Case 8 -

Pulmonary Langerhans Cell Histiocytosis Dr. Andras Khoor Department of Laboratory Medicine and Pathology Mayo Clinic Jacksonville FL, USA

Case History: 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 Click to view with ImageScope Click to view with a Web-Based Viewer Diagnosis Pulmonary Langerhans cell histiocytosis forming a 0.8 cm solitary nodule Commentary 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. [1] To our knowledge, only 3 other patients have been described in the English literature, [2, 3, 4] only 2 in peer-reviewed journals. [2, 4] Fichtenbaum et al [2] 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 [4] 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 [3] 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. [5] 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, [6, 7] endobronchial, [8] and mediastinal lymph node involvement. [9] 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. [10] 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. [3] 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. [11] 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. [12] Granulocyte-macrophage colony-stimulating factor may be partially responsible for the focal accumulation of Langerhans cells in early lesions of PLCH. [13] The prognosis of patients with pulmonary PLCH is generally good. A minority of patients develop progressive pulmonary disease that is ultimately fatal. [3] 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. References Khoor A, Myers JL, Tazelaar HD, Swensen SJ: Pulmonary Langerhans cell histiocytosis presenting as a solitary nodule. Mayo Clin Proc 2001, 76:209-211. Fichtenbaum CJ, Kleinman GM, Haddad RG: Eosinophilic granuloma of the lung presenting as a solitary pulmonary nodule. Thorax 1990, 45:905-906. Hammar SP: Pulmonary Histiocytosis X (Pulmonary Langerhans' Cell Granulomatosis). Pulmonary Pathology. Edited by Dail DH, Hammar SP. New York, Springer-Verlag, 1994, pp 567-596 ten Velde GP, Thunnissen FB, van Engelshoven JM, Wouters EF: A solitary pulmonary nodule due to eosinophilic granuloma. Eur Respir J 1994, 7:1539-1540. Lacronique J, Roth C, Battesti JP, Basset F, Chretien J: Chest radiological features of pulmonary histiocytosis X: a report based on 50 adult cases. Thorax 1982, 37:104-109 Pomeranz SJ, Proto AV: Histiocytosis X. Unusual-confusing features of eosinophilic granuloma. Chest 1986, 89:88-92 Fridlender ZG, Glazer M, Amir G, Berkman N: Obstructing tracheal pulmonary Langerhans cell histiocytosis. Chest 2005, 128:1057-1058. O'Donnell AE, Tsou E, Awh C, Fallat ME, Patterson K: Endobronchial eosinophilic granuloma: a rare cause of total lung atelectasis. Am Rev Respir Dis 1987, 136:1478-1480. Brambilla E, Fontaine E, Pison CM, Coulomb M, Paramelle B, Brambilla C: Pulmonary histiocytosis X with mediastinal lymph node involvement. Am Rev Respir Dis 1990, 142:1216-1218 Hammar S, Bockus D, Remington F, Bartha M: The widespread distribution of Langerhans cells in pathologic tissues: an ultrastructural and immunohistochemical study. Hum Pathol 1986, 17:894-905 Dacic S, Trusky C, Bakker A, Finkelstein SD, Yousem SA: Genotypic analysis of pulmonary Langerhans cell histiocytosis. Hum Pathol 2003, 34:1345-1349. Yousem SA, Colby TV, Chen YY, Chen WG, Weiss LM: Pulmonary Langerhans' cell histiocytosis: molecular analysis of clonality. Am J Surg Pathol 2001, 25:630-636. Tazi A, Bonay M, Bergeron A, Grandsaigne M, Hance AJ, Soler P: Role of granulocyte-macrophage colony stimulating factor (GM-CSF) in the pathogenesis of adult pulmonary histiocytosis X. Thorax 1996, 51:611-614.