Final Diagnosis -- Primary Adenoarcinoma of the Lung




Pulmonary Langerhans cell histiocytosis (LCH), also called eosinophilic granuloma of the lung, pulmonary Langerhans cell granulomatosis or pulmonary histiocytosis X, is an uncommon interstitial lung disease that primarily affects young adults who smoke [1,2,3]. It represents a variant of systemic LCH that initially presents, and usually remains confined, in the lung.

LCH is characterized by an abnormal proliferation of atypical Langerhans' cells (LCs), found in densely packed aggregates (a virtually diagnostic feature). Early, inflammatory lesions are composed of a central, compact mass of LCs admixed with lymphocytes (the only other abundant cell type), eosinophils, macrophages and neutrophils, more peripherally located. These granuloma are centered on small bronchioles, destroy the bronchiolar wall and often extend into the adjoining bronchovascular structures producing the so-called stellate lesions, characteristic of this disorder. In areas not involved by granuloma, the lung architecture is normal, but non-specific lesions associated with cigarette smoking (respiratory bronchiolitis, accumulation of pigmented macrophages in the alveoli, small lymphoid aggregates in the alveolar walls) are commonly present. In late stage lesions LCs are present only in small numbers or they may be entirely absent, although pigment-laden macrophages and lymphoid follicles persist at the periphery. The lesions heal by fibrosis. In some cases, irreversible interstitial and honeycomb fibrosis occurs. Because eosinophils are not a prominent part of the pathology, and the older lesions are often devoid of eosinophils, the term "eosinophilic granuloma" is a misnomer.

Differentiated from the monocyte-macrophage line, the LCs are important antigen-presenting cells of the immune system. They are normally found in the skin, the reticuloendothelial system, the lung, and the pleura and can be found in association with cigarette smoking in otherwise healthy individuals. They may also be found in other pulmonary disorders such as idiopathic pulmonary fibrosis [4], reactive eosinophilic pleuritis, chronic interstitial pneumonia, eosinophilic pneumonia and nonspecific scars [5]. LCs differ from other histiocytes in being CD1a-positive [6]. Histologically, LCs are medium size (15 microns diameter) cells with pale staining cytoplasm, a large nucleus and nucleoli, and, on electron microscopy, they have classic pentalaminar cytoplasmic inclusions or Birbeck granules (X-bodies). These structures have been identified as infoldings of the cell membrane, possibly because of antigen processing. The granule protein has been isolated, and a gene for what is now known as "Langerin" has been cloned [7]. A staining technique using an antibody to Langerin is a definitive way to identify LCs in tissue biopsies. In LCH the abnormal cells are immature dendritic cells that present antigen poorly and are proliferating at a moderate rate [8].

Patients usually present to medical attention with abnormalities incidentally detected on chest radiographs, following a spontaneous pneumothorax or with respiratory or constitutional symptoms, especially fever or weight loss. Routine laboratory studies are noncontributory [9].

High-resolution CT scanning of the chest demonstrates characteristic combination of multiple cysts and nodules, with a mid to upper zone predominance, and interstitial thickening. Honeycombing can be seen in advanced disease.

18 cases of malignant tumors have been reported in association with pulmonary LCH. The prevalence of this relation varies from 5 - 48% [10,11,12]. These associated malignancies were lung carcinomas (bronchogenic carcinoma - 5 cases, squamous cell, large cell, and adenocarcinoma - 2 cases each, and adenosquamous carcinoma - 1 case), lymphoma (2 cases - Hodgkin's disease and lymphocytic lymphoma), and extrapulmonary carcinomas ( transitional cell carcinoma of bladder, infiltrating mediastinal ganglioneuroma and infiltrating ductal carcinoma - 1 case each) [10-12]. The malignancy may precede, follow, or occur concomitantly with the pulmonary LCH.

Multiple attempts have been made to explain the association between LCH and neoplasia. Common factors involved in carcinogenesis were examined. A viral etiology of LCH has not been proven [13]. The cause of this disease is currently unknown. Single clone proliferation produces uni- or multisystem disease in children, although no cytogenetic abnormalities have been found [14]. On the other hand, pulmonary LCH in adults appears to be a reactive process, non-clonal in origin [15]. Some authors have hypothesized that patients with pulmonary LCH-associated scarring are at increased risk of developing lung carcinoma [12].The occurrence of this disorder years after the pulmonary neoplasia was diagnosed seem to contradict this theory. Another hypothetical factor that might contribute is immune suppression, resulting in depressed immune surveillance. The carcinogenic effect of cigarette smoke is probably the cause of most of these disorders.

This case presents a patient with bilateral pulmonary eosinophilic granulomas associated with primary adenocarcinoma of the lung. With this case we are adding new data to the growing number of reported cases on association between pulmonary LCH and neoplasia. In light of this correlation, the diagnosis of pulmonary LCH strongly advocates stopping tobacco smoking and long-term medical follow-up.


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Contributed by Laurentia Nodit, MD, Douglas Johnson, MD, Gregorio Remigio MD and Samuel Yousem, MD

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