Charcot-Leyden crystals: pathology and diagnostic utility.

Abstract

Eosinophilia is associated with several diseases of the upper respiratory tract. The predominance of eosinophils in nasal tissue, secretions, and lavage fluid has been used as an aid in the diagnosis of allergic rhinitis. Charcot-Leyden crystals, considered to be a morphologic hallmark of eosinophil-related disease, are often also found in inflamed nasal tissue and paranasal sinus contents of patients with allergic rhinitis. These bipyramidal-shaped crystals are composed of the enzyme lysolecithin acylhydrolase, one of several eosinophilic proteins that damage respiratory epithelium and contribute to the pathology of allergy in the upper respiratory tract.

Introduction

Several diseases of the upper respiratory tract are associated with increased numbers of eosinophilic leukocytes, with or without blood eosinophilia, in the nasal mucosa and its secretions. (1-2) In patients with nasal polyps, marked infiltration of the polypoid tissue with activated eosinophils is a common finding. (3) Nasal challenge with antigen usually results in an eosinophil-rich infiltrate of inflammatory ceils into the paranasal sinuses, (4) as early as 30 minutes after exposure. (5)

Charcot-Leyden crystals (CLCs) are accepted as a morphologic hallmark of eosinophil-related disease in which there is active eosinophilic inflammation or proliferation. (4,6) Therefore, it is not surprising to find these distinctive bipyramidal-shaped crystals within inflamed nasal tissue and paranasal sinus contents in patients with allergic rhinitis (figure 1). CLC formation and the presence of these crystals within tissue and secretions of the upper respiratory tract, however, represent more than just an intriguing crystalline artifact. As discussed in this article, these crystals contain biologically active substances that contribute to the pathology of allergy in the upper respiratory tract.

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Pathophysiology

CLCs were first described more than a century ago. (7,8) They have since been observed in many human tissues, neoplasms, body secretions, and fecal material. (9,10) CLC protein has been localized to crystalloid-free granules within eosinophils. (11,12) Cytoplasmic granules that are found in mature human eosinophils consist of 4 categories (13): (1) large crystalloid-containing secondary granules, (2) large and medium-sized crystalloid-free primary granules, (3) small granules, and (4) microgranules. Once the eosinophil has migrated into tissue, it becomes active and releases inflammatory mediators from these granules. These include major basic protein, eosinophilic cationic protein, eosinophil peroxidase, platelet-activating factor, and CLC protein. (14) When released, CLC protein aggregates to form distinctive crystals.

CLCs are composed of the single CLC protein called lysolecithin acylhydrolase, which has lysophospholipase activity. (15,16) This protein comprises approximately 10% of the total cellular protein in eosinophils. Its true biologic function is not known. However, lysolecithin acylhydrolase is one of several eosinophil proteins with cytotoxic properties involved in the eosinophil's antiparasitic, antineoplastic, and immune functions. This enzyme also has been shown to damage the respiratory epithelium and increase vascular permeability. (17,18) Even after the disintegration of eosinophils, CLCs may retain their enzyme activity and continue to degrade lysophospholipids. (15)

Diagnostic utility

The predominance of eosinophils in nasal tissue, secretions, and lavage fluid has been used as an easy, sensitive, and specific aid in the diagnosis of allergic rhinitis. (19,20) CLCs, as alluded to before, are a morphologic hallmark of eosinophil-related disease. Eosinophils are almost always present near the crystals. (21) The fragile crystals are evident via light microscopy as eosinophilic compass-needle-like structures. They stain pink to red with hematoxylin-eosin and black with iron-hematoxylin stains. (22) They also stain with Giemsa (figure 2) and Mallory's phosphotungstic acid stain. The crystals are birefringent with polarized light (figure 3) and are readily detected with an epifluorescent microscope. (23) Their presence in specimens from the upper respiratory tract should always lead to a careful search for associated fungal hyphae and spores. (24,25) It is extremely important to recognize allergic fungal sinusitis and to be able to differentiate it from other forms of sinusitis, because the treatments and prognoses for these disorders differ significantly. (25)

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References

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From the Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston.

Reprint requests: Liron Pantanowitz, MD, Department of Pathology, Beth Israel Deaconess Medical Center, 300 Brookline Ave., Boston, MA 02215. Phone: [phone]; fax: [phone]; e-mail: [e-mail]