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(Chest. 1999;115:1452-1455.)
© 1999 American College of Chest Physicians

Pulmonary Langerhans' Cell Histiocytosis*

Radiologic Resolution Following Smoking Cessation

Nesrin Mogulkoc, MD; Ali Veral, MD; Paul W. Bishop, MB, BCh; Ülkü Bayindir, MD; C. Anthony C. Pickering, MD and Jim J. Egan, MD

* From Ege University Hospital, (Drs. Mogulkoc, Veral, and Bayindir), Izmir, Turkey; and Wythenshawe Hospital, (Drs. Bishop, Pickering, and Egan), Manchester, UK.

Correspondence to: Nesrin Mogulkoc, MD, North West Lung Research Center, Wythenshawe Hospital, Southmoor Road, Wythenshawe, Manchester, M23 9LT, United Kingdom; e-mail: 100046.1102{at}compuserve.com


   Abstract
TOP
 Abstract
Introduction
 Case Reports
 Discussion
 References
 
We describe two patients with histologically proven pulmonary Langerhans' cell histiocytosis in whom radiologic improvement occurred following smoking cessation. The patients had 23- and 25-pack-year smoking histories, respectively. High-resolution CT revealed multiple small nodules, located predominantly in the upper and middle lung fields. There was a close temporal relationship between smoking cessation and radiologic improvement.

Key Words: Langerhans' cell granulomatosis • Langerhans' cell histiocytosis (LCH) • pulmonary histiocytosis X • smoking cessation


   Introduction
TOP
 Abstract
 Introduction
Case Reports
 Discussion
 References
 
Langerhans' cell histiocytosis (LCH), also referred to as Langerhans' cell granulomatosis or pulmonary histiocytosis X, is an uncommon parenchymal lung disease of unknown etiology occurring almost exclusively in cigarette smokers.1 The natural history is extremely variable. Although spontaneous improvement in patients with LCH has been described, the role of smoking cessation in the natural history remains controversial.2 3 We describe two patients with biopsy specimen-proven LCH in whom radiologic improvement occurred following smoking cessation.


   Case Reports
TOP
 Abstract
 Introduction
 Case Reports
Discussion
 References
 
Case 1
A 43-year-old woman was admitted to the hospital with a 3-month history of a nocturnal cough associated with intermittent chest tightness. She had been previously well with no history of dust or chemical exposures. She was a smoker, starting at the age of 20 years and averaging 20 cigarettes a day. Physical examination revealed sparse fine late inspiratory crackles at both bases. Breast examination was normal. Routine hematologic studies were normal; there was no peripheral eosinophilia, the erythrocyte sedimentation rate was 42 mm/h, anti-nDNA was 40 IU/mL (normal, 0 to 29), and rheumatoid screen, antinuclear antibodies, avian, and aspergillus precipitins were all negative. Angiotensin-converting enzyme was 10 IU/L (normal, 15 to 55), and C-reactive protein (CRP) was 60 mg/L (normal, 0 to 5). Serum {alpha}-fetoprotein, human chorionic gonadotropin, carcinoembryonic antigen, and thyroid function test results were normal. Chest radiography showed multiple focal nodules throughout both lungs with sparing of the costophrenic angles.

High-resolution CT (HRCT) confirmed the presence of multiple small nodules, many of which had central cavitation, forming cysts 1 to 5 mm in diameter (Fig 1 , top, A). Abdominal ultrasound was normal. Pulmonary function tests showed an FEV1/FVC ratio of 82% and a total lung capacity (TLC) of 89%. Diffusing capacity of the lung for carbon monoxide (DLCO) was 62% of predicted. Bronchoscopy was normal with BAL total cell count of 0.15 x 106 cells per milliliter. The differential cell count was as follows: macrophages, 72%; neutrophils, 11%; lymphocytes, 3%; eosinophils, 1%; and columnar cells, 13%. There were no malignant cells and culture was negative. Transbronchial biopsy specimens showed normal lung mucosa and parenchyma.



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  		Figure 1. Lung HRCT from patient 1. At the time of presentation, there are multiple widely distributed small nodules, many of which show central cavitation (top, A). Five months later, the extensive nodularity of the previous HRCT had improved (center, B). Ten months after first presentation, there has been almost complete resolution of the nodular disease with only mild residual hypodensity in the upper lobes (bottom, C).

 
The patient underwent an open lung biopsy. Macroscopic examination showed several ill-defined gray nodules, the largest being 0.5 cm in diameter. On histologic examination, the lungs showed alveolar emphysema and ill-defined stellate nodules with cuboidalized entrapped alveoli, with eosinophils, histiocytes, and Langerhans' cells. The lesions appeared to be of varying age—some fibrotic, some cellular (Fig 2 , top, A). In the cellular nodules there were many S-100- and CD1a-positive cells. The diagnosis of LCH was made, and she was advised to stop smoking. No other therapy was given.



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  		Figure 2. Lung biopsy specimens from both patients show LCH nodules. Top, A: The nodule from patient 1 shows a characteristic stellate appearance with both fibrotic and cellular areas (hematoxylin-eosin, original magnification x50). Center, B: in both cases, the cellular population is predominantly of Langerhans' cells with delicately folded nuclei and eosinophils (hematoxylin-eosin, original magnification x200). Bottom, C:the Langerhans' cells stain strongly for CD1a in both cases (hematoxylin-eosin, original magnification x200).

 
Serial follow-up examination confirmed an objective improvement with complete remission of symptoms. Within 3 months, lung function improved to an FEV1/FVC ratio of 92%, a TLC of 108%, and a DLCO of 73% predicted. Serial HRCTs were performed 3, 5, 10, and 24 months following presentation. Three months after smoking cessation, there was an objective radiologic improvement with almost complete resolution of the extensive nodularity observed on the initial HRCT scan (Fig 1 , center, B). The HRCT scan taken 10 months after presentation (Fig 1 , bottom, C) showed several small low-density areas, particularly in the upper lobes, which have visible walls.

Case 2
A 47-year-old female smoker with a 25-pack-year smoking history presented with a nonproductive cough and night sweats for 2 months. Physical examination was normal. Routine hematologic and biochemical studies were within normal limits. There was no peripheral eosinophilia. Erythrocyte sedimentation rate was 30 mm/h, antinuclear antibody was negative, and CRP was 19 mg/L. A diagnosis of tuberculosis or metastatic lung disease was considered. Carcinoembryonic antigen, CA 19–9, CA 125, and CA 15–3 were normal. Chest radiography showed nodular shadows between 3 and 10 mm in diameter, mostly in the upper lobes. Isolated nodular lesions were confirmed by HRCT (Fig 3 , top, A), with sparing of the bases and costophrenic angles. Abdominal ultrasound was normal. Results of pulmonary function studies were within normal levels, with an FEV1/FVC ratio of 99%, a TLC of 100%, and DLCO of 98% of predicted. Arterial blood gas analysis on room air showed PaO2 of 86.1 mm Hg, PaCO2 of 38.3 mm Hg, and an oxyhemoglobin saturation of 96% at rest. Bronchoscopic examination showed no endobronchial abnormalities, and BAL was culture-negative for Mycobacterium tuberculosis. There were no malignant cells in BAL. The differential cell count was as follows: macrophages, 89%; neutrophils, 2%; lymphocytes, 2%; eosinophils, 3%; and columnar cells, 4%. Transbronchial biopsy specimen of the posterior segment of the right upper lobe revealed nonspecific inflammation.



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  		Figure 3. HRCT scan from patient 2 showing early disease with round nodules 3 to 10 mm in diameter at presentation (top, A). Rapid reduction in size of the nodules 2 months after smoking cessation (center, B). Complete radiologic resolution of the disease within 6 months of presentation (bottom, C).

 
The patient underwent a thoracoscopic lung biopsy. Macroscopic examination showed multiply firm nodules that were well demarcated and pale compared with surrounding normal lung tissue. Histologic evaluation demonstrated tiny granulomas. These granulomas were composed of histiocytes with indented nuclei, fibroblasts, varying amounts of collagen fibers, and eosinophils. The densely packed aggregates of histiocytes were positive for S-100 protein and CD1a staining (Fig 2 , center, B and bottom, C).

The patient was advised to give up smoking. Two months later, her symptoms had resolved and the appearance of the abnormal shadows on the chest radiography and HRCT had improved significantly (Fig 3 , center, B). By 6 months, there was complete radiologic resolution (Fig 3 , bottom, C). Further HRCT scans taken at 12 and 23 months after presentation showed persistent remission.


   Discussion
TOP
 Abstract
 Introduction
 Case Reports
 Discussion
References
 
The etiology of LCH remains obscure, but the vast majority (up to 97%) of the patients are current smokers or ex-smokers. The course of this disease is variable, ranging from spontaneous remission to progressive disease and death.1 4 Since remission of the LCH may occur spontaneously even in those who continue to smoke,5 the effect of smoking cessation is often difficult to resolve. We describe two patients in whom there was a close temporal and sustained relationship between smoking cessation and radiologic improvement.

It has been suggested that radiologic sparing of the costophrenic angles is a good prognostic indicator for LCH.1 Both of our patients had this feature, in addition to relatively normal lung functions. The presence of florid granulomatous lesions containing large numbers of Langerhans' cells but relatively little fibrous scarring, in both cases, also suggests the potential for spontaneous resolution of the disease. Increased CRP levels were also observed in both cases. Therefore, our patients may have had an active phase of the disease followed by clearing of the process independent of the smoking cessation. Nevertheless, resolution of the disease coincided with smoking cessation.

Because of the rare occurrence and the high rate of the spontaneous remissions of the disease, there are no reliable data on the efficiency of smoking cessation on the course of the disease. Reviewing the literature, we identified five published cases in which improvement was attributed to smoking cessation. One of these patients2 showed complete resolution of chest radiography findings, but this patient had no CT scan of the thorax. Igarashi et al6 described two patients in whom improvement of radiologic findings was observed following smoking cessation. Recently Tazi et al5 presented data on four patients, two of whom demonstrated radiographic improvement following smoking cessation and two other patients who showed spontaneous resolution despite continuing to smoke.

It is assumed that tobacco products are a major risk factor for LCH.7 8 9 10 Increased numbers of pulmonary neuroendocrine cells with bombesin-like immunoreactivity have been identified in biopsy specimens collected from patients with LCH.11 Bombesin-like peptides (BLPs) are chemotactic for peripheral blood monocytes, stimulating the phagocytic function of tissue macrophages, and promoting the release of cytokines such as interleukin-1 beta and granulocyte/macrophage colony-stimulating factor. It has been shown that a proportion of cigarette smokers have increased neuroendocrine cells and increased BLP levels.11 12 13 Therefore, such smokers may be at greater risk of developing smoking-related lung disease such as LCH.11 12 13

There is also evidence implicating the role of the enzyme, CD10/neutral endopeptidase (CD10/NEP), in the development of smoking-related lung injury. CD10/NEP plays a role in inactivating BLPs and cigarette smoke may impair CD10/NEP activity.12 Therefore, a low CD10/NEP enzymatic activity as a consequence of smoking or a genetically determined deficiency may increase BLP levels in patients with LCH.12 It remains to be determined whether asymptomatic smokers with increased BLP levels are those predisposed to develop LCH.

Patients with LCH require long-term follow-up to detect potential disease progression and relapse. Despite apparent clinical stability, ongoing injury may result in gradually progressive respiratory impairment and death after many years.5 6 Therefore, despite remaining well after 2 years follow-up, both patients require long-term follow-up.


   Footnotes
 
Abbreviations: BLPs = bombesin-like peptides; CD10/NEP = CD10/neutral endopeptidase; CRP = C-reactive protein; DLCO = diffusing capacity of the lung for carbon monoxide; HRCT = high-resolution CT; LCH = Langerhans' cell histiocytosis; TLC = total lung capacity

Received for publication October 13, 1998. Accepted for publication November 23, 1998.


   References
TOP
 Abstract
 Introduction
 Case Reports
 Discussion
 References
 

  1. Costabel, U, Corrin, B (1995) Rare interstitial lung disorders. Brewis, R Corrin, B Geddes, DMet al eds. Respiratory medicine ,1453-1475 WB Saunders London, UK.
  2. Von Essen, S, West, W, Sitorius, M, et al (1990) Complete resolution of roentgenographic chances in a patient with pulmonary histiocytosis X. Chest 98,765-767[Abstract/Free Full Text]
  3. Matsuyama, W, Mizoguchi, A, Iwami, F, et al (1997) Clinical investigation of three cases of pulmonary eosinophilic granuloma. Nippon Kyobu Shikkan Gakkai Zasshi 35,1407-1412
  4. Soler, P, Kambouchner, M, Valeyre, D, et al (1992) Pulmonary Langerhans cell granulomatosis (histiocytosis X). Annu Rev Med 43,105-115[ISI][Medline]
  5. Tazi, A, Montcelly, L, Bergeron, A, et al (1998) Relapsing nodular lesions in the course of adult pulmonary Langerhans cell histiocytosis. Am J Respir Crit Care Med 157,2007-2010[Abstract/Free Full Text]
  6. Igarashi, T, Nakawaga, A, Nishino, M, et al (1995) Improvement of pulmonary eosinophilic granuloma after smoking cessation in two patients. Nippon Kyobu Shikkan Gakkai Zasshi 33,1125-1129
  7. Powers, MA, Askin, FB, Cresson, DH (1984) Pulmonary eosinophilic granuloma—25 year follow up. Am Rev Respir Dis 129,503-507[ISI][Medline]
  8. Friedman, PJ, Liebow, AA, Sokoloff, J (1981) Eosinophilic granuloma of lung. Medicine 60,385-396[Medline]
  9. Hance, AJ, Basset, F, Saumon, G, et al (1986) Smoking and interstitial lung disease. Ann N Y Acad Sci 465,643-656[Abstract]
  10. Crystal, RG, Bitterman, PB, Rennard, SI, et al (1984) Interstitial lung diseases of unknown cause: disorders characterized by chronic inflammation of the lower respiratory tract. N Engl J Med 310,235-244[ISI][Medline]
  11. Aguayo, SM, King, TE, Jr, Waldron, JA, Jr, et al (1990) Increased pulmonary neuroendocrine cells with bombesin-like immunoreactivity in adult patients with eosinophilic granuloma. J Clin Invest 86,838-844
  12. Aguayo, SM (1994) Determinants of susceptibility to cigarette smoke: potential roles for neuroendocrine cells and neuropeptides in airway inflammation, airway wall remodelling, and chronic airflow obstruction. Am J Respir Crit Care Med 149,1692-1698[Abstract]
  13. Casolaro, MA, Bernaudin, JF, Saltini, C, et al (1988) Accumulation of Langerhans cells on the epithelial surface of the lower respiratory tract in normal subjects in association with cigarette smoking. Am Rev Respir Dis 137,406-411[ISI][Medline]



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This Article
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