What Is Langerhans Cell Histiocytosis?

Langerhans' cell histiocytosis (LCH) is a group of diseases characterized by a large number of Langerhans cell proliferation, infiltration, and granulomatous formation that lead to organ dysfunction. . The organs commonly affected by LCH include bones (especially skull and central axis bones), lungs, central nervous system (especially the hypothalamus region), and skin, which are classified by the number of affected organs (Table 4-28-1). According to the number of affected organs, LCH can be divided into two categories: single organ involvement and multiple system involvement (Table 1). The former is usually accompanied by the involvement of a single organ (such as lungs, bones, and skin), and is more common in adults, and the prognosis is better; the latter mostly involves multiple systems such as Letterer-Siwe disease, Han-Xu-Ke Syndrome (Hand-Schüller- Christian disease), which occurs in children, has a poor prognosis. PLCH refers to a disease in which Langerhans cells only affect the lungs or the lungs are one of the organs involved in multiple systems, and their development process and prognosis are different from those of multiple systems involving LCH. ^[1]

Ye Qiao

(Deputy Chief Physician)

Beijing Institute of Respiratory Diseases, Beijing Chaoyang Hospital, Capital Medical University

Pulmonary Langerhans' cell histiocytosis (PLCH) is a relatively rare type of lung disease that usually develops in young people and is closely related to smoking. Most of them show a benign and prolonged course. Pulmonary histopathology is characterized by Langerhans cell proliferation and infiltration, forming multiple bronchiolar interstitial nodules and cysts in both lungs.

Western Medicine Name: Lung Langerhans cell histiocytosis
English name: pulmonary Langerhans'cell histiocytosis, PLCH
Affiliated Department: Internal Medicine-Respiratory Medicine

The main symptoms: Dry cough, shortness of breath after exercise
Main cause: Smoking
Multiple groups: youth
Contagious: Non-contagious

Langerhans cell histiocytosis disease classification

Langerhans' cell histiocytosis (LCH) is a group of diseases characterized by a large number of Langerhans cell proliferation, infiltration, and granulomatous formation that lead to organ dysfunction. . The organs commonly affected by LCH include bones (especially skull and central axis bones), lungs, central nervous system (especially the hypothalamus area), and skin. According to the number of affected organs, LCH can be divided into two categories: single organ involvement and multiple system involvement (Table 1). The former is usually accompanied by the involvement of a single organ (such as lungs, bones, and skin) and is more common in adults with a better prognosis; the latter mostly involves multiple systems such as Letterer-Siwe disease, Han-Xu-K Syndrome (Hand-Schüller- Christian disease), which occurs in children, has a poor prognosis. PLCH refers to a disease in which Langerhans cells only affect the lungs or the lungs are one of the organs involved in multiple systems, and their development process and prognosis are different from those of multiple systems involving LCH. ^[1]

Table 1 Brief classification of adult Langerhans cell histiocytosis

Single organ involvement

Multiple system involvement

-Lungs (accounting for more than 85% of cases of lung involvement)

-Bones

-Skin

-Pituitary

-Lymph nodes

-Other parts: thyroid, liver, spleen, brain

-Multiple organ diseases with lung involvement (5% to 15% of cases of lung involvement)

-Multiple organ disease without lung involvement

-Multiple Organ Tissue Cell Disease

Causes of Langerhans cell histiocytosis

The incidence of PLCH is closely related to tobacco exposure. The vast majority (90% -100%) of patients with PLCH have a history of smoking, especially smoking more than 20 packs

PLCH related pictures (11 photos)

Year In the past, the incidence of men was higher than that of women. Recent studies have found that there is no significant difference in the incidence of PLCH between men and women. This difference may be related to the increase in the number of female smokers. Most PLCH patients are heavy smokers, but patients with a shorter smoking history can also develop PLCH. After quitting smoking, the chest image of PLCH patients can be improved. In the end stage of PLCH patients undergoing lung transplantation, PLCH may recur if smoking continues. Although the incidence of PLCH is related to tobacco exposure, there is no correlation between the amount of smoking and the severity of PLCH disease. Case reports indicate that PLCH can also develop after radiotherapy and / or chemotherapy for lymphoma. The majority of PLCH cases are sporadic, and there have been reports of individual cases of LCH families. The correlation between the incidence and genes is unknown. There is no evidence that occupational or geographic factors are associated with the onset of PLCH. Except for tobacco, the role of viruses and other exogenous substances in the pathogenesis of PLCH is unknown. ^[2]

Pathogenesis of Langerhans cell histiocytosis

The bombesin hypothesis suggests that increased bombesin-like peptide production contributes to the pathogenesis of PLCH. Bombesin is a neuropeptide produced by neuroendocrine cells that increases production in the lungs of smokers. Bombesin-like peptides have chemotactic effects on monocytes, promote mitosis of epithelial cells and fibroblasts, and stimulate cytokine secretion. Tobacco inhalation can cause airway neuroendothelial cells to release bombesin-like peptides (BLP), which further activate alveolar macrophages and release cytokines such as tumor necrosis factor (TNF-) and granulocytes. -Macrophage colony-stimulating factor (GM-CSF) or other mediators may enhance the recruitment and activation of Langerhans cells. At the same time, bombesin peptide can also stimulate the proliferation of fibroblasts and promote the formation of pulmonary fibrosis. Other antigens in smoke, such as tobacco glycoprotein (TGP), are an immunostimulant that can induce lymphocyte proliferation and production of lymphokines. Nicotine in tobacco can significantly reduce the phagocytosis of dendritic cells, inhibit dendritic cells from producing pro-inflammatory factors (especially IL-12), and reduce the ability of dendritic cells to induce T cells to differentiate into T helper type 1 cells.

The expression of adhesion molecules that regulate the interaction of leukocytes and endothelial cells in PLCH lung tissue has changed. The expression of intercellular adhesion molecule-1 of LCs and the expression of other leukocyte adhesion molecules such as 1 and 2 integrin can be seen in the lung tissue of PLCH patients. The importance of these findings and their relevance to PLCH remains to be elucidated.

In addition, PLCH may be associated with malignant tumors. Lymphomas, including Hodgkin's lymphoma and non-Hodgkin's lymphoma, have been reported to be associated with PLCH. ^[3]

Pathological manifestations of Langerhans cell histiocytosis

The pathological features of PLCH are characteristic clusters of Langerhans cells, with a significant increase in number. They are mainly distributed around the small airways. Their morphology is similar to that seen in normal tissues. The cytoplasm is weakly eosinophilic and has obvious staining. Grooved nuclear membrane (Figure 1). In formalin-fixed paraffin-embedded tissue sections, Langerhans cytoplasm S-100 (Figure 2a) and cell surface CD1a (Figure 2b) were positive. Under the electron microscope, a five-layered rod-like structure can be seen in Langerhans cells, called Birbeck particles.

PLCH lung specimens showed scattered nodules with varying degrees of cystic changes in both lungs. Masses in the bronchi can also be seen, and single nodular lesions are rare. Double upper middle lobe involvement is significant, and the bottom of the lung is usually not affected. The nodules are irregular in shape and have star-shaped edges. End-stage manifestations of dense fibrosis and cystic cavity changes, showing a honeycomb lung. In the course of disease progression, the pathological manifestations are: nodules, cystic nodules, thick-walled cysts, and thin-walled cysts.

Under low magnification, relatively normal lung tissue with scattered stellate interstitial nodules centered on the bronchioles is the main histopathological feature of PLCH. The lesions are uneven in phase, and nodules, cysts, and fibrous plaques coexist. (image 3). Nodules and cysts can also be spaced along the pleura and leaflets. Nodules with diameters ranging from 1mm to 5mm can be seen in most cases. Nodules contain a mixed population of cells with varying numbers of Langerhans cells, eosinophils, lymphocytes, plasma cells, fibroblasts, and cytoplasmic soot-containing macrophages. As the disease progresses, the nodules gradually decrease, the cyst space gradually increases, and the Langerhans decreases or disappears in the end stage. Interstitial fibrosis and the formation of small cysts can be seen. The lesions spread widely to the lung parenchyma and surround the bronchial vascular structure. Disease-specific lesions forming so-called stellate lesions. Respiratory bronchiolitis caused by smoking with interstitial lung disease (RB-ILD) and desquamative interstitial pneumonia (DIP) -like reactions are seen in the lungs around the nodule and sac cavity, that is, the alveoli of smokers in the alveolar cavity Aggregation of macrophages. Emphysema is also common. The histopathological changes of the nodular shadow in the chest image were stellate interstitial nodules, and the cystic shadow was dilated bronchioles.

When pneumothorax occurs, reactive eosinophilic pleurisy can occur, and mesothelial cell proliferation, chronic inflammation, and eosinophil infiltration can be seen, which are non-specific. Patients with end-stage PLCH are associated with pulmonary hypertension, which is mainly related to the involvement of pulmonary arterioles and pulmonary veins. The vascular wall can be seen with thickening and intimal hyperplasia. Langerhans cells in the lung may participate in pulmonary blood vessels by producing cytokines and growth factors Reconstruction. ^[4-5]

Clinical manifestations of Langerhans cell histiocytosis

The clinical manifestations of PLCH are very different. One quarter of patients have no respiratory symptoms and are therefore easily missed. If symptoms occur, the most common are dry cough and difficulty breathing after exercise. About one-third of patients have systemic symptoms such as weight loss, fatigue, fever, night sweats, and loss of appetite. When patients have systemic symptoms, care should be taken to check for potential tumors. About 10% of patients have spontaneous pneumothorax due to subpleural capsular rupture, which can be the first symptom of this disease. Chest pain is uncommon. During the development of the disease, chest pain occurs in about one fifth of patients, although chest pain can occur in the disease involving the ribs. Hemoptysis is rare and only occurs in 5% of patients with PLCH. Most of them are not caused by PLCH, suggesting that pulmonary fungus balls or lung cancer may be associated. In 5% -15% of patients, because Langerhans cells are involved in other organs or systems, corresponding symptoms may occur, such as liver or spleen, and abdominal discomfort may occur; superficial lymph nodes are involved, and corresponding lymphadenopathy is enlarged; hypothalamus is involved, Thirst, diabetes insipidus may occur. Physical examination showed no abnormalities in the lungs, and clubbing fingers were rare. End-stage patients can see signs of pulmonary hypertension and pulmonary heart disease. ^[6]

Langerhans cell histiocytosis auxiliary examination

1. In the early stage of PLCH of chest radiograph, chest radiograph showed infiltration of micro-nodules or reticulo nodules with unclear borders of the lungs, with the upper and middle lungs as the focus, and the costosacral angle was usually not affected (Figure 4a). Cystic changes are characteristic changes of the disease and can coexist with nodules. At the end of PLCH, multiple adjacent cysts with a diameter of more than 2 cm can be seen, which is difficult to distinguish from emphysema or lymphangioma (LAM). PLCH chest radiographs show pneumothorax, and in rare cases osteolytic damage to the ribs. Pleural effusion and hilar lymphadenopathy are rare. When combined with pulmonary hypertension, a chest radiograph showed widening of the right lower pulmonary artery trunk, swelling of the pulmonary artery segment, and enlargement of the right ventricle (Figure 4b). A few early patients (<10%) had normal chest radiographs.

2. Chest HRCT Chest HRCT has characteristic features and distribution characteristics, which is an important basis for the clinical diagnosis of PLCH. Early lesions are dominated by central lobules with small changes in the cystic cavity (Figure 5). As the disease progresses, cysts, fibrosis, and honeycomb lungs appear. The cystic cavity changes are relatively late, with irregular and thick cystic walls and varying diameters, showing a diffuse distribution, centered on the upper and middle lung fields (Figure 6). In the later stages, cystic cavities can appear throughout the lungs. The lung lesions in patients with PLCH showed a change pattern from nodules to cystic nodules, thick-walled cysts, and then thin-walled cysts.

3. Decreased DLCO in lung function was seen in 60% to 90% of patients. Common vital capacity (VC) and total lung capacity (TLC) decreased, and the ratio of residual gas capacity (RV) to TLC increased. 20% to 30% of patients have restricted airflow, and the ratio of forced expiratory volume (FEV1) to vital capacity (VC) decreases in the first second. At the end of the disease, a small number of patients show restricted ventilation dysfunction and diffusion disorder. 10% to 15% of patients have normal resting pulmonary function. Arterial blood gas analysis is related to the extent of lung involvement.

4. Bronchoscopy and bronchoalveolar lavage bronchoscopy showed no abnormalities in the trachea and bronchi, or the trachea-bronchial mucosa exhibited non-specific inflammatory changes related to smoking. A bronchial mucosal biopsy is not helpful for diagnosis, but it is useful for excluding other diagnoses. Due to the focal distribution of lung lesions, the diagnosis rate of transbronchial transmural lung biopsy (TBLB) is low (10% to 40%), and PLCH lungs show cystic lesions, which increases the risk of pneumothorax. Bronchoalveolar lavage fluid (BALF) cell analysis is helpful for diagnosis and differential diagnosis. CD1a (OKT6) positive Langerhans cells in BALF are greater than 5% (normally less than 1%). Combined with chest imaging, it can prompt the diagnosis of PLCH. But the sensitivity is low (25% -50%), because in many diseases, CD1a-positive cells in BALF increase to varying degrees (2% -5%). It is worth noting that in smokers with normal chest imaging, CD1a-positive cells in BALF can reach 3%. BALF analysis can help identify diffuse lung diseases such as sarcoidosis, allergic pneumonia, tuberculosis, lung cancer, and alveolar bleeding.

5. Surgical lung biopsy The lung tissue obtained by surgical lung biopsy is accurate and has high diagnostic value. Although surgical lung biopsy is the gold standard for disease diagnosis, it is somewhat traumatic. If you have clinical manifestations and typical imaging data, you can make a clinical diagnosis and avoid surgical lung biopsy.

6. Laboratory tests are not specific. Peripheral blood eosinophils, immunoglobulins, autoantibodies, and serum angiotensin-converting enzymes are usually in the normal range.

Langerhans cell histiocytosis disease diagnosis

Middle-aged and young smokers, the HRCT of the chest showed diffuse nodules and cystic cavity shadows in the lungs. The upper middle lung field does not involve the costosacral angle. Combined with CD1a-positive Langerhans cells in BALF, it is more than 5%. Diagnosed as PLCH. Due to the small tissue mass obtained by TBLB and the low positive diagnosis rate, surgical lung biopsy is usually required for cases that cannot be diagnosed clinically. Lung tissue pathology showed typical stellate interstitial nodules and cysts with bronchioles as the center, and lung Langerhans cells were positive for CD1a and S-100 staining, which can be diagnosed. Patients with PLCH also need to be examined for involvement of extrapulmonary organs, such as the hip bone (Figure 7), skin, pituitary, lymph nodes, thyroid, liver, and spleen. If the patient has no history of tobacco exposure, PLCH cannot usually be diagnosed.

Langerhans cell histiocytosis disease treatment

1. Quit smoking and quit smoking is the primary treatment measure. 50% to 75% of patients' disease is stable or improved 6 to 24 months after smoking cessation, symptoms are relieved, and imaging lesions partially or completely disappear (Figure 8a, b). At the same time, quitting smoking can also reduce the risk of lung cancer, chronic obstructive pulmonary disease, and cardiovascular and cerebrovascular disease.

2, glucocorticoids have systemic symptoms, imaging or pulmonary function deterioration, empirical application of glucocorticoids. The initial dose of prednisone is 0.5 mg / kg to 1 mg / kg per day, and then it is gradually reduced and taken continuously for 6 to 12 months. However, the efficacy of hormones has not been proven.

3. Cytotoxic drugs Cytotoxic drugs such as vincristine, methotrexate, cyclophosphamide, etoposide and cladribine can be used in patients with multiple organ involvement who do not respond to smoking cessation or do not respond to hormone therapy. The efficacy of cytotoxic drugs is unknown.

4. Patients with PLCH at the end of lung transplantation with severe respiratory failure or pulmonary hypertension should consider lung transplantation. Before lung transplantation, the patient must quit smoking. After lung transplantation, if the patient smokes again, the transplanted lung may still have PLCH. ^[7]

Langerhans cell histiocytosis disease prognosis

The natural course and prognosis of the disease vary greatly from individual to individual. About 50% of patients have a good prognosis, symptoms and imaging show partial or complete remission, 30% to 40% of patients with PLCH continue to progress gradually, and 10% to 20% of patients have symptoms. Progressive, such as recurrent pneumothorax, combined with respiratory failure and pulmonary hypertension. The prognostic factors of PLCH include high age of onset, persistent systemic symptoms, recurrence of pneumothorax, extrapulmonary involvement, diffuse changes in lung cystic cavity, and pulmonary hypertension. The 1-, 2-, and 5-year survival rates were 63.6%, 57.2%, and 53.7%, respectively. PLCH was recurred in 20% (8/29 cases) after lung transplantation. Smoking and extrapulmonary involvement may be risk factors for relapse.