© 2007 American Thoracic Society doi: 10.1164/rccm.200703-514ED
S-LAM in a Man?University of Cincinnati College of Medicine, Cincinnati, Ohio and National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland Lymphangioleiomyomatosis (LAM) ranks prominently among the most gender-restricted diseases of the lung, and perhaps of any organ outside of the genitourinary tract. LAM is caused by mutations in the same genes that have been implicated in the tuberous sclerosis complex (TSC) (1, 2), a heritable disease that affects men and women equally, and most classically presents with cognitive impairment, seizures, skin lesions, and renal tumors (3). It has been estimated that, worldwide, approximately 250,000 to 300,000 women have LAM (4, 5). In 85 to 90% of this population, composed overwhelmingly of women who are yet to be diagnosed, LAM is associated with germline mutations in TSC genes (6). These patients have TSC and their disease is termed TSC-LAM. The remaining 10 to 15% of affected women do not have germline mutations in TSC genes and do not have TSC (7). Hundreds of these biopsy-documented sporadic LAM (S-LAM) cases have appeared in the literature, and TSC gene mutations restricted to the infiltrating smooth muscle cells of their lung, lymphatic, and renal lesions have been found when genetic analysis of those tissues has been performed (1, 8). In contrast, biopsy-documented TSC-LAM has been previously reported in only three men. In this issue of the Journal (pp. 96–98), Schiavina and colleagues describe the first-known case of S-LAM in a male (9). This is an exciting and provocative discovery, which, if confirmed, expands the clinical spectrum of LAM and raises a new set of interesting questions about the role of TSC gene mutations, estrogen, and LAM cell origin in LAM pathogenesis. Mounting evidence suggests a remarkable paradigm for LAM as a "benign" metastatic disease that begins with somatic loss of function mutations in both parental TSC alleles of a cell at an unknown, most likely extrapulmonary, site (10–12). The resultant deficiency or dysfunction of either of the TSC gene products, tuberin or hamartin, derepresses a number of cellular functions regulated through the Akt signaling pathway and provides the LAM cell with all of the machinery required for a cancerlike phenotype. This includes the ability to grow, divide, and survive in a dysregulated, nutrient-independent manner; the capacity to migrate and stimulate the growth of lymphatic channels to facilitate spread (13, 14); and the competence to implant, infiltrate, and destroy tissue (15). A number of plausible theories for the marked female predominance in LAM can be formulated in the context of this model, including an important role for estrogen in cellular mutagenesis, growth, migration, or tissue remodeling. Estrogen signaling is known to intersect with the Akt pathway, and one popular hypothesis is that estrogen may free the nascent LAM cell from feedback inhibition of Akt signaling that develops in cells that lack the regulatory functions of tuberous sclerosis proteins (16). Alternatively, the LAM cell may originate in an organ that is unique to females, such as the uterus or ovary (17). Enthusiasm for LAM gender-bias theories based on female hormones or anatomy and the "two hit" model was somewhat dampened by the first incontrovertible evidence for LAM in males with TSC (18). Given that every cell in these men has at least one TSC mutation, however, it seems plausible that a special "gender-independent" germline "first hit" and a strategic second hit might give rise to a LAM cell. This type of event might also occur in females, but would be difficult to recognize. The current case presents a serious challenge to this hypothesis, in that one would have to postulate a gender-independent LAM cell developing from two separate somatic mutations, a decidedly unlikely event. Although fatherhood, male phenotypic features, and a normal karyotype leave no doubt about the gender of the patient in Schiavina and colleagues' report, and the diagnosis of pulmonary LAM appears to be conclusive, proving the absence of TSC is challenging. Was the diagnosis of TSC truly excluded by physical examination and by rigorous, state-of-the-art diagnostic modalities? TSC-LAM can certainly present as the sole clinical manifestation of TSC (17). If this individual does, in fact, have S-LAM, what is the genetic basis for the disease? In the description of the genetic analysis, TSC mutations were not identified in the lung tissue. This result was unexpected and there are several possible explanations. Laser-capture microdissection, which is more sensitive than mechanical dissection, would have been the preferred procedure for isolating tissue for genetic studies. A negative result by the genetic analyses employed does not exclude the presence of TSC gene mutations, since introns were not screened and all genetic methods have a finite mutation detection rate. It is also possible that an etiologic genetic defect is present but that it is not in the TSC genes. Other upstream or downstream components of the TSC signaling pathway, such as adenosine monophosphate kinase (AMPK), the guanine nucleotide-binding protein Rheb, mammalian target of rapamycin (mTOR), or the ribosomal protein S6, may have been affected. Several investigators have been searching for the first example of non-TSC1 (hamartin gene) or non-TSC2 (tuberin gene)–associated LAM; perhaps this case would be a good place to look. In the end, we must acknowledge that we know very little about the role of gender or hormonal influences on the pathogenesis of LAM, and that it is possible that LAM may result from gain-of-function mutations that do not conform to the tumor suppressor model. One gets the sense that the discovery of S-LAM in men is a milestone in the understanding of LAM that we are not quite ready to interpret scientifically. At the very least, this case and other reports of LAM in men should remind us that LAM should be considered in the differential of male patients with unexplained obstructive lung disease or progressive dyspnea, pneumothorax, chylothorax, or radiographic evidence of lung cysts. LAM is in a unique position among the interstitial lung diseases, in that we have learned a tremendous amount about the molecular and cellular pathogenesis of the disease in a very short period of time (19). Much of this progress is attributable to the vision of women with LAM who have organized and volunteered in a fashion that has facilitated meaningful research. Clinical trials for tuberous sclerosis and LAM that are underway in the United States and Europe are a testament to the success of their approach. Let's hope that the (slowly) expanding community of men with LAM will emulate the wisdom and generosity of women with this clinical entity, and volunteer to help us unlock the secrets of the remarkable gender restriction in this fascinating disease. FOOTNOTES Conflict of Interest Statement: F.X.M. serves on the boards of the LAM Foundation and the Tuberous Sclerosis Alliance; he is the principal investigator of a LAM Clinical Trial (MILES), which is supported in part by Wyeth Pharmaceuticals (drug + $200,000). J.M. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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