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About Lymphangioleiomyomatosis: Its Symptoms, Causes, Treatments

LAM Lung Disease (Lymphangioleiomyomatosis)

Lymphangioleiomyomatosis SUMMARY

Lymphangioleiomyomatosis (LAM) is a rare disease that predominantly affects women, especially in childbearing years. It occurs sporadically or in association with tuberous sclerosis complex. This is characterized by an abnormal proliferation of immature smooth muscle cells (LAM cells), which grow aberrantly in the airway, parenchyma, lymph, and pulmonary blood vessels, which determines a progressive evolution towards respiratory failure. It is multisystemic, affecting lymph nodes and producing abdominal tumors. Given its low prevalence, the difficulty of establishing an early diagnosis, the absence of curative treatment and the difficulty of obtaining information, they fit LAM within the chapter of the so-called Rare Diseases.

Introduction to Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare disease that predominantly affects women, especially in childbearing years. It is characterized by an abnormal proliferation of immature smooth muscle cells (LAM cells), which grow aberrantly in the airway, parenchyma, lymph, and pulmonary blood vessels and determine the appearance of cystic lung lesions. The disease has no treatment, with a progressive and inexorable evolution towards respiratory failure that conditions the death of the patients. The mechanism by which this distortion of the lung architecture occurs is unknown. It is multifocal in nature, affecting axial lymph nodes in the chest, abdomen and retroperitoneum, and the appearance of lymphangiomas and angiomyolipomas is not uncommon, especially at the renal level.

Given its low prevalence, the difficulty of establishing an early diagnosis and the absence of a curative treatment, LAM falls within the chapter of the so-called Rare Diseases. In this context, interest in LAM has led to the creation of patient registries, together with exponential growth in research both at the clinical level 4 and at the level of their basic cellular pathology.

There are two forms of presentation, a sporadic form (S-LAM) and another linked to the tuberous sclerosis complex (TSC-LAM) that occurs in up to 40% of women with TSC. TSC, an autosomal dominant neurocutaneous syndrome, is associated with the formation of hamartomas at the level of the central nervous system, skin, eyes, abdominal organs, especially the kidney, and the lung. Patients with S-LAM may present with extrapulmonary manifestations observed in the TSC, such as angiomyolipomas, axial lymphadenopathy and abdominal lymphangiomas, but not cutaneous, ocular or central nervous system manifestations, manifestations that are required to establish the diagnosis of TSC based on criteria from Gómez. Both disorders originate from mutations in the genes for tuberous sclerosis, genes involved in the regulation of critical cellular signals for energy control and in cellular nutrition processes.

Pathogenesis

The LAM cell

The LAM cell, the central axis of this disease, is a unique type of mesenchymal cell that expresses specific smooth muscle markers, continuously proliferates and invades the lung parenchyma, forming nodular growths, as well as small scattered intraparenchymal accumulations. It has an immature smooth muscle type phenotype and, in accordance with this assumption, it expresses smooth muscle α-actin, as well as other markers of muscle differentiation, sometimes sharing, given its immaturity character, markers of striated muscle differentiation (myogenin, MyoD1). ). However, it is the positivity against HMB-45 (monoclonal antigen against the gp100 glycoprotein of premelanosomes) that differentiates it from other cell types. Thus, it is an anomalous cellular element with a dual phenotypic expression, with simultaneous features of antigenic expression in the smooth and melanocytic muscle direction, data that suggests an origin in the neural crest.

There are two subtypes of LAM cells , one fusiform, with myofibroblastic morphological appearance, and the other of larger and polygonal cells with epithelioid appearance. The expression of the premelanosomal marker HMB-45 is variable and appears in inverse correlation with the expression of nuclear cell proliferation antigen (PCNA) or with the proliferation index established by analysis of the Ki67 antigen (MIB-1). Furthermore, gp100 expression and proliferation markers (PCNA, Ki67) delimit the two LAM cell subtypes.

While the spindle cell subtype shows low gp100 expression and a high percentage of PCNA / Ki67 immunoreactive cells, the epithelioid cell subtype exhibits an inverse pattern. Although the functional differences of the two subtypes are currently unknown, Finlay has suggested that the spindle cell subtype could represent the proliferative component of LAM lesions. Another hypothesis is that these two cell types would correspond to different phases in the differentiation or maturation of the LAM cell or that, in fact, they were the members of two different phenotypes.

Recently, it has been shown that LAM cells also show positivity, among others, against CD63 and PNL2, both markers of melanocytic differentiation. Thus, Zhe et al have established three cellular subtypes based on the expression of these markers: those cells that only show immunoreactivity against CD63, those that also react against PNL2, and a third group with those that react against HMB- Four. Five.

These LAM cell subpopulations differ in their proliferative capacity, with the least mitotic activity showing positivity against PNL2. The positive subgroup against HMB-45 shows a proliferative activity of 6%, similar to that found by Zhe et al in PNL2 immunoreactive cells.

The incidence of this disease in women, mainly of childbearing age, with clinical manifestations that worsen with pregnancy and with the administration of estrogens, led to consider the existence, in the LAM cell, of receptors against estrogens (RE) and / or progesterone (RPg), data not present in smooth muscle cells of normal configuration. It has been verified that the presence of RE / RPg is generally established in larger LAM cells, of epithelioid habit, negative against HMB-45, and with less expressive hormone receptors, less differentiated and more active LAM cells proliferative.

The origin of the LAM cell is controversial. Although it was initially thought that they were derived from smooth muscle cells of the airway or pulmonary vessels, these cells are currently known to be found throughout the lung territory without any predominant location. Although its origin is uncertain, there are clinical and genetic data, and, above all, a behavior in cell cultures, which suggests that the LAM cell has neoplastic potential, showing an increase in cell motility and in the ability to invade the collagen matrix. , even in the absence of any environmental stimulus.

Genetics of LAM

As already mentioned, a close similarity has been recognized between the lesions observed in the LAM and in the TSC with lung involvement, so the hypothesis that both processes have a common pathogenic mechanism has been maintained. It is important to note that approximately a third of TSC cases are de novo, that is, their origin is in a mutation of the germ line cells of the parents, which affects the descendants, but is not present in the rest. of parent cells.

In 1993 the TSC2 gene (Tuberous Sclerosis Complex 2) located on chromosome 16p13 was identified , and in 1997 the TSC1 gene (Tuberous Sclerosis Complex 1), located on chromosome 9q34. The proteins encoded by the aforementioned genes took their name from the phenotypic characteristics of patients with TSC, hamartin for the protein produced by TSC1 and tuberin for that produced by TSC2.

The variable and focal nature of TSC hamartomas suggests that their development follows the “two-hit” model proposed by Knudson, whereby two independent mutations are necessary for tumor development to begin. First there is a mutation in one of the copies of the gene and later another mutation would affect the other allele. It would also be possible if one of the copies of the gene is inherited mutated (first step) and then another mutation or deletion affected the remaining undamaged copy of the gene.

Injury genetic analysis of patients with TSC has revealed a loss of heterozygosity (LOH) in both TSC1 and TSC2, which highlights the tumor suppressive role of both genes. These findings reveal that these tumors develop following the Knudson model outlined above. The first mutation is expressed in germ cells, while a second one occurs in affected tissues, leading to the appearance of tumors. Approximately 300 mutations in both genes have been described, being four times more frequent in the case of the TSC2 gene. These observations have suggested the possibility that both genes could be involved in the pathogenesis of S-LAM. Thus, Smolarek et al they have been able to verify LOH in TSC2 in patients with S-LAM, not observing any mutation in the TSC1 gene. This same group of authors has not shown germline mutations in S-LAM.

Hamartin and tuberin

The proteins encoded by the TSC1 and TSC2 gene are called hamartin and tuberin, respectively. These two proteins form a complex involved in signal transduction from cell membrane receptors. The main role of the hamartin-tuberin complex is to inhibit mTOR (mammalian target of rapamycin), a central regulator of cell growth through protein synthesis. The mechanism by which the hamartin-tuberin complex keeps mTOR inactive involves Rheb (Ras Homologued Enriched in Brain), a GTPase from the RAS family or small GTPases. For mTOR to perform its action, it requires Rheb-GTP, however the hamartin-tuberin complex keeps Rheb bound to GDP, a lower energy form.

When mTOR is activated, it acts as a kinase that phosphorylates and activates S6K (S6 Kinase), an enzyme that stimulates ribosomal protein synthesis, based on the phosphorylation of the S6 ribosomal protein. Although the phosphorylation of S6K is influenced by multiple other signals, such as insulin, amino acids, etc., the hamartin-tuberin complex has been shown to block the action of S6K by inhibiting its phosphorylation by maintaining mTOR in a state disabled. Furthermore, mTOR activates the 4E-BP1 protein (4E-Binding Protein 1), which binds to the translation and initiation factor F4E, releasing it from the state of inhibition and allowing ribosomes to carry out the protein synthesis necessary for growth and proliferation. cell .

Rapamycin, an immunosuppressive agent capable of inhibiting S6K phosphorylation, is a drug used to prevent rejection in transplant patients, given its powerful inhibitory effect on lymphocyte activation. Its effect is produced by binding a protein, FKBP12, establishing a rapamycin-FKBP12 complex that directly inhibits mTOR.

Other kinases involved in transduction, transcription, cell cycle, or apoptosis also seem to play a decisive role in the regulation of the hamartin-tuberin complex. Akt / PKB, a cytosolic kinase linked to membrane receptors such as insulin, promotes the dissociation of the hamartin-tuberin complex by phosphorylation of tuberin. An overexpression of Akt / PKB leads to a degradation of the aforementioned complex, so that extracellular growth factors such as insulin can condition the influence of mTOR, creating permissive conditions for cell growth. In this sense, it is important to point out the overexpression of receptors for extracellular factors in the LAM cell, such as epidermal growth factor, platelet-derived growth factor or, more recently, vascular endothelial growth factor A.

Another recent finding deepens the knowledge of these pathways. An intact and functional hamartin-tuberin complex appears to be necessary for the proper functioning of Akt / PKB. As described, excess phosphorylated S6K, such as that which occurs with a defective hamartin or tuberin, would act as a negative feed-back on Akt / PKB reducing its expression. This mechanism would explain in part the benign nature of the tumors observed in TSC and LAM cells. The loss of hamartin or tuberin produces S6K activation favoring cell proliferation, but in turn an inhibition of Akt / PKB occurs, obtaining the opposite effect and therefore slowing down cell growth.

Other kinases that also regulate the hamartin-tuberin complex have been described, such as MAPKs (Mitogen Activated Protein Kinases), ERK2 (Extracellular Signal-regulated Kinases), or AMP kinases. LAM cells have also been found to show impairment in the interferon gamma-JAK-STAT pathway. This finding led to trials of interferon gamma, both alone and associated with rapamycin, with promising results at the experimental level.

Role of estrogens

Under normal conditions, estrogens bind to an intracellular receptor, ERα (Estrogen Receptor α). This binding activates a pathway that includes PDGFß (Platelet Derived Growth Factor ß) and ERK ½ (Extracellular signal-Reguled Kinase ½) that leads to cell growth. The tuberin interacts with the ERα producing its inhibition. This process is influenced by calmodulin, a major intracellular calcium-binding protein that can regulate a large number of proteins by modifying different cellular functions. Its binding to tubin has been shown, which produces an alteration in its action on ERα that would not be finally inhibited. Another effect of ERα is its interaction on the Akt / PKB pathway. The result would be permissive, which, as previously mentioned, produces an inactivation of the hamartin-tuberin complex. On the other hand, estrogens also act through non-genomic pathways that promote different phosphatases that exert their action on tuberin, dephosphorylating it, which leads to its degradation.

The microenvironment of the LAM cell

The hamartin-tuberin complex plays a key role in the regulation of the actin cytoskeleton and in cell migration. These actions are carried out through interaction with members of the Rho GTPase family . The alteration of the hamartin-tuberin complex finally produces a remodeling of the cytoskeleton and abnormal cell motility. These actions are also influenced by mTOR, through its binding to different proteins (rictor or raptor), although its mechanism of action is not precisely known.

Role of metalloproteinases

The extracellular matrix provides structural stability to the lung tissue and participates in the regulation of multiple critical cellular functions. Metalloproteinases (MMP) act as a functional component of the extracellular matrix and play, among others, a fundamental role in lymphangiogenesis . It is a well-known fact that degradation of the extracellular matrix contributes to invasion and metastasis in malignant tumors . MMPs that act as proteolytic enzymes catalysing reactions in which zinc participates are involved in this process.

LAM cells, and especially the spindle cell phenotype, overexpress different MMPs (MMP-1, MMP-2, MMP-9 and MMP-14, among others), which would determine the protein degradation of the extracellular matrix , favoring cell migration. Furthermore, a decrease in the expression of tissue inhibitor of metalloproteinases (TIMP) -3It has been observed in LAM, which could contribute to an imbalance in the MMP / TIMP relationship with an increase in MMP-dependent proteolysis. On the other hand, MMPs can stimulate cell growth since they degrade proteins that bind insulin growth factor by inactivating it. The expression of MMP is the same in lung LAM cells as in angiomyolipomas, which supports the theory of a common origin, according to which one of the lesions would come from the other, constituting a “benign metastasis”.

Doxycycline, an MMP inhibitor, affects the growth and migration of neoplastic cells, angiogenesis, and lymphangiogenesis, as well as in the growth of muscle cells, so its use could be effective in the treatment of LAM.

Pathogenesis of cystic lung disease in LAM

LAM cells proliferate in the lymphatic vessels of the lung and in the mediastinal, retroperitoneal, and pelvic lymph nodes. In its growth new lymphatic channels are created in what is a true lymphangiogenesis. The cells that line these channels express various markers of the lymphatic endothelium such as VEGF-C (Vascular Endothelial Grown Factor) or VEGF-D. Elevated levels of the latter have been detected in serum from patients with the disease. These new lymphatic vessels pass through the accumulations of LAM cells, dividing them and some of them may detach. This action would explain a mechanism of possible distant metastasis.

LAM cell clusters are in close proximity to the airway and blood vessels, which can obstruct them. Difficult blood flow can cause bleeding and hemoptysis. Airway involvement produces air trapping, which ultimately results in cystic changes in the lung parenchyma. The formation of cysts at the pulmonary level would also be favored by the alteration of the extracellular matrix produced by the MMPs. The obstruction of the lymphatic vessels explains another of the typical signs of LAM, chylothorax.

Pathological anatomy

Architecturally, and verifiably in lesional macroscopy, LAM manifests as a disease with characteristic features, which includes the existence of bilateral cystic lung structures, generally between 0.5 and 2cm of larger diameter, although they can reach up to 10cm, associated with enlarged lungs and alveolar emphysema.

In its morphopathology, LAM is characterized by an abnormal proliferation of oval or elongated cells, of muscular habit, known as LAM cells, whose abnormal growth is associated with the cystic destruction of the pulmonary interstitium. LAM cells can affect any structure of the lung, including the pleura, bronchiolar walls, pulmonary arteries, venules, small airways, as well as lymph, mediastinal, hilar, mesenteric, and retroperitoneal nodes.

In this way, the LAM cell proliferates forming nodules around the bronchi, blood vessels, as well as lining the walls of the cysts. LAM cell nodules are centrally composed of spindle cells, which express smooth muscle markers, such as α-muscle-specific smooth actin (α-AMS), desmin (DM), and vimentin (VT), and are surrounded by a subtype of epithelioid habit with immunoreactivity for HMB-45. Both LAM cell proliferation lesions, cysts and nodules are found together in variable proportions and their presence can be very scarce, and difficult to recognize, in the initial stages of the disease.

Based on architectural characteristics, Matsui et al have proposed a score , called the LAM Histologic Score (LHS), with three degrees of prognostic severity (grades 1, 2 and 3) based on the percentage of lung tissue affected by the cystic and proliferative component ; the proportion of affected parenchyma is correlated with survival, and these authors also observe a correlation between this gradation and the amount of intra-alveolar hemosiderin pigment (Berlin Blue or positive Perls stain), due to obstruction (destruction) of septal capillaries, the amount of hemosiderin and ferric pigment being greater in the highest degrees of Matsui.

Apart from the lesions described, other associated lesional findings can also be observed in the lung, such as multifocal micronodular pneumocyte hyperplasia, clear cell lung tumor (sugar tumor) and non-necrotizing granulomas. Likewise, and in an associated extrapulmonary way, patients with LAM can also present angiomyolipomas and abdominal lymphangiomas.

Prevalence

The prevalence and incidence of LAM is unknown and, probably, underestimated due to its clinical latency and the absence of specific laboratory tests . It is estimated in one case per million inhabitants for S-LAM and would be more frequent in TSC-LAM, in which up to 40% of women with TSC could have LAM lesions.

Derived from the genetic alterations described above, TSC-LAM should be 5 to 10 times more frequent than S-LAM. This data is not confirmed in the different registries and could be due to the fact that the form associated with TSC is milder or that the other associated comorbidities put lung involvement in the background. In our country, it is estimated that the prevalence may be between one and two patients per million inhabitants.

The disease usually manifests in women of childbearing age with an average occurrence of over 35 years. However, cases have also been described in postmenopausal women, although some were receiving hormone replacement therapy. Other cases have been diagnosed in adolescents and in men with TSC, but they are exceptional.

Although cases of LAM have been reported in men with TSC 79 , S-LAM occurs exclusively in women. A currently controversial fact is the possibility of AML in a man without TSC, as published by Schiavina. However, it has been a matter of controversy.

Clinical

Manifestations Respiratory manifestations

In S-LAM, the symptoms derived from lung involvement are predominant. The three most frequent findings are exertional dyspnea, pneumothorax and cough.

Dyspnea on exertion is reported by most patients and is the result of obstruction to air flow and the replacement of the lung parenchyma by cysts. Its establishment is slow and progressive, and 5 or 6 years usually pass from the onset of dyspnea to the establishment of the diagnosis.

Pleural pathology is a common complication in LAM and contributes substantially to the morbidity associated with this disease . The first pneumothorax is the sentinel event that guides diagnosis in a large proportion of patients. Its incidence varies between 39 and 81%, according to different authors, with recurrence of pneumothorax being very characteristic of LAM, with an incidence between 61 and 81%. Regarding treatment, a conservative attitude such as rest or endothoracic drainage conditions a recurrence rate of 66%, so an interventionist attitude is recommended, although talc pleurodesis or pleurectomy carry a recurrence rate of 27 and 32 %, respectively. The cause of these poor results compared to those obtained in pneumothorax secondary to other pulmonary pathologies is unknown. It is possible that the large profusion of blebs on the lung surface limits the apposition of the visceral pleura with the parietal pleura, making the pleural fusion incomplete.

Chylothorax has an incidence that varies between 7 and 31%. Clinically, it presents as progressive dyspnea accompanied by chest pain and non-productive cough. It is produced by several mechanisms, the most important is obstruction or rupture of the thoracic duct. Also due to leakage from pleural lymphatics or transdiaphragmatic flow of chylous ascites. Its management is difficult because it usually recurs if the treatment has consisted only of endothoracic drainage. In addition, it produces a nutritional deficit and a certain degree of immunosuppression, so it is necessary to monitor the patient’s weight, blood count, electrolytes, prealbumin and serum albumin and total proteins. Measures aimed at reducing chyle production consist of the use of light chain fatty acids in the diet or treatment with octreotide. However, recurrence is the norm, so treatment should consist of a pleurodesis, or a pleurectomy, leaving the thoracic duct ligation in the most severe cases.

Other respiratory symptoms such as hemoptysis and chiloptisis occur in a small number of patients. They are due to obstruction by the LAM cells of the blood and lymphatic capillaries.

Extrapulmonary manifestations

The most frequent extrapulmonary manifestations consist of lymphadenopathies, lymphangioleiomyomas, chylous abdominal collections, and the appearance of angiomyolipomas. Although it is exceptional, LAM can start with abdominal pain, and even with a picture of an acute abdomen.

The enlargement of the abdominal lymph nodes usually affects the retroperitoneal, retrocrural or pelvic territory. It is diagnosed by CT in almost a third of patients, but by itself it does not cause any symptoms.

Lymphangioleiomyomas are large cystic masses that result from obstruction of the lymphatic vessels. They occur more frequently in the abdomen, retroperitoneum and pelvis, although they have also been described in the mediastinum and neck. The symptoms they produce consist of nausea, bloating, edema in the legs and urinary disorders. Normally, these manifestations worsen during the day, which has been related to the increase in the size of lymphangiomas as a result of the accumulation of lymphatic fluid in lower areas of the body due to standing.

Chylous ascites is present in 10% of patients and occurs in advanced stages of the disease. It is related to abdominal lymphatic obstruction and the presence of chylothorax.

The most frequent abdominal alteration is angiomyolipoma of predominantly renal location. They affect 40% of patients with S-LAM and up to 80% in TSC-LAM. They are benign tumors made up of dysplastic blood vessels, smooth muscle, and adipose tissue.

The diagnosis is based on CT, since most are asymptomatic. However, they can cause flank pain, hydronephrosis, hematuria and loss of kidney function. In patients with S-LAM angiomyolipomas are usually unilateral, small, solitary and restricted to the kidney, while in those with TSC-LAM they are larger, bilateral, multiple, multi-organ (affecting the spleen or liver) and with a greater tendency to hemorrhage. This last complication seems related to the profusion of aneurysms within the tumor mass and size, so those that exceed 4cm seem to be more predisposed to bleeding, so active treatment is recommended.

Other much less frequent alterations have also been described, such as chiluria or chylopericardium. The incidence of meningiomas also seems to be higher in patients with LAM, regardless of its association with TSC, compared to the general population.

Pregnancy can aggravate the symptoms of LAM, mainly because it seems to favor the appearance of pneumothorax and chylothorax, as has been observed in several clinical series. Furthermore, it can worsen angiomyolipomas, causing greater growth and increasing the chances of bleeding. In contrast, other patients have pregnancies that do not exacerbate their symptoms, which together with the little useful information on the true effect of pregnancy on LAM, advises that the final decision be made individually in each case.

Diagnosis

The mean age of the patients at the time of diagnosis is around 35 years, according to multiple series consulted. The diagnosis of LAM requires a high-resolution pulmonary CT (RCHT) that demonstrates the presence of thin-walled cysts and, on the other hand, a positive biopsy that includes an immunohistochemical study with HMB-45 or a compatible clinical context, such as the presence of Clinically confirmed CTS, angiolipomatosis, or chylothorax.

Physical examination is usually normal, and only some abnormal chest sounds such as wheezing can be detected. Unlike other interstitial lung diseases, acropachy does not usually appear.

The analytical blood study and chest X-ray do not usually show pathological findings in the initial stages. Subsequently, a reticulonodular pattern and bullae or cysts may appear, as well as signs of pulmonary hyperinflation. In more advanced stages, there may be a honeycomb pattern similar to that of other interstitial lung diseases.

TCHR is one of the most important diagnostic tests. It shows multiple thin-walled cysts spread in a homogeneous way by all the lung fields next to conserved parenchymal areas. The size of the cysts is small, usually less than 1cm. The size of the cysts has been correlated with the possibility of pneumothorax, resulting in sizes greater than 5mm associate a higher probability. Another frequent finding is the existence of pulmonary non-calcified nodules ranging from 2 to 10mm. Its distribution is random throughout the lung fields. In addition, the study by TCHR allows the diagnosis of other processes such as chylothorax, lymphangioleiomyomas or angiomyolipomas. The latter have a characteristic appearance when showing a mixed density with hypoattenuation zones derived from their adipose component.

A number of differences have been established between S-LAM and TSC-LAM. In the first, lymphatic involvement is more frequent: dilation of the thoracic duct, chylous pleural effusion, ascites and the presence of lymphangioleiomyomas. The presence of non-calcified pulmonary nodules and angiomyolipomas, both renal and hepatic, are more prevalent in TSC-LAM.

Gasometry may be compatible with respiratory failure in approximately 5% of patients, although most show parameters close to normal.

Spirometry usually shows an obstructive pattern in more than half of the patients, of whom 25% have a positive bronchodilator test, and a decrease in diffusion capacity. The rest may have a mixed pattern or minimal alterations. Total lung capacity, residual volume, and the relationship between the two are usually increased as an expression of pulmonary hyperinflation and air trapping, respectively. Patients with pleural effusion or who have undergone pleurodesis may present a restrictive pattern. The decrease in the carbon monoxide diffusion capacity (DLCO) is another of the most frequent data. In a recent study the mean of the values obtained was 67.6±1.61ml / min / mmHg 4 . Likewise, the annual average decrease has been estimated at 0.69ml / min / mmHg per year.

Exercise tolerance measured in stress tests is less. It is due to lower oxygen consumption, lower anaerobic threshold, excessive and abnormal ventilatory response with high respiratory rate, excessive minute ventilation, and reduced respiratory reserve. The volume of dead space, both at rest and on effort, which is greater than normal, also contributes.

The pressure in the pulmonary artery at rest is within normal limits, but increases with small levels of effort. This implies the need for specific tests to determine the possible existence of pulmonary hypertension in all these patients.

Another cornerstone of diagnosis is biopsy and subsequent pathological study. It can be obtained from the lung parenchyma or from some lymph node. The finding of LAM cells would confirm the diagnosis. It is not uncommon for a retroperitoneal mass suspected of lymphoma or ovarian cancer to be biopsied, demonstrating the presence of LAM cells.

Differential diagnosis with pulmonary emphysema and Langerhans cell histiocytosis (HCL) is required. To do this, the smoking history and the shape of the cysts are very useful. Other diseases that can simulate a LAM are: Sjögren’s syndrome , follicular bronchiolitis, interstitial lymphocytic pneumonitis , hypersensitivity pneumonitis , amyloidosis, light chain deposition disease , bronchopulmonary dysplasia, sarcoma of metastatic endometrial cells, low-grade leiomyosarcoma, Birt-Hogg-Dubé syndrome and lymphangiomatosis.

Forecast

The course of the disease is widely variable and no relevant prognostic factors are known.

An example of this variability is mortality at 10 years from the establishment of symptoms, which varies between 10 and 90% according to the series consulted. Cases diagnosed in the octogenarians or courses of the disease over 30 years have also been reported.

The deterioration of the gas exchange is the most important factor that worsens the prognosis. The average loss of FEV1 is 120ml per year, although it varies according to the series consulted. Patients with a positive bronchodilator test show a faster decrease in FEV1, although the cause is unknown. The decrease in DLCO also has a good correlation with histological degrees of severity, one of the predictors of time to transplant and death. This deterioration is greater in the presence of pneumothorax or chylothorax.

The initial presentation with pneumothorax appears to occur in younger women and associates a better prognosis with 10-year survival rates of 89%. Conversely, when dyspnea is the initial symptom, survival is lower, around 47%. These figures have not been confirmed in other studies in which survival is independent of pneumothorax.

The quantified HRCT measures the amount of parenchyma affected by cysts and is significantly correlated with functional impairment.

Histological factors such as the predominance of cystic lesions or the percentage of lung tissue affected by the cystic and proliferative component have already been discussed above.

Much of this variability during the course of the disease could be explained by the polymorphism of the genes involved and by the identification of such polymorphisms .

Treatment

There is currently no curative treatment for this pathology. Treatment with progesterone, currently in force, and other alternatives that include the use of gonadotropin-releasing agonists, or tamoxifen have been questioned in recent years. For one criticizes that are based on small series of cases, mainly retrospectives and even in a single clinical case, and that has not been tested randomized clinical one . Furthermore, the presentation of side effects related to the taking of these medications (water retention, bloating, nausea) is not uncommon, and may even motivate their suspension. Recently, a possible relationship between progesterone treatment and a higher incidence of meningiomas has been reported in these patients .

On the other hand, in a retrospective analysis, it was found that progesterone treatment did not slow down the decrease in FEV1 and in fact seemed to accelerate the fall in DLCO when compared with untreated patients . Other works have not confirmed this trend . There is also no evidence that oophorectomy manages to slow down the progression of LAM, so this more aggressive therapeutic approach is much less indicated than it was a few years ago .

The results with interferon alfa were not as expected, given the absence of notable benefits and associated side effects.

Recently, and derived from the knowledge of the pathogenesis in which mTOR is a fundamental piece, inhibiting agents of this compound are being tested in the treatment of LAM and TSC. There are several clinical trials, both in phase I and II, that include sirolimus and everolimus. The preliminary results are encouraging and a greater experience is awaited .

Other drugs currently under study and with therapeutic potential are Rheb inhibitors, selective estrogen antagonists, tyrosinkinase inhibitors, MMP inhibitors, angiogenesis inhibitors, and lymphangiogenesis inhibitors.

Although it is advisable to use treatment with bronchodilators in patients with a positive bronchodilator test, the effect obtained has been low, as has the use of inhaled or systemic corticosteroids.

LAM and lung transplant

The usefulness of PD in LAM has been controversial due to the low incidence of this disease, its systemic nature and the impact that the disease itself could have on perioperative morbidity and mortality. Currently, TP can be a good alternative for these patients, as it must meet a series of internationally accepted criteria for performing a TP.

According to the International Society for Heart and Lung Transplantation registry, 1% of all PDs performed annually are in patients diagnosed with LAM . This fact has conditioned that it was necessary to wait some time to gather more or less extensive series that demonstrated the usefulness or not of the TP.

Although recurrences of the disease have been reported in transplant patients, and although the existence of pleural adhesions due to the disease itself or due to previous pleural procedures can condition intra or postoperative bleeding, especially if it is necessary to use extracorporeal circulation during the performance of the TP 95 , recent publications , some of which include the experience of the United States or Europe, provide a survival of around 80, 75 and 65% at one, three and five years, respectively, and conclude that, although perioperative complications related to LAM are frequent, TP could be considered a valid therapy in these patients, since the results are comparable to those obtained in other lung diseases, not only in terms of survival, but also in terms of quality of life .

Conflict of interests

The authors declare that they have no conflict of interest.

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