| Lymphangioleiomyomatosis |
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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.
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| Classification and external resources |
| ICD-10 |
J84.81 |
| ICD-9-CM |
516.4 |
| ICD-O |
9174/1 |
| OMIM |
606690 |
| DiseasesDB |
30755 |
| eMedicine |
med/1348 radio/415 |
| MeSH |
D018192 |
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[edit on Wikidata]
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Lymphangioleiomyomatosis (LAM) is a rare, progressive, systemic disease that typically results in cystic lung destruction and predominantly affects women, especially during child bearing years.[1] 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.[2][3][4][5] 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,[6][7] but symptomatic LAM in males is extremely rare.[8][9] Sporadic LAM occurs exclusively in women, with one published exception to date.[9] Both TSC-LAM and S-LAM are associated with mutations in tuberous sclerosis genes.[10] Lung destruction in LAM is a consequence of diffuse infiltration by neoplastic smooth muscle-like cells, which invade all lung structures including the lymphatics, airway walls, blood vessels, and interstitial spaces.[11] The consequence of obstruction of the vessels and airways include chylous fluid accumulations, hemoptysis, airflow obstruction and pneumothorax. The typical disease course is characterized by progressive dyspnea on exertion, punctuated by recurrent pneumothoraces and, in some patients, chylous pleural effusions or ascites.[12] Modern estimates for median survival in LAM have varied from 10 to 30 years, based on whether hospital based or population based cohorts are studied.[13][14][15] Most patients have dyspnea on exertion with daily activities by 10 years after symptom onset and many will require supplemental oxygen over that interval.[16] An FDA approved drug for treatment of LAM, sirolimus, is now available for stabilization of lung function decline.[17] Lung transplant remains the option of last resort for patients with advanced disease.[18]
Contents
- 1 Signs and symptoms
- 2 Pathophysiology
- 3 Genetics
- 4 Pathology
- 5 Radiology
- 6 Pulmonary function studies
- 7 Diagnosis
- 8 Other therapeutic considerations
- 9 Pharmacological treatment
- 10 Pregnancy
- 11 Air travel
- 12 Prognosis
- 13 Epidemiology
- 14 Clinical research
- 15 Patient Registry
- 16 In media
- 17 See also
- 18 References
- 19 External links
Signs and symptoms
The average age of onset of symptoms is in the early to mid 30s.[19][20][21][22] Exertional dyspnea and spontaneous pneumothorax have been reported as the initial presentation of the disease in 49% and 46% of patients, respectively.[22]
The diagnosis is typically delayed by 5 to 6 years,[19][20][21][22] often initially misdiagnosed as bronchial asthma, emphysema, chronic bronchitis, or chronic obstructive pulmonary disease. The first pneumothorax precedes the diagnosis of LAM in 82% of patients.[16][23] There is a consensus clinical definition of LAM that includes the following listed features for establishing a LAM diagnosis:
- Fatigue
- Cough
- Hemoptysis (rarely massive)
- Chest pain
- Chylous complications arising from lymphatic obstruction, including
- Chylothorax
- Chylous ascites
- Chylopericaridium
- 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.[2][24] Angiomyolipomas can sometimes spontaneously bleed, causing pain or hypotension.
- Cystic lymphangiomyomas or lymph nodes with hyodense centers, which mimic necrotizing lymphomas, ovarian or renal cancers, or other malignancies can occur in the retroperitoneum, pelvis or mediastinum.[25][26][27][28]
Pathophysiology
A variable percentage of cells within the LAM lesion contain mutational inactivation of the Tuberous Sclerosis Complex (TSC1 or TSC2) tumor suppressor genes.[10][29][30] TSC1 mutations cause a less severe clinical phenotype than do TSC2 mutations.[31] The discovery of TSC1/2 gene function as negative regulator of the mammalian target of rapamycin complex 1 (mTORC1)[32][33] led to successful use of rapamycin analog sirolimus in clinical trials[17][34] and FDA approval of sirolimus for treatment of LAM.
TSC1 and TSC2 form a tumor suppressor complex that regulates activity of the 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 the 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.[35] The mTORC1 consists of five proteins including Raptor positively regulates mTOR activity.[36][37][38] The mTORC2 consists of six proteins including mTOR and Rictor, which defines the activation level of mTORC2[39][40][41] and modulates the assembly of the actin cytoskeleton through Rho GTPases,[42][43][44] and Rac1 is required for mTOR activation.[45] In TSC2-null and human LAM cells, Rho GTPase activity is required for cell adhesion, motility, proliferation and survival.[46][47][48] Loss of TSC1/TSC2 in LAM not only induces uncontrolled LAM cell growth but also increases LAM cell viability. Upregulation of STAT1 and STAT3[49][50][51][52] and autophagy[53] are known mediators of LAM cell viability and survival.
LAM cells behave, in many ways, like metastatic tumor cells.[54] Several studies have demonstrated that LAM cells appear to arise from an extrapulmonary source and migrate to the lung.[10] Although increased LAM cell migration and invasiveness is rescued by TSC2 re-expression in experimental studies,[47] the cellular and molecular mechanisms of neoplastic transformation and lung parenchymal destruction by LAM cells remain unknown. Lung remodeling may be mediated by an imbalance between matrix degrading metalloproteases (MMPs) and their endogenous inhibitors TIMPs.[55] The invasive cell phenotype in LAM is associated with TIMP-3 downregulation[56] and TSC2-dependent upregulation of MMPs.[57][58][59][60]
Clinical and histopathological evidence demonstrate the lymphatic involvement in LAM.[28][55][61][62][63][64][65][66] 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.[55] VEGF-D serum levels are increased in LAM[67] compared to other cystic lung diseases including pulmonary Langerhans cell histiocytosis, emphysema, Sjögren syndrome, or Birt-Hogg-Dubé syndrome.[68] VEGF-D levels correlate with the severity of LAM, evaluated as a measure of CT grade, the abundance of chylous effusions and lymphatic involvement.[69] VEGF-D, a secreted homodimer glycoprotein and a member of the VEGF family of growth factors, is known for its role in cancer lymphangiogenesis and metastasis.[70][71][72] Proteolytic processing of VEGF-D affects cognate binding to VEGFR3.[73] Histopathologically, LAM lesions are surrounded by cells that stain for VEGFR3, the lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) and podoplanin.[61][74] VEGF-D binds to the receptor protein tyrosine kinases VEGFR-2 and VEGFR-349 in humans, and to VEGFR3 in mice.[72][75] Surprisingly, knock-out of VEGF-D in mice has little effect on development of lymphatic system.[76] During tumorigenesis, however, VEGF-D promotes formation of tumor lymphatic vessels and facilitates metastatic spread of cancer cells.[71][72] Little is known, however, about a role of abnormal lymphatics and VEGF-D in LAM etiology and pathogenesis.
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).[77][78] 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.[79] The TSC1 gene is located on chromosome 9q34 and the TSC2 gene is located on chromosome 16p13. TSC-LAM occurs in women who have germline mutations in either the TSC1 or the TSC2 gene.[80]
Sporadic LAM is primarily associated with somatic TSC2 gene mutations.[10][81] 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.[10][80][81] 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.
On a cellular basis, LAM cells carry bi-allelic inactivation of the TSC2 genes, consistent with the “two-hit” tumor suppressor gene model originally proposed by Alfred Knudson, MD, PhD.[82][83] 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.[84] LOH can be detected in microdissected LAM cells,[10][85] in angiomyolipomas and lymph nodes from women with LAM,[29] and in LAM cells isolated from the blood and urine, referred to as circulating LAM cells.[86][87]
Interestingly, angiomyolipomas and pulmonary LAM cells from women with the sporadic form of LAM carry identical mutations in TSC2.[10] This, together with the fact that recurrent LAM after lung transplantation carries the same TSC2 mutations as the original LAM,[88] has led to the “benign metastasis” hypothesis that LAM cells can migrate or metastasize from one site to another.[77][78]
Pathology
Grossly, LAM lungs are enlarged and diffusely cystic, with dilated air spaces as large as several centimeters in diameter.[89][90] 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.[89]
There are two major cell morphologies in the LAM lesion: small spindle-shaped cells and cuboidal epithelioid cells.[91] 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.[91] This immunohistochemical marker is very useful diagnostically, because other smooth muscle–predominant lesions in the lung do not react with the antibody.[92] The spindle-shaped cells of the LAM lesion are more frequently proliferating cell nuclear antigenpositive than the cuboidal cells, consistent with a proliferative phenotype.[91] 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,[93][94][95] but not in adjacent normal lung tissue.[96] 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.[97][98] Unlike the dilated air spaces in emphysema, the cystic spaces found in LAM may be partially lined with hyperplastic type II cells.[99]
Radiology
Chest Radiograph The chest radiograph in patients 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. “pseudofibrotic”) appearance.[19][22] Pleural effusion and pneumothorax may also 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 decrease lung volumes.
High-Resolution Computed Tomography The high-resolution computed tomography (HRCT) chest scan is much more sensitive than the chest radiograph in detecting cystic parenchymal disease and is almost always abnormal at the time of diagnosis, even when the chest radiograph and pulmonary function assessments are normal.[19][21][22][100] The typical CT shows diffuse round, bilateral, thin-walled cysts of varying sizes ranging from 1 to 45 mm in diameter.[21][22] The numbers of cysts varies in LAM from a few to almost complete replacement of the normal lung tissue. The profusion of cysts tends to be milder in patients with TSC-LAM than S-LAM, perhaps explained in part by ascertainment of patients with TSC-LAM earlier in the disease process by screening.[25] Pleural effusions are seen on CT in 12% of patients with S-LAM and 6% of patients with TSC-LAM. Other CT features include linear densities (29%), hilar or mediastinal lymphadenopathy (9%), pneumothorax, lymphangiomyomata, and thoracic duct dilation.[21][22] Ground-glass opacities (12%) suggest the presence of interstitial edema due to lymphatic congestion. In patients with TSC, nodular densities on HRCT may represent multifocal micronodular pneumocyte hyperplasia (MMPH) made up of clusters of hyperplastic type II pneumocytes.[5][101][102] MMPH may be present in males or females with TSC in the presence or absence of LAM, but not in patients with S-LAM.[103] MMPH is not typically associated with physiologic or prognostic consequences, but one case of respiratory failure due to MMPH has been reported.[104] A review of diffuse cystic lung disease with specifics regarding LAM and the most common diseases in the differential diagnosis provides useful information to guide clinical decision-making.[105][106]
Ventilation-Perfusion Scans Chu and associates[21] reported that ventilation-perfusion scans were abnormal in 34 of 35 women with LAM. The most common abnormality was nonspecific diffuse heterogeneity, usually grossly matched. These authors also described an “unusual,” “speckling pattern” on the perfusion images in 74% of patients, consisting of “small, often peripheral collections of radioisotope.”
Positron Emission Tomography LAM and AML lesions do not typically exhibit increased uptake of 18F-fluorodeoxyglucose on positron emission tomography (PET) scanning.[107][108] Other neoplasms (or sources of inflammation) should therefore be considered in known or suspected LAM cases in which FDG-PET results are positive.[109]
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, and AML size correlates with the prevalence of pulmonary cysts in patients with TSC.[2] Avila and associates[25] reported the results of CT imaging in 256 patients with S-LAM and 67 patients with TSC-LAM who were referred to the National Institutes of Health. Renal AMLs were present in 32% of patients with S-LAM and 93% of patients with TSC-LAM. Hepatic AMLs were present in 2% of patients with S-LAM and 33% of patients with TSC-LAM. Ascites was uncommon, seen in fewer than 10% of patients with LAM. Abdominal lymphangiomyomas, often containing both cystic and solid components, were seen in 29% of patients with S-LAM and 9% of patients with TSC-LAM.
Central Nervous System Imaging 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[110] 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.[13]
Pulmonary function studies
Pulmonary function testing in patients with LAM may be normal or may reveal obstructive, restrictive, or mixed patterns, with obstructive physiology being the most common abnormality. Quality controlled lung function data were collected prospectively by the NHLBI Registry, a 5-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%.[24] Restriction, defined as a total lung capacity less than the lower limit of normal, was seen in 11%. Hyperinflation was unusual, 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.[111][112] The obstructive physiologic defect in LAM is primarily attributable to airflow obstruction.[113] 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.[19][19][20][22] It is not unusual for DLCO to be reduced out of proportion to forced expiratory volume in 1 second (FEV1).[111] Reduction in DLCO and increase in residual volume are generally considered to be the earliest physiologic manifestations of LAM.
Cardiopulmonary exercise testing in a much larger cohort of patients with LAM revealed a reduced maximal oxygen consumption (VO2 max) and anaerobic threshold in 217 patients.[114][115] 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, and 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.[115] Zafar and colleagues[116] reported an increase in intraparenchymal shunts in dyspneic patients with LAM, which may contribute to resting and exercise hypoxemia.
Diagnosis
Micrograph of lymphangioleiomyomatosis. H&E stain.
CT scan of the lungs in a patient with lymphangioleiomyomatose showing numerous thin walled cysts within the lungs.
LAM can come to medical attention in several different ways, most of which involve triggering scanning of the chest by 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. Screening of women with TSC with HRCT reveals that about 20% of women have cystic change by age 20 and about 80% of women have cystic changes after age 40.[5] LAM is sometimes revealed by chest CT scan in patients who present with an apparent primary spontaneous pneumothorax but more often CT scanning is not ordered (in the United States) until recurrences occur. Progressive dyspnea on exertion without the exacerbations and remissions that are characteristic of asthma or COPD sometimes prompt the astute clinician to order a chest CT. A review of the chest CT by an expert familiar with LAM may increase the diagnostic accuracy.[117] Chylothorax can also bring LAM to attention.
In some cases, the diagnosis of LAM 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.[68][118]
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 and widely used technique, but transbronchial biopsy has a yield of over 50% and can also be effective.[119][120] 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 yield the diagnosis.[121][122][123][124] In all cases, review by an expert pathologist who is familiar with LAM is advised.
Diagram 1 outlines a proposed algorithm for the diagnosis of LAM
Diagram 1. Outlines a proposed algorithm for the diagnosis of LAM. CT: computed tomography; TSC: tuberous sclerosis complex; AML: angiomyolipoma; VEGF-D: vascular endothelial growth factor D; TBBx: transbronchial biopsy; VATS: video-assisted thoracoscopic surgery.
Other therapeutic considerations
Pneumothorax. Pneumothoraces in patients with LAM tend to recur, especially after conservative management such as observation, aspiration, or simple tube thoracostomy. Over 65% of patients with LAM develop pneumothorax during the course of their illness, averaging 3.5 pneumothoraces in those who have at least one pneumothorax.[23] The LAM Foundation Pleural Consensus Group advocated for the use of a pleural symphysis procedure with the first pneumothorax, given the greater than 70% chance of recurrence.[23] 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.[23] Although pleurodesis is clearly not a contraindication to transplantation, it can result in increased perioperative bleeding.
Chylothorax. Chyle does not generally cause pleural inflammation or fibrosis, and small stable chylous effusions rarely require intervention once the diagnosis of LAM is made. Shortness of breath may mandate drainage, however, and in some cases repeatedly. Sirolimus is very effective for chylous effusions and most experts believe it should be used as the first line of therapy.[125] Imaging the source of the leak with heavy T2 weighted MRI or contrast lymphangiography is an advised for refractory effusions.[126] Some leaks are amenable to embolization through catheters threaded from groin lymph nodes into the thoracic duct. Thoracic duct ligation can also be considered, but since thoracic effusions sometimes originate from ascites that is 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.[127]
Angiomyolipoma. Renal angiomyolipomas (AMLs) may require embolization or cauterization for control of bleeding, a complication that is thought to be more common when the diameter of the tumor exceeds 4 cm.[128] Others contend that the extent of aneurysmal change determines 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.[129] 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 has recently been approved by the U.S. Food and Drug Administration for the treatment of AMLs.[130]
Lymphangioeleiomyoma. Lymphangioleiomyomas are fluid filled hypodense structures that are present in the retroperitoneal regions of the abdomen and pelvis in about 30% of patients with LAM. They generally do not require intervention and, indeed, biopsy or resection can lead to prolonged leak. mTOR inhibitors are very effective at shrinking the size of lymphangioleiomyomas, and can lead to total resolution.
Management-other. Estrogen-containing medications can exacerbate LAM[131] 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 patients with LAM, because up to 17% to 25% of patients with LAM have bronchodilator-responsive airflow obstruction.[21][24] 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 this young, motivated population with obstructive lung disease, but studies to assess the effect of this intervention on exercise tolerance, conditioning, and quality of life have not been done.
Pharmacological treatment
Sirolimus is an mTOR inhibitor that stabilizes lung function and improves some measures of life in patients with LAM.[17] Sirolimus was FDA approved for use in LAM in May 2015, based on the results of the Multicenter International LAM Efficacy and Safety of Sirolimus (MILES) Trial. The 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 rapidly declining patients who are approaching the abnormal range for FEV1. Sirolimus also appears to be effective for the treatment chylous effusions and lymphangioleiomyomas. The benefits of sirolimus only persist while treatment continues, so the safety of long term therapy must be addressed in future studies.
Potential side effects from mTOR inhibitors include swelling in the ankles, acne, oral ulcers, dyspepsia, diarrhea, elevation of cholesterol and triglycerides, hypertension, and headache. Sirolimus pneumonitis and latent malignancy are more serious concerns, but occur infrequently. Sirolimus inhibits wound healing. It is important to stop therapy with the drug for 1–2 weeks before and after elective procedures that require optimal wound healing. Proper precautions must be taken to avoid prolonged sun exposure because sirolimus enhances the risk of skin cancer.
Treatment with another mTOR inhibitor, Everolimus, was reported in a small open label trial to be associated with improvement in FEV1 and six-minute walk distance.[132] 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 has also been shown to useful predictive and prognostic biomarker.[69] A 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 progesterone, GnRh agonists (Lupron, goserelin) and tamoxifen are not rountinely recommended.
Doxycycline had no effect on the rate of lung function decline in a double blind trial.[133] Although the study was underpowered, the absence of any evidence for a beneficial effect suggests the drug should not be used to treat LAM.
Sirolimus is often effective as first line management for chylothorax.[125] If chylous leakage or accumulations persist despite medical treatment, imaging with heavy T2 weighted MRI, MRI lymphangiography or thoracic duct lymphangiography should be considered. Pleural fusion procedures can be considered in refractory cases.
Pregnancy
Patients should be advised that pregnancy has been reported to result in exacerbations of LAM in some cases.[109][134][135][136][137] However, the risk associated with pregnancy in LAM has not been rigorously studied and decisions regarding the advisability of pregnancy should be made on an individual basis. In a survey of 318 patients who indicated on their LAM Foundation intake forms that they had had at least one pregnancy, 163 patients responded to a second survey focusing on lung collapse.[138] 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 diagnosis of LAM. 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[16][22] suggest that pregnancy is associated with pleural complications in patients with LAM. Unfortunately, the more pressing question of whether pregnancy accelerates the decline in lung function in LAM may never be fully addressed, because so 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.
Air travel
Air travel is not typically restricted in patients with LAM. In a survey of 276 patients who answered a LAM Foundation questionnaire, there were eight cases of radiographically documented pneumothorax associated with 454 flights. In five of the 8 cases, however, symptoms that were consistent with pneumothorax may have been present before boarding. Other symptoms and signs, including anxiety (22%), chest pain (12%), shortness of breath (14%), cyanosis (2%), and hemoptysis (0.4%), were noted in 10% to 20% of flights. The conclusion from the study was that, although there were adverse events during flight in patients with LAM, air travel is well tolerated by most patients with LAM. A recent study of 281 patients with LAM who had routine chest radiograph after traveling to the National Institutes of Health identified seven with acute pneumothorax. There was no difference in the incidence of pneumothorax in patients who traveled by ground versus air.[139] In advising patients with LAM about air travel, it is reasonable to consider several factors, including a history of frequent or recent pneumothoraces, and the overall extent of cardiopulmonary impairment. Patients with poor cardiopulmonary reserve may tolerate even small pneumothoraces poorly. It is prudent for patients with LAM to seek medical evaluation including a chest radiograph before boarding a plane if pleuritic chest pain or unexplained shortness of breath is present. Hypoxemia during flight presents independent risks. Patients should consult with their physicians regarding recommendations for on-board oxygen use. In most cases, however, air travel in patients with LAM should not be restricted.
Prognosis
Survival estimates vary widely, appear to be dependent on mode of presentation or ascertainment, and have generally trended upward over the past few decades, probably due to earlier recognition through more widespread use of CT scanning. In a recent population based cohort ascertained by surveying patients registered with the LAM Foundation, the median survival was found to be 29 years.[14] 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.[19][20][22][140]
Patients with LAM 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.[141] 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.[142] In other series from Europe, the rate of decline in FEV1 was considerably higher, estimated at approximately 100 to 120 mL/yr.[22][143][144] In the MILES trial, patients in the placebo group lost 134 cc/yr.[17] 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.
Epidemiology
LAM is a disease almost completely restricted to women with only a handful of cases reported in men.[8][9] 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 3.4-7.8/million women. The incidence of the disease (the number of new cases each year) is between 0.23-0.31/million women/year in the USA, UK and Switzerland. The variation between countries and between adjacent states in the USA, suggest that a significant number of women with LAM remain either undiagnosed or their symptoms are attributed to other diseases.[145] It has been known for some time that adult women with tuberous sclerosis are more likely to develop LAM than women without tuberous sclerosis. Recently, cohorts of patients with tuberous sclerosis have been screened for LAM using CT scanning and 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.[7] 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.[5] Although the prevalence of tuberous sclerosis at 1 in 6000 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.
Other than female sex and tuberous sclerosis, there are no known risk factors for LAM. Although use of supplemental oestrogen is not associated with development of LAM,[146] one study suggested that use of the oestrogen containing contraceptive pill was associated with an earlier age at onset of LAM.[147]
Clinical research
LAM is one of the rare lung diseases currently being studied by the Rare Lung Diseases Consortium (RLDC). The RLDC is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR) of the National Center for Advancing Translational Sciences (NCATS), one of the centers of the US National Institutes of Health (NIH). The RLDC is dedicated to developing new diagnostics and therapeutics for patients with rare lung diseases, through collaboration between the NIH, patient organizations and clinical investigators.
Patient Registry
LAM Patients, families, and caregivers are encouraged to join the NIH Rare Lung Diseases Consortium Contact Registry. This is a privacy protected site that provides up-to-date information for individuals interested in the latest scientific news, trials, and treatments related to rare lung diseases. They can also register with The LAM Foundation to keep up-to-date on what’s happening across the LAM community and to connect with other patients and families that may be sharing the same experiences.
In media
In "Lucky Thirteen", the fifth episode of the fifth series of "Dr House MD", Spencer (Angela Gots) was diagnosed with Lymphangioleiomyomatosis (LAM), though later it was found to be a case of Sjögren's syndrome.
See also
References
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External links
- Australia: LAM Australia Research Alliance
- Austria: LAM Austria
- Brazil: ASSOCIAÇÃO LAM DO BRASIL
- Canada: LAM Canada
- China: LAM China
- France: Association FLAM
- Germany: LAM Selbsthilfe Deutschland
- Israel: Israel LAM Organization
- Italy: LAM Italia
- Japan: J-LAM
- Mexico: LAM Mexico
- New Zealand: LAM Charitable Trust
- The Netherlands: LAM-Nederland
- Romania: OSC Agency, LAM Romania
- Spain: AELAM
- Sweden: LAM Academy
- United Kingdom: LAM Action
- United States: The LAM Foundation
- American Thoracic Society (US): Patient Information Series – Lymphangioleiomyomatosis
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Vascular tissue neoplasm (ICD-O 9120–9179) (C49+C46/D18, 171+176/215)
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| Blood |
- Hemangiosarcoma
- Blue rubber bleb nevus syndrome
- Hemangioendothelioma
- Composite
- Endovascular papillary
- Epithelioid
- Kaposiform
- Infantile
- Retiform)
- Spindle cell
- Proliferating angioendotheliomatosis
- Hemangiopericytoma
- Venous lake
- Kaposi's sarcoma
- African cutaneous
- African lymphadenopathic
- AIDS-associated
- Classic
- Immunosuppression-associated
- Hemangioblastoma
- Hemangioma
- Capillary
- Cavernous
- Glomeruloid
- Microvenular
- Targeted hemosiderotic
- Angioma
- Cherry
- Seriginosum
- Spider
- Tufted
- Universal angiomatosis
- Angiokeratoma
- Pyogenic granuloma
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| Lymphatic |
- Lymphangioma/lymphangiosarcoma
- Lymphangioma circumscriptum
- Acquired progressive lymphangioma
- PEComa
- Cystic hygroma
- Multifocal lymphangioendotheliomatosis
- Lymphangiomatosis
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| Either |
- Angioma/angiosarcoma
- Angiofibroma
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