ADOPTING ORPHAN DISEASES RARE INTERSTITIAL LUNG DISEASES

adoptingorphandiseaseskapak

LYMPHANGIOLEIOMYOMATOSIS

Lauran A. Hipp1 Nishant Gupta2

1The Ohio State University, Faculty of Medicine, Department of Pulmonary, Critical Care and Sleep Medicine, Columbus, USA
2Cincinnati University, Faculty of Medicine, Department of Pulmonary, Critical Care, and Sleep Medicine, Cincinnati, USA

Hipp LA, Gupta N. Lymphangioleiomyomatosis. In: Altinisik G, McCormack FX, editors. Adopting Orphan Diseases: Rare Interstitial Lung Diseases. 1st ed. Ankara: Türkiye Klinikleri; 2025. p.91-106.

ABSTRACT

Lymphangioleiomyomatosis (LAM) is a female-predominant, low-grade systemic neoplasm characterized by the proliferation of abnormal smooth muscle-like cells resulting in progressive cystic lung disease. Other key manifestations of LAM include recurrent spontaneous pneumothoraces, lymphatic complications such as lymphadenopathy and chylous effusions, and renal AML. LAM occurs almost exclusively in women and appears to be estrogen-responsive, with symptoms worsening during pregnancy and with the use of estrogen-containing drugs. LAM occurs in two forms: sporadically (S-LAM) or in association with tuberous sclerosis complex (TSC-LAM).

LAM occurs from biallelic loss of function mutations in either TSC1 on chromosome 9q34 or TSC2 on chromosome 16p13, with TSC2 mutations being more common. LAM is classified as a perivascular epithelioid cell tumor (PEComa). LAM cells migrate or metastasize to distant sites despite appearing morphologically benign. The origin of LAM cells has been a mystery for decades, although recent evidence seems to suggest the uterus as the likely source of origin. One proposed mechanism for the migration of LAM cells is the fragmentation or “shedding” of LCCs into the lymphatic system and extra-lymphatic spaces. Once in the lymphatic system, LCCs attach to lymphatic channels through interactions with the lymphatic endothelial cell layer. LAM cells can then proliferate and form new LAM cell clusters.

The average age of diagnosis of LAM is around 35 years, although there is wide variability. The most common presenting manifestations leading to an initial diagnosis of LAM are related to the pulmonary involvement of LAM. Approximately one third of patients with LAM present with spontaneous pneumothorax. Another one third of patients present with other pulmonary symptoms such as shortness of breath, wheezing, cough, or hemoptysis. The most common reported symptoms in women with LAM include dyspnea on exertion and chronic fatigue. Increasing use of thoracic CT scans (e.g., coronary calcium scoring scans) has also resulted in incidental discovery of cystic lung disease and early discovery of LAM in several instances and is becoming more common. Renal AMLs can be seen in about one-third of women with sporadic LAM where they mostly tend to be single lesions and unilateral.

The natural course of LAM is a slow progressive decline in lung function. Approximately 25% of patients require supplemental oxygen after 10 years. After symptom onset, the estimated transplant-free survival is 90% at 10 years and 64% at 20 years. In patients with TSC, LAM is the second most common cause of death and the leading cause of death in adult women with TSC.

Definitive diagnosis of LAM must have three components: 1) supportive clinical history; 2) characteristic CT findings of lung cysts; and 3) one of the following: TSC, renal angiomyolipomas, serum VEGF-D ≥ 800pg/mL, chylous pleural effusion or chylous ascites, lymphangioleiomyomas, presence of LAM cells in effusions or lymph nodes, or histopathological confirmation by biopsy of the lung or biopsy of abdominopelvic tumors. All attempts must be made to establish a definitive diagnosis of LAM prior to initiation of treatment with mTOR inhibitors.

General principles of management in LAM include pharmacological therapy to address the underlying molecular mechanisms driving the pathogenesis of LAM, management of LAM-associated complications, and supportive care such as: 1. Trial of bronchodilators with continued use in patients with evidence of clinical benefit; 2. Vaccination against common respiratory pathogens such as pneumococcus,

influenza, RSV, and SARS-CoV-2; 3. Regular exercise and consideration of pulmonary rehabilitation to address dyspnea and muscular deconditioning; 4. Supplemental oxygen therapy as indicated based on resting or exertional desaturation; 5. Screening for osteoporosis, especially in postmenopausal patients and patients with limited physical activity due to LAM; 6. Assessing for and proactively addressing mental health concerns such as anxiety and depression; and 7. Counseling to stay physically active, maintain healthy nutrition and avoidance of pulmonary toxins such as cigarette smoke.

The last two decades have seen tremendous progress in LAM including, but not limited to, improved understanding of the molecular pathogenesis, discovery of a blood-based diagnostic biomarker, advent of a safe and effective suppressive therapy, publication of clinical practice guidelines, and the establishment and expansion of a worldwide network of clinics that not only provides high quality clinical care but also facilitates collaborative research in LAM as well as multiple other rare lung diseases. With close collaboration among the LAM patients, scientists and clinicians, LAM is well poised to continue to be an exemplar of how to make meaningful progress in a rare disease in the future as the LAM community continues its journey towards improved understanding of the molecular perturbations that drive LAM and use that knowledge to develop novel, remission inducing therapies for LAM.

Keywords: Rare interstitial lung disease; Lymphangioleiomyomatosis; LAM; Pneumothorax; Angiomyolipoma; Sirolimus

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