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LYMPHANGIOLEIOMYOMATOSIS
Vaishnavi Suresh Nair
Lymphangioleiomyomatosis (LAM) is a rare disorder resulting
from proliferation in the lung, kidney, and axial lymphatics o...
LAM
OF
LUNGS
LAM typically occurs in premenopausal
women, suggesting the involvement of
female hormones in disease pathogenesis.
LAM c...
Proliferation of lymphangioleiomyomatosis (LAM) cells
may obstruct bronchioles,possibly leading to airflow
obstruction, ai...
R
Race
No racial predilection has been reported for
lymphangioleiomyomatosis (LAM).
Sex
Lymphangioleiomyomatosis (LAM) pri...
CLINICAL MANIFESTATIONS
Common lymphangioleiomyomatosis (LAM) symptoms include the
following:
Dyspnea
Cough
Less common ...
Causes
The etiology of lymphangioleiomyomatosis
(LAM) is unknown; however, the fact that the
condition occurs primarily i...
Laboratory Studies
Vascular endothelial growth factor-D (VEGF-D)
levels, above a certain threshold, are found in
lymphang...
Imaging Studies
*Chest radiographs in lymphangioleiomyomatosis (LAM)
may be normal. Fine reticular or reticulo-nodular int...
*CT scan and high-resolution CT scan findings include
the following:
 Diffuse thin-walled cysts - The defining appearance...
Other Tests
Pulmonary function testing, decreased diffusing capacity for
carbon monoxide is the most common abnormality s...
Procedures
Histologic diagnosis can be made by performing an open
lung, video-assisted thoracoscopic, or transbronchial b...
Histologic Findings
Linear sub-
pleural
proliferation
of LAM cells
at the
periphery of
a cyst
Microscopic pathology
In histological sections of the lung, the following are observed:
Proliferation of lymphangioleiom...
Macroscopic pathology
Cysts are evenly distributed in all lung fields. Lymph nodes
(retroperitoneal and pelvic) may appea...
Figure 1. Chest CT scan of a patient with LAM (A)
showing numerous thin-walled cysts distributed
throughout the lungs. (B)...
In involved lymph nodes and the thoracic duct, there are
interlacing bundles of LAM cells, which may invade the walls of
...
Figure 6. Left panel: close-up of LAM
nodule (hematoxylin-eosin). Right
panel: same nodule showing positive
immunocytochem...
TREATMENT
 General care for patients with lymphangioleiomyomatosis (LAM) addresses
the following findings:
 Pleural effu...
Possible options for hormonal manipulation include the
following:
Medroxyprogesterone - Utility not known; recent case se...
New experimental therapies include the following:
Rapamycin - Shrinks angiomyolipomas and improves lung
function, but res...
THANK YOU

Lymphangioleiomyomatosis
Lymphangioleiomyomatosis
Lymphangioleiomyomatosis
Lymphangioleiomyomatosis
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Lymphangioleiomyomatosis

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Lymphangioleiomyomatosis

  1. 1. LYMPHANGIOLEIOMYOMATOSIS Vaishnavi Suresh Nair
  2. 2. Lymphangioleiomyomatosis (LAM) is a rare disorder resulting from proliferation in the lung, kidney, and axial lymphatics of leiomyoma (LAM cells) that exhibit features of neoplasia. Cystic destruction of the lung with progressive pulmonary dysfunction(pneumothorax , dyspnea), and the presence of abdominal tumors (eg, angiomyolipomas [AML], lymphangioleiomyomas) characterize the disease.
  3. 3. LAM OF LUNGS
  4. 4. LAM typically occurs in premenopausal women, suggesting the involvement of female hormones in disease pathogenesis. LAM can occur with increased frequency in patients with tuberous sclerosis complex (TSC), an autosomal dominant disorder due to mutations in the TSC1 or TSC2 gene.
  5. 5. Proliferation of lymphangioleiomyomatosis (LAM) cells may obstruct bronchioles,possibly leading to airflow obstruction, air trapping, formation of bullae, and pneumothoraces. Obstruction of lymphatics may result in lymphangioleiomyomas, chylothorax, and chylous ascites. Obstruction of venules may result in hemosiderosis and hemoptysis. Excessive proteolytic activity, which relates to an imbalance of the elastase/alpha1-antitrypsin system or metalloprotease (MMPs) and their inhibitors (tissue inhibitors of metalloproteases [TIMPs]), may be important in lung destruction and formation of cysts. PATHOLOGY
  6. 6. R
  7. 7. Race No racial predilection has been reported for lymphangioleiomyomatosis (LAM). Sex Lymphangioleiomyomatosis (LAM) primarily is a disease of women (esp in premenopausal time /pregnancy) ; however, rare case reports describe LAM in men with TSC. Age Although primarily a disease of women of childbearing age, lymphangioleiomyomatosis (LAM) has also been reported in postmenopausal patients. EPIDEMIOLOGY:
  8. 8. CLINICAL MANIFESTATIONS Common lymphangioleiomyomatosis (LAM) symptoms include the following: Dyspnea Cough Less common symptoms (findings) are associated with the following: Pneumothorax, pneumoperitoneum Chylothorax, chylous ascites Lymphedema Exacerbations of LAM have been reported to occur during pregnancy and menstruation, as well as with exogenous estrogen use. LAM may be present in approximately 30-40% of patients with tuberous sclerosis complex (TSC).
  9. 9. Causes The etiology of lymphangioleiomyomatosis (LAM) is unknown; however, the fact that the condition occurs primarily in premenopausal women and that it is exacerbated by high estrogen states suggests a role for hormones. The link with TSC suggests a genetic component.
  10. 10. Laboratory Studies Vascular endothelial growth factor-D (VEGF-D) levels, above a certain threshold, are found in lymphangioleiomyomatosis (LAM) but not other cystic lung diseases. Hence, a serologic test for VEGF-D may be useful for diagnosis. A prior study has shown that high levels of VEGF-D are associated with lymphatic involvement (eg, lymphangioleiomyomas, adenopathy) in LAM.
  11. 11. Imaging Studies *Chest radiographs in lymphangioleiomyomatosis (LAM) may be normal. Fine reticular or reticulo-nodular interstitial infiltrate with preserved lung volumes is the most commonly observed abnormality. Pleural effusions may be present. Patients may present with pneumothorax. *CT or MRI scanning of the head may reveal an incidental or symptomatic meningioma, which occurs with increased frequency in patients with LAM . *On bone densitometry, patients with LAM exhibit accelerated osteoporosis
  12. 12. *CT scan and high-resolution CT scan findings include the following:  Diffuse thin-walled cysts - The defining appearance in LAM  Adenopathy and thoracic duct dilatation  Pleural effusion  Pneumothorax  Ground-glass opacities - May be present, perhaps representing alveolar hemorrhage or interstitial disease  Pericardial effusion  Multifocal multinodular pneumocyte hyperplasia (MMPH) - Can be seen in patients with tuberous sclerosus complex (TSC), but the pathology is distinct from LAM *Abdominal imaging by either ultrasound or CT scan may demonstrate the following:  Angiomyolipoma (AML) - Benign tumors (kidney, liver, spleen) containing smooth muscle, thick-walled blood vessels, and mature adipose tissue  Retroperitoneal or mediastinal lymphangioleiomyomas
  13. 13. Other Tests Pulmonary function testing, decreased diffusing capacity for carbon monoxide is the most common abnormality seen, and it is often markedly reduced.Hypoxemia at rest, worsening with exercise, is a common finding. On spirometry, airflow obstruction is the most frequent abnormality; restriction or mixed obstruction and restriction can also be seen. Lung volumes may show an increased ratio of residual volume to total lung capacity
  14. 14. Procedures Histologic diagnosis can be made by performing an open lung, video-assisted thoracoscopic, or transbronchial biopsy (TBB); the amount of tissue obtained from TBB may be insufficient to confirm a diagnosis. Lymphangioleiomyomatosis (LAM) cells react with human melanoma black (HMB)–45, an antibody generated against an extract of melanoma.HMB-45 staining is used for the identification of LAM cells and may help in confirming LAM on TBB. With classic high-resolution CT scans of the lung and associated findings of LAM (eg, tuberous sclerosis complex, angiomyolipoma, lymphangioleiomyomas), histologic confirmation may be unnecessary.
  15. 15. Histologic Findings Linear sub- pleural proliferation of LAM cells at the periphery of a cyst
  16. 16. Microscopic pathology In histological sections of the lung, the following are observed: Proliferation of lymphangioleiomyomatosis (LAM) cells (spindle- shaped cells with small nuclei, larger epithelioid cells with clear cytoplasm and round nuclei) having a smooth muscle cell phenotype. Loss of alveoli with cyst formation Aggregates of LAM cells abutting cystic spaces Distal airway narrowing, thickened arterial walls with venous occlusion, and hemosiderosis
  17. 17. Macroscopic pathology Cysts are evenly distributed in all lung fields. Lymph nodes (retroperitoneal and pelvic) may appear pale and spongy; large chyle-filled cysts can be found within the axial lymphatic system. The thoracic duct may be large, spongy, and sausage-like.
  18. 18. Figure 1. Chest CT scan of a patient with LAM (A) showing numerous thin-walled cysts distributed throughout the lungs. (B) The lung parenchyma is almost completely replaced by very small cysts. Figure 2. Abdominal CT scan of a patient with LAM showing angiomyolipomas involving both kidneys. Figure 3. Abdominal CT scan of a patient with LAM showing a large lymphangioleiomyoma located in the retroperitoneal area and surrounding the aorta and inferior vena cava. Figure 4 A and B. LAM nodule comprising spindle- shaped cells and larger epithelioid cells (A). Nodules of various sizes (B) are seen in involved lung (hematoxylin-eosin; original magnification x50). Figure 5. Immunohistochemistry of LAM cells. Immunoperoxidase method and counterstaining with hematoxylin. A and B: Immunoreactivity with a-smooth muscle actin antibodies. LAM cells show strong reactivity (A). Pulmonary vascular smooth muscle cells are also strongly positive (arrow). LAM cells in the walls of the lung cysts are also strongly reactive (arrow) (B) (original magnification x250 for each). C: Immunoreactivity with monoclonal antibody HMB- 45. Immunoreactive cells are distributed in the periphery of LAM lung nodules (arrow) (original magnification x250). D: Immunoreactivity with monoclonal antibody HMB-45. Higher- magnification view of tissue shown in C. A strong granular reaction is present in large epithelioid LAM cells adjacent to epithelial cells covering LAM lung nodules (arrow) (D)
  19. 19. In involved lymph nodes and the thoracic duct, there are interlacing bundles of LAM cells, which may invade the walls of the lymphatics. Immunohistochemical staining of LAM lesions demonstrates the following: Reactivity with anti–alpha-smooth actin antibodies, which is consistent with smooth-muscle differentiation Estrogen and progesterone receptors Immunoreactivity with the monoclonal antibody HMB-45, which recognizes LAM cells with epithelioid features; rarely, spindle cells are also HMB-45 positive Renal and hepatic AMLs, as well as lymphangioleiomyomas, can also be detected with HMB-45 antibody
  20. 20. Figure 6. Left panel: close-up of LAM nodule (hematoxylin-eosin). Right panel: same nodule showing positive immunocytochemistry stain for HMB 45 (original magnification x200). Figure 7. Characteristics of LAM cells (A-C). Reaction of LAM cells cultured from lung and pulmonary artery smooth muscle cells (PASM) with monoclonal antibody against SMA (A). Reaction of cultured LAM cells and melanoma cells (MALME-3M) with monoclonal antibody HMB-45 (B). Fluorescence in situ hybridization (FISH) for TSC1 (green) and TSC2 (red) in LAM cells showing normal presence of two of each alleles as well as abnormal presence of TSC2 alleles (left) (C). FISH for TSC1 (green, arrow) and TSC2 (red, arrowhead) in LAM cell with one (right) or two TSC2 (left) alleles (C). Bar, 20 µm.
  21. 21. TREATMENT  General care for patients with lymphangioleiomyomatosis (LAM) addresses the following findings:  Pleural effusions - Consider chemical pleurodesis; surgical obliteration of the pleural space; medium-chain triglyceride (MCT [not a component of chyle]), lipid-free diet to reduce chyle flow (utility unknown)  Ascites - Paracentesis, MCT diet (utility unknown)  Airways disease and hypoxemia - Bronchodilators may be of benefit[25] ; supplemental oxygen, pulmonary rehabilitation, smoking cessation  Standard vaccination for respiratory infections  Osteoporosis - Standard surveillance and treatment; avoid exogenous estrogens  Lung transplantation
  22. 22. Possible options for hormonal manipulation include the following: Medroxyprogesterone - Utility not known; recent case series does not support its use Gonadotropin-releasing hormone agonists - Utility not known; few case reports support their use Tamoxifen does not appear to be effective and is not recommended due to estrogen receptor agonist activity Rate of decline in lung function trends to be less in postmenopausal women (eg, surgical oophorectomy, age)
  23. 23. New experimental therapies include the following: Rapamycin - Shrinks angiomyolipomas and improves lung function, but response is not sustained Doxycycline - Antiangiogenic, antibiotic, and matrix effects Aromatase inhibitors - Antiestrogenic effect
  24. 24. THANK YOU 

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