TSC2, cathepsin K, and β-catenin as immunohistochemical markers for lymphangioleiomyomatosis.

The diagnosis of lymphangioleiomyomatosis (LAM) can be straightforward when LAM cells are abundant, but may be difficult with subtle lesions mimicking emphysema or with lung architecture obscured by parenchymal collapse. A variety of markers have been proposed for immunohistochemical confirmation of LAM. The is increasing evidence from sequencing studies that tuberous sclerosis 2 (TSC2) is frequently mutated in sporadic LAM, and TSC2 expression/loss can now be demonstrated by immunohistochemistry but TSC2 immunohistochemistry has not been reported in LAM. Here we examined the immunohistochemical performance of TSC2, β-catenin, cathepsin K, and HMB-45 in 10 cases of pulmonary LAM (4 with florid lesions, 6 with only subtle lesions), 6 cases of pelvic nodal LAM, and two cases of micronodular pneumocyte hyperplasia (MNPH), the latter a common finding in TSC LAM cases. TSC2 loss was observed in all cases in both florid and subtle lesions, nodal LAM, and MNPH. HMB45 was focally positive in 5/10 pulmonary and 3/6 nodal cases. β-catenin was variably, but sometimes weakly, expressed in 6/6 nodal cases and 10/10 pulmonary case but was often difficult to interpret in subtle lesions. Cathepsin K showed consistent strong positivity in all pulmonary and nodal cases. We conclude that, in well inflated lung with obvious LAM lesions, β-catenin, cathepsin K, and TSC2 are easy to interpret. In subtle cases Cathepsin K staining is the easiest to interpret but TSC2 staining also picks up subtle cases and offers the advantage of confirming the genetic change that implies a potential response to mTOR inhibitor therapy.