Lymphangioleiomyomatosis Workup

Updated: Dec 22, 2019
  • Author: Joel Moss, MD, PhD; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
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Workup

Approach Considerations

Diagnostic Criteria

In its 2010 guidelines for diagnosis and management of LAM, the European Respiratory Society (ERS) proposed the following diagnostic criteria [13] :

LAM is considered associated with TSC (TSC-LAM) when TSC is present. Otherwise LAM is considered sporadic. A diagnosis is confirmed based on either:

  • Characteristic or compatible lung high-resolution computed tomography (HRCT), and lung biopsy fitting the pathological criteria for LAM; or
  • Characteristic lung HRCT and any of the following: angiomyolipoma (kidney); thoracic or abdominal chylous effusion; lymphangioleiomyoma or lymph-node involved by LAM; and definite or probable TSC .

A LAM diagnosis is probable based on either:

  • Characteristic HRCT and compatible clinical history that includes pneumothorax (especially multiple and/or bilateral) and/or altered lung function tests; or
  • Compatible HRCT and any of the following: angiomyolipoma (kidney); and thoracic or abdominal chylous effusion.

The criteria above is only for females. In males, LAM is very rare without TSC and rare with TSC; diagnosis requires both characteristic or compatible HRCT and typical pathological features on lung biopsy.

The 2017 American Thoracic Society/Japanese Respiratory Society guidelines support a clinical diagnosis of LAM based on HRCT findings typical for LAM (eg, diffuse, thin-walled, round) and accompanied by any of the following clinical features: TSC, renal angiomyolipoma, cystic lymphangioleiomyoma, or chylous pleural effusions in the chest and/or abdomen. The guidelines give a strong recommendation for the use of vascular endothelial growth factor D testing to establish the diagnosis of LAM before considering lung biopsy in patients with cystic abnormalities on HRCT characteristic of LAM, but no other confirmatory clinical features. [6]

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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 or follow-up. [25, 26] A prior study has shown that high levels of VEGF-D are associated with lymphatic involvement (eg, lymphangioleiomyomas, adenopathy) in LAM. [27, 28]

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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.

high-resolution computed tomography (HRCT) (HRCT) is the recommended imaging for the diagnosis of LAM. According to ERS guidelines, lung cysts are the defining lesion and appear in all patients with LAM. They typically range from 2–5 mm in diameter but can be as large as 30 mm. They are usually round and are distributed evenly throughout the lungs with normal lung parenchyma. Wall thickness ranges from barely perceptible to 2 mm but has been reported as measuring up to 4 mm. [13]

Other findings include the following:

  • 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, abnormal 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. [29]

On bone densitometry, patients with LAM exhibit accelerated osteoporosis. [30]

See Lymphangioleiomyomatosis Imaging for more information.

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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. [20, 31] Hypoxemia at rest, worsening with exercise, is a common finding. [32]

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) [33] ; 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. [34] HMB–45 staining is used for the identification of LAM cells in biopsy specimans.

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, especially if vascular endothelial growth factor D (VEGF-D) levels are elevated. [13]

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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 [35] These are usually found in the walls of the cystic air spaces, where their growth may be overt and nodular, although some cases may be very subtly infiltrative, to the extent that multiple levels are required to identify the lesional cells. [4]

  • 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

  • S100-negative [4]

  • Estrogen and progesterone receptors

  • VEGF-D

  • 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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