Dr. Avila and Dr. Dwyer are Clinical Staff Radiologists in the Diagnostic Radiology Department, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD.

Lymphangioleiomyomatosis(LAM) is a rare, idiopathic disease that affects women and is characterized by progressive smooth muscle proliferation in the lymphatics, blood vessels, and airways. ¹ Parenchymal cysts are the principal pulmonary finding in patients with LAM. These may vary in size from a few millimeters to many centimeters, and may vary in extent from a few scattered cysts to diffuse replacement of the lung. ^2-5 Some observers think that the cysts develop as a result of air trapping distal to small airways narrowed by smooth muscle proliferation. ^5,6 Others have shown LAM cells to produce matrix metalloproteinases that destroy both collagen and elastin in the pulmonary interstitium. This suggests enzymatic breakdown of lung parenchyma in the pathogenesis of the cysts. ⁷ In addition to these findings, patients with LAM have other interesting pulmonary and abdominal imaging findings. Radiologists should be aware of these to properly diagnose the disease. This article will address the major imaging features of LAM and indicate their prevalence in our NIH experience.

Pulmonary findings

Chest radiography--The classic chest radiographic manifestations of LAM include: interstitial lung disease, recurrent pneumothoraces, and chylous pleural effusions. ⁶ The interstitial changes on radiographs actually result from superimposition of parenchymal cysts, which are the hallmark of this disease (figure 1A). ⁸ Evaluation of the pulmonary cysts in LAM is best done with CT; chest radiographs often fail to demonstrate or may underestimate the extent of disease. ^2,3,8 More than 90% of patients may have lung cysts on CT scans that are not apparent on radiographs. Only when the cysts are >1 cm in diameter are they recognized clearly on chest radio-graphs. ⁹

CT and high-resolution CT (HRCT)--HRCT demonstrates that all patients with LAM have pulmonary cysts. The cysts are better seen on HRCT than on conventional CT scanning. HRCT shows no evidence of interstitial lung disease, such as thickening of the interlobular septae or reticulation in patients with LAM. Usually, the cysts are distributed evenly throughout the lungs and vary in size from millimeters to many centimeters (figure 1B). Cyst size on CT does not correlate significantly with disease severity; patients with the greatest extent of disease do not necessarily have the largest cysts. ⁹

Less common findings on chest CT include: pneumothorax, pericardial effusion, dilated thoracic duct, pleural effusions, and precarinal and retrocrural lymph nodes. ⁹

Ventilation/perfusion scans--On ventilation scans, patients with LAM may have a pattern of "well-defined hot spots," which are postulated to represent accumulation of radionuclide in peripheral cysts. ⁴ Presumably, aerosol DTPA droplets that adhere to the cyst walls coalesce and result in focal collections of activity superimposed on a background of activity within normal alveoli. This pattern of uptake has been termed "speckling" and has been noted in approximately two-thirds of patients with LAM. The degree of speckling correlates with the extent of disease on CT scans and chest radiographs and with pulmonary dysfunction. While the pattern is nonspecific in its milder forms, it has a very distinctive appearance in its severe form (figure 1C). ⁹

Pulmonary function studies--The results of pulmonary function studies are abnormal in most patients with LAM. Commonly, FEV1%, FEV1/ FVC%, and DLCO% LAM are significantly lower than the predicted values. In contrast, the FVC and TLC (total lung capacity) are similar to the predicted values. All major imaging parameters of lung structure and function (overall ventilation, perfusion, speckling, extent of disease on CT, average pulmonary cyst size on CT, and extent of disease on chest radio-graphs) correlate significantly with degree of impairment of FEV1%, DLCO%, and FEV1/FVC%, but not with FVC% or TLC%. Cyst size correlates significantly with worsening scintigraphic abnormalities, including speckling. ⁹

Abdominopelvic findings

More than three-quarters of patients with LAM have positive abdominal CT or sonography examinations, or both. Common abdominal findings include: renal angiomyolipomas (in more than half of patients); enlarged abdominal lymph nodes (in more than a third); and lymphangioleiomyomas (in more than 20%). ¹⁰

Renal masses--The renal angiomyolipoma (AML), also called renal hamartoma, is the most common tumor associated with LAM. ¹¹ Renal AML is a benign tumor that contains vascular, muscle, and fatty elements. A presumptive diagnosis can be made by the demonstration of fat within the mass. Fat is usually diagnosed on CT scans by very low attenuation numbers (less than -10 Hounsfield units [HU]) and on ultrasound by a hyperechogenic appearance. Neither CT nor ultrasound provides a definitive diagnosis, since other benign tumors and even renal cell cancer can contain fat. Given the high incidence of AML, a renal mass that contains fat in a patient with LAM is most likely an AML. A major complication of renal AMLs is hemorrhage, which may present as flank pain or shock and may lead to nephrectomies if the correct diagnosis is not made. ¹² The recommended management of renal angiomyolipomas is based on tumor size and symptoms. ¹³ Patients with asymptomatic lesions <4 cm may be followed with yearly sonography or CT. Lesions >=4 cm should be followed by semiannual sonography or CT. Knowledge of the increased incidence of AMLs in patients with LAM may be helpful in guiding therapy. If a patient with renal pain or hematuria is known to have a renal AML, partial nephrectomy or embolization should be considered rather than a more radical procedure. ¹³ Thin-section nonenhanced CT is essential for visualization of the fat content of angiomyolipomas (figure 2).

CT or sonography alone may not be sufficient to detect renal angiomyolipomas. Sonography may miss the AMLs if they are isoechoic to normal renal parenchyma and do not deform the renal contour or if they are adjacent to normal renal sinus fat. CT may fail to find small AMLs because of partial volume artifact. ¹⁰ Hence, in difficult cases, both studies should be performed to ascertain the correct diagnosis. A minority of renal AMLs may have an atypical appearance with no evidence of fat within the lesion; some may have a solid or even complex appearance. Given an atypical renal mass, biopsy should be recommended to exclude a malignant renal neoplasm. ¹⁰

Enlarged abdominal lymph nodes--More than a third of patients with LAM have enlarged abdominal lymph nodes. The adenopathy may be quite extensive; some of the lymph nodes may measure up to 4 cm in diameter. Biopsy material obtained from lymph nodes demonstrates replacement of the lymph nodes with smooth muscle. Some of the abdominal lymph nodes may contain central areas of low attenuation, ranging in attenuation from -72 HU to +50 HU (figure 3). Such low Hounsfield numbers may indicate chylous lymph collections or fat within the lymph nodes. Patients with LAM do not characteristically have enlarged axillary or inguinal lymph nodes; this may help in differentiating LAM from lymphoma. ¹⁰

Lymphangioleiomyoma--More than one-fifth of patients with LAM have lymphangioleiomyomas (figure 4). These are complex lymphatic masses resulting from dilatation and mural thickening of lymphatics due to proliferation of smooth muscle cells in their walls. ^10,14 The lymphangioleiomyomas are located most commonly in the retroperitoneum, but may involve the pelvis or chest and rarely involve the neck region. These masses may be large and have volumes ranging from 10 to 1500 cc. Although most are lobulated and well-defined, they may infiltrate the retroperitoneum and have ill-defined borders. The majority have thin walls and contain low attenuation material consistent with chyle. The areas of low attenuation within the lymphangio-leiomyomas range in density from 3 to 25 HU. ¹⁰ Sonography may show cystic components, or thick, echogenic rinds surrounding a central hypoechoic area. ¹⁰

The abdominal adenopathy and lymphangioleiomyomas may be misdiagnosed as a neoplastic process, such as lymphoma. Indeed, some patients who were asymptomatic from their lung disease were diagnosed to have LAM from lymph node biopsies performed to exclude lymphoma. ¹¹

Abdominopelvic ascites­­Approximately 10% of patients with LAM have abdominopelvic ascites, this ranges in attenuation from -10 to +21 HU, the variation is thought to be related the amount of chyle contained in the fluid. ¹⁰ Overdistension of lymph cysts may result in rupture and chylous ascites, the onset of ascites sometimes accompanied by a marked decrease in the size of the cystic retroperitoneal masses. ¹⁵

Dilatation of thoracic duct­­Less than one-tenth of patients have dilated thoracic ducts. Dilatation of the thoracic duct may be seen either as the result of lymphatic obstruction and smooth muscle proliferation or as a result of thoracic duct ligation to prevent recurrent pleural effusions in some patients. ¹⁰

Fatty liver masses­­Approximately 5% of patients have fatty liver lesions consistent with AMLs or lipomas. These may be single or multiple. The CT attenuation measurements of the hepatic lesions range from -21 to -94 HU; all are echogenic on sonography. ¹⁰

Symptoms related to abdominal involvement with LAM

Patients with LAM may have abdominal symptoms related to their disease, including flank pain and hematuria, due to intratumoral hemorrhage. They may resolve spontaneously or lead to partial nephrectomy because of persistent or worsening symptoms. ¹⁰

Patients with lymphangioleiomyo-mas may report the following symptoms: bloating and increased abdominal girth; abdominal pain; nocturia; perineal swelling; and chylous vaginal discharge. Edema of the lower extremities and paresthesias are reported by patients with masses extending into the pelvis. Two patients have had thoracic masses posterior and adjacent to the heart, one reported Horner's syndrome and the other recurrent palpitations. ¹⁰ Patients with ascites may experience bloating.

Correlation of abdominopelvic imaging findings with severity of lung disease

Patients with more severe lung disease are more frequently found to have enlarged abdominal lymph nodes, renal AMLs, and lymphangio-leiomyomas than those patients with less severe lung disease. ¹⁰

Differential diagnosis

Despite the suggestive appearance of LAM on CT scans, the differential diagnosis, includes tuberous sclerosis (TSC), Langerhans cell histiocytosis, and emphysema. ^5,16-20

LAM can occur alone (referred to as "sporadic LAM") or in association with TSC. ²¹ TSC is an autosomal dominant genetic disorder with pulmonary, renal, and lymph node findings similar to LAM. It is thought that LAM may be a "forme-fruste" of TSC. ^16,22 A hallmark of TSC is the presence of multiple renal AMLs, which occur in 40% to 80% of patients (mostly female) usually bilaterally. In LAM, more than 50% of patients have solid renal masses; but in contrast, these are multiple in less than one-fifth. Although in TSC the AMLs occur in both genders, the cystic lung disease is only found in women. ²³ Patients with TSC have brain and skin findings (cortical tubers, subependymal nodules, retinal hamartomas, facial angiofibromas, periungual fibromas) not found in patients with LAM. ²⁴ Patients with TSC have increased risk of renal cell carcinoma (1% to 2%) and clear cell carcinoma; however, to date, there has been no increased incidence of renal cancer reported in patients with LAM. ^17,25 Specific genetic abnormalities in chromosomes 9q34 (TSC1) and 16p13 (TSC2) have been discovered in TSC. ^26,27 Although no genetic defect has been discovered in LAM, some AMLs and abdominal lymph nodes from women with LAM have been found to have loss of heterozygosity in chromosome 16p13, this finding is similar to that seen in TSC and suggests that LAM may be caused by mutations of the TSC2 gene. ²¹

As in LAM, pulmonary cysts are a primary morphologic feature in histiocytosis X. However, the cyst walls in Langerhans cell histiocytosis are often more variable in thickness than those seen in LAM. In addition, pulmonary nodules and cavitary nodules are a common feature of histiocytosis X. ¹⁹ Furthermore, histiocytosis X characteristically involves the upper two-thirds of the lungs and spares the costophrenic angles, whereas LAM involves the lungs diffusely. ^18,19

In emphysema, the lung cysts have almost imperceptible walls compared with the cysts in LAM that have well-defined walls. Although emphysema may be seen diffusely in the lungs, it may also be distributed segmentally. In patients with LAM, the cysts are distributed diffusely bilaterally. ²⁰

Conclusion

Pulmonary LAM has a characteristic appearance of cysts surrounded by normal lung on CT scans, and an abnormal speckling pattern on ventilation/perfusion scintigrams. LAM has many associated thoracic and abdominal findings that should be recognized by radiologists in order to help expedite the diagnosis and prevent misdiagnosis that could lead to unnecessary biopsies or surgeries. Renal AML should be followed in order to plan embolic therapy or partial nephrectomy in patients with developing or worsening symptoms. Atypical renal AML should be followed and biopsy performed if there is rapid growth of the mass. AR

Acknowledgment

The authors would like to thank Dr. Clara Chen from the Nuclear Medicine Department at the Warren G. Magnuson Clinical Center for the use of the ventilation/perfusion scintigram.