Occurrence: either sporadic or in patients with tuberous sclerosis complex (TSC). The disease occurs primarily in premonopausal women with only a few cases seen in men with TSC or postmenopausal women taking estrogen-replacement therapy.
LAM is associated with mutations in the TSC1 and TSC2 genes. These affect the hamartin-tuberin complex, which inhibits the mammalian target of rapamycin (mTOR) pathway. A defect in the hamartin-tuberin complex allows mTOR to run unchecked, resulting in cellular proliferation..There is also an increase in matrix metalloproteins (MMPs).
TAM involves proliferation of immature smooth muscle and perivascular epithelioid (LAM) cells. The proliferating cells:
(1) are positive for actin and desmin
(2) are positive for HMB-45 and other melanocyte markers.
(3) have estrogen and progesterone receptors.
LAM is classified as a perivascular epithelioid cell tumor (PEComa).
The patient may develop:
(1) lympangiomyomas (benign tumors that occur along axial lymphatics in the abdomen and pelvis)
(2) chylous ascites and/or chyluria
(3) features of TSC if present, including renal angiomyolipomas, cerebral calcifications and cognitive defects.
(4) worsening symptoms during pregnancy or after exposure to estrogens or progestins.
Features of pulmonary disease:
(1) LAM cell proliferation with multifocal cystic and/or solid areas
(2) dyspnea that progresses over time to respiratory failure
(3) chronic cough
(4) chest pain
(5) pneumothorax
(6) hemoptysis
(7) chyloptysis
(8) chylous pleural effusions
Laboratory findings:
(1) elevated serum levels of VEGF-D (vascular endothelial growth factor)
(2) elevated urine levels of matrix metalloproteins (MMPs)
Therapies have targeted features of the LAM proliferation:
(1) removal of estrogen and progesterone sources and/or blocking of the estrogen receptor
(2) doxycycline (an inhibitor of matrix metalloproteins)
(3) sirolimus (also called rapamycin, which inhibits mammalian target of rapamycin [mTOR] signaling)
