Macroscopically, the specimen from the left lower lobe was 4 x 2.5 x 1.5 cm and from the upper lobe was 4 x 1.8 x 1.5cm, both with cystic features on the cut surface (Figure 2).
Figure 2: Macroscopically, we notice diffuse cystic changes in the lung parenchyma.
On microscopic examination, proliferating LAM cells, heterogeneous epithelioid and spindle-shaped immature muscle-like proliferating cells, were found in the cystic space of the lung parenchyma (Figure 3). An immunohistochemical stain was positive for contractile proteins (smooth muscle actin and desmin), the melanocytic marker HMB-45 (Figure 4), estrogen receptor (ER), progesterone receptor (PR), and CD56 in the LAM cells. Pan cytokeratin, EMA, CEA, S-100 protein, chromogranin, and CD34 stains were negative. The Ki-67 proliferation index was 1%.
Figure 4: The positive stain of HMB-45 prominent in the epithelioid cells (immunoreactivity; x400).
The TSC1 gene is located on the long arm of chromosome 9 (9q34) and encodes the protein hamartin (130 kDa), whereas TSC2 is located on the short arm of chromosome 16 (16p13.3) and encodes the protein tuberin (198 kDa)[2-4]. Mutations in TSC1 and TSC2 genes cause LAM cells to exhibit features of coexpression contractile proteins (smooth muscle actin and desmin) and melanocytic markers (HMB- 45, HMSA-1, Melan-A/MART-1). This suggests this lesion should be considered a deficiency or dysfunction of the encoded proteins hamartin or tuberin, respectively, which is believed to constitute activation of mTOR, leading to increased protein translation and, ultimately, inappropriate cellular proliferation, migration, and invasion[2]. LAM cells are suggested to be of perivascular epithelioid cell origin. However, the origin of LAM cells is still unclear. In addition to contractile proteins and melanocytic markers, there have been reports in the literature demonstrating other positive markers such as CD1a[2], CD63, PNL2[3], cathepsin-k[5], B7-H3[6], and the presence of estrogen receptor (ER) and progesterone receptor (PR) in 50% of epithelioid LAM cells[2].
In our case, during the differential diagnosis, we noticed CD56 expression; so far, no studies in the literature have examined this marker in LAM cases. A large series is required to verify the reliability of this antibody. A study of CD56 in soft tissue tumors revealed positivity in the gastrointestinal and uterine smooth muscle cells but negativity in the vascular smooth muscle cells and normal skeletal striated muscle cells[7].
Initially, LAM cells were believed to originate from either the airway or vascular smooth muscle cells, but this hypothesis is not supported by the diffuse existence of LAM cells throughout the lungs and the irregular distribution within the nodules, without the formation of organized layers. Another hypothesis—based on some clinical, genetic, and cell culture studies—is that LAM cells may originate from angiomyolipomas and be brought into the lungs. However, about one-third of S-LAM cases are without angiomyolipomas, and in such cases, LAM cell origin cannot be explained by metastatic or neoplastic cell dissemination. Another hypothesis about the origin of LAM cells is that they begin as donor cells from a nonhost source. The source of non-host cells could be an organ donor, a blood transfusion, or fetal cells persisting in maternal circulation. Evidence for the non-host cell theory remains elusive[1,2]. Recent studies on angiolipomas, a PEC-cell-associated group of tumors, showed positive neural stem cell markers for NG2 and L1, suggesting these cells (PECs) may originate from defective differentiating precursor stem cells[8]. We believe a large LAM series study on NG2 and L1 antibodies would enlighten us on the histogenesis of the defective differentiating precursor stem cells. Unfortunately, the origin of these cells is still uncertain.
During the early stages of the disease, it is easy to misdiagnose LAM cells that infiltrate as normal or emphysematous[2]. Benign metastasizing leiomyoma is not usually associated with cysts, and the nodules of smooth muscle are generally larger than those seen in LAM. Patients always have a history of uterine leiomyoma, and the smooth muscle cells are negative for melanocytic markers, such as HMB-45 and Melan-A[9]. Langerhans cell histiocytosis can present with cyst formation radiographically; however, the predilection of the small nodules or nodules with cystic changes in the mid- and upper-lung zones and the infiltrating Langerhans cell (positive for CD1a, S100, and langerin) and eosinophils will differentiate it from LAM. Diffuse pulmonary lymphangiomatosis shows diffuse proliferation of lymphatic vascular spaces and smooth muscles, mimicking LAM. The disease usually affects children of either sex rather than women of childbearing age. Compared with LAM, the smooth muscle proliferation is less marked, without extension into the alveoli or cyst formation, and is negative for HMB-45 staining. Minute pulmonary meningothelial nodules are lesions histologically composed of small nests of epithelioid meningothelial cells positive for EMA but negative for HMB-45[2]. In diffuse pulmonary neuroendocrine cell hyperplasia, epithelial markers like CEA and neuroendocrine markers like chromagranin are positive[10]. In multifocal micronodular pneumocyte hyperplasia, EMA, cytokeratin, and surfactant apoprotein A and B are positive, whilst HMB-45, smooth muscle actin, desmin, CEA, ER, PR, and p53 are negative[11,12].
Treatment of LAM involves several hormone-based treatments, such as bilateral oophorectomy, gonadotropinreleasing hormone agonists, tamoxifen, or progesterone. Inhaled bronchodilator therapy may provide symptomatic relief. Lung transplantation has been accepted as therapies for end-stage pulmonary LAM. Novel macrolide agent sirolimus (rapamycin), acting as an mTOR inhibitor, has shown promising results in the treatment of LAM. Other therapeutic targets—such as MMP inhibition by an MMP inhibitor (doxycycline), Rhed GTPase inhibition by 3-hydroxy-3-methylglutaryl-coenzyme A inhibitors (statins), or JAK-STAT3 pathway inhibition by interferon-γ—may also have potential for the treatment of LAM[13]. We used hormone-based tamoxifen citrate 20 mg, administered twice daily, on our patient. The prognosis of the disease varies. The five-year survival rate is between 50 and 97%.
We present this rare case to emphasize the pathogenesis and the differential diagnosis of LAM, especially in the early stage of the disease when lesions may be considered normal or the result of emphysematous changes.
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