Lung
Mesenchymal tumors
Lymphangioleiomyomatosis


Topic Completed: 1 December 2015

Minor changes: 14 September 2020

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PubMed Search: Lymphangioleiomyomatosis [title] lung

Roseann Wu, M.D., M.P.H.
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Cite this page: Wu R. Lymphangioleiomyomatosis. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/lungtumorlymphangioleiomyomatosis.html. Accessed September 21st, 2020.
Definition / general
  • Rare progressive lung disease in women due to mutations in tuberous sclerosis genes, resulting in activation of the mTOR complex 1 signaling network (J Clin Invest 2012;122:3807)
  • Severe impairment of diffusion with air trapping and expanding lung volumes leading to dyspnea with pneumothorax or emphysema, without a smoking history
Essential features
  • Rare, progressive, cystic destruction of lung tissue due to proliferation of spindled and epithelioid cells with "perivascular" phenotype
  • Predominantly seen in young women of reproductive age
  • Linked to mutations in TSC1 and TSC2 (Tuberous Sclerosis Complex) and renal angiomyolipoma
Terminology
  • First reported in 1937 by Van Stossel (OMIM - LAM)
  • Abbreviation: LAM
  • Historical cases published under various terms, including lymphangiomyomatosis, lymphangioma, lymphangiomyoma, lymphangiopericytoma, leiomyomatosis, lymphangiomatous malformation, intrathoracic angiomatous hyperplasia (Arch Pathol Lab Med 2010;134:1823)
Epidemiology
  • Rare (3 - 8 per million women), 30% of females with TSC, 10 - 15% of men with TSC
  • Almost all sporadic cases are in young white women, average age 35
  • Rare cases in men or postmenopausal women on hormone replacement
Sites
  • May diffusely involve both lungs
  • Extrapulmonary locations are unusual but include lymph nodes in the pelvis, mediastinum, retroperitoneum (Thorax 2013;68:111)
  • Associated with renal angiomyolipoma
Pathophysiology
  • Progressive cystic destruction of lung due to proliferation of smooth muscle-like cells
  • Tuberous sclerosis complex-lymphangioleiomyomatosis (TSC-LAM) caused by mutations in TSC1 or TSC2, but only TSC2 mutations are reported in sporadic LAM
  • Mutations lead to upregulated mTOR, leading to cellular proliferation, migration and invasion (Am J Respir Crit Care Med 2015;191:1354)
  • Matrix metalloproteinases contribute to lung destruction
  • LAM cells have potential to metastasize
Etiology
  • Cells show perivascular, epithelioid morphology and immunohistochemical staining but origin unclear
  • May be due to metastases or migration of smooth muscle progenitor cells from uterus, since uterine involvement is a common manifestation (Am J Surg Pathol 2011;35:1776)
Clinical features
  • Associated with tuberous sclerosis, renal angiomyolipoma
  • Most common symptom is dyspnea; may present with fever, cough, chest pain, hemoptysis
  • Disease worsened by pregnancy, oral contraceptives or menstruation, improves post-menopause
  • Complications: spontaneous pneumothorax, chylous pleural effusion, respiratory failure, death
Diagnosis
  • High resolution computed tomography (HRCT) shows characteristic cystic changes and elevated VEGF-D, especially in patient with tuberous sclerosis, angiomyolipoma, lymphadenopathy or chylothorax
  • Transbronchial or video assisted thoracoscopic (VAT) lung biopsy may be needed
Laboratory
  • Serum VEGF-D >800 pg/ml in woman with typical cystic changes on HRCT is diagnostic (Chest 2010;138:674)
Radiology description
  • Chest radiograph often normal or near normal with expanded lung volumes; occasionally cystic changes
  • CT with smooth, round or oval cysts, 2-5 mm diffusely throughout both lungs; extreme apices may be spared (Semin Roentgenol 2015;50:23)
  • PET negative
Radiology images

Images hosted on other servers:
Computed tomography

Computed tomography

Various images Various images

Various images

Prognostic factors
  • Poorer prognosis: dyspnea is presenting feature, weight loss, supplemental oxygen therapy, reversible airflow obstruction, high VEGF-D (Eur Respir J 2015;46:1471)
  • Better prognosis: pneumothorax is presenting feature, older age at diagnosis, higher FEV1 and DLCO at diagnosis (Eur Respir J 2015;46:1471)
Case reports
Treatment
  • Lung transplantation, but may recur in lung allografts (Hum Pathol 2003;34:95)
  • Also embolization, bronchodilators, pleurodesis
  • Oophorectomy, hormone manipulation (progesterone or antiestrogens) show mixed results
  • mTOR inhibitors (sirolimus, everolimus) may stabilize lung function in selected patients (N Engl J Med 2011;364:1595)
Gross description
  • Diffuse emphysematous-like changes to cystic spaces separated by thick, gray white septa
  • Honeycomb appearance, evenly distributed cysts ranging 0.5 to 2 cm or larger
Gross images

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Multiple cysts

Multiple cysts

Profuse involvement

Profuse involvement (Figure 6e)

Microscopic (histologic) description
  • Changes may be subtle in early stage disease or mimic emphysema
  • Thin walled cystic air spaces and patchy, disordered, clustered to nodular proliferation of bland spindled and cuboidal epithelioid cells around airways, lymphatics, blood vessels
  • Spindle cells are located centrally with peripheral epithelioid cells
  • Cyst walls are lined by alveolar and bronchiolar epithelium
  • Resembles renal angiomyolipoma in that smooth muscle appears to spin off muscle coats of these structures, extending towards adjacent alveoli
  • Muscle cells have optically clear cytoplasm, intracytoplasmic glycogen
  • Hemosiderin pigment is common
Microscopic (histologic) images

Contributed by Roseann Wu, M.D., M.P.H. and Yale Rosen, M.D.
Multiple cysts

Multiple cysts



Images hosted on other servers:
Various stains

Various stains

HMB45, SMA

HMB45, SMA

Thin walled, rounded cysts

Thin walled, rounded cysts

Eosinophilic cytoplasm

Eosinophilic cytoplasm

LAM nodule

LAM nodule

Low power

Low power

Cytology description
  • Well organized, tightly cohesive, globular clusters in chylous effusions, with moderate nuclear-to-cytoplasmic ratio (Acta Cytol 2009;53:402)
Cytology images

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Outer flattened cells

Outer flattened cells

SMA, HMB45, D20

SMA, HMB45, D240

Positive stains
Electron microscopy description
Molecular / cytogenetics description
Differential diagnosis
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