Lymphangioleiomyomatosis

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Lymphangioleiomyomatosis (LAM)
Other names	lymphangiomyomatosis, LAM
Figure A shows the location of the lungs and airways in the body. The inset image shows a cross-section of a healthy lung. Figure B shows a view of the lungs with LAM and a collapsed lung (pneumothorax). The inset image shows a cross-section of a lung with LAM.
Specialty	Pulmonology

Lymphangioleiomyomatosis (LAM) is a rare, progressive and systemic disease that typically results in

The average age of onset is the early-to-mid-30s.[3]^[4][5][6] 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.^[6]

Diagnosis is typically delayed 5 to 6 years.^[3][4][5][6] The condition is often misdiagnosed as asthma or chronic obstructive pulmonary disease. The first pneumothorax, or lung collapse, precedes the diagnosis of LAM in 82% of patients.^[7][8] The consensus clinical definition of LAM includes multiple symptoms:^{[citation needed]}

• 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.^[9][10] 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.[11]^[12][13][14]

Lung destruction in LAM is a consequence of diffuse infiltration by

Most people have dyspnea on exertion with daily activities by 10 years after symptom onset. Many patients require supplemental oxygen over that interval.^[7]

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).^[17][18] 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.^[19] 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.^[20]

Sporadic LAM is primarily associated with somatic TSC2 gene mutations.^[21][22] 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.^[20][21][22] Because of the large size of the genes (together they have more than 60 exons) and because mutations can be located virtually anywhere within the genes, mutation detection is often challenging.^{[citation needed]}

On a cellular basis, LAM cells carry

Angiomyolipomas and pulmonary LAM cells from women with the sporadic form of LAM carry identical mutations in TSC2.[21] This, together with the fact that recurrent LAM after lung transplantation carries the same TSC2 mutations as the original LAM,^[30] has led to the "benign metastasis" hypothesis that LAM cells can migrate or metastasize from one site to another.^[17][18]

Pathophysiology

A variable percentage of cells within the LAM lesion contain mutational inactivation of the tuberous sclerosis complex (TSC1 or TSC2) tumor suppressor genes.^[21][27][31] TSC1 mutations cause a less severe clinical phenotype than TSC2 mutations.^[32] The discovery of TSC1/2 gene function as negative regulator of the mammalian target of rapamycin complex 1 (mTORC1)^[33][34] led to successful use of rapamycin analog sirolimus in clinical trials^[35][36] and FDA approval of sirolimus for treatment of LAM.

TSC1 and TSC2 form a tumor suppressor complex that regulates

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.

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.^[70][81]

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.^[82][83] 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.^{[63][84][85][86]}

Diagram 1 outlines a proposed algorithm for the diagnosis of LAM.^{[citation needed]}

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.^[3][6] Pleural effusion and pneumothorax may be apparent. Preservation of lung volumes in the presence of increased interstitial markings is a radiographic hallmark of LAM that helps distinguish it from most other interstitial lung diseases, in which alveolar septal and interstitial expansion tend to increase the lung's elastic recoil properties and decreased lung volumes.^{[citation needed]}

Computed tomography

The

LAM and AML lesions do not typically exhibit increased uptake of 18F-fluorodeoxyglucose on positron emission tomography (PET) scanning.^[94][95] Other neoplasms (or sources of inflammation) should therefore be considered in known or suspected LAM cases in which FDG-PET results are positive.^[96]

Abdominal imaging

Abnormalities on abdominal imaging, such as renal AML and enlarged lymphatic structures, are also common in LAM. Fat density within a

Central nervous system abnormalities, such as cortical or subependymal tubers and astrocytomas, are common in patients with TSC, including those with TSC-LAM, but are not found in women with S-LAM. Moss and associates^[97] 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.^[98]

Pulmonary function studies

Pulmonary function testing in patients with LAM may be normal or may reveal obstructive, restrictive or mixed patterns. Obstructive physiology is the most common abnormality. Quality-controlled lung function data were collected prospectively by the NHLBI Registry, a five-year study of patients with LAM in centers around the United States. Spirometry revealed obstructive changes in about 57% of patients and normal results in 34%.^[10] Restriction, defined as a total lung capacity less than the lower limit of normal, was seen in 11%. Hyperinflation was present in about 6%. The average residual volume was 125% of predicted when measured by plethysmography, but was only 103% of predicted determined with gas dilution methods, suggesting significant air trapping in noncommunicating airspaces. Approximately 25% of patients with obstructive physiology may demonstrate bronchodilator responsiveness but may be less in more severe obstruction.^[99][100] The obstructive physiologic defect in LAM is primarily attributable to airflow obstruction.^[101] 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.^[3][4][6] It is not unusual for DLCO to be reduced out of proportion to forced expiratory volume in 1 second (FEV1).^[99] Reduction in DLCO and increase in residual volume are generally considered to be LAM's earliest physiologic manifestations.^{[citation needed]}

Cardiopulmonary exercise testing in a much larger cohort of patients with LAM revealed a reduced maximal oxygen consumption (

There are two major cell morphologies in the LAM lesion: small spindle-shaped cells and cuboidal epithelioid cells.[107] 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.^[107] This immunohistochemical marker is very useful diagnostically, because other smooth muscle-predominant lesions in the lung do not react with the antibody.^[108] 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.^[107] Compared with cigar-shaped normal smooth muscle cells, spindle-shaped LAM cells contain less abundant cytoplasm and are less eosinophilic. Estrogen and progesterone receptors are also present in LAM lesions,^{[109][110][111]} but not in adjacent normal lung tissue.^[112] 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.^[113][114] Unlike the dilated airspaces in emphysema, the cystic spaces found in LAM may be partially lined with hyperplastic type II cells.^[115]

Treatment

An FDA-approved drug for treatment of LAM, the

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.[8] The LAM Foundation Pleural Consensus Group advocated the use of a pleural symphysis procedure with the first pneumothorax, given the greater than 70% chance of recurrence.^[8] Chemical sclerosis, mechanical abrasion, talc poudrage and pleurectomy have been effective in patients with LAM, but mechanical abrasion is preferred for those who may require pulmonary transplantation in the future. About half of LAM patients who have undergone transplant have had a prior pleurodesis procedure, and more than 75% of those had had prior bilateral pleurodesis.^[8] Although pleurodesis is not a contraindication to transplantation, it can result in increased perioperative bleeding.^{[citation needed]}

Treatment of chylothorax

Chyle does not generally cause pleural inflammation or fibrosis. Small stable chylous effusions rarely require intervention once the LAM diagnosis is made. Shortness of breath may mandate possibly repeated drainage. Sirolimus is effective for chylous effusions and most experts believe it should be used as the first line of therapy.^[65] Imaging the source of the leak with heavy T2-weighted MRI or contrast lymphangiography is an advised for refractory effusions.^[117] 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.^[118]

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.^[119] 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.^[120] 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.^[121]

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.^[35] It is approved by the FDA for use in LAM, based on the results of the Multicenter International LAM Efficacy and Safety of Sirolimus (MILES) Trial. MILES data supports the use of sirolimus in patients who have abnormal lung function (i.e. FEV1<70% predicted). Whether the benefits of treatment outweigh the risks for asymptomatic LAM patients with normal lung function is not clear, but some physicians consider treatment for declining patients who are approaching the abnormal range for FEV1. Sirolimus also appears to be effective for the treatment chylous effusions and lymphangioleiomyomatosis. The benefits of sirolimus only persist while treatment continues. The safety of long term therapy has not been studied.^{[citation needed]}

Potential side effects from mTOR inhibitors include swelling in the ankles, acne, oral ulcers,

Treatment with another mTOR inhibitor, everolimus, was reported in a small, open-label trial to be associated with improvement in FEV1 and six-minute walking distance.^[122] 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.^[71] Higher baseline VEGF-D levels predicts more rapid disease progression and a more robust treatment response.

Hormonal approaches to treatment have never been tested in proper trials. In the absence of proven benefit, therapy with

Sirolimus is often effective as first-line management for chylothorax.[65] 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.^{[citation needed]}

Other management

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.[125] Data from earlier, large case series indicated that 38% to 78% of patients were alive at 8.5 years from the time of disease onset.^{[3][4][6][126]}

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.^[127] 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.^[128] In other series from Europe, the rate of decline in FEV1 was considerably higher, estimated at approximately 100 to 120 mL/yr.^{[6][129][130]} In the MILES trial, patients in the placebo group lost 134 cc/yr.^[35] There was some evidence in these studies that rate of decline in lung function correlates with initial DLCO, with menopausal status and high baseline VEGF-D.

Estimates of median survival vary from 10 to 30 years, depending on whether hospital-based or population-based cohorts are studied.^{[98][125][131]}

Epidemiology

LAM is almost completely restricted to women.^[132][133] While lung cysts consistent with LAM are reported in some men with tuberous sclerosis, very few of these men develop symptoms. The prevalence of LAM is estimated using data from registries and patient groups and is between 3.4 and 7.8/million women. The number of new cases each year is between 0.23 and 0.31/million women/year in the US, UK and Switzerland. The variation between countries and between adjacent states in the US, suggest that a significant number of women with LAM remain either undiagnosed or their symptoms are attributed to other diseases.^[134] 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.^[135] In a further retrospective study of women with TSC who underwent CT scanning to detect LAM, 25% of those in their 20s had lung cysts whereas 80% of women in their 40s were affected, suggesting that the development of LAM is age dependent at least in tuberous sclerosis-related LAM.^[79] Although the prevalence of tuberous sclerosis at 1 in 6,000 births is much greater than that of LAM, most pulmonary clinics see more cases of sporadic than tuberous sclerosis–LAM: probably due to a combination of low levels of screening for LAM in tuberous sclerosis and in many, the absence of symptoms.^{[citation needed]}

Female sex and tuberous sclerosis are the only known risk factors. Although use of supplemental estrogen is not associated with development of LAM,^[136] one study suggested that use of estrogen-containing contraceptive pills was associated with earlier onset.^[137]

It occurs in more than 30% of women with

Mild cystic changes consistent with LAM have been described in 10–15% of men with TSC,[140]^[135] but symptomatic LAM in males is rare.^[132][133] Sporadic LAM occurs exclusively in women, with one published exception to date.^[133] Both TSC-LAM and S-LAM are associated with mutations in tuberous sclerosis genes.^[21]

Pregnancy

Pregnancy has been reported to exacerbate LAM in some cases.^{[96][141][142][143][144]} 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.^[145] 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^[6][7] 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.^{[citation needed]}

Society

The LAM Foundation was founded in 1995 as a grassroots organization to provide patient advocacy and research funding.^[146] 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 "

See also

• Perivascular epithelioid cell tumour

References