Background
Eosinophilic granuloma, also known as pulmonary histiocytosis X (PHX) or pulmonary Langerhans cell histiocytosis X (PLCH), is an uncommon interstitial lung disease that is epidemiologically related to tobacco smoking. It chiefly affects young adults, primarily occurring in the third or fourth decades of life. [1]
PLCH is a clonal disorder with recurrent MAPK pathway alterations identified in 85% of these lesions, including BRAF-V600E in 38-64% of cases. [2, 3] Diagnosis of PLCH is confirmed by the presence of CD1a and/or langerin (CD207) on immunohistochemical (IHC) staining. Mutational analysis for BRAFV600E or MAPK-ERK mutations is required, as this will be useful in determining the appropriate treatment. [4, 2] Targeted therapies are used to treat patients with symptomatic disease that does not improve with smoking cessation. [4, 2, 5]
Since the initial classification of histiocytosis disorders in 1987 by the Histiocyte Society, this organization has made a number of revisions, most recently in 2016. The current classification divides disorders into the following five groups [6] :
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L group - Langerhans diseases
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C group - Cutaneous and mucocutaneous histiocytoses
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M group - Malignant histiocytoses
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R group - Rosai-Dorfman disease (RDD)
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H group - Hemophagocytic lymphohistiocytosis HLH) and macrophage activation syndrome (MAS)
The L group includes Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and extracutaneous juvenile xanthogranuloma (JXG). PLCH is categorized as a subtype of LCH. [6]
Pathophysiology
PLCH is histologically characterized by parenchymal infiltration of the lungs by activated Langerhans cells (LCs). LCs are differentiated cells of the dendritic cell system and are closely related to the monocyte-macrophage line. These antigen-presenting cells are normally found in the skin, reticuloendothelial system, heart, pleura, and lungs. They may be identified by immunohistochemical staining or by the presence of Birbeck granules on electron microscopy. The pathophysiology of PLCH involves the clonal proliferation and accumulation of LCs within the lung parenchyma. These LCs are characterized by the expression of CD1a and CD207 (Langerin) markers.
PLCH is similar to pediatric histiocytic disorders (Letterer-Siwe disease and Hand-Schüller-Christian disease). However, PLCH differs from pediatric histiocytoses, which involve multiple organs, in that it usually manifests in a single organ: the lung. About 4-20% of patients with PLCH also have cystic lesions in the bones. Other organ systems are only rarely affected. [7]
The accumulation of LCs in the lungs is hypothesized to occur in response to exposure to cigarette smoke. Supporting this hypothesis is the finding that the initial histologic and radiographic findings are peribronchiolar. In addition, the disease is most prominent in the upper and middle lung zones, as is the case with other smoking-related lung diseases.
The granulomatous infiltrates seen in PLCH are composed of LCs, eosinophils, lymphocytes, macrophages, plasma cells, and fibroblasts, which form nodules centered on the terminal and respiratory bronchioles, causing destruction of the airway walls. In the late stages of the disease, fibrotic stellate scarring occurs, and end-stage PLCH is characterized by this scarring, along with cystic spaces and honeycombing.
Etiology
No occupational causes or geographic predispositions are recognized for PLCH. People with this condition almost invariably are cigarette smokers. Antigenic stimulation from one or more components of tobacco smoke is likely responsible for the disease.
Given that only a few tobacco smokers develop the disease, it is likely that other susceptibility factors (eg, host genetics and environmental exposures) play an important role in pathogenesis. Some reports in the literature have described PLCH developing following radiation therapy or chemotherapy for lymphoma. Additional investigation is needed to further our understanding of this disease process.
Limited data have suggested that nicotine vaping and cannabis smoking could be risk factors for the development of PLCH. [8, 9, 10]
Epidemiology
US and international statistics
PLCH is a rare disorder, and the true US prevalence is unknown. At one specialty referral center in the United States, PLCH was identified in fewer than 5% of patients who underwent lung biopsy for the diagnosis of interstitial lung disease. [11] At another center, 15 cases of PLCH were found after lung biopsy, compared with 274 cases of sarcoidosis. [12] PLCH is estimated to account for 3% of all diffuse lung diseases in adults. [11]
In a study from Belgium, 3% of patients evaluated at 20 pulmonary referral centers were diagnosed with PLCH. [13] A large Japanese study estimated the prevalence of PLCH to 0.27 per 100,000 population for males and 0.07 per 100,000 for females, on the basis of hospital discharge diagnoses over a 1-year period. [14] Scant epidemiologic data are available regarding this disease in the developing world.
Age-, sex-, and race-related demographics
The peak incidence of PLCH occurs in the 20- to 40-year age bracket. [5] Severe lung involvement in children is rare. A French nationwide cohort study by Le Louet et al reported that out of 1482 children under age 15 years with Langerhans cell histiocytosis, lung involvement occurred in 111 (7.5%). Among the most severe cases, 41% were associated with multisystem disease. [15]
No sex predilection is recognized for PLCH.
Because of the rarity of PLCH , no definitive epidemiologic data related to racial background are available.
Prognosis
The prognosis for PLCH is highly variable. Some patients with PLCH have spontaneous remissions, especially when they stop cigarette smoking, whereas others progress to end-stage fibrotic lung disease. The outlook is significantly related to smoking cessation: In most patients who continue to smoke, the disease progresses, whereas in those who successfully quit smoking, the disease often stabilizes or regresses.
Retrospective studies have suggested that the following factors are associated with a poorer prognosis in PLCH [16, 17] :
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Extremes of age
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Extensive cysts and honeycombing radiographically
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Prolonged corticosteroid therapy
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Multisystem involvement other than bone (including diabetes insipidus related to pituitary involvement)
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Recurrent pneumothorax
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Sever pulmonary artery hypertension
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Abnormal pulmonary function, including reduced gas exchange, as measured by diffusing capacity for carbon monoxide; obstructive ventilatory defect (reduced ratio of forced expiratory volume in 1 second [FEV1] to forced vital capacity [FVC], or FEV1/FVC); and/or evidence of air trapping (high residual volume/total lung capacity)
Young men who have diabetes insipidus have the worst prognosis.
Favorable signs include the radiographic finding of sparing of the costophrenic angles and a cellular, nonfibrotic biopsy specimen.
Mortality/morbidity
In one retrospective study, median survival was 12.5 years after diagnosis. [16] A European study showed similar findings, with a median survival of 13 years. [17]
As noted, smoking worsens both morbidity and mortality.
Although PLCH is rare in children, a study of 111 children younger than 15 years reported an overall mortality of 5%; among those hospitalized with severe lung involvement, mortality was 35%. [15]
Patients with PLCH also seem to have a higher risk of developing secondary malignancies, such as lymphoma, multiple myeloma, myelodysplastic syndrome, and other cancers. [16]
Patient Education
The public must be educated about the likely etiologic role of cigarette smoking in PLCH. It is believed that PLCH is largely preventable through smoking cessation.
Patients should be instructed to report the development of hemoptysis promptly. This symptom may indicate malignancy or superimposed infection by bacteria or fungi (eg, Aspergillus species).
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Low-power photomicrograph of lung-tissue specimen that demonstrates classic stellate nodule of pulmonary Langerhans cell histiocytosis X (PLCH) on hematoxylin-eosin stain.
