Lymphangioleiomyomatosis

The average age of onset is the early-to-mid-30s. Exertional dyspnea (shortness of breath) and spontaneous pneumothorax (lung collapse) have been reported as the initial presentation of the disease in 49% and 46% of patients, respectively. The consensus clinical definition of LAM includes multiple symptoms: • Fatigue • Cough • Coughing up blood (rarely massive) • Chest pain • Chylous complications arising from lymphatic obstruction, including • Chylothorax • Chylous ascites • Chylopericardium • Chyloptysis • Chyluria • Chyle in vaginal discharge • Chyle in stool • Angiomyolipomas (fatty kidney tumors) are present in about 30% of patients with sporadic LAM and up to 90% of patients with TSC-LAM. Angiomyolipomas can sometimes spontaneously bleed, causing pain or low blood pressure. • Cystic lymphangiomas or lymph nodes with hypodense centers, which mimic necrotizing lymphomas, ovarian or renal cancers, or other malignancies can occur in the retroperitoneum, pelvis or mediastinum. Lung destruction in LAM is a consequence of diffuse infiltration by neoplastic smooth muscle-like cells that invade all lung structures including the lymphatics, airway walls, blood vessels and interstitial spaces. The consequences of vessel and airway obstruction include chylous fluid accumulations, hemoptysis, airflow obstruction and pneumothorax. The typical disease course displays progressive dyspnea on exertion, spaced by recurrent pneumothoraces and in some patients, chylous pleural effusions or ascites. Most people have dyspnea on exertion with daily activities by 10 years after symptom onset. Many patients require supplemental oxygen over that interval. ==Genetics==

LAM occurs in two settings: in the disease tuberous sclerosis complex (TSC-LAM) and in a sporadic form, in women who do not have TSC (sporadic LAM). In both settings, genetic evidence indicates that LAM is caused by inactivating or "loss of function" mutations in the TSC1 or TSC2 genes, which were cloned in 1997 and 1993, respectively. The TSC1 gene is located on the long arm of chromosome 9 (9q34) and the TSC2 gene is located on the short arm of chromosome 16 (16p13). TSC-LAM occurs in women who have germline mutations in either the TSC1 or the TSC2 gene. Sporadic LAM is primarily associated with somatic TSC2 gene mutations. Germline and somatic mutations in LAM include many types of mutations spread across the genes, with no clear "hot spots," including missense changes, in-frame deletions and nonsense mutations. The second hit event in LAM cells is often loss of the chromosomal region containing the wild-type copy of the TSC2 gene; this is referred to as loss of heterozygosity or LOH. LOH can be detected in microdissected LAM cells, in angiomyolipomas and lymph nodes from women with LAM, Angiomyolipomas and pulmonary LAM cells from women with the sporadic form of LAM carry identical mutations in TSC2. has led to the "benign metastasis" hypothesis that LAM cells can migrate or metastasize from one site to another. ==Pathophysiology==

A variable percentage of cells within the LAM lesion contain mutational inactivation of the tuberous sclerosis complex (TSC1 or TSC2) tumor suppressor genes. TSC1 mutations cause a less severe clinical phenotype than TSC2 mutations. The discovery of TSC1/2 gene function as negative regulator of the mammalian target of rapamycin complex 1 (mTORC1) led to successful use of rapamycin analog sirolimus in clinical trials and FDA approval of sirolimus for treatment of LAM. TSC1 and TSC2 form a tumor suppressor complex that regulates mammalian target of rapamycin (mTOR) signaling complex by directly controlling the activity of the small GTPase Rheb via the GTPase activating protein (GAP) domain of TSC2. Rheb binds to Raptor and controls the activity of mTOR complex 1 (mTORC1) that directly phosphorylates p70 S6 kinase (S6K1) and 4E-BP1. mTOR forms two physically and functionally distinct multiprotein complexes: the rapamycin-sensitive mTORC1 and the rapamycin-insensitive mTORC2. MTORC1 consists of five proteins including Raptor that positively regulate mTOR activity. MTORC2 consists of six proteins including mTOR and RICTOR, which defines the activation level of mTORC2 and modulates the assembly of the actin cytoskeleton through Rho GTPases, and Rac1 is required for mTOR activation. In TSC2-null and human LAM cells, Rho GTPase activity is required for cell adhesion, motility, proliferation and survival. Loss of TSC1/TSC2 in LAM induces uncontrolled LAM cell growth and increases LAM cell viability. Upregulation of STAT1 and STAT3 and autophagy are known mediators of LAM cell viability and survival. LAM cells behave, in many ways, like metastatic tumor cells. LAM cells appear to arise from an extrapulmonary source and migrate to the lung. The invasive cell phenotype in LAM is associated with TIMP-3 downregulation and TSC2-dependent upregulation of MMPs. Clinical and histopathological evidence demonstrate the lymphatic involvement in LAM. The prevailing hypothesis is that LAM lesions secrete the lymphangiogenic factor VEGF-D, recruit lymphatic endothelial cells (LECs) that form lymphatic vessels and induce lung cysts. compared to other cystic lung diseases, including pulmonary Langerhans cell histiocytosis, emphysema, Sjögren's syndrome, or Birt–Hogg–Dubé syndrome. VEGF-D levels correlate with the severity of LAM, evaluated as a measure of CT grade (the abundance of chylous effusions and lymphatic involvement). VEGF-D is a secreted homodimeric glycoprotein and a member of the VEGF family of growth factors, is known for its role in cancer lymphangiogenesis and metastasis. Proteolytic processing of VEGF-D affects cognate binding to VEGFR3. Histopathologically, LAM lesions are surrounded by cells that stain for VEGFR3, the lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) and podoplanin. VEGF-D binds to the receptor protein tyrosine kinases VEGFR-2 and VEGFR-349 in humans, and to VEGFR3 in mice. Surprisingly, knock-out of VEGF-D in mice has little effect on lymphatic system development. Nevertheless, during tumorigenesis VEGF-D promotes formation of tumor lymphatic vessels and facilitates metastatic spread of cancer cells. However, little is known about a role of abnormal lymphatics and VEGF-D in LAM pathogenesis. ==Diagnosis==

of lymphangioleiomyomatosis. H&E stain LAM can come to medical attention in several ways, most of which trigger a chest CT. Thin-walled cystic change in the lungs may be found incidentally on CT scans of the heart, chest or abdomen (on the cuts that include lung bases) obtained for other purposes. HRCTs of TSC patients reveals that about 20% of women have cystic change by age 20 and about 80% of women have cystic changes after age 40. Chylothorax can also bring LAM to attention. In some cases, a LAM diagnosis can be made with confidence on clinical grounds (without biopsy) in patients with typical cystic changes on high resolution CT scanning of the lung and findings of tuberous sclerosis, angiomyolipoma, lymphangioleiomyoma, chylothorax or serum VEGF-D > 800 pg/ml. If none of these clinical features are present, a biopsy may be necessary to make the diagnosis. Video-assisted thoracoscopic lung biopsy is the most definitive technique, but transbronchial biopsy has a yield of over 50% and can also be effective. The safety of the latter procedure in patients with diffuse cystic disease and the profusion of cystic change that predicts an informative biopsy are incompletely understood, however. Cytology of chylous fluids, aspirated abdominal nodes or lymphatic masses can also be diagnostic. Diagram 1 outlines a proposed algorithm for the diagnosis of LAM. Chest radiograph The chest radiograph may appear relatively normal, even late in the disease, or may suggest hyperinflation only. As the disease progresses, the chest radiograph often demonstrates diffuse, bilateral and symmetric reticulonodular opacities, cysts, bullae or a "honeycomb" (i.e., pseudo fibrotic) appearance. The typical CT shows diffuse round, bilateral, thin-walled cysts of varying sizes ranging from 1 to 45 mm in diameter. MMPH may be present in males or females with TSC in the presence or absence of LAM, but not in patients with S-LAM. MMPH is not typically associated with physiologic or prognostic consequences, but one case of respiratory failure due to MMPH has been reported. Ventilation-perfusion scans In one study ventilation-perfusion scans were abnormal in 34 of 35 LAM patients. Other neoplasms (or sources of inflammation) should therefore be considered in known or suspected LAM cases in which FDG-PET results are positive. Abdominal imaging Abnormalities on abdominal imaging, such as renal AML and enlarged lymphatic structures, are also common in LAM. Fat density within a renal mass is pathognomonic of AMLs. AMLs are more prevalent and more frequently bilateral and large in patients with TSC-LAM than in patients with S-LAM. AML size correlates with the prevalence of pulmonary cysts in patients with TSC. reported that women with S-LAM and TSC-LAM may have an increased incidence of meningioma, but the significance of that finding has been challenged. The obstructive physiologic defect in LAM is primarily attributable to airflow obstruction. The earliest change in initial pulmonary function testing in various case series was abnormal gas transfer, as assessed by the diffusing capacity for carbon monoxide (DLCO), described in 82% to 97% of patients. Exercise-induced hypoxemia was found even in patients who did not have resting abnormalities in FEV1 and DLCO. In most patients, exercise was thought to be ventilation limited, owing to airflow obstruction and increased dead-space ventilation. Disease progression is usually accompanied by a progressive obstructive ventilatory defect. Decline in FEV1 is the most commonly used parameter to monitor disease progression. Although resting pulmonary hypertension appears to be unusual in LAM, pulmonary arterial pressure often rises with low levels of exercise, related in part to hypoxemia. Pathology Grossly, LAM lungs are enlarged and diffusely cystic, with dilated air spaces as large as several centimeters in diameter. Microscopic examination of the lung reveals foci of smooth muscle-like cell infiltration of the lung parenchyma, airways, lymphatics, and blood vessels associated with areas of thin-walled cystic change. LAM lesions often contain an abundance of lymphatic channels, forming an anastomosing meshwork of slit-like spaces lined by endothelial cells. LAM cells generally expand interstitial spaces without violating tissue planes but have been observed to invade the airways, the pulmonary artery, the diaphragm, aorta, and retroperitoneal fat, to destroy bronchial cartilage and arteriolar walls, and to occlude the lumen of pulmonary arterioles. LAM cells stain positively for smooth muscle actin, vimentin, desmin, and, often, estrogen and progesterone receptors. The cuboidal cells within LAM lesions also react with a monoclonal antibody called HMB-45, developed against the premelanosomal protein gp100, an enzyme in the melanogenesis pathway. The spindle-shaped cells of the LAM lesion are more frequently proliferating cell nuclear antigen positive than the cuboidal cells, consistent with a proliferative phenotype. but not in adjacent normal lung tissue. LAM lesions express lymphatic markers LYVE-1, PROX1, podoplanin and VEGFR-3. The smooth muscle-like cells of AMLs are morphologically and immunohistochemically similar to LAM cells, including reactivity with antibodies directed against actin, desmin, vimentin, and HMB-45 as well as estrogen and progesterone receptors. Unlike the dilated airspaces in emphysema, the cystic spaces found in LAM may be partially lined with hyperplastic type II cells. ==Treatment==

An FDA-approved drug for treatment of LAM, the mTOR inhibitor sirolimus, is available for stabilization of lung function decline. Lung transplantation remains the last resort for patients with advanced disease. Treatment of pneumothoraces Pneumothoraces in LAM patients tend to recur, especially after conservative management such as observation, aspiration or simple tube thoracostomy. Over 65% of LAM patients develop pneumothorax during the course of their illness, averaging 3.5 pneumothoraces in those who have at least one pneumothorax. Some leaks are amenable to embolization through catheters threaded from groin lymph nodes into the thoracic duct. Thoracic duct ligation can be considered, but since thoracic effusions sometimes originate from ascites that are siphoned into the chest by the bellows action of the thorax, it is important to rule out an abdominal source before considering this option. Pleural symphysis may be required to prevent nutritional and lymphocyte deficiencies that can result from repeated taps or persistent drainage. Chemical pleurodesis is generally an effective therapy for chylothorax, as is mechanical abrasion and talc poudrage. Treatment of renal angiomyolipoma Renal angiomyolipomas (AMLs) may require embolization or cauterization for control of bleeding, a complication that is thought to be more common when tumor diameter exceeds 4 cm. The extent of aneurysmal change may determine bleeding risk. Serial abdominal imaging should be performed to assess AML size at 6- to 12-month intervals, at least until trends in growth are clear. Nephron sparing partial resections may be considered for very large tumors. Nephrectomy is sometimes required for tumors with intravascular extension or other reasons, but is rarely the approach of choice for AMLs that can be managed by less invasive means. Everolimus is approved by the US Food and Drug Administration (FDA) for AML treatment. Treatment of lymphangioleiomyoma Lymphangioleiomyomatoses are fluid-filled hypodense structures present in the retroperitoneal regions of the abdomen and pelvis in about 30% of LAM patients. They generally do not require intervention. Biopsy or resection can lead to prolonged leakage. mTOR inhibitors are effective at shrinking the size of lymphangioleiomyomatosis, and can lead to total resolution. Medication Sirolimus is an mTOR inhibitor that stabilizes lung function and improves some measures of life in LAM patients. Serum levels of VEGF-D and collagen IV were reduced by treatment. Adverse events were generally consistent with those known to be associated with mTOR inhibitors, although some were serious and included peripheral edema, pneumonia, cardiac failure and Pneumocystis jirovecii infection. Escalating doses of everolimus were used, up to 10 mg per day; higher than what is typically used clinically for LAM. Serum VEGF-D concentration is useful, predictive and prognostic biomarker. Sirolimus is often effective as first-line management for chylothorax. If chylous leakage or accumulations persist despite treatment, imaging with heavy T2 weighted MRI, MRI lymphangiography or thoracic duct lymphangiography can be considered. Pleural fusion procedures can be considered in refractory cases. Other management Estrogen-containing medications can exacerbate LAM and are contraindicated. Agents that antagonize the effects of estrogen have not been proven to be effective for treatment, but no proper trials have been done. A trial of bronchodilators should be considered in LAM patients, because up to 17–25% have bronchodilator-responsive airflow obstruction. Oxygen should be administered to maintain oxyhemoglobin saturations of greater than 90% with rest, exercise and sleep. Bone densitometry should be considered in all patients who are immobilized and/or on antiestrogen therapies, and appropriate therapy instituted for osteoporotic patients. Proper attention should be paid to cardiovascular health following natural or induced menopause. Immunizations for pneumococcus and influenza should be kept up to date. Pulmonary rehabilitation seems to be particularly rewarding in young, motivated patients with obstructive lung disease, but studies to assess this intervention's effect on exercise tolerance, conditioning and quality of life have not been done. ==Prognosis==

Survival estimates vary, dependent on mode of presentation or ascertainment, and have generally trended upward, probably due to earlier recognition through more widespread use of CT scanning. In a recent population-based cohort survey, median survival was found to be 29 years. Patients typically develop progressive airflow obstruction. In a cohort of patients in the United Kingdom, 10 years after symptom onset, 55% of 77 patients were breathless walking on flat ground and 10% were housebound. The average annual rate of decline in FEV1 and DLCO in 275 patients studied in a single pulmonary function laboratory at the NHLBI was 75 ± 9 mL, and 0.69 ± 0.07 mL/min/mm Hg, respectively. In other series from Europe, the rate of decline in FEV1 was considerably higher, estimated at approximately 100 to 120 mL/yr. In the MILES trial, patients in the placebo group lost 134 cc/yr. ==Epidemiology==

LAM is almost completely restricted to women. Adult women with tuberous sclerosis are more likely to develop LAM than women without tuberous sclerosis. Cohorts of patients with tuberous sclerosis have been screened for LAM using CT scanning. In a retrospective study of adults with tuberous sclerosis, CT demonstrated lung cysts in 42% of 95 women and 13% of 91 men. In general, lung cysts were larger and more numerous in women than in men. one study suggested that use of estrogen-containing contraceptive pills was associated with earlier onset. It occurs in more than 30% of women with tuberous sclerosis complex (TSC-LAM), a heritable syndrome that is associated with seizures, cognitive impairment and benign tumors in multiple tissues. Most LAM patients who present for medical evaluation have the sporadic form of the disease (S-LAM), however, which is not associated with other manifestations of tuberous sclerosis complex. Mild cystic changes consistent with LAM have been described in 10–15% of men with TSC, but symptomatic LAM in males is rare. Sporadic LAM occurs exclusively in women, with one published exception to date. ==Pregnancy==

Pregnancy has been reported to exacerbate LAM in some cases. However, the risk has not been rigorously studied. In a survey of 318 patients who indicated that they had had at least one pregnancy, 163 responded to a second survey focusing on lung collapse. A total of 38 patients reported a pneumothorax with pregnancy, consistent with an incidence of pneumothorax in pregnancy of at least 10% (38 of 318). In one third of patients, the pneumothorax during pregnancy led to the LAM diagnosis. Pneumothoraces were almost twice as frequent on the right as on the left, and four women presented with bilateral spontaneous pneumothorax. Most pneumothoraces took place during the second and third trimesters. This study and others suggest that pregnancy is associated with pleural complications in LAM patients. Few women with a known LAM diagnosis choose to become pregnant and patients in whom LAM is diagnosed during pregnancy rarely have baseline pulmonary function tests available, complicating resolution of this question. ==Society==

The LAM Foundation was founded in 1995 as a grassroots organization to provide patient advocacy and research funding. Today, the LAM Foundation provides support and education for women with LAM and their families, engages doctors and scientists to continue to learn more about the disease, and raises funds for the continued study of LAM. It seeks safe and effective treatments, and ultimately a cure, for lymphangioleiomyomatosis. It is headquartered in Cincinnati, Ohio. == In popular culture ==

In "Lucky Thirteen", the fifth episode of the fifth season of House, Spencer (Angela Gots) was diagnosed with LAM, though later it was found to be a case of Sjögren's syndrome. ==See also==