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Pulmonary lymphangioleiomyomatosis (LAM) is an uncommon disease reported to occur exclusively in women. We describe a phenotypically normal man with pulmonary LAM. Fluorescence in situ hybridization (FISH) studies performed on the lung biopsy confirmed a normal XY genotype. Our patient also had stigmata of tuberous sclerosis complex (TSC), including facial angiofibromas and renal angiomyolipoma. Immunohistochemical stains of both LAM and renal angiomyolipoma showed positive immunoreactivity for hamartin (TSC1) and loss of immunoreactivity for tuberin (TSC2). Loss of heterozygosity (LOH) for TSC2 was further demonstrated in the renal angiomyolipoma. Coupled with the results of immunostains, these findings are consistent with TSC2 mutation.

Objective: To determine whether renal angiomyolipomas from women with pulmonary lymphangioleiomyomatosis (LAM) express estrogen receptor (ER) and progesterone receptor (PR)., Design: Retrospective study of archival tissue., Patients: Twelve women with LAM and angiomyolipomas., Setting: Fox Chase Cancer Center., Interventions: ER and PR expression was studied using immunohistochemistry. The hormonal status of the patients at the time of resection of the angiomyolipoma was determined., Results: Ten of the angiomyolipomas had ER immunoreactivity (83%), and all 12 had PR immunoreactivity (100%). The ER and PR positivity was in the smooth muscle component of the angiomyolipomas only. For five women, pulmonary LAM specimens were also available; two were ER positive (40%), and all five were PR positive (100%). All four angiomyolipomas from women receiving progesterone therapy were ER and PR positive. One tumor from a woman receiving tamoxifen was ER negative and strongly PR positive. One woman was pregnant; her tumor was ER and PR positive., Conclusions: ER and PR expression is frequent in renal angiomyolipoma cells from women with LAM. PR was more consistently present than ER in angiomyolipomas and in LAM. Our data suggest that angiomyolipoma growth could be affected by hormonal factors. If the growth of LAM-associated angiomyolipomas slows during hormonal therapy, there are two potential implications for LAM patients: first, angiomyolipoma size could serve as a measurable indication of response to hormonal therapy; and second, surgical removal of angiomyolipomas might be avoided in some cases.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by seizures, mental retardation, and hamartomatous tumors in multiple organs, including subependymal giant cell astrocytomas, cardiac rhabdomyomas, and renal angiomyolipomas. Mutations in two genes are associated with TSC: TSC1, which was cloned in 1997, and TSC2, which was cloned in 1993. We report here the expression of hamartin, the product of the TSC1 gene, in normal human tissues and in renal angiomyolipomas from TSC1- and TSC2-linked patients. By Western blot analysis, hamartin is strongly expressed in brain, kidney, and heart, all of which are frequently affected in TSC. By immunohistochemical analysis, the expression pattern of hamartin in normal human tissues was almost identical to that of tuberin, the product of the TSC2 gene. This is consistent with the recent finding that tuberin and hamartin interact and with the clinical similarity between TSC1- and TSC2-linked disease. Strong hamartin expression was seen in cortical neurons, renal tubular epithelial cells, pancreatic islet cells, bronchial epithelial cells, and pulmonary macrophages. Hamartin was also expressed in endocrine tissues, including islet cells of the pancreas, follicular cells of the thyroid, and the zona reticularis of the adrenal cortex. In eight angiomyolipomas from a TSC1-linked patient, no hamartin expression was detected, whereas tuberin, the product of the TSC2 gene, was expressed. In 19 angiomyolipomas from a TSC2-linked patient, in whose angiomyolipomas loss of tuberin expression had previously been shown, hamartin expression was present. These data suggest that tuberin and hamartin immunoreactivity can distinguish tumors with underlying TSC1 mutations from those with TSC2 mutations. This differentiation might have diagnostic implications.