During the past year we have published a number of papers on various aspects of the ultrastructure and histochemistry of the lesions associated with lymphangioleiomyomatosis (LAM) a multisystem disorder that affects women almost exclusively and is characterized by: 1) proliferation of abnormal smooth muscle cells (LAM cells) in the lung and along axial lymphatics of the thorax and abdomen, and 2) formation of pulmonary parenchymal cystic lesions. The results of these studies can be summarized as follows: 1. Two types of LAM cells are recognizable: 1) small, spindle-shaped cells that have a high rate of proliferation, a low rate of apoptosis, a high content of membrane-type-1 matrix metalloproteinase (MT-1-MMP), the enzyme that activates MMP-2 (gelatinase A) a protease thought to be involved in the connective tissue destruction that mediates the formation of the pulmonary cysts, and 2) large, more highly differentiated epithelioid LAM cells, which are reactive for HMB-45 antibody (a biomarker for LAM), contain an abundance of receptors for estrogen and progesterone, and have low rates of proliferation. Both types of LAM cells contain a variety of proteins associated with smooth muscle cells, thus indicating their derivation from the latter cells. 2. The hormonal receptors in LAM cells are markedly downregulated by treatment of the disorder with hormones. 3. The cystic lesions in LAM differ morphologically from those in emphysema in that they are lined by proliferating type II pneumocytes rather than by type I pneumocytes. 4. The LAM lesions in extrapulmonary locations are morphologically and immunohistochemically similar to those in pulmonary LAM. However, because of their location, their proliferation induces obstruction to lymphatic flow and leads to the formation of large, multicystic masses. These can present difficult diagnostic problems.5. We report two patients in whom pulmonary lymphangioleiomyomatosis (LAM) affected the retroperitoneal lymph nodes and was associated with endosalpingiosis. These lesions were large, encapsulated masses with multiple cysts containing chylous fluid. Both were characterized by proliferating LAM cells that formed fascicles separated by slit-like channels. Some cysts were lined by ciliated epithelium resembling that of Fallopian tubes. Other cysts were lined either by flattened endothelial cells or by a mixture of these cells and epithelial cells. Many LAM cells gave a positive reaction with HMB-45 antibody. Most LAM cells in fascicles were reactive for smooth muscle actin and desmin. In one patient, many of the epithelial cells and some of the subjacent LAM cells were positive for estrogen and progesterone receptors. 6. LAM cells show evidence of incomplete melanogenesis, which leads to the formation of premelanomones (stage 2 and stage 3 melanosomes). Fully melanized (stage 4 melanosomes) do not develop in LAM cells, and the reasons for this are the subject for continuing study. 7. Correlations were made between clinical and follow-up data and histopathologic findings on 105 women with pulmonary LAM. The actuarial survival (to pulmonary transplantation or death) of the patients from the time of lung biopsy was 85.1% and 71.0% after 5 and 10 years, respectively. The histologic severity of LAM, graded as a LAM histologic score (LHS), was determined on the basis of semiquantitative estimation of the percentage of tissue involvement by the two major features of LAM, i.e., the cystic lesions and the infiltration by LAM cells in each case: LHS-1,<25%, LHS-2, 25-50% and LHS-3,>50%. Analysis by the Kaplan-Meier method revealed significant differences in survival for patients with LHS 1, 2, and 3 (p=0.0026). The 5 & 10 year survivals were: 100% & 100% for LHS-1, 89.9% & 74.6% for LHS-2 and 59.1% & 47.3% for LHS-3, respectively. Thus, the present study suggests that the LHS may provide a basis for determining the prognosis of LAM.
