Sarcoidosis Granulomas Research Articles

Normolipemic papular xanthomatosis in erythrodermic atopic dermatitis

We describe papular xanthomatosis that progressively developed in a patient with long-standing erythrodermic atopic dermatitis and normal lipid metabolism and without an associated systemic disease. Light microscopy showed a lobulated aggregate of sometimes foamy histiocytes. Ultrastructurally, these histiocytes contained lipid inclusions and lacked features of Langerhans or epithelioid cells. Other granulomatous skin diseases such as tuberculosis, sarcoidosis, or foreign body granuloma were excluded by histologic study, polarizing microscopic examination, electron microscopy, and microbiologic investigations. Nevertheless, these xanthomas showed an antigen expression pattern similar to that found in noninfectious granulomas (CD1a −, MS-1 −, CD11c +, MRP-8 -14 + , 25F9 +, RM 3 1 ± , CD36 (+)), indicating that normolipemic papular xanthomatosis may be a reactive process and should not be included among the true cutaneous non-Langerhans cell histiocytoses.

Predominant Myocardial Sarcoidosis

Unexpected autopsy findings of a predominantly myocardial sarcoidosis are reported. For a period of two years prior to death, the 42-year-old man suffered from atypical angina pectoris and ventricular arrythmias with episodic ventricular fibrillation. Echocardiography revealed a non-obstructive hypertrophic cardiomyopathia. He succumbed to sudden cardiac arrest. Sarcoidosis granulomas were widespread in the ventricular and atrial myocardium with intensive involvement of the sinus node, atrioventricular node, and the main bundle of His. According to a review of the previous literature on this subject, an obviously deleterious obstructive granulomatous angiitis of the sinus node's central artery was found for the first time.

Immunohistochemical localization of transforming growth factor-beta 1 in the nonnecrotizing granulomas of pulmonary sarcoidosis.

Sarcoidosis is a chronic inflammatory disease of unknown cause characterized by the formation of nonnecrotizing granulomas in affected tissues, most notably the lungs. Granuloma healing may result in pulmonary fibrosis and respiratory impairment in some patients. Transforming growth factor-beta 1 (TGF-beta 1) is a potent cytokine that promotes fibrosis by enhancing the synthesis of extracellular matrix components, including fibronectin and the alpha 5 beta 1 fibronectin receptor. The role of TGF-beta 1 in promoting lung fibrosis in the setting of pulmonary sarcoidosis has not yet been investigated. Accordingly, we determined the extent and distribution of TGF-beta 1 in lung tissue obtained from seven patients with clinical and histologic features of pulmonary sarcoidosis. The tissue distributions of TGF-beta 1, the TGF-beta 1 binding proteoglycan decorin, fibronectin, and the alpha 5 beta 1 fibronectin receptor were assessed immunohistochemically. In all cases, the epithelioid histiocytes comprising nonnecrotizing granulomas of pulmonary sarcoidosis contained abundant TGF-beta 1. We further demonstrated decorin, fibronectin, and the alpha 5 beta 1 fibronectin receptor within nonnecrotizing granulomas and in the fibrous tissue surrounding the lesions. TGF-beta 1 staining was also observed in bronchiolar epithelial cells, hyperplastic Type II pneumocytes, and occasional alveolar macrophages. This study demonstrates enhanced tissue localization of TGF-beta 1 and related extracellular matrix proteins associated with the nonnecrotizing granulomas of pulmonary sarcoidosis. Through its actions on matrix protein synthesis, TGF-beta 1 may modulate the fibrotic repair process accompanying granuloma healing in sarcoidosis.

Sarcoid neuropathy

In a case of subacute sensory and motor polyneuropathy associated with sarcoidosis, multiple epineurial and endoneurial granulomas were demonstrated in a sural nerve. Neighbouring nerve fibres were displaced by the granulomas and some were undergoing axonal degeneration. Ultrastructural and teased fibre studies showed axonal atrophy and degeneration with secondary demyelination. Histochemical studies indicated the presence of HLA-DR antigen on epithelioid cells in the granulomas. A non-specific inflammatory process in the nerve does not cause significant primary demyelination.

Germ Cell Tumors Masquerading as Central Nervous System Sarcoidosis

The diagnosis of central nervous system sarcoidosis is uncertain without typical multisystem involvement. We describe two patients with isolated central nervous system mass lesions whose biopsy results were consistent with sarcoidosis. After a progressive clinical course, they were found to have diencephalic germinomas. Germ cell tumors, in particular, should be considered in the differential diagnosis of central nervous system sarcoidosis as they are potentially treatable, occur in intracranial locations favored by sarcoidosis mass lesions, and may be surrounded by granulomatous inflammation that can be mistaken for the noncaseating granulomas of sarcoidosis.

Histological examination of granulomas in sarcoidosis and miliary tuberculosis

Histological examination of granulomas in sarcoidosis and miliary tuberculosis

Chronic lung diseases: specific diagnosis by using CT.

We evaluated patterns of abnormal lung parenchyma on CT scans in six specific chronic lung diseases and then applied those findings in the differential diagnosis of these lung parenchymal patterns in 56 subjects. There were 48 patients with chronic lung diseases (43 with histologic proof) consisting of usual interstitial pneumonia (n = 20), sarcoidosis (n = 16), lymphangitic carcinomatosis (n = 7), lymphangioleiomyomatosis (n = 2), drug toxicity (n = 2), and eosinophilic granuloma (n = 1). Including eight CT scans of normal control subjects, 56 CT scans were assessed independently by two readers (R1 and R2). Chest radiographs, most of which were obtained within 1 week of CT examination, were available in 48 of the 56 subjects. CT scans were evaluated for specific parenchymal features including disease distribution, lung distortion, thickening of bronchovascular bundles and polygon walls, bronchiectasis, cysts, and nodules, to determine the association of each abnormal feature with the different diseases. Diagnosis was then made from the overall CT appearance of the lungs and, on a separate occasion, from the appearance of the chest radiograph. The correct diagnosis was made from the CT appearance in 54 of 56 patients (R1) and in 50 of 56 patients (R2). Correct diagnoses were made from the chest radiographs in 42 of 48 patients (R1) and 43 of 48 patients (R2). We have identified features that are reproducible and useful when describing CT scans of patients with chronic lung diseases. Interpretation of the appearance of the lung on CT scans was accurate in diagnosing usual interstitial pneumonia, sarcoidosis, and lymphangitic carcinomatosis.

Changes in phospholipids in bronchoalveolar lavage fluid of patients with interstitial lung diseases.

We analyzed phospholipids of human bronchoalveolar lavage (BAL) fluids from patients with interstitial lung diseases; idiopathic pulmonary fibrosis (IPF), sarcoidosis, and eosinophilic granuloma (EG) and compared them to those of normal subjects. The content of phospholipid/ml of BAL fluid was significantly decreased in IPF. There was a significant decrease in phosphatidylglycerol (PG) and an increase in phosphatidylinositol (PI) in IPF but not in sarcoidosis and EG. Thus, the PG to PI ratio was significantly decreased in IPF. The dipalmitoyl species of phosphatidylcholine (PC) was found to be significantly decreased in IPF and sarcoidosis by molecular species analysis using high performance liquid chromatography. In contrast, the unsaturated species were increased in these diseases. The decrease in dipalmitoyl PC appeared to be a common feature in interstitial lung diseases. The changes in phospholipids in BAL fluids, especially decreases in DPPC and PG to PI ratio in IPF, appear to indicate that damage of alveolar Type II cells and/or of metabolic disturbance in pulmonary surfactant occurs in IPF.

Calcium oxalate in sarcoid granulomas. With particular reference to the small ovoid body and a note on the finding of dolomite.

The nature, prevalence, and specificity of birefringent calcific particles in granulomas of sarcoidosis have been examined, including histochemical reactions, single particle, and microchemical analyses. Particular attention was paid to small ovoid forms of which most were calcium oxalate monohydrate. Larger crystals, those within giant cells, and the birefringent component of a Schaumann complex were also calcium oxalate. Small ovoids appeared to originate in macrophages and to be precursors of other forms; they were found in 86% of lymph nodes and 73% of surgical lung specimens. They were not specific for sarcoidosis. Organisms could not be certainly identified in them. Their origin is discussed in relation to activated macrophages, calcium, and oxalate metabolism, and the role of calcium oxalate in granulomas is considered. Four particles from two cases were dolomite and two were a calcium-sulphur compound. The biologic origin of dolomite is reviewed.

Suppression associated lymphocyte markers in lesions of sarcoidosis.

The presence within the epithelioid granulomas of sarcoidosis of lymphocytes of the "helper" (T4 positive) phenotype suggests that, as in granulomatous diseases of known aetiology, active cell mediated immunity plays a part in the disease. It has, however, been noted that T8 positive lymphocytes are also found on occasion in the granulomas. The presence of cells bearing markers associated with suppressor activity in various lesions of sarcoidosis has been investigated with a range of monoclonal antibodies. T4 positive cells were present in all granulomas; T8 positive lymphocytes were present within the epithelioid cell areas in proportions that varied from 5 to 55/100 of T4 cells. Other lymphocyte markers associated with suppression (Leu8 and SN130) were very rare on lymphocytes within granulomas but common on both T4 positive and T8 positive lymphocytes in the perigranulomatous mantle, which suggests that expression of these markers was down regulated in the granuloma or that cells bearing them are unable to migrate into the granuloma. Nevertheless, suppressor cell mechanisms could mediate the spontaneous resolution of most cases of sarcoidosis, and the presence or absence of cells bearing suppression associated phenotypes in the granuloma or its mantle may have prognostic importance.

Cadmium-chloride-induced air-space enlargement with interstitial pulmonary fibrosis is not associated with destruction of lung elastin. Implications for the pathogenesis of human emphysema.

To determine whether lung elastin is lost during the evolution of cadmium-induced air-space enlargement with pulmonary fibrosis, the lung elastin of 5- to 7-day-old golden Syrian hamster pups was radiolabeled by giving [3H]valine. At maturity, a single intratracheal instillation of 0.5 ml of 0.025% CdCl2 solution was given. Lung mechanics, histologic examination, and biochemistry were studied 5, 10, 21, 42, 105, and 180 days after the cadmium treatment. The animals developed fibrosis and air-space enlargement with decreased lung volumes, compliance, and forced expiratory flow; their functional residual capacity was increased. The total lung collagen and total lung elastin were increased, but there was no loss of radiolabel in lung elastin. We conclude that CdCl2-induced air-space enlargement with pulmonary fibrosis is not accompanied by loss of neonatally formed lung elastic fibers. We hypothesize that air-space enlargement with fibrosis represents a stereotyped response of the lung to fibrosing injuries, which we hypothesize is due to forces from more fibrotic and atelectatic areas causing overdistension of less abnormal air spaces. The air-space enlargement of fibrosing human diseases such as sarcoidosis and eosinophilic granuloma may have a similar basis. Evidence is reviewed that human centrilobular emphysema may be a form of focal air-space enlargement with interstitial fibrosis; there may be mechanisms in addition to elastase-antielastase imbalance that cause human emphysema.

Localization of angiotensin converting enzyme (ACE) in granulomas of sarcoidosis cutaneous lesions.

AbstractUsing an immunofluorescent technique, the localization of angiotensin converting enzyme (ACE) was investigated in granuloma lesions from the skin of three sarcoidosis cases. Specific fluorescence was observed in epithelioid cells in the sarcoidosis granulomas examined. However, it was not found in any other granulomatous diseases observed as controls, which included granuloma annulare, foreign body granuloma and lupus miliaris disseminatus faciei. These results indicate that ACE is specifically localized in the epithelioid cells in cutaneous granuloma lesions of sarcoidosis; in one case, it was also observed in Langhans giant cells. Therefore, it is suggested that examination for ACE in cutaneous lesions using an immunofluorescent technique is very useful for the diagnosis of sarcoidosis in the skin. We suggest that epithelioid cells of granulomas in sarcoidosis cutaneous lesions may play an important role in the increase of serum ACE activity.

Granulomatous pancreatitis--granulomas in chronic pancreatitis.

Granulomatous pancreatitis can be described only in infectious granulomas and pancreatic involvement by systemic granulomatosis. The presence of classical chronic tryptic pancreatitis in addition to individual sarcoidosis granulomas in one of our cases of sarcoidosis, shows that pancreatitis in a patient with generalized granulomatosis should not necessarily be considered granulomatous pancreatitis. A variety of foreign-body granulomas found in the pancreas may be explained by previous surgical operations, and other foreign bodies introducted iatrogenically. Occasionally, the pancreas in chronic pancreatitis contains granulomas that must be considered foreign body granulomas, although the causal foreign body cannot be identified. We believe that we can identify inspissated secretion that has passed out of the ductal system into the interstitium as the foreign body responsible. It is not possible to establish whether such iatrogenic measures as manipulations of the duct with back-up of the secretion within the ductal system, has any causative involvement in this secretion oedema. However, the absorption of the individual parenchymal secretions is impaired to such a degree that any extravasated remain "in situ" for a lengthy period. The absorption of the aqueous constituents leads to inspissation, so that it can finally be absorbed only through the formation of foreign body granulomas. The same granulogenic property in highly scarred pancreatic parenchyma is also recognizable in the abnormal degradation mode of normally absorbable Ethibloc, and in the excessive arterial and periarterial reactions following angiography. The presence of granulomas within the parenchyma of the pancreas in chronic pancreatitis, many of which have been induced by endogenous and/or exogenous foreign bodies would not lead us to refer to a granulomatous pancreatitis, since the remaining sections of the parenchyma manifest typical necroses and scar foci of chronic pancreatitis. We would characterize these granulomas by the term "granulomas in chronic pancreatitis", and differentiate this from granulomatous pancreatitis.

Diagnosis of sarcoidosis

There is no single specific test available for the clinician to diagnose sarcoidosis with certainty. Alternatively, the diagnosis, in the majority of cases, is not problematic and depends upon identifying typical pathologic features in combination with a compatible clinical presentation. A histologic diagnosis alone is unsatisfactory since the noncaseating granulomas of sarcoidosis are identical to those found in other disease states including berylliosis, hypersensitivity pneumonitis, the noncaseating granulomas of tuberculosis and the fungal diseases, in lymph nodes adjacent to some malignancies, and in lymph nodes draining inflammatory sites (such as in Crohn's disease). Even in the more obvious cases of sarcoidosis, it is important to examine tissue for acid-fast and fungal organisms. Primary tuberculosis, coccidiodomycosis, or histoplasmosis may occasionally mimic sarcoidosis presenting with bilateral hilar adenopathy, pulmonary infiltrates, and erythema nodosum.

Immunohistochemical study of lysozyme in lupus miliaris disseminatus faciei.

The lysozyme activity in tissue samples from patients with lupus miliaris disseminatus faciei (LMDF), sarcoidosis and foreign body granuloma was investigated using the immunoperoxidase technique. The majority of epithelioid cells and giant cells in LMDF and sarcoidosis showed strong lysozyme staining in their cytoplasm. However, most macrophages and giant cells in foreign body granulomas, including granulomatous reactions to epidermal cysts and other foreign materials, stained weakly for lysozyme or were negative. These results suggest that LMDF is different from the foreign body reaction to inert substances, and may be induced by an immunological mechanism associated with cell-mediated immunity.

In vitro formation of macrophage-epithelioid cells and multinucleated giant cells by 1 alpha,25-dihydroxyvitamin D3 from human circulating monocytes.

1 alpha,25-Dihydroxyvitamin D3, the active form of vitamin D3, induced maturation of circulating monocytes to form macrophage-epithelioid cells and multinucleated giant cells in vitro. Calcitriol not only promoted the differentiation of monocytes, as shown by the marked morphological changes and enhanced secretion of lysozyme, but also induced their prominent proliferation, as exhibited by enhanced DNA synthesis and the increased number of monocyte cell nuclei. The proliferation of monocytes was observed after the addition of physiological concentrations of calcitriol. Multinucleated giant cells were frequently observed among the monocytes. These marked morphological changes and the proliferation of monocytes were not observed in control cultures, which did not include calcitriol. These results indicate that calcitriol plays a critical role in the formation of the sarcoid granuloma and give an explanation of some of the clinical findings on sarcoidosis. In view of the evidence that sarcoid macrophages convert 25(OH)D3 to calcitriol, our results raise the possibility that the active metabolite of vitamin D3, which may be produced by macrophage-epithelioid cells, induces the differentiation and proliferation of circulating monocytes into macrophage-epithelioid cells, which in turn form sarcoidosis granulomas. This autostimulation mechanism of sarcoid granuloma formation may provide a model for future studies.

Transepithelial elimination of granulomas in cutaneous tuberculosis and sarcoidosis

Transepithelial elimination of granulomas was observed in histologic specimens taken from involved skin of a patient with disseminated tuberculosis and two patients with sarcoidosis. This phenomenon, previously also observed in other granulomatous disorders, represents one of the skin's several mechanisms to rid itself of endogenous or exogenous waste material.

T-zone histiocytes in granulomatous skin diseases.

We investigated the distribution of T-zone histiocytes by immunohistochemical demonstration of S-100 protein in granulomatous skin diseases (granuloma annulare, 8 cases; necrobiosis lipoidica, rheumatoid nodule, sarcoidosis, lupus vulgaris, and foreign-body granuloma; 5 cases each). T-zone histiocytes were regularly found in the lymphohistiocytic mantle, but also occasionally between epitheloid cells. Our results show that, besides the monocyte-macrophage system, T-zone histiocytes consistently contribute to the formation of cutaneous granulomas. These findings may indicate a role of delayed-type hypersensitivity.

A quantitative histomorphologic analysis of lymph node granulomas in Sarcoidosis in relation to radiological stage I and II.

In a detailed study of granulomas in lymph nodes of 19 patients with Sarcoidosis we assessed and correlated a number of features, with size, development and radiographic staging of the disease. Except with the epithelioid cells the number of constituent cells (lymphocytes, giant cells and polymorphs), size, confluency and degree of necrosis of the granulomas were found to be very variable within a single gland. This indicates that the granulomas are in different stages of activity at a given time. All the features studied showed little or no correlation with the radiographic staging, which suggests that the latter is not a good index of the extent of the disease.

Ultrastructural demonstration of Fc gamma-receptors in sarcoid skin lesions.

Immune complexes of horseradish peroxidase oxidase (HRP) and rabbit IgG antibodies to HRP were used to study the Fc gamma-receptors in granulomas of cutaneous sarcoidosis. Cryostat sections of skin biopsies were incubated with HRP-anti-HRP, and the peroxidase activity was demonstrated with 3,3-diaminobenzidine tetrahydrochloride and H2O2. Most cells in the granulomas, both epithelioid and giant cells, were stained. By electron microscopy, the reaction products were localized to the plasma membranes of the cells as well-defined granular deposits. No reaction product was demonstrated intra- or extracellularly.