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Collagenolytic (necrobiotic) granulomas: part 1--the "blue" granulomas.

A collagenolytic or necrobiotic non-infectious granuloma is one in which a granulomatous infiltrate develops around a central area of altered collagen and elastic fibers. The altered fibers lose their distinct boundaries and exhibit new staining patterns, becoming either more basophilic or eosinophilic. Within the area of altered collagen, there may be deposition of acellular substances such as mucin (blue) or fibrin (red), or there may be neutrophils with nuclear dust (blue), eosinophils (red), or flame figures (red). These color distinctions can be used as a simple algorithm for the diagnosis of collagenolytic granulomas, i.e. "blue" granulomas vs. "red" granulomas. Eight diagnoses are included within these two groupings, which are discussed in this two-part article. In this first part, the clinical presentation, pathogenesis, and histologic features of the "blue" collagenolytic granulomas are discussed. These are the lesions of granuloma annulare, Wegener's granulomatosis, and rheumatoid vasculitis. In the subsequent half of this two-part series, the "red" collagenolytic granulomas will be discussed; these are the lesions of necrobiosis lipoidica, necrobiotic xanthogranuloma, rheumatoid nodules, Churg-Strauss syndrome, and eosinophilic cellulitis (Well's syndrome).

Arthritis, Rheumatoid↗

Collagenolytic (necrobiotic) granulomas: part II--the 'red' granulomas.

A collagenolytic or necrobiotic non-infectious granuloma is one in which a granulomatous infiltrate develops around a central area of altered collagen and elastic fibers. The altered fibers lose their distinct boundaries and exhibit new staining patterns, becoming either more basophilic or eosinophilic. Within the area of altered collagen, there may be deposition of acellular substances such as mucin (blue) or fibrin (red), or there may be neutrophils with nuclear dust (blue), eosinophils (red), or flame figures (red). These color distinctions can be used as a simple algorithm for the diagnosis of collagenolytic granulomas, i.e. 'blue' granulomas vs. 'red' granulomas. Eight diagnoses are included within these two groupings, which are discussed in this two-part article. In the previously published first part, the clinical presentation, pathogenesis and histologic features of the 'blue' collagenolytic granulomas were discussed. These are the lesions of granuloma annulare, Wegener's granulomatosis, and rheumatoid vasculitis. In this second half of the series, the 'red' collagenolytic granulomas are discussed; these are the lesions of necrobiosis lipoidica, necrobiotic xanthogranuloma, rheumatoid nodules, Churg-Strauss syndrome, and eosinophilic cellulitis (Well's Syndrome).

Churg-Strauss Syndrome↗

[Experimental hypersensitivity pneumonitis and enhancement of granuloma formation by low dose irradiation with increased interleukin-1 activity of granuloma in genetically low responder mouse (C3H)].

Possible enhancing effects by low dose total body irradiation on pulmonary granuloma formation induced by intratracheal injection of ovalbumin-coupled beads in low responder C3H mouse were studied. The low dose (3.5 Gy) irradiation increased the size of granuloma in low responder C3H mouse as large as the granuloma formed in high responder C57BL/10 mouse. The resolution of granuloma which usually disappeared within 9 days was also prolonged by the irradiation. Increase in IL-1 activity of lung extracts but not IL-2 activity was parallel to the enhancement of granuloma formation and/or the delayed resolution of granuloma. These results indicated that the radiation-sensitive cells might regulate IL-1 producing cell, possibly macrophages which made pulmonary granuloma.

Alveolitis, Extrinsic Allergic↗

Idiopathic uterine granulomas: report of a series with morphological similarities to idiopathic ovarian cortical granulomas.

Granulomas in the uterine corpus and cervix are rare, with most examples obviously a result of a previous operative or ablative procedure. In this report, we describe 8 cases where granulomas, not associated with a previous procedure, were identified as an incidental finding in the myometrium or cervical stroma. A review of the clinical records revealed no obvious cause for the granulomatous inflammation, and we propose the term "idiopathic uterine granulomas." In all cases, the granulomas, which in most cases were multiple, were well circumscribed and intimately related to thin-walled vascular channels that showed no evidence of vasculitis. This resulted in a characteristic histological appearance similar to that seen with so-called "idiopathic ovarian cortical granulomas." Although local and systemic causes of granulomatous inflammation should be excluded, granulomas in the myometrium and cervical stroma may occur without an obvious underlying cause.

Adult↗

A patient with hepatic granuloma formation and angiotensin-converting enzyme production by granuloma cells during clinical relapse of hepatitis A.

Elevation of the serum angiotensin-converting enzyme (sACE) level and hepatic granulomas were found during a clinical relapse in a 22 year old patient with acute viral hepatitis type A (AVH-A). The serum transaminase level and sACE level remained high for more than 6 months. In the biopsied specimen of the liver, fibrous rings of granulomas composed of collagen types I, III, and V were observed. Furthermore, the localization of ACE was visible in the rough endoplasmic reticulum of epithelioid cells of granulomas in the liver under electron microscopy using the indirect immunoperoxidase method. These results suggest that granuloma cells in the liver caused by hepatitis A may be involved in ACE production. In addition, other diseases associated with the presence of granulomas in the liver, such as lymphoma, cytomegalovirus infection, visceral leishmaniasis, and lupoid hepatitis, were ruled out. However, the hepatic granulomas disappeared with the healing of AVH-A. In this regard, the present case is considered to be one of the very few cases of hepatic sarcoidosis.

Adult↗

[The dynamics of antigen and antibody in Schistosoma japonicum egg granuloma and its relationship with the granuloma response].

Synchronous Schistosoma japonicum egg granuloma in the lung of mouse model and PAP (peroxidas-anti-peroxidase) technique were employed to study the dynamics of antigen and antibody in the egg granuloma of S. japouicum and its relationship with the granuloma formation. The granulomatous response began on the 3.5 day after egg injection and increased to the maximal size at the 4th week. Lymphocyte populations and macrophage comprised an important part of lesions during the time of acute granulomatous response (7-28 day). Using PAP staining, the SEA within egg could be detected at high level on the first day after egg injection and then declined gradually. On the contrary, the SEA around egg was minimal at the first week and increased to the peak at the 4th week, then decreased gradually. No antibody could be detected throughout the experimental period (35 days). The results suggested that 1) the antigen of Schistosoma egg is the essential factor for the granuloma formation. 2) S. japonicum egg granuloma could be formed in unsensitized mouse. 3) The mechanism of egg granuloma formation of S. japonicum is similar to that of S. mansoni.

Animals↗

Cutaneous extravascular necrotizing granuloma (Churg Strauss granuloma).

Churg Strauss granuloma (cutaneous extravascular necrotizing granuloma) is a distinct entity which is associated with systemic immunoreactive or autoimmune diseases in a majority of cases. Typically, Churg Strauss granuloma presents as symmetrical papules or nodules on the extremities. There are two histological patterns: the classic pattern reveals palisading granuloma with central degenerated collagen, interspersed polymorphonuclear leukocytes, and leukocytoclastic debris; the focal basophilic necrosis pattern does not show palisading granuloma. We report two cases of Churg Strauss granuloma with different histopathological patterns.

Adult↗

Granuloma annulare--a genetic disorder that sustain an incomplete foreign-body granuloma reaction.

Granuloma annulare (GA) is a common dermatosis characterized by an annular arrangement of erythematous papules, plaques, rarely nodules or patches. It is a type of non-infectious granuloma with unknown etiology. Hypothesis. The immune reaction always begins with the foreign-body granuloma formation. However, if during the process the antigen is recognized as too small the immune reaction stops the granuloma development. In the case of GA the dysfunctional control mechanism continues to sustain the granulomatous formation. Because the target does not exist anymore, the initiated process starts the "search" for a new target (circular spreading). Different histological and clinical presentations depends on which gene of the control mechanism is dysfunctional, while the distribution depends on the type of antigen and its distribution at the start of the immune reaction. The disappearance of GA after biopsy, that occurs in some cases, could be attributable to the specific defective gene involved (the biopsy can disrupt only some type of GA). So, new therapies for solitary GA formations could be directed to the disruption and creation of a new and healthy immune response from the point of disruption. A comparative analysis of the gene expression of GA and the foreign-body granuloma in the same patient, and GA among different patients could clarify which genes are involved in granulomatous formations. The cells affected by those genetic defects are probably histiocytes and lymphocytes (both always present in GA). Because of some similarity, necrobiosis lipoidica could also be a specific type of GA.

Foreign-Body Reaction↗

The spectrum of primary cutaneous elastolytic granulomas and their distinction from granuloma annulare: a clinicopathological analysis.

AIMS: Actinic granuloma (AG) and annular elastolytic giant cell granuloma (AEGCG) are terms commonly applied to cutaneous lesions characterized by elastolysis, elastophagocytosis and a multinucleated cell infiltrate. The aim of this study was to clarify the relationship of these lesions to granuloma annulare (GA) which they resemble clinically. METHODS AND RESULTS: The clinicopathological data of 20 patients whose biopsies showed the histology of elastolytic granuloma as well as those of previously published cases with identical tissue changes were analysed to assess differences between AG, AEGCG and GA. The tissue changes of AG and AEGCG are identical and differ substantially from GA because of the predominant elastolysis and elastophagocytosis in the absence of necrobiosis and palisading granuloma. Actinic and/or thermal injury could be elicited frequently in the patient's history, but not always. CONCLUSIONS: AG may be considered as an aetiopathological subdivision of AEGCG. Patients with biopsies showing both GA and AEGCG are occasionally encountered. AEGCG is easily differentiated from incidental elastolysis which may be seen in a variety of aetiologically unrelated processes.

Adult↗

Schistosomal granuloma modulation. III. Schistosma haematobium worms accelerate S. mansoni soluble egg antigen-induced hepatic granuloma formation in vivo.

Recurrent experimental evidence indicates that schistosomal egg granuloma formation at least in the murine model results from a host response generated against both egg- and worm-derived antigens. Further experiments aimed at identifying the existence in vivo of cross-sensitization between Schistosoma haematobium worms and S. mansoni-derived egg antigens were performed with respect to S. mansoni egg antigen-induced granuloma formation and fibrogenesis in the liver. Male OF1 mice bisexually infected with S. haematobium or S. mansoni were hepatically challenged (cecal vein injection) with S. mansoni SEA (soluble egg antigen)-coupled Sepharose beads at the end of prepatent infection (8-10 days prior to the start of egg deposition). The mean granuloma volume (MGV) of in-vivo-generated synchronized hepatic granulomas (8 days old) and the fibrotic response were estimated. Just like S. mansoni-infected rodents, mice carrying an S. haematobium infection generated an accelerated hepatic granulomogenesis [respective MGVs 4.72 +/- 0.56 and 5.41 +/- 0.75 x 10(6) microm3; P < 0.0001 versus unsensitized (MGV 3.00 +/- 0.40 x 10(6) microm3) mice] and an enhanced fibrotic response against S. mansoni SEA. They also had significantly enlarged spleens (P < 0.0001) and moderately enlarged livers (P = 0.02) as compared with S. haematobium-infected mice that were not challenged with SEA. From these observations we infer that in vivo, S. haematobium worms can positively modulate S. mansoni egg antigen-induced granuloma formation and hepatic fibrogenesis, resulting in more severe liver pathology.

Animals↗

Granuloma dual RNA-seq reveals composite transcriptional programs driven by neutrophils and necrosis within tuberculous granulomas.

Mycobacterial granulomas lie at the center of tuberculosis (TB) pathogenesis and represent a unique niche where infecting bacteria survive under nutrient-restricted conditions and in the face of a host immune response. The granuloma's necrotic core, where bacteria reside extracellularly in humans, is difficult to assess in many experimentally tractable models. Here, using necrotic mycobacterial granulomas in adult zebrafish, we develop dual RNA sequencing (RNA-seq) across different host genotypes to identify the transcriptional alterations that enable bacteria to survive within this key microenvironment. Using pharmacological and genetic interventions, we find that neutrophils within mature, necrotic granulomas promote bacterial growth, in part through up-regulation of the bacterial devR regulon. We identify conserved suites of bacterial transcriptional programs induced only in the context of this unique necrotic extracellular niche, including bacterial modules related to K+ transport and rpf genes. Analysis of Mycobacterium tuberculosis strains across diverse lineages and human populations suggests that granuloma-specific transcriptional modules are targets for bacterial genetic adaptation in the context of human infection.

Animals↗

Delayed type hypersensitivity granuloma formation around Schistosoma mansoni eggs in vitro. IV. Granuloma formation in human schistosomiasis.

Peripheral blood mononuclear cells, obtained from 42 school-age Egyptian children, were isolated on Ficoll-hypaque density gradients and assayed for granuloma formation. A granuloma index (G.I.) which classified the cellular reactions to Schistosoma mansoni eggs was determined for each patient. Morphologic criteria to assess the cellular reactivity included cell adherence, blast cell transformation, cell migration, and circumoval accumulation of inflammatory cells around the egg. The difference between the mean granuloma index of uninfected controls (G.I. = 1.25 +/- 0.04) and infected patients (G.I. = 1.58 +/- 0.05) was statistically significant (P less than 0.01; Student's t-test). There was no correlation between the granuloma indices and infection intensities determined by quantitative egg counts or between anti-major serological antigen antibody titers. These data demonstrate the feasibility of studying granulomatous hypersensitivity in human schistosomiasis utilizing an in vitro model of granuloma formation and peripheral blood cells.

Adolescent↗

Ultrastructural characteristics of macrophages in dermal leprosy granulomas: macrophages in leprosy granulomas.

The characteristics of the cells of mononuclear phagocyte series (MPS) in the dermal granulomas of tuberculoid and lepromatous leprosy were studied by elereron microscopy. In the tuberculoid granulomas, majority of the cells of MPS (epithelioid cells) showed a distinct appearance. They were seen in close association with a large number of activated lymphocytes. The cells of MPS had a prominent nucleus. Their cytoplasm contained mainly rough endoplasmic reticulum, developed golgi and was free of M. leprae or its products. In contrast, the cells of MPS (macrophages) in lepromatous leprosy had a large nucleus. Their cytoplasm contained mainly whole M. leprae organisms/its phagocytosed products and rough endoplasmic reticulum. There was paucity of lymphocytes in these granulomas. These observations support the view that the cells of MPS in the tuberculoid granulomas may be secretory while those in the lepromatous granulomas were phagocytic.

Granuloma↗

[Palisading granuloma of the penis: a variant of subcutaneous granuloma annulare].

INTRODUCTION: Subcutaneous granuloma annulare on the penis has only been reported exceptionally. OBSERVATION: A 41 year-old man presented with four small, asymptomatic nodules on the glans penis. Histological examination of a biopsy revealed a deep palisading granuloma progressing not only around the alcian-blue necrobiosis areas but also around the smooth muscle fibers. The lesion regressed spontaneously after two years of progression. DISCUSSION: Palisading granuloma of the penis appears to be a most particular clinical form of subcutaneous granuloma annulare. It is characterized by small single or multiple nodules localized on the penis. On histological examination, the granuloma is deep and concentrates around the network of smooth muscle fibers of dartoic origin.

Adult↗

[Experimental epithelioid cell granuloma formation in Lewis rats induced by injection of cell wall fragments derived from alpha-streptococcus--etiologic relationship between bacterial cell wall and sarcoid granuloma].

We observed the presence of epithelioid granulomas in follicles near lacunae in the tonsils from patients with active sarcoidosis. Bacteria isolated in these tissues were mostly alpha-streptococci. The present study was undertaken to determine whether alpha-streptococcus can induce granuloma formation. Streptococcal cell wall (SCW) fragments were injected into the foot pads of female Lewis rats. Epithelioid granulomas were abundantly formed in popliteal lymph nodes when SCW aqueous suspension was injected four times. SCW antigens were detected in macrophages in the granuloma but not in epithelioid cells, by immunoperoxidase method. These findings suggest that macrophages transform into epithelioid cells after phagocytosis and digestion of SCW, and that components of bacterial cell wall such as SCW may induce the granuloma formation in sarcoidosis.

Adult↗

The Churg-Strauss granuloma: cutaneous, necrotizing, palisading granuloma in vasculitis syndromes.

The cutaneous, necrotizing, palisading granuloma (Churg-Strauss granuloma) was observed on histopathologic study of skin specimens from seven patients. Two patients had Wegener's granulomatosis and one patient each had allergic granulomatosis, limited Wegener's granulomatosis, bacterial endocarditis, systemic lupus erythematosus, and rheumatoid arthritis. The microscopic picture consists of extravascular, palisading, dermal granuloma. The center of the granuloma consists of basophilic fibrillar necrosis in which linear bands of destroyed tissue are interspersed with masses of polymorphonuclear leukocytes and leukocytoclastic debris. This necrotic leukocytic mass is surrounded by histiocytes and some lymphocytes. The clinical lesions are symmetric, erythematous papules or nodules on the extremities. The histopathologic picture of the Churg-Strauss granuloma is unique and, as demonstrated in these cases, indicates the presence of systemic vasculitis.

Granulomatosis with Polyangiitis↗

Cutaneous extravascular necrotizing granuloma (Winkelmann granuloma): confirmation of the association with systemic disease.

BACKGROUND: An unusual palisading granuloma has been described in patients with immunoreactive diseases. Multiple names have been given to this lesion. OBJECTIVE: Our aim was to verify whether a distinct palisading granuloma can be used as a marker for systemic disease. We also propose unifying nomenclature. METHODS: Thirty-four biopsy specimens from 22 patients were selected for study on the basis of histologic criteria. The medical histories of these patients were subsequently reviewed for clinical information. RESULTS: At least 21 of the 22 patients with cutaneous extravascular necrotizing granuloma had evidence of an underlying immunoreactive systemic illness. In each, the systemic disease preceded or was diagnosed concurrently with the cutaneous lesions. CONCLUSION: The cutaneous extravascular necrotizing granuloma has unique clinical and histologic features. In a great majority of cases, a systemic immunoreactive disease is present.

Adult↗

Aspiration cytology of malignant neoplasms associated with granulomas and granuloma-like features: diagnostic dilemmas.

BACKGROUND: Malignant lymphomas and solid tumors that mimic or are associated with epithelioid granulomas are widely recognized in surgical pathology, but have received little attention in the cytopathology literature. In this study the authors present their experience with six such cases in which the presence of granulomas or granuloma-like features posed a diagnostic difficulty on fine-needle aspiration cytology (FNAC). METHODS: Clinical data, FNAC, and follow-up surgical specimens from six patients presenting with neck masses were reviewed. RESULTS: Only one case was diagnosed confidently as metastatic squamous cell carcinoma with an extensive granulomatous response; the other five were interpreted as "atypical" with descriptive cytology and a differential diagnoses including granulomatous inflammation, in addition to a caveat of "cannot exclude malignancy." Biopsy studies in these cases were recommended in view of the atypical cytologic findings and strong clinical suspicion of malignancy in each case. The histologic findings in two cases revealed Hodgkin's disease with exuberant granulomatous response. The remaining three cases were found to be malignant neoplasms with epithelioid morphologic features and included one example each of diffuse large cell lymphoma, anaplastic carcinoma of the thyroid, and lymphoepithelial carcinoma. CONCLUSIONS: Malignancies associated with granulomas and tumor cells mimicking epithelioid histiocytes may be difficult to diagnose accurately on FNAC. The cytologic differential diagnosis of a "granulomatous" process should include malignant neoplasms. Excisional biopsy studies may be required for definitive diagnosis.

Adult↗