DOI: 10.1148/rg.253055006
RadioGraphics 2005;25:803-828
From the Archives of the AFIP
Lymphangioleiomyomatosis: Radiologic-Pathologic Correlation1
Gerald F. Abbott, MD,
Melissa L. Rosado-de-Christenson, MD,
Aletta Ann Frazier, MD,
Teri J. Franks, MD,
Robert D. Pugatch, MD and
Jeffrey R. Galvin, MD
1 From the Dept of Diagnostic Imaging, Brown Medical School, Rhode Island Hospital, 593 Eddy St, Providence, RI 02903 (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. (e-mail: gabbott{at}lifespan.org).
 |
Abstract
|
|---|
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 21–62 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 27–50 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, FEV1 = forced expiratory volume in 1 second, H-E = hematoxylineosin, HMB = human melanin black, IPF = idiopathic pulmonary fibrosis, LAM = lymphangioleiomyomatosis, TSC = tuberous sclerosis complex
|
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.
|
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 normal-to-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 (FEV1 [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 [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.
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.
View larger version (156K):
[in this window]
[in a new window]
[Download PPT slide]
|
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.
|
|
View larger version (156K):
[in this window]
[in a new window]
[Download PPT slide]
|
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).
|
|
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).
View larger version (148K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 3a. 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.
|
|
View larger version (114K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 3b. 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.
|
|
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).
View larger version (79K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 4a. LAM in a 39-year-old woman with dyspnea. High-resolution CT scans (obtained at descending levels) demonstrate bilateral diffuse small thin-walled cysts with relative sparing of the lung apices (cf a with b and c). Note the moderate left pleural effusion.
|
|
View larger version (91K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 4b. LAM in a 39-year-old woman with dyspnea. High-resolution CT scans (obtained at descending levels) demonstrate bilateral diffuse small thin-walled cysts with relative sparing of the lung apices (cf a with b and c). Note the moderate left pleural effusion.
|
|
View larger version (92K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 4c. LAM in a 39-year-old woman with dyspnea. High-resolution CT scans (obtained at descending levels) demonstrate bilateral diffuse small thin-walled cysts with relative sparing of the lung apices (cf a with b and c). Note the moderate left pleural effusion.
|
|
View larger version (118K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 5a. 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).
|
|
View larger version (102K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 5b. 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).
|
|
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 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 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).
View larger version (173K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 6a. 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.
|
|
View larger version (124K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 6b. 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.
|
|
View larger version (142K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 6c. 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.
|
|
View larger version (139K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 6d. 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.
|
|
View larger version (118K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 6e. 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.
|
|
View larger version (102K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 7a. 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.
|
|
View larger version (109K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 7b. 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.
|
|
View larger version (114K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 7c. 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.
|
|
View larger version (84K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 8a. 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 thin-walled cysts. Although many cysts are small (2–5 mm), some are larger (10 mm).
|
|
View larger version (108K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 8b. 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 thin-walled cysts. Although many cysts are small (2–5 mm), some are larger (10 mm).
|
|
View larger version (121K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 8c. 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 thin-walled cysts. Although many cysts are small (2–5 mm), some are larger (10 mm).
|
|
View larger version (132K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 9a. LAM in a 46-year-old woman who developed progressive dyspnea during pregnancy. (a) High-resolution CT scan shows severe lung involvement by numerous thin-walled 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.
|
|
View larger version (169K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 9b. LAM in a 46-year-old woman who developed progressive dyspnea during pregnancy. (a) High-resolution CT scan shows severe lung involvement by numerous thin-walled 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.
|
|
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 inter-lobar fissures (Figs 6, 8, 10). Small (1–2-mm) nodules (Fig 8b, 8c) were demonstrated by high-resolution 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.
View larger version (132K):
[in this window]
[in a new window]
[Download PPT slide]
|
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.
|
|
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 imaged with CT. Only retrocrural lymphadenopathy was demonstrated at high-resolution CT in one patient.
View larger version (166K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 11a. 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, x200; hematoxylin-eosin [H-E] stain) demonstrates a sub-pleural cyst with marginal round and elongated clusters of LAM cells.
|
|
View larger version (118K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 11b. 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, x200; hematoxylin-eosin [H-E] stain) demonstrates a sub-pleural cyst with marginal round and elongated clusters of LAM cells.
|
|
View larger version (122K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 11c. 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, x200; hematoxylin-eosin [H-E] stain) demonstrates a sub-pleural cyst with marginal round and elongated clusters of LAM cells.
|
|
View larger version (107K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 11d. 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, x200; hematoxylin-eosin [H-E] stain) demonstrates a sub-pleural cyst with marginal round and elongated clusters of LAM cells.
|
|
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.
View larger version (113K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 12a. 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.
|
|
View larger version (126K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 12b. 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.
|
|
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) and moderate lung involvement, and larger cysts with variable shapes observed in patients with severe lung disease (Fig 13).
View larger version (88K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 13a. 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.
|
|
View larger version (125K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 13b. 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.
|
|
View larger version (101K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 13c. 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.
|
|
View larger version (85K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 13d. 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.
|
|
View larger version (130K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 14a. 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) High-resolution 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.
|
|
View larger version (128K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 14b. 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) High-resolution 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.
|
|
View larger version (148K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 14c. 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) High-resolution 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.
|
|
Pleural effusions were demonstrated by high-resolution 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 1966. 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 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 FEV1 and the FEV1-to-forced vital capacity (FEV1/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 FEV1. Paciocco and colleagues (22) used a high- resolution 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 FEV1 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% 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 Reckling-hausen 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 sub-ependymal 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 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
Top
Abstract
LEARNING OBJECTIVES FOR TEST...
