A case of multiorgan Langerhans' cell histiocytosis presented with pneumothorax

Pulmonary Langerhans' cell histiocytosis (LCH) represents an uncommon clinical disorder with unpredictable clinical presentation and outcome. Lung involvement may occur either in isolation or as part of a multiorgan disease. A 43-year-old woman was admitted to our hospital with acute left chest pain and shortness of breath. Spontaneous left pneumothorax was detected. All laboratory tests, including pulmonary function studies, were normal. Radiological findings posed high suspicion for LCH and lung biopsy confirmed this diagnosis. Further studies identified small cystic lesions in the scalp and liver. The diagnosis of multiple organ LCH involvement was made. Spontaneous pneumothorax might be the presenting clinical symptom of LCH. The present case emphasizes the capricious nature of LCH and the importance of an individualized therapeutic approach.     

A case of pulmonary Langerhans' cell histiocytosis]

A 42-yr-old woman was referred to our hospital because of multiple small nodules in a chest radiograph. She had no symptoms such as dyspnea, cough or sputum. A chest CT revealed many centrilobular small nodules and thin-walled cysts with predominance in the peripheral area of the lungs. The specimens obtained by thoracoscopic surgery showed granulomas with scattered eosinophils and numerous Langerhans' cells. The Langerhans' cells were positive for both S-100 protein and CD1a. These findings are compatible with pulmonary Langerhans' cell histiocytosis (LCH). Since the granulomas showed no fibrotic changes, the LCH may have been in its early stages. However, there were clusters of lymphocytes and macrophages around the terminal and respiratory bronchioles, and cystic lesions without cellular infiltrates, in the specimens. The former histologic findings suggested respiratory bronchiolitis causing interstitial lung disease and the latter are indistinguishable from centrilobular emphysema. Therefore, these smoking-related diseases may have been superimposed on the LCH in this patient.     

Pulmonary Langerhans cell histiocytosis associated with lingual carcinoma

A 57-year-old man who was a heavy smoker was admitted to our hospital for further evaluation of abnormal shadows on a chest X-ray film. Chest radiography and a computed tomography (CT) scan revealed nodular lesions and multiple thin-walled cysts in both lungs. Histopathological examination of one of these cystic lesions showed that the predominant cellular population was Langerhans cells, with the cytoplasm testing positive for S-100 protein and the cell membrane showing a positive reaction for CD1a. The pathological diagnosis was pulmonary Langerhans cell histiocytosis (LCH). A lingual carcinoma that had been detected simultaneously was treated with neoadjuvant therapy and the patient was advised to stop smoking. However, only limited improvement was seen on follow-up chest CT. In view of this, a radical resection of the lingual carcinoma was performed. There was a subsequent dramatic improvement in the pulmonary LCH. Langerhans cells may play a role in the immune response to tumors. In this patient, we suggest the possibility that both the habitual smoking and the lingual carcinoma may have contributed to the development of pulmonary LCH.     

A case of pulmonary Langerhans cell histiocytosis in a young woman with coeliac disease

Pulmonary Langerhans cells histiocytosis (pulmonary LCH) is an idiopathic unusual lung disease and its association with other systemic diseases has been rarely observed. Here, we describe a young non-smoking woman with concomitant pulmonary LCH and coeliac disease that, despite therapy, suddenly deteriorated. To the best of the authors' knowledge, this is the first report in the medical literature describing an association of coeliac disease with pulmonary LCH. Considering the concomitant occurrence of both diseases in our patient and the severe course of pulmonary LCH observed, we hypothesise that coeliac disease and pulmonary LCH might be related by a common disturbance in immunity and the onset and/or the course of pulmonary LCH could be influenced or markedly worsened by the presence of coeliac disease.     

Spontaneous pneumomediastinum and hemopneumothoraces secondary to cystic lung metastasis

We report a case of a cystic metastasis to the lung from an angiosarcoma of the scalp in a 75-year-old man who complained of hemoptysis. A chest CT scan showed multiple thin-walled pulmonary cysts, bilateral pneumothoraces, small nodules and pneumomediastinum. Histologic examination revealed pleural infiltration of angiosarcoma cells. One month later, a high-resolution CT scan showed that the cysts had rapidly developed into large lesions.     

Pulmonary Langerhans cell histiocytosis--evaluation of the disease activity and treatment response using PET-CT (SUV(max) Pulmo/SUV(max) Hepar index). Description of own experience and literature review

Pulmonary Langerhans cell histiocytosis (LCH) manifests with dyspnoea and a cough with no significant expectoration, with spontaneous pneumothorax being the first symptom in some patients. The disease is caused by multiple granulomas in terminal bronchioles, visible on high resolution CT (HRCT) as nodules. During the further course of the disease, these nodules progress through cavitating nodules into thick-walled and, subsequently, thin-walled cysts. LCH may affect the lungs only or multiple organs simultaneously. Pulmonary LCH may continually progress or remit spontaneously. Treatment is indicated in patients in whom pulmonary involvement is associated with multi-system involvement or when a progression of the pulmonary lesions has been confirmed. To document the disease progression, examination of the lungs using HRCT is routinely applied. Increasing number of nodules suggests disease progression. However, determining the number of nodules is extremely difficult. Measuring radioactivity of the individual small pulmonary loci (nodules) using PET is not possible due to the high number and small size of the nodules. Our centre has a register of 23 patients with LCH; the pulmonary form had been diagnosed in 7 patients. A total of 19 PET and PET-CT examinations were performed in 6 of these patients. PET-CT was performed using the technique of maximum fluorodeoxyglucose accumulation in a defined volume of the right lung--SUV(max) Pulmo. In order to compare the results of examinations performed using the same and different machines over time as well as in order to evaluate pulmonary activity, the maximum fluorodeoxyglucose accumulation in a defined volume of the right lung (SUV(max) Pulmo) to maximum fluorodeoxyglucose accumulation in a defined volume of the liver tissue (SUV(max) Hepar) ratio (index) was used. The disease progression was evaluated using the SUV(max) Pulmo/SUV(max) Hepar index in the six patients with pulmonary LCH. The index value was compared to other parameters characterising the disease activity (HRCT of the lungs, examination of pulmonary function and clinical picture). The SUV(max) Pulmo/SUV(max) Hepar index correlated closely with other disease activity parameters. The traditional PET-CT examination is useful in detecting the LCH loci in the bone, nodes and other tissue but not in the presence of diffuse involvement of pulmonary parenchyma. Measuring the maximum fluorodeoxyglucose accumulation in a defined volume of the right lung and expressing this activity as the SUV(max) Pulmo/SUV(max) Hepar index appears to be a promising approach. Our initial experience suggests that the results obtained using this method correlate well with other parameters that characterise activity of pulmonary LCH. However, this is a pilot study and further verification is required.     

Cystic lung disease in Birt-Hogg-Dube syndrome

BACKGROUND: To describe the clinical, radiologic, and histopathologic aspects of cystic lung disease occurring in patients with Birt-Hogg-Dubé (BHD) syndrome, a rare, inheritable, multisystem disorder. METHODS: We retrospectively reviewed five patients with BHD syndrome evaluated at the Mayo Clinic Rochester from 1998 through 2005. RESULTS: Mean age (+/- SD) at the time of pulmonary evaluation was 56.4 +/- 4.8 years; four patients were men. Three patients had not received a diagnosis of BHD syndrome at the time of initial CT of the chest. Three patients had a smoking history, and two were nonsmokers. Two patients had a history of recurrent pneumothoraces. Pulmonary function tests available in four patients revealed normal results in one patient and mild airflow obstruction or nonspecific pattern of abnormalities in three patients. CT of the chest revealed cystic lung disease in all five patients; cysts were round to oval in shape, ranged widely in size, and were randomly distributed throughout the lungs, except for a predilection to involve the lung bases more extensively. Three patients with a smoking history had more severe cystic changes compared to nonsmokers and included both patients with recurrent pneumothoraces. Surgical lung biopsy available in one patient revealed emphysema-like changes. Follow-up CT scans available in four patients revealed relative stability over a median interval of 20 months (range, 3 to 66 months). CONCLUSION: We conclude that cystic lung disease in BHD syndrome varies widely in severity, mimics pulmonary lymphangioleiomyomatosis, and may be worsened by smoking.     

Simultaneous bilateral spontaneous pneumothoraces

Seven cases (1.9%) of simultaneous bilateral pneumothoraces were found in a retrospective study of 377 patients with spontaneous pneumothorax during the period from July, 1977 to June, 1989. Their symptoms were essentially those of unilateral pneumothorax, but with more severe dyspnea. All but two cases, both young, had underlying pulmonary diseases. Three (two lung cancers and one metastatic lung disease) had malignant pulmonary disease. During this period, five lung cancer patients were complicated with pneumothorax, and two of them had simultaneous bilateral pneumothoraces. Therefore the frequency of bilateral pneumothoraces in the lung cancer patients associated with pneumothorax is high. In these three patients with malignant disease, tube drainage was carried out but all died of respiratory failure. Two senile patients had small bilateral pneumothoraces. Bed rest without invasive treatment led to successful cure. Two younger patients without underlying pathology initially underwent tube drainage, followed by operation. We conclude that many patients with simultaneous bilateral spontaneous pneumothoraces have underlying pulmonary disease, the frequency of lung cancer being particularly high. Young patients without underlying disease should be operated on following alleviation of symptoms by tube drainage. Older patients and patients with malignancy should be treated with great care and individually.     

Multiple spontaneous pneumothoraces revealing Birt-Hogg-Dube syndrome

The Birt-Hogg-Dubé (BHD) syndrome is associated with cutaneous disorders including fibrofolliculomas and trichodiscomas, and also lung pneumatocysts and kidney tumours. The BHD syndrome occurs as a consequence of an autosomal dominantly inherited genodermatosis, linked to multiple germline mutations in the 14 exons of the BHD gene, mapped on 17p11.2 and encoding for folliculin (FLCN). The size and number of lung pneumatocysts are extremely variable and the cysts are surrounded by normal pulmonary tissue. In the absence of smoking lung function is usually unimpaired. The lung cysts are frequently complicated by the development of recurrent pneumothoraces. Treatment of pneumothorax in patients with the BHD syndrome is similar to the approach taken for patients with spontaneous pneumothorax. Lung cysts in the BHD syndrome are a rare cause of cystic pulmonary lesions. However, they must be systematically evaluated since kidney tumours occur in one third of patients. We report a case of classical BHD syndrome with specific cutaneous involvement, recurrent pneumothoraces complicating lung cysts, an exon 12 germline mutation on BHD gene and a familial history suggesting other related cases. This observation allows us to update this orphan disease, to consider BHD in the differential diagnosis of lung cysts and, above all, to highlight the high frequency and the prognostic significance of associated kidney tumours.     

A case of multisystem Langerhans' cell histiocytosis with lung deterioration over 15 years]

We report a case of multisystem Langerhans cell histiocytosis (LCH) with lung, bone and pituitary involvement. A 20-year-old man developed thirst, polydipsia and polyuria in 1983. He had right femur pain from 1988 and osseous LCH was diagnosed based on the operated specimen in 1989. From July 1990, he had right chest pain on coughing and dyspnea and was admitted in November 1990. LCH involving the lungs was diagnosed by CT images and diabetes insipidus was also detected. Steroid therapy was started from 1991, but he discontinued it in 1998. Though he stopped smoking, his clinical symptoms worsened and he experienced bilateral pneumothoraces in 2002 and since then he has been receiving home oxygen therapy. Pulmonary LCH is thought to have a good prognosis, but in recent studies, its survival rate appears low. We report a case of multisystem LCH with lung deterioration over about 15 years.     

Complete remission of nodular pulmonary Langerhans cell histiocytosis lesions induced by 2-chlorodeoxyadenosine in a non-smoker

Pulmonary Langerhans cell histiocytosis (LCH) is an uncommon cause of interstitial lung disease. Corticosteroids and chemotherapeutic agents are frequently used to treat symptomatic patients but their efficacy is unclear. We describe a 66-year-old with biopsy-proven pulmonary and systemic LCH, whose pulmonary abnormalities responded dramatically to treatment with 2-chlorodeoxyadenosine (2-CdA). We propose that, in selected cases, 2-CdA should be considered in the management of pulmonary LCH.     

Natural course of isolated pulmonary langerhans' cell histiocytosis in a toddler. 3-year follow-up

Isolated pulmonary Langerhans' cell histiocytosis (LCH) is distinctly rare under the age of 15 years, since the majority of patients are young adult males with heavy smoking habits. Isolated pulmonary involvement suggests that antigens inhaled from cigarette smoke are involved. Here we present a case of LCH restricted to the lungs in a toddler whose parents were heavy smokers. Since LCH was not medically treated for 3 years due to parental refusal, the disease can be regarded as having followed its natural course. During the 3-year follow-up, the disease progressed to severe pulmonary fibrosis resulting in honeycomb lungs. Based on the comparative immunohistochemical analyses of the cells obtained from bronchoalveolar lavages during the disease course, it appears that the evolution of fibrosis is rather a result from the accumulating alveolar macrophages than from the persistence of the Langerhans' cells. Passive cigarette smoking may be considered a significant risk factor in both the pathogenesis and development of pulmonary LCH in a small child.     

Bronchoscopic diagnosis of Langerhans cell histiocytosis and lymphangioleiomyomatosis

Limited data are available regarding the role of bronchoalveolar lavage (BAL) and transbronchial lung biopsy (TBB) as diagnostic tools in pulmonary Langerhans' Cell Histiocytosis (LCH) and lymphangioleiomyomatosis (LAM). The aim of this study was to review our experience regarding the value of these two techniques in the diagnosis of these cystic lung diseases. Records of 452 patients with the presumptive diagnosis of interstitial lung disease were reviewed; 67 had a clinical-radiological diagnosis of either LCH (n?=?27) or LAM (n?=?40). Of 16 patients with LCH who underwent BAL, four specimens (25%) contained cells which had positive immunoreactivity for CD1a. Of three patients with negative BAL fluid who had TBB, only one had a positive tissue diagnosis. Ten LCH patients were diagnosed by surgical lung biopsy of which five had negative BAL fluid. The remaining 12 patients were diagnosed by clinical and radiologic features. Standard examination of BAL fluid was of no diagnostic value in LAM. TBB was performed in seven patients and was diagnostic in six, not resulting in complications. All 13 patients who underwent surgical lung biopsies had a positive histopathologic diagnosis The remaining 21 patients were diagnosed by clinical and radiologic features. We suggest that BAL may assist in the diagnosis of LCH whereas TBB may be useful in the diagnosis of LAM, thus avoiding the need for surgical biopsy.     

Clinical and radiological evolution in patients with pulmonary Langerhans' cell histiocytosis

BACKGROUND: Pulmonary Langerhans' cell histiocytosis (LCH) is a diffuse, smoking-related lung disease characterised pathologically by proliferation of abnormal Langerhans' cells, cyst formation and vascular abnormalities, and physiologically by a decreased diffusing capacity. The aim of this study was to describe our experience with pulmonary LCH at our institution during the past 30 years, with particular reference to diagnosis and long-term outcome. PATIENTS AND METHODS: Seven patients, two men and five women, mean age 33 years (range 26-49 years), who had been evaluated for pulmonary LCH, were retrospectively studied. All available clinical, diagnostic and pathological data were included. RESULTS: The patients presented with symptoms of dyspnoea, cough, pleuritic pain, anorexia and fatigue. Chest X-ray and high-resolution computed tomography (HRCT) showed bilateral nodular and cystic lesions, with a predilection for the middle and upper lung zones. In the majority of patients, lung function tests showed a decrease in diffusing capacity. In six patients the diagnosis of pulmonary LCH was made after immunohistochemical examination of an open lung biopsy specimen. In one patient a confident diagnosis was made radiologically. During serial follow-up, median seven years (range 1-28 years), three patients stopped smoking and in four patients the tobacco consumption remained unchanged. For the whole group the evolution was benign, with all patients being asymptomatic or showing improvement in symptoms and regression of radiological signs. CONCLUSION: Radiographic studies often provide clues to the diagnosis, but may not obviate the need for open lung biopsy in the majority of cases. Our study shows that irrespective of smoking cessation, spontaneous regression of symptoms and radiological signs and long-term survival are possible.     

Nonsense mutations in folliculin presenting as isolated familial spontaneous pneumothorax in adults

RATIONALE: Approximately 10% of patients who have a spontaneous pneumothorax have a positive family history. OBJECTIVES: We sought to identify DNA sequence variations that confer susceptibility to pneumothoraces. METHODS: We collected 12 families that had at least 2 first-degree relatives with a spontaneous pneumothorax. All affected family members had no obvious stigmata of known genetic disorders associated with pneumothoraces. We used haplotype analysis, DNA sequencing, and restriction fragment analysis of mutations to evaluate the individuals in these families. MAIN RESULTS: In 2 of the 12 families the disorder cosegregated with markers flanking a candidate locus, FLCN. Sequencing the linked alleles revealed 2 mutations predicted to introduce premature stop codons in 2 of the 12 families. Most mutations in FLCN cause a rare disease, Birt-Hogg-Dubé syndrome, characterized by autosomal dominant inheritance of multiple benign skin lesions, renal tumors, pulmonary blebs, and pneumothoraces. None of the family members with the nonsense mutations had the skin manifestations of Birt-Hogg-Dubé syndrome or renal cancer. Pathologic examination of lung tissue from three affected nonsmokers revealed blebs and underlying emphysema. CONCLUSIONS: Isolated familial spontaneous pneumothorax can be caused by mutations of the FLCN gene. Because development of a pneumothorax and/or pulmonary blebs may be the earliest or the only clinical manifestation of FLCN mutations, pulmonologists should be alert to the contribution of this gene toward this familial form of emphysema.     

The association of pulmonary lymphangioleiomyomatosis with renal and hepatic angiomyolipomas in a prepubertal girl: a previously unreported entity

Pulmonary lymphangioleiomyomatosis (PLAM) is a rare, diffuse progressive interstitial lung disease that affects females of childbearing age and is characterized by diffuse proliferation of abnormal smooth muscle fibers predominantly developing in the lung and leading to cystic destruction. A prepubertal 13-year-old girl with PLAM associated with renal and hepatic angiomyolipomas who was treated by nephroureterectomy and thoracoscopic pleurodesis is presented. To the best of our knowledge, this is the first reported case of PLAM associated with renal and hepatic angiomyolipomas at the prepubertal age. After evaluating the clinicopathologic features of this rare entity, the authors conclude that PLAM should be considered in the differential diagnosis of cystic pulmonary pathologies in children, particularly teenagers. The most important clinical aid is to bear this rare entity in mind when a child presents with renal and/or hepatic angiomyolipomas. Thoracoscopic pleurodesis is the most effective treatment modality for recurrent pneumothoraces.     

Bronchiolitis obliterans and the risk of pneumothorax after transbronchial biopsy

The safety of bronchoscopy and specifically transbronchial biopsy has not been studied in patients with bronchiolitis obliterans. We discuss two patients with bronchiolitis obliterans as a complication of graft versus host disease following allogeneic stem cell transplant. Both underwent bronchoscopy and transbronchial biopsy, which was complicated by pneumothoraces. Patients with bronchiolitis obliterans have an increased risk of spontaneous air leak syndromes. Although no data exists regarding the safety of transbronchial biopsies in patients with airflow obstruction in general, they appear to have increased rates of pneumothoraces following transthoracic biopsies. It is important to consider the potentially increased risk of pneumothoraces when deciding to pursue bronchoscopy and transbronchial biopsy in patients with bronchiolitis obliterans.     

Langerhans cell histiocytosis in children: from the bench to bedside for an updated therapy

Langerhans cell histiocytosis (LCH) is a rare disease, affecting subjects of any age, with extremely variable clinical manifestations. Although most patients with LCH have localized disease, requiring local or even no therapy, those patients with disseminated, ‘multi‐system’ disease require specific therapy because they may be at risk for morbidity or even mortality. The current standard of care has developed empirically, based mainly on the experience of treating children with leukaemia and other haemo‐proliferative disorders. At the time of writing, the combined use of vinblastine and prednisone remains the standard of care for children with multi‐system LCH. The combination of cytarabine and cladribine is the current standard for second‐line therapy of refractory cases with vital organ dysfunction. Recent advances in the knowledge of the pathogenesis of LCH may support a change in treatment strategy. Evidence of mutations that aberrantly activate RAF/MEK/ERK signalling in over two thirds of patients with LCH may direct a target therapy strategy. Vemurafenib, a small molecule widely used in the treatment of melanoma, is the main candidate for testing in prospective trials for patients with evidence of BRAF^V600E mutation on lesional tissue. Additional molecules, including the recently approved trametinib, could follow. Identification of mutations in other genes in the remaining multisystem LCH cases could contribute to define a scenario in which target therapy becomes the main therapeutic choice in this intriguing disorder. However, because the long‐term risks and benefits of these agents in children are unknown, and other effective treatments exist for many LCH patients, the optimal indications for administering a tyrosine kinase inhibitor to children is an open question.     

Pulmonary Langerhans' cell histiocytosis

Pulmonary Langerhans' cell histiocytosis (PLCH) is an uncommon but important cause of interstitial lung disease, and it occurs predominantly in adult cigarette smokers. PLCH belongs to the spectrum of Langerhans' cell histiocytosis (LCH), diseases characterized by uncontrolled proliferation and infiltration of various organs by Langerhans' cells. Other clinical entities within this spectrum of LCH are seen in adults and children and vary in severity from mild disease that requires no therapy to severe disseminated forms with extensive organ involvement and high mortality. Organ systems involved by LCH may include skin, bone, pituitary gland, lymph nodes, and lungs. Although LCH is approximately three times more common in children than adults, pulmonary involvement is much more common in adults with LCH, in whom it frequently occurs as the sole organ involved with disease. This article summarizes recent advances and current understanding of PLCH.