Pulmonary Langerhans cell histiocytosis (LCH) is a proliferative disorder of Langerhans cells, which infiltrate into both lung and bone. However, pulmonary LCH occurs commonly in the lung tissue alone, suggesting that LCH is distinctly different from other disseminated forms of histiocytosis, such as Hand-Schüeller-Christian disease and Letterer-Siwe disease, and should be considered as a separate type of histiocytosis. LCH is more common in adults. The characteristic histopathological finding in LCH is clusters of Langerhans cells consisting of large histiocytes with indistinct cell borders containing an abundant eosinophilic cytoplasm and folded or indented nuclei. Immunohistochemical analysis or electron microscopy can be used to confirm the diagnosis. Of the most widely used methods, S-100 protein and CD1a analysis are considered the most reliable. In S-100-positive cases, Langerhans cells with strong nuclear and cytoplasmic staining are seen. In CD1a positive cases, the cell membrane of the Langerhans cells is strongly stained. LCH is found almost exclusively in cigarette smokers. However, LCH in association with malignant neoplasia is rare and in general has only been documented in isolated case reports. An association has been reported with primary pulmonary carcinoma, but occasionally carcinoma arising from a variety of extrapulmonary sites has been found in combination with LCH. Our case suggests that habitual smoking and lingual carcinoma may contribute to the development of pulmonary LCH.

In February 1999 a 57-year-old man was admitted to our hospital for investigation of an abnormality on a chest X-ray film. He had been a smoker since the age of 20 and had smoked, on average, 40 cigarettes per day. Prior to the chest X-ray examination he had been well and there was no history of exposure to chemical toxins. The findings on physical examination were normal, except for some roughening of the surface of the tongue. Blood test results, including hematological, blood chemistry and tumor marker analysis, were all normal. Chest radiography and computed tomography (CT) scans revealed nodular lesions and multiple thin-walled cysts in both lungs (Figs. 1, 2). There were no abnormal findings in either the sputum culture or cytological examination. Pulmonary function testing showed normal findings. Bronchoscopy and a transbronchial lung biopsy (TBLB) were performed and some specimens were taken from the right S8 cystic lesion. On histopathological examination, the predominant cell population was found to be Langerhans cells with indistinct cell borders containing an eosinophilic cytoplasm with folded or indented nuclei. There was no evidence of malignancy (Fig. 3). The cytoplasm of these cells stained positive for S-100 protein (Fig. 4A), whilst the cell membrane was positive for CD1a (Fig. 4B). The pathological diagnosis was pulmonary Langerhans cell histiocytosis (LCH). On further investigation, no other LCH lesions were found, and in particular there were no bone lesions. In view of the diagnosis of pulmonary LCH, the patient was advised that cessation of smoking was likely to be of therapeutic benefit. During the same hospital admission, the patient complained that he had noted an abnormal sensation in his tongue, and a tongue biopsy was performed. Histopathological examination of the biopsy specimen showed a moderately differentiated squamous cell carcinoma with some keratinization (Fig. 5). In view of this finding, he was admitted to the otolaryngology department of another hospital in March 1999, where the lingual carcinoma was found to be at stageIVA (T3N2bM0). This was treated with neoadjuvant therapy for 2 months (cisplatin 70 mg/m² intravenously on day 1 plus 5-fluorouracil 700 mg/m² intravenously on day 1 to 5). There was no change in the clinical stage of the lingual carcinoma at a follow-up examination. The patient had abstained from smoking during the period of the neoadjuvant therapy. When the chest CT was repeated in June 1999, there had been a slight improvement in the appearance of the pulmonary LCH (Fig. 6). In July 1999 he underwent radical resection of the lingual carcinoma. A month later (in August 1999) there had been a dramatic improvement in the appearance of the pulmonary LCH on chest CT (Fig. 7). Thereafter, his postoperative course was uneventful and there was no exacerbation of pulmonary LCH.

Langerhans cell histiocytosis (LCH) is now thought to be the same condition as eosinophilic granuloma of the lung. The key feature that is common to pulmonary eosinophilic granuloma, Hand-Schüeller-Christian disease and Letterer-Siwe disease is a proliferation of Langerhans cells that possess characteristic Birbeck granules within the cytoplasm. However, since the latter two diseases have a wide and varied clinical spectrum, they probably should not be included under the diagnostic label of LCH. Hand-Schüeller-Christian disease and Letterer-Siwe disease seem to neither trigger nor follow pulmonary eosinophilic granuloma. LCH primarily affects adults, usually in the third decade. The disease is characterized by proliferation and infiltration of histiocytes into bone and lung. In adult patients with LCH, the lesions are confined mostly to the lungs, although they may be multifocal. The Langerhans cells have dendritic projections with pale-staining cytoplasm because of the lack of phagocytic granules, whilst the alveolar macrophages appear darker due to pigmentation within the cytoplasm from smoking by-products. The abundant Langerhans cells in the LCH lesions have indented nuclei and enlarged nucleoli. When they are immunostained, the cytoplasm and nuclei of the Langerhans cells are positive for S-100, while the cell membranes are positive for CD1a. Electron microscopy shows deeply indented nuclei and Birbeck granules. These granules are multilaminar structures, 40 to 45 nm in diameter, with a zipper-like central core, which is about 10 nm in length. Electron microscopy was not performed in this case, but an immunostained biopsy of the lesions showed the presence of characteristic Langerhans cells with the cytoplasm being positive for S-100 and the cell membrane being positive for CD1a. In addition, a thorough investigation showed no extra-pulmonary histiocytic lesions. In view of this, a diagnosis of pulmonary LCH was made. Cigarette smoking is thought to predispose to the development of pulmonary LCH, and this may explain the higher incidence of the disease in young adults who have started to smoke recently. However, at the time of diagnosis, this patient had a history of having smoked 2 packets of cigarettes a day for 37 years, which is a history of heavy smoking. Therefore, it is possible that other factors may also have contributed to the development of pulmonary LCH. Previous reports documented that several patients with pulmonary LCH showed a marked improvement following smoking cessation for a few months (1, 2). Therefore, we do not rule out a possibility that the improvement in the present patient was due to smoking cessation. However, since our patient exhibited a dramatic improvement one month after the radical resection of lingual carcinoma, we speculate that the development of pulmonary LCH in our patient is related not only to habitual smoking but also to the presence of lingual carcinoma. Egeler et al (3) have shown that there is an association between malignancy and LCH in 3.5% of patients with LCH (4 out of 116). In this study, LCH, or pulmonary eosinophilic granuloma, has been reported to develop in some cases as a reactive process to lung cancer. However, there have been no reports on the development of LCH as a response to lingual carcinoma.

Dendritic cells have potent antigen-presenting capabilities. Many researchers have shown an interest in the use of these antigen-presenting cells in the development of strategies for immune intervention in malignant tumors (4). Dendritic cells are known to exhibit differences in relation to both their maturational state and the microenvironment. The dendritic cells with Birbeck granules that are found in the respiratory epithelium are positive for CD1a and negative for ICAM-1, while more than 50% are positive for FcR. Similar findings have been reported for the Langerhans cells that are specific to the epidermis (Langerhans-type dendritic cells). The close resemblance between Langerhans cells and dendritic cells suggests that Langerhans cells may also be able to mount an immune response to tumors. Several reports (5, 6) have documented the presence of Langerhans cells in both squamous cell carcinoma (24%, 95/391 patients) and adenocarcinoma of the uterine cervix (54%, 32/59). In both types of cervical cancer, the five-year survival rate of those patients with stage III disease where the Langerhans cells were infiltrating into the lesions was significantly higher than in those where there was no such infiltration. In addition, the presence of Langerhans cell infiltration of the tumor has been reported to indicate a better prognosis in patients with nasopharyngeal carcinoma who are receiving radiotherapy or patients with gastric cancer in whom surgical treatment is performed. Although most reports suggest that Langerhans cell infiltration into a tumor is an indicator of good control of cellular proliferation, one study has reported that this infiltration may be associated with a poorer outcome in patients with lung cancer (7). Opinions regarding the infiltration of tumors by Langerhans cells are still varied, but there is a strong possibility that Langerhans cells may play an important role in the immune response against tumors. In this case, we believe that the Langerhans cells may have been recruited to the lung in response to the development of lingual carcinoma.

Depending on their origin, dendritic cells can be classified into two types. One line, the lymphoid dendritic cell, is derived from lymphoid cells, whilst the other line, myeloid dendritic cells, arises from myeloid cells. The myeloid dendritic cells develop from precursor cells that are common to the monocyte-macrophage line (4). Myeloid dendritic cells may also develop from CD14+ monocytes and these cells differentiate into immature dendritic cells in the presence of GM-CSF and IL-4. Incubation of immature dendritic cells with TGF-β, CD40 ligand, and TNF-α results in the production of mature dendritic cells. Annels et al recently reported that there is expression of the immature dendritic cell marker CCR6 and overexpression of CCL20/MIP-3α, the ligand for CCR6 in the lesions of LCH, and those cytokines also cause the retention of other lesions of LCH (8). To our regret, we have not performed such immunohistochemical analysis, so we can not decide whether or not these leisonal Langerhans cells are in the immature state and the source of their cytokine production.

In this case there was no significant infiltration of Langerhans cells into the lingual carcinoma lesions. In one study, it has been reported that pulmonary LCH in patients with lung cancer occurs in areas other than the site of the tumor (9). In this case, it is possible that the LCH that developed only in the lung could have been induced by the cytokines released from the lingual carcinoma cells and habitual smoking. Egeler et al have suggested that treatment of an underlying malignant tumor should first be considered for control of LCH since LCH is a reactive process to tumors and may be induced by the release of cytokines from these tumors (10). This suggestion is consistent with the clinical course that was observed in this patient after resection of the lingual carcinoma.

We have described a 57-year-old male heavy smoker who had a simultaneous diagnosis of pulmonary LCH and lingual carcinoma. This is an unusual case report since we are suggesting that the two factors of habitual smoking and lingual carcinoma may have contributed to the development of pulmonary LCH. Since LCH may be induced by the release of cytokines from tumors as a reactive process, treatment of the underlying malignant tumor should be considered for control of LCH.