%) or lower (11%) lung zones (Figs 1, 2). The radiographic findings in our series were discordant with those in the preceding reports, since interstitial opacities were seen as predominantly involving the lower lung zones in 95% of patients with LAM and abnormal chest radiographic findings. Interlobular septal thickening has been observed in 7% 9% of chest radiographs of patients with LAM in two published series (38,45) and has been attributed to dilatation of lymphatic channels secondary to obstruction of lung and pleural lymphatics (8). None of the patients in our series demonstrated this radiographic finding. Lung volumes have been reported as normal at chest radiography in 55% 78% of affected patients and increased in 22% 45% (Fig 1) (1). In our series, lung volumes were increased in 53% of patients, normal in 44%, and reduced in 3%. Pneumothorax is a common clinical and radiographic presenting manifestation of LAM, reported in 39% 53% of patients (Fig 3) (1,15,47). However, the underlying lung may appear normal, as demonstrated in two of seven patients (29%) in one series (45) and in three of 13 (23%) of patients in our series. Pleural effusion (secondary to chylothorax) is a common radiographic feature, occurring in 10% 20% of patients, and may be unilateral or bilateral (Fig 2) (1,47). However, 44% of patients in our series exhibited pleural effusions. In our series, the radiographic findings in patients with LAM were indistinguishable from those in patients with TSC-LAM. The two groups of patients had similar frequencies of radiographic abnormalities (75%), interstitial reticular opacities (75%) that were predominantly basilar, and ancillary findings (pneumothorax, pleural effusion). These results agree with those of other reports and the hypothesis that LAM and TSC-LAM may represent two forms of the same disease (45). Computed Tomography. The CT manifestations of LAM are distinctive, characterized by numerous thin-walled cysts surrounded by normal lung parenchyma and distributed diffusely and bilaterally (Figs 7, 8) (1,15,44,45). Conventional CT and high-resolution CT findings are almost always abnormal at the time of diagnosis, and typically demonstrate parenchymal cysts, even when the chest radiographs appear normal or reveal only pleural effusion or pneumothorax (Fig 11) (1,44,45,47). In concordance with previous reports, the cystic changes of LAM in the patients in our series were apparent at conventional chest CT (performed with 5 10-mm collimation), whereas individual cysts, their extent, and distribution were better seen at high-resolution CT (44,45). Cysts typically range from 2 to 5 mm in diameter but have been reported to be as large as 25 mm (1,45). The majority of cysts in our series measured 2 5 mm (Figs 4, 5, 7, 11) and less commonly were 6 10 mm in diameter. The largest cyst in our series measured 30 mm in diameter in one patient with severe cystic lung disease (Fig 9).

19 RG f Volume 25 Number 3 Abbott et al 821 Figure 22. LAM. Close-up photograph of a cut section of right lung parenchyma demonstrates extensive cystic changes that extend to apposing pleural surfaces along the interlobar fissures. Müller and colleagues (1) analyzed CT findings in patients with LAM by using a scoring system that divided the lung into three zones and established a visual estimate of disease extent representing the percentage of abnormal lung parenchyma. Cystic spaces demonstrated at CT were categorized as predominantly less than 0.5 cm, equal to cm, or greater than 1 cm in diameter. They found good correlation between the predominant cyst size and disease extent at CT. Parenchymal involvement of 25% generally correlated with cyst sizes of cm, disease involving 25% 80% of the lung correlated with cyst sizes of cm, and disease involving 80% of the lung was associated with cyst sizes of 1 cm (1). Our series is in concordance with those results: Four patients with mild disease (as defined in the Materials and Methods section above) had cysts measuring 2 5 mm (and occasionally up to 8 mm) (Fig 5a), 10 patients with moderate disease had cysts measuring 2 10 mm (Fig 8b), and four patients with severe involvement had cysts that predominantly measured 6 12 mm (Figs 6, 9, 12). Cysts in LAM exhibit a variety of shapes, including round, polygonal, and ovoid (15,45). Round cysts are most commonly reported (Figs 4, 5), with polygonal shapes found in increasing numbers in patients with more severe parenchymal involvement (Figs 6, 9) (45). The findings in our series agree with that observation. Cyst wall thickness ranges from barely perceptible to 2 mm thick in most series (1,44,48 50) but has been described as measuring up to 4 mm (45). In our series, cyst walls ranged from being barely perceptible to 2 mm thick in 78% of patients, with walls measuring 4 mm seen in 22%. Interestingly, in nine patients (50%) in our series studied by high-resolution CT (four with moderate, three with severe, and two with mild cystic lung disease), a pseudo-beaded appearance of the major interlobar fissures was seen (Figs 8b, 10). We found no pathologic correlate for this appearance. It may be related to the presence of apposing subpleural cysts and summation of the fissures with cyst walls oriented roughly perpendicular to them (Fig 22). However, in some cases the pseudo-beaded appearance was seen in the absence of subpleural cyst profusion (Fig 8b). The finding could also be related to dilated lymphatic channels in adjacent interlobular septa. To our knowledge, this imaging feature has not been previously described. Although CT typically demonstrates cysts distributed diffusely throughout both lungs (1,45), one report described apical sparing of cystic changes in a patient with mild disease (51). Other studies report preferential involvement of either the upper or lower lung zones at high-resolution CT in 7% 11% of patients with LAM (1,48). In 50% of the patients in our series, CT demonstrated a diffuse distribution of pulmonary cysts, whereas 39% showed relative sparing of the apical lung zones and 11% demonstrated sparing of the lower lungs. Patchy areas of ground-glass attenuation have been described in patients with LAM and are thought to represent foci of pulmonary hemorrhage (1). Small nodules have also been reported but are not considered a characteristic imaging feature of the disease (51,52). Small nodules were demonstrated by high-resolution CT in two patients in our series. Unfortunately, a pathologic correlate for these nodules could not be established. Lung parenchyma interposed between the cysts of LAM is typically normal, although thickened interlobular septa have been described at high-resolution CT in rare cases (45,49). These findings were not demonstrated in our series. Occasionally, a chylous effusion is suggested at chest CT based on low-attenuation ( 17-HU) fluid that may relate to the presence of fat (53). More often, however, the high protein content of chylous effusions contributes to higher attenuation values, and the collections are indistinguishable from pleural effusions arising from other causes (53). Pneumothorax is a common imaging manifestation of LAM and is characteristically associated with CT demonstration of parenchymal cysts (Fig 11b) (15,45). In our series, all patients with pneumothorax who were studied by CT demonstrated parenchymal cysts. Hilar and mediastinal lymphadenopathy is reported to occur in up to 50% of chest CT scans of patients with LAM (44) but was not demonstrated in any of our patients.

20 822 May-June 2005 RG f Volume 25 Number 3 Figure 23. Pulmonary Langerhans cell histiocytosis in a 32-year-old man. (a, b) High-resolution CT scans demonstrate a small right pneumothorax and irregular, bizarre-shaped cysts that predominantly involve the upper lung zones (a) with relative sparing of the lung bases (b). Nodules are demonstrated in the intervening lung parenchyma. The CT findings in patients with LAM are reported as indistinguishable from those in patients with TSC-LAM (16,15,45,54). Although our series of patients with TSC-LAM is small (n 4), our findings agree with those observations, with high-resolution CT features of TSC- LAM being indistinguishable from those in patients with LAM only (Figs 13, 14). Some reports state that patients with TSC-LAM are relatively asymptomatic compared with individuals with LAM only (12). Two of three patients with TSC- LAM in our series presented initially with pneumothorax but were previously asymptomatic. A third patient had no pulmonary symptoms, and lung cysts were discovered incidentally at abdominal CT (Fig 14). The fourth patient had a history of progressive dyspnea and hemoptysis. Other Findings. Renal angiomyolipomas have been observed on abdominal CT scans of 20% 54% of patients with LAM (55). These tumors are characterized by CT evidence of soft tissue, fat, and enhancing vessels in variable proportions within a renal mass (55). However, fat is not detectable at CT in up to 5% of renal angiomyolipomas, and therefore absence of fat in renal tumors in patients with LAM does not exclude the diagnosis (55). All four angiomyolipomas demonstrated in the patients in our series had fat attenuation on CT scans (Figs 13c, 14b). Reports of LAM in older series describe enlarged abdominal and retroperitoneal lymph nodes seen at lymphangiography associated with abnormal filling with contrast material and intranodal cystic changes (44). A more recent series of 35 patients with LAM described CT evidence of retroperitoneal and pelvic lymphadenopathy in 77% and 11% of patients, respectively (15). In our series, abdominal lymphadenopathy was demonstrated in two patients with LAM (11%) but was not evident in any of our four patients with TSC-LAM. Imaging Differential Diagnosis. The highresolution CT features of LAM are distinct from those of other diffuse lung diseases. Imaging findings are diagnostic when diffuse bilateral thinwalled pulmonary cysts are demonstrated in women of childbearing age (1,52). However, the combination of preserved or increased lung volumes and reticular opacities that may resemble cystic lung disease at radiography can also be seen in pulmonary Langerhans cell histiocytosis and in centrilobular emphysema. IPF typically manifests with bilateral basilar reticular opacities. However, affected patients exhibit progressive reduction in their lung volumes. It should also be noted that pulmonary Langerhans cell histiocytosis, emphysema, and IPF affect both men and women.

21 RG f Volume 25 Number 3 Abbott et al 823 Figure 24. Centrilobular emphysema in a 59-yearold man. High-resolution CT scan demonstrates multifocal areas of low attenuation with imperceptible walls. The findings predominantly involved the upper lung zones. Figure 25. Paraseptal emphysema in a 21-year-old woman with an 11-pack-year history of cigarette smoking. High-resolution CT scan demonstrates areas of low attenuation that have evident walls and are arrayed in a single subpleural tier that extends along interlobar fissures. Figure 26. IPF in a 64-year-old man. High-resolution CT scan demonstrates subpleural and basal predominance of honeycomb cystic changes with distortion of adjacent lung parenchyma. The imaging features of pulmonary Langerhans cell histiocytosis include nodules and cysts that demonstrate a characteristic predilection for the upper lung zones and relative sparing of the lung bases (56). LAM is distinctively characterized by a diffuse distribution of cysts and does not typically spare the lung bases, although we refer to a small number of observations of lung base sparing in LAM in our data and elsewhere in our discussion. Irregular cysts are common in pulmonary Langerhans cell histiocytosis but uncommon in LAM. The parenchyma between the cysts found in the former disease frequently contains nodules (Fig 23), whereas the intervening lung parenchyma in LAM is usually normal (51). The so-called cystic changes of centrilobular emphysema exhibit imperceptible walls and are chiefly distributed in the upper lung zones (Fig 24), whereas the cysts in LAM have thin but perceptible walls and are evenly distributed throughout the lungs (45,52). The cystic low-attenuation areas seen in paraseptal emphysema have evident walls, but they are arrayed in a single subpleural tier, in contrast to the diffuse and random distribution of the cystic spaces in LAM (Fig 25). At chest radiography, the interstitial opacities seen in end-stage IPF are not as delicate as those typically seen in LAM (50). Lung volumes in IPF often appear reduced, compared with the normal or increased lung volumes typical of LAM. The diffuse distribution of cysts seen at high-resolution CT of patients with LAM is easily distinguished from the subpleural and basal predominance of the honeycomb subpleural cystic abnormalities that characterize IPF (49,51). It is also notable that the honeycomb cysts in IPF are surrounded by abnormal and distorted parenchyma (Fig 26), whereas the cysts in LAM have normal intervening lung architecture (52).