Lymphangioleiomyomatosis Workup

  • Author: Joel Moss, MD, PhD; Chief Editor: Zab Mosenifar, MD   more...
 
Updated: Apr 2, 2012
 

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.[14, 15] A prior study has shown that high levels of VEGF-D are associated with lymphatic involvement (eg, lymphangioleiomyomas, adenopathy) in LAM.[16]

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Imaging Studies

Chest radiographs in lymphangioleiomyomatosis (LAM) may be normal. Fine reticular or reticulonodular interstitial infiltrate with preserved lung volumes is the most commonly observed abnormality. Pleural effusions may be present. Patients may present with pneumothorax.

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

CT or MRI scanning of the head may reveal an incidental or symptomatic meningioma, which occurs with increased frequency in patients with LAM[17] .

On bone densitometry, patients with LAM exhibit accelerated osteoporosis.[18]

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Other Tests

Pulmonary function testing, decreased diffusing capacity for carbon monoxide is the most common abnormality seen, and it is often markedly reduced.[9, 19] Hypoxemia at rest, worsening with exercise, is a common finding.[20]

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.

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Procedures

Histologic diagnosis can be made by performing an open lung, video-assisted thoracoscopic, or transbronchial biopsy (TBB)[21] ; 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.[22] 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.[23]

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Histologic Findings

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 sausagelike.

Microscopic pathology

In histological sections of the lung, the following are observed[1] :

  • 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[24]
  • Loss of alveoli with cyst formation
  • Aggregates of LAM cells abutting cystic spaces
  • Distal airway narrowing, thickened arterial walls with venous occlusion, and hemosiderosis

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
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Contributor Information and Disclosures
Author

Joel Moss, MD, PhD  Deputy Chief, Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health

Joel Moss, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Chest Physicians, American Society for Biochemistry and Molecular Biology, American Society for Clinical Investigation, American Thoracic Society, Association of American Physicians, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Coauthor(s)

Arnold S Kristof, MDCM, FRCPC  Associate Professor of Medicine, Department of Medicine, Respiratory and Critical Care Divisions; Associate Member, Department of Microbiology and Immunology; Research Director, Meakins-Christie Laboratories, McGill University Faculty of Medicine; Attending Physician, Respiratory and Critical Care Divisions, McGill University Health Centre, Royal Victoria Hospital, Canada

Arnold S Kristof, MDCM, FRCPC is a member of the following medical societies: American College of Chest Physicians, American Society for Biochemistry and Molecular Biology, American Thoracic Society, and Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Specialty Editor Board

Ryland P Byrd Jr, MD  Professor, Department of Internal Medicine, Division of Pulmonary Medicine and Critical Care Medicine, Program Director of Pulmonary Diseases and Critical Care Medicine Fellowship, East Tennessee State University, James H Quillen College of Medicine; Medical Director of Respiratory Therapy, James H Quillen Veterans Affairs Medical Center

Ryland P Byrd Jr, MD is a member of the following medical societies: American College of Chest Physicians and American Thoracic Society

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Harold L Manning, MD  Professor, Departments of Medicine, Anesthesiology and Physiology, Section of Pulmonary and Critical Care Medicine, Dartmouth Medical School

Harold L Manning, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

Timothy D Rice, MD  Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, St Louis University School of Medicine

Timothy D Rice, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Physicians

Disclosure: Nothing to disclose.

Chief Editor

Zab Mosenifar, MD  Director, Division of Pulmonary and Critical Care Medicine, Director, Women's Guild Pulmonary Disease Institute, Professor and Executive Vice Chair, Department of Medicine, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine

Zab Mosenifar, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, and American Thoracic Society

Disclosure: Nothing to disclose.

Additional Contributors

John A Kelly, MB, BCh, MD † Assistant Professor of Medicine and Microbiology and Immunology, Dartmouth Medical School; Staff Pulmonologist, White River Junction Veterans Affairs Medical Center.

Acknowledgments

This work was supported in part by the Division of Intramural Research, National Institutes of Health, National Heart, Lung, and Blood Institute (J.M.) as well as National Institutes of Health R01-CA125436, Tuberous Sclerosis Alliance, LAM Foundation, LAM Canada (A.K.).

References

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  3. Moss J. LAM and Other Diseases Characterized by Smooth Muscle Proliferation. ed. New York, NY: Marcel Decker; 1999.

  4. Hayashi T, Fleming MV, Stetler-Stevenson WG, Liotta LA, Moss J, Ferrans VJ, et al. Immunohistochemical study of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in pulmonary lymphangioleiomyomatosis (LAM). Hum Pathol. Sep 1997;28(9):1071-8. [Medline].

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  14. Young LR, Vandyke R, Gulleman PM, Inoue Y, Brown KK, Schmidt LS, et al. Serum vascular endothelial growth factor-D prospectively distinguishes lymphangioleiomyomatosis from other diseases. Chest. Sep 2010;138(3):674-81. [Medline]. [Full Text].

  15. Seyama K, Kumasaka T, Souma S, Sato T, Kurihara M, Mitani K, et al. Vascular endothelial growth factor-D is increased in serum of patients with lymphangioleiomyomatosis. Lymphat Res Biol. 2006;4(3):143-52. [Medline].

  16. Glasgow CG, Avila NA, Lin JP, Stylianou MP, Moss J. Serum vascular endothelial growth factor-D levels in patients with lymphangioleiomyomatosis reflect lymphatic involvement. Chest. May 2009;135(5):1293-300. [Medline]. [Full Text].

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  30. Taveira-DaSilva AM, Hathaway O, Stylianou M, Moss J. Changes in lung function and chylous effusions in patients with lymphangioleiomyomatosis treated with sirolimus. Ann Intern Med. Jun 21 2011;154(12):797-805, W-292-3. [Medline]. [Full Text].

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  32. Williams JM, Racadio JM, Johnson ND, Donnelly LF, Bissler JJ. Embolization of renal angiomyolipomata in patients with tuberous sclerosis complex. Am J Kidney Dis. Jan 2006;47(1):95-102. [Medline].

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  34. Kitaichi M, Nishimura K, Itoh H, Izumi T. Pulmonary lymphangioleiomyomatosis: a report of 46 patients including a clinicopathologic study of prognostic factors. Am J Respir Crit Care Med. Feb 1995;151(2 Pt 1):527-33. [Medline].

 
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