Moderators: Dr. Elizabeth Brambilla, Dr. John English and Dr. Donald Guinee
Case 8 -
Pulmonary Langerhans Cell Histiocytosis
Dr. Andras Khoor
Department of Laboratory Medicine and Pathology
Jacksonville FL, USA
A 45-year-old male cigarette smoker presented with an asymptomatic solitary pulmonary nodule in the
left upper lobe. He underwent thoracotomy and wedge excision of the lesion. After the operation, he
continued to smoke. Twenty-one years later, at the age of 66 years, he presented with a new asymptomatic
solitary nodule in the right upper lobe. CT showed only a single pulmonary nodule with no evidence of
interstitial lung disease. Since the second lesion was benign by radiographic criteria, no biopsy was
performed. However, the original wedge excision was re-reviewed.
Case 8 - Slide 1
Pulmonary Langerhans cell histiocytosis forming a 0.8 cm solitary nodule
Pulmonary Langerhans cell histiocytosis (PLCH), also known as pulmonary Langerhans cell
granulomatosis, pulmonary eosinophilic granuloma, and pulmonary histiocytosis X, is an uncommon
interstitial lung disease characterized by an abnormal proliferation of Langerhans cells. Most
patients are cigarette smokers in their third and fourth decades of life. Men are more commonly affected
than women, by a ratio of 1.5:1. Characteristically, patients present with nonspecific respiratory
complaints and bilateral reticulonodular infiltrates.
In our patient, PLCH presented as an asymptomatic solitary pulmonary nodule, a rare manifestation of
this disease.  To our knowledge, only 3 other patients have been described in the English
only 2 in peer-reviewed
Fichtenbaum et al 
described a 58-year-old man with a 42-pack-year history of cigarette smoking in whom a nodule (1.0 cm in
greatest dimension) was detected in the right middle lobe on a preoperative chest radiograph. He was
asymptomatic with no radiographic abnormalities 2 years later. ten Velde et al  described a
42-year-old man with a 40-pack-year history of smoking and an asymptomatic solitary pulmonary nodule. At
wedge resection, the nodule proved to be PLCH. No other lesions developed during a 3-year follow-up. In
his textbook, Hammar  includes a chest radiograph of a 65-year-old man who had an isolated
nodule of PLCH in the left upper lobe but provides no other information about the patient.
Typically, PLCH presents as bilateral reticulonodular infiltrates with or without cysts. 
The lesions predominate in the middle and upper lung fields, usually sparing the costophrenic angles.
Although PLCH is a common cause of spontaneous pneumothorax, this probably occurs in less than 25% of
patients. Unusual manifestations include intratracheal,
endobronchial,  and
mediastinal lymph node involvement. 
The diagnostic feature of PLCH is proliferation of Langerhans cells. These modified macrophages are
immunoreactive for S-100 protein and CD1a and contain Birbeck granules at an ultrastructural level.
Immunohistochemical and electron microscopic studies of various pulmonary specimens have revealed that
the presence of Langerhans cells is not limited to PLCH.  Langerhans cells can reside in
adenocarcinomas, squamous cell carcinomas, normal lung and various inflammatory and fibrosing conditions,
e.g., idiopathic pulmonary fibrosis, and hypersensitivity pneumonia. In these conditions the role of
Langerhans cells is unknown, but they may have an immunologic function, such as antigen processing, and
presentation to T lymphocytes.
Classic lesions of PLCH may be confused histologically with usual interstitial pneumonia, desquamative
interstitial pneumonia, chronic eosinophilic pneumonia, or reactive eosinophilic pleuritis, none of which
were present in the current case. Rather, in the current case the differential diagnosis included forms
of nonneoplastic and low-grade inflammatory masses, the main one being inflammatory myofibroblastic
tumor. The term inflammatory myofibroblastic tumor (ie, also termed plasma cell granuloma or inflammatory pseudotumor)
has been applied to a histologically heterogeneous group of lung lesions characterized by various
combinations of mononuclear inflammatory cells and macrophages set in a fibrous stroma. In the current
case, the loosely cohesive clusters of characteristic S-100 protein and CD1a-positive macrophages
associated with eosinophils in a cigarette smoker helped to establish the diagnosis of PLCH. Central
fibrotic scarring (as seen in this case) is characteristic of the lesions of PLCH as they age.
The etiology and pathogenesis of PLCH are poorly understood. However, a strong association exists
between PLCH and cigarette smoking. Furthermore, cigarette smoking is associated with a significant
increase in the number of Langerhans cells present in the pulmonary parenchyma.  Reported
studies show that the systemic form of Langerhans cell histiocytosis is a clonal expansion of Langerhans
cells associated with aberrant expression of several oncogenes or tumor-suppressor genes.  In
contrast, PLCH appears to be primarily a reactive process in which nonmalignant clonal evolution of
Langerhans cells may arise in the setting of nonclonal Langerhans cell hyperplasia. 
Granulocyte-macrophage colony-stimulating factor may be partially responsible for the focal accumulation
of Langerhans cells in early lesions of PLCH. 
The prognosis of patients with pulmonary PLCH is generally good. A minority of patients develop
progressive pulmonary disease that is ultimately fatal.  Factors associated with a poor
prognosis include older age at diagnosis and severe airflow obstruction with air trapping. Our patient
had a uniquely long clinical follow-up and was asymptomatic 31 years after surgery. Although he
developed a contralateral radiographically benign solitary nodule, he had no associated interstitial
disease as documented by symptoms, pulmonary function tests, or chest radiographs.
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