Respiratory Ward - Histiocytosis X

Cases from the Respiratory Ward

DISCUSSION: PULMONARY LANGERHANS CELL HISTIOCYTOSIS - CASE PRESENTATION

Mr AL

35 year old male resident of Soweto.Was previously well and now presents with a 6 week history of a dry cough associated with decreased effort tolerance.No history of weight loss or night sweats. He is a smoker of 20 cigarettes per day for the past 15 yrs. He works in a factory that makes foam rubber mattresses. Otherwise he has been well.

On Examination, the patient was not distressed. He was hemodynamically stable. His respiratory rate was 30. He was not cyanosed nor was he clubbed. On cardiac examination there were no signs of pulmonary hypertension. On respiratory examination, the breath sounds were normal and there were a few, scattered end inspiratory crackles bilaterally. The rest of his examination was normal.

Relavent investigations were as follows;( CXR and CT scan are below )

• pO2 63 mmHg
• pCO2 31 mmHg
• Full blood count, electrolytes and liver functions were normal

The Pulmonary function tests showed evidence of obstruction;

• FVC: 2.39 (71%)
• FEV1: 1.33 (47%)
• FEV1/FVC: 56%
• TLC: 5.14 (105%)
• RV: 2.80 (234%)
• DLCO: 16.26 (78%)
• DLVA: 3.97 (93%)

The patient was not subjected to an open lung biopsy as he absconded from hospital. However, a presumptive diagnosis of histiocytosis X was made on the basis of the CXR and CT Scan of the chest aswell as the clinical picture.

CASE DISCUSSION

Definition: the histiocytoses are an ill understood and heterogeneous group of syndromes, characterised by an abnormal proliferation of histiocytes. A classification of the histiocytoses was proposed by the Histiocyte Society in 1987, in an attempt to standardize nomenclature.

This discussion will deal with pulmonary Langerhans Cell Histiocytosis (LCH). Previously LCH was called Histiocytosis X, and was classified according to;

• GENERALISED DIFFUSE ( LETTERER-SIWE)
• GENERALISED MULTIFOCAL (HAND-SCHULLER-CHRISTIAN)
• LOCALISED (EOSINOPHILIC GRANULOMA)

This classification and the syndromes mentioned in it are now considered to be outmoded, and should no longer be used.

In spite of the wide clinical spectrum of disease in LCH, the pathological lesions are uniform in all forms. Further discussion will be centered on pulmonary LCH.

EPIDEMIOLOGY

Pulmonary LCH is a rare condition. In a series of 502 open lung biopsies for chronic , diffuse , infiltrative lung disease ? LCH was identified in 3.4%. Isolated pulmonary disease affects predominantly young and middle aged adults. Over 90% of patients are smokers and approximately twice as many males as females are affected.

PATHOGENESIS AND AETIOLOGY

The pathogenesis has not been fully elucidated, but numerous theories have been proposed.

The disease process appears to fit well with and uncontrolled immune response to an unknown antigen, initiated or propagated by Langerhans cells (LC).

2 classes of antigen presenting cells are found in the lung: monocyte/macrophage and dendritic cell/ langerhans cell lineages. The LC are extremely potent antigen presenting cells which express peptide antigen in association with their own HLA molecules for recognition by T cells as well as secreting IL-1 and PGE-2.

LC are derived from dendritic cells and form a continuous network intercalated between epithelial cells in intraparenchymal airways. They are identified by the expression of CD 1a surface antigen and by the presence of pentalaminar Birbeck granules, which look like tennis raquets on electron microscopy.

Cigarette smoking can double the number of LC in the parenchymal airways ( but not in larger airways), probably by increasing their recruitment to the lung and accelerating differentiation from dendritic cells to LC.

Langerhans cells accumulate preferentially at sites of epithelial hyperplasia, possibly following secretion of the cytokine GM-CSF by the hyperplastic epithelium.

The reasoning that LCH is an abnormal immune response to an antigen is based on the following arguments:

1. LC and lymphocytes are the predominant cell types in early lesions- and the only described function of LC is to act as apc.
2. The evolution of pathological changes follows the same steps as other granulomatous processes, namely initial predominance of apc and lymphocytes followed by infiltration by inflammatory cells and then progressive replacement by macrophages and fibrosis.
3. No other pathogenetic mechanism explains the findings as well

Immediately the question arises as to what the possible antigen could be. The bronchiolar distribution and the high incidence of smoking in affected patients is suggestive of an inhaled antigen. However this does not explain disease in non smokers, and extrapulmonary disease.

A proposed theory is that the bronchial epithelial cells could serve as the antigen. Epithelial hyperplasia is known to be associated with increased numbers of LC at these sites and the hyperplastic epithelium could express neoantigens ( stress proteins) ? not present in normal epithelial cells, that would serve as antigenic stimulus. Once the immune response was triggered a vicious cycle would be triggered with epithelial destruction, and release of immune mediators inducing hyperplasia of adjacent epithelium, leading to further destruction.

This would account for the high incidence of affected smokers as cigarette smoke induces epithelial hyperplasia.

PATHOLOGICAL FINDINGS

Characteristic pathological findings consist of destructive granulomatous lesions, occurring around bronchioles, with normal pulmonary parenchyma lying between granulomas. As previously mentioned granulomas evolve through stages: from initial LC plus lymphocytes to infiltration with inflammatory cells, to end stage lesions with rare LC, and numerous pigment laden macrophages and fibrosis.

Light microscopy and EM studies of open lung biopsies from 62 patients (with normal control specimens) showed the importance of luminal fibrosis and elastic fibre degradation in the process of pulmonary structural remodelling.

The steps of structural remodelling are deemed to occur as follows:

1. Epith cell damage and detachment from the basement membrane.
2. Migration of LC, inflammatory cells and myofibroblasts into intra alveolar spaces.
3. Late stage ? formation of extra cellular components leading to obliteration of alveoli and coalescence of alveolar walls.
4. Degradation of elastic fibres in alveolar walls adjacent to granulomatous lesions, giving rise to irregularly dilated alveolar spaces.

Reconstruction of granulomas using serial sections suggests that the lesions arise in the terminal bronchiole or the proximal respiratory bronchiole, and with time extends distally, ultimately reaching alveoli. In the same lesion therefore : proximal fibrosis exists with distal cellularity and relative abundance of LC.

CLINICAL FEATURES

Symptoms:

• 60% cough
• 40% dyspnoea
• 10-25% asymptomatic
• 20% pleuritic chest pain ? most commonly due to spontaneous pneumo
• 15-30% constitutional symptoms
• 5-10% extrapulmonary manifestations (bone, diabetes insipidus)

Examination is often unremarkable with crackles heard in only 10-20% of patients and clubbing being seen rarely. Although classified under interstitial lung disease ? from the pathological lesion it may be more appropriately classified as a bronchiolitis, which would also explain many of the clinical features unusual for ILD.

SPECIAL INVESTIGATIONS

Lung function tests show a characteristically mixed or mild restrictive / obstructive picture with decreased transfer factor. Lab tests are unhelpful: ACE and Eosinophil count are normal.

RADIOLOGICAL FINDINGS

CXR:

1. diffuse reticulonodular opacities superimposed on multiple small cysts ar ring shadows 5-10 mm in diameter with predominance in mid- upper zones, and sparing the costophrenic angles.
2. Changes are not always symmetrical. Lung volumes are preserved or increased ? in contrast to other fibrosing lung disorders.

HRCT chest:

1. thin walled lung cysts (<10mm) , some confluent or with bizarre shapes
2. nodules (1-5mm) some centrilobular and peribronchial
3. upper lobe predominance
4. cavitary nodules
5. fine reticular opacities, ground glass opacities.

HRCT shows no central / peripheral predominance of lesions. Intervening lung parnchyma appears normal in many patients.

HRCT can differentiate pts with nodules only from other diseases causing pulmonary nodules (sarcoid, silicosis, TB, metastasis), by the centrilobular distribution of nodules and sparing of the costophrenic angles. In addition fibrosis can be distinguished from fibrosis due to CFA by the sparing of the lung bases, the presence of normal surrounding lung parenchyma, and the preservation of lung volumes.

DIAGNOSIS

The diagnosis can often be made with a fair degree of accuracy from the clinical picture, and the radiological features in a young smoker. It is usually confirmed by open lung biopsy ? specimen sent for EM, and occasionally by transbrochiole biopsy. Brochiolar lavage is a less invasive method of making the diagnosis. The presence of > 4% LC among total BAL cells (characterised by positive CD1 immunostaining , or the presence of Birbeck granules on EM) is diagnostic. However BAL has a high false negative rate , being positive in only 50% of sufferers.

PROGNOSIS

Death in PLCH is mainly due to terminal respiratory failure and secondly to the development of pulmonary neoplasms. The natural course is variable: 25% undergo complete remission, 50% stabilise, and 25 % undergo progressive deterioration. Mortality is 2-6%.

A survival analysis was performed on 45 patients with pulmonary LCH. A univariante analysis demonstrated diminished survival associated with:

1. older age at diagnosis (26y)
2. lower FEV12/FVC ratio (<0,66)
3. high RV/TLC ratio (>0,33)
4. steroid therapy during follow up

Multivariate analysis showed the FEV1/FVC ratio and age to be of the best prognostic value. Other poor prognostic features include : recurrent pneumothoraces, extensive initial radiological changes, and decreased transfer factor at diagnosis.

Good prognosis was associated with complete cessation of smoking and sparing of the cosphrenic angles. Too few patients underwent HRCT in order for HRCT determinants of survival to be identified.

ASSOCIATED MALIGNANCIES

This is an interesting area with minimal data, but a number of case reports. Malignancy associated with pulmonary LCH appears to occur in a number of different clinical settings, namely:

1. Ca lung assoc. with pulmonary LCH ? probably share a common aetiological agent ie smoking
2. Discovery of lymphoma with the simultaneous discovery of nodal or extranodal LCH
3. Histiocytosis developing following treatment of lymphoma with DXT
4. Malignancy following pulmonary LCH possibly representing malignant transformation.

Malignancy is usually Hodgkin?s disease or malignant histiocytosis.

TREATMENT

The only certain therapy is to stop smoking. Because of the high rate of spontaneous remission and rarity of the disease ? no reliable data concerning the efficacy of various treatment schedules on survival exist. To date steroids, chemotherapy(cyclophosphamide,methotrexate,vinblastine,vincristine,chlorambucil) , combination therapy and allogenic bone marrow transplant have been used. Since it is no longer considered to be a malignancy, the use of aggressive chemo is difficult to justify ,in view of the serious side effects.

Current recommendation for patients with single organ disease is a period of close observation with complete cessation of smoking, with consideration for the introduction of steroids or chemotherapy if progression is evident.

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