The effects of leukemic infiltrates in various organs in chronic lymphocytic leukemia

Although the presence of leukemic infiltrate in isolated organs of patients with chronic lymphocytic leukemia has been reported, the effects of leukemic infiltration into various organs of such patients have never been comprehensively studied. To determine the effects of leukemic infiltration we reviewed the histologic sections of multiple organs in 47 cases of chronic lymphocytic leukemia at the University of Maryland Hospital. The leukemic infiltrates were seen in spleen (100 per cent), lymph nodes (100 per cent), liver (98 per cent), kidney (90 per cent), adrenal (71 per cent), heart (64 per cent), and pancreas (37 per cent). After exclusion of the known causes of fibrosis in these organs, the association of fibrosis with leukemic infiltration was as follows: liver (44 per cent), kidney (89 per cent), heart (44 per cent), pancreas (60 per cent), and adrenal (3 per cent). The heart showed endocardial, myocardial, and epicardial infiltrates associated with fibrosis, with severe endocardial fibroelastosis in one case. The liver showed expansion of the portal tracts, bridging infiltration, bridging fibrosis, and cirrhosis with pseudolobule formation.In patients whose livers showed bridging fibrosis or pseudolobule formation, the mean duration of chronic lymphocytic leukemia was 4,4 years, compared to 2.6 years in those showing no significant fibrosis, suggesting that the degree of infiltration and fibrosis was positively correlated with the duration of leukemia. The kidney showed interstitial and periglomerular fibrosis and tubular atrophy only in areas of leukemic infiltration, whereas no fibrosis or atrophy was observed in noninfiltrated areas. The renal lesions closely resembled the chronic inflammatory conditions of the kidney. In foci of leukemic infiltration the pancreas showed parenchymal destruction and fibrous scars, thereby resembling chronic pancreatitis. The adrenals showed replacement of medullary cells by dense leukemic infiltrates, and fibrosis was observed in one case. A strong association between fibrosis and the lymphocytic infiltration of chronic lymphocytic leukemia in various organs has been demonstrated. We therefore suggest that chronic lymphocytic leukemia may cause significant tissue destruction. Further studies are needed in this area.     

Uncommon type of meningiomas with conspicuous plasmo-lymphocytic infiltration. An immunohistochemical and histochemical study

Two cases of meningioma revealing conspicuous plasmo-lymphocytic tissue and hyalinized fibrous tissue components are reported. Histopathological examination of the plasmo-lymphocytic infiltration was performed. Both lesions showed polyclonality of plasma cells as revealed by positive reactions for IgG and paraimmunoglobulin kappa- and lambda-light chains, and amyloid infiltration into the fibrous stroma and blood vessel walls. The histochemical and immunohistochemical characteristics of the lesion in relation to its etiology are briefly discussed.     

The association between chronic lymphocytic thyroiditis and thyroid tumors

An association between lymphocytic thyroiditis and thyroid papillary carcinoma is still controversial. To assess the relationship, a histopathologic analysis of surgically resected thyroid tumors together with the frequency and severity of chronic lymphocytic infiltration of the thyroid among patients with follicular adenoma, follicular carcinoma, and papillary carcinoma was performed. The prevalence of lymphocytic infiltrate, which is indicative of autoimmune thyroiditis, was significantly higher in patients with papillary carcinoma (58%) than in patients with follicular carcinoma (20%) or follicular adenoma (14%). The lymphocytic infiltration within the tumor compared with the severity of thyroiditis in the nontumorous tissue. Therefore, the association between chronic lymphocytic thyroiditis and papillary carcinoma was confirmed. The possibility that an immunologic mechanism involved in the pathogenesis of papillary carcinoma stimulates lymphocytic infiltration in the thyroid tissue through an autoimmune mechanism is suggested.     

Multiple Pulmonary Hyalinizing Granulomas Associated with Systemic Idiopathic Fibrosis

A 41 year-old man with progressive nodular infiltration of the lung of about 2 years'duration died of cardiac and respiratory failure. Autopsy revealed bilateral multiple pulmonary hyalinizing granulomas (PHGs) diagnosed on the basis of the characteristic dense hyaline collagen bundles with nonspecific inflammatory infiltration. Constrictive pericarditis, retroperitoneal fibrosis, mediastinal fibrosis, fibrous thickening of the peritoneal and pleural surfaces, and fibrosis of soft tissue of the neck, flank, and hepatic hilar region were present, therefore, a diagnosis of systemic idiopathic fibrosis was made. The patient had anti thyroglobulin and anti-thyroid microsomal antibodies and lymphocytic thyroiditis. The inflammatory process of PHG of the present case was active and the clinical course was progressive. PHG seems to be a lesion belonging to the systemic idiopathic fibrosis complex. Immunologic abnormalities may be related to PHG and systemic idiopathic fibrosis.     

Multiple pulmonary hyalinizing granulomas associated with systemic idiopathic fibrosis.

A 41-year-old man with progressive nodular infiltration of the lung of about 2 years' duration died of cardiac and respiratory failure. Autopsy revealed bilateral multiple pulmonary hyalinizing granulomas (PHGs) diagnosed on the basis of the characteristic dense hyaline collagen bundles with nonspecific inflammatory infiltration. Constrictive pericarditis, retroperitoneal fibrosis, mediastinal fibrosis, fibrous thickening of the peritoneal and pleural surfaces, and fibrosis of soft tissue of the neck, flank, and hepatic hilar region were present, therefore, a diagnosis of systemic idiopathic fibrosis was made. The patient had anti-thyroglobulin and anti-thyroid microsomal antibodies and lymphocytic thyroiditis. The inflammatory process of PHG of the present case was active and the clinical course was progressive. PHG seems to be a lesion belonging to the systemic idiopathic fibrosis complex. Immunologic abnormalities may be related to PHG and systemic idiopathic fibrosis.     

HLA class II antigen expression and the autoimmune thyroid response in patients with benign and malignant thyroid tumors

To further understand the relationship between the immune system and the neoplastic human thyroid cell we investigated the degree of intrathyroidal lymphocytic infiltration and thyroid HLA class II expression in 17 patients with thyroid tumors. In another 60 thyroid tumor patients the association of thyroidal lymphocytic infiltration with thyroid autoantibody production was analyzed. In total 117 thyroid tissues were examined including tissue obtained at autopsy (n = 28), fetal thyroid tissue (n = 4), thyroid samples obtained from areas distant from benign follicular adenomas (n = 5), and 80 abnormal thyroids including patients with benign (n = 53) or malignant (n = 24) thyroid tumors and Hashimoto's thyroiditis (n = 3). Normal adult and fetal thyroid tissue had no significant lymphocytic infiltration and no detectable HLA-DR, -DP, or -DQ antigens on their thyroid follicular epithelial cells. The degree of lymphocytic infiltration in the nonneoplastic thyroid tissue of thyroid glands with benign and malignant thyroid tumors varied considerably and correlated with the presence and titer of serum thyroid autoantibodies measured by sensitive ELISA techniques. However, all but one of the benign follicular adenomas had thyroid cells negative for HLA class II determinants despite the presence of infiltrating lymphocytes, while 7 of 10 thyroid carcinomas expressed class II antigen (principally HLA-DR) even when only minor degrees of lymphocytic infiltration were present. These data indicate a correlation between lymphocytic infiltrates and serum thyroid autoantibody titers but the relationship with HLA class II expression is more complex. Since we have previously shown that HLA class II antigen expression can be induced by local interferon-gamma secretion, presumably from activated T cells, we conclude that estimates of simple thyroid lymphocytic infiltration and serum autoantibody secretion do not correlate with the degree of intrathyroidal T-cell activation. Furthermore, our observation of increased expression of HLA class II antigens in thyroid cancer suggests considerable cellular heterogeneity in susceptibility to HLA class II antigen induction in human thyroid disease.     

Lymphocytic infiltration and HLA-DR expression of salivary glands in bone marrow transplant recipients: a prospective study.

Lymphocytic infiltration and epithelial HLA-DR expression of lip salivary glands were studied by means of an immunohistoenzymatic staining technique in patients undergoing repeated lip salivary gland biopsies before, and 12, 26, 52 and 104 weeks after bone marrow transplantation (BMT). Within 12 weeks of transplantation, lymphocytes, mainly of the anti-Leu3a+ T ''helper'' phenotype, were seen infiltrating the salivary glands of all the patients, reaching a maximum between 26 and 52 weeks. Epithelial HLA-DR expression, present at the 12th week after BMT, was seen close to the lymphocytic infiltrates in all the specimens. Two years after BMT, lymphocytic infiltrates and epithelial HLA-DR expression were still noted in about half of the specimens but not seen in the remaining ones. No correlations were found between immunohistopathology and earlier or persistent chronic graft-versus-host disease or immunosuppressive treatment. The significance of the findings as well as their resemblance to idiopathic connective tissue diseases, notably Sjögren''s syndrome, are discussed.     

Lymphocytic infiltration and survival in rectal cancer.

Lymphocytic infiltration was assessed semiquantitatively in 447 specimens of rectal cancer. Corrected five year survivals for pronounced, moderate, and little lymphocytic infiltration were 92%, 65% and 36%, respectively. Grading was shown to be reproducible in an intraobserver study (observed agreement 81%, expected agreement 34%, kappa coefficient 0.72). In the multivariate survival analysis of grade and stage related variables lymphocytic infiltration was the only grade related variable to be accepted within the prognostic model. This model also included the number of lymph node metastases and the extent of tumour spread. It is suggested that the conservation of the normal interactive traffic between epithelium and mucosa associated lymphoid tissue (MALT) signals a low grade growth. This is supported by the association between lymphocytic infiltration and the expression of secretory component by malignant epithelium.     

Mobile Encapsulated Bodies Comprising Fat Necrosis and Fibrous Tissue in the Abdominal Cavity of Cows

The microscopical features of 18 samples of fat necrosis and/or fibrous tissue removed from the abdominal cavity during laparotomy from 15 cows were studied. The nodular, ivory-coloured mobile structures were free-floating in the abdominal cavity, were not attached to any abdominal tissues or organs, and were completely surrounded by a fibrous capsule. Abdominal fat necrosis (bovine lipomatosis) was not observed in any animal. The structures comprised either necrotic fat, fibrous tissue or varying proportions of both. Focal calcification and mild inflammatory cell infiltration and accumulations of haemosiderin were also present. Microscopically, the lesions resembled encapsulated fat necrosis occurring in human subcutaneous tissue. The mechanisms of development of these mobile encapsulated bodies in cows is unknown and it is not clear how, in the absence of a blood supply, there can be inflammatory cell infiltration, calcification and proliferation of fibroblasts.     

Age-related fibromuscular dysplasia in the human left ventricle papillary muscles arteries

We describe histologically cases of patients between 31 and 60 years of age who had fibromuscular dysplasia (FMD) in the tunica media (TM) of the left ventricle papillary muscles (PM) arteries. We also compared them with our previous findings in subjects younger than 30 years of age. We examined histologically samples taken from the tip of the anterior PM of the left ventricle in 200 healthy male hearts. In 33 cases (16.5 %), FMD was in the TM. We divided these cases into three subgroups (A, B, C) based on the degree of replacement of smooth muscle cells by fibrous tissue, and thus identified 17, 11 and 5 cases, respectively. Until the age of 41, the typical lesions were often localized within the TM. Beyond that age, the fibrous tissue increased in the TM wall and in the surrounding area of the vessels, causing dysfunction of the PM. Degenerative lesions, as well as inflammatory infiltration, were found after the age of 53. The findings of this study will be useful to cardiologists and cardiac surgeons, in pointing out that, after the age of 44 years old, some PM and their supporting valves may present a degree of dysfunction.     

Distribution of CD45RA and CD45RO T-lymphocyte subsets in rheumatoid arthritis synovial tissue

We have characterized the lymphocytes in the synovium of patients with rheumatoid arthritis (RA) by immunohistochemistry using monoclonal antibodies directed against B lymphocytes, T lymphocytes, and antibodies directed against CD45RA and CD45RO, which define T-cell subsets. Both CD45RA+ and CD45RO+ T lymphocytes were detected in the perivascular regions. CD45RA+ lymphocytes were present primarily in perivascular areas of moderate to large lymphocytic infiltration. Some synovial perivascular lymphocytic aggregates were organized into focal areas of CD45RA+ B lymphocytes surrounded by CD45RO+ T lymphocytes. In areas of diffuse lymphocytic infiltration, the T lymphocytes were CD45RO+. These data suggest that both CD45RO+ and CD45RA+ T lymphocytes enter the RA synovial tissue via the synovial vasculature and that, once in the tissue, the CD45RA+ T lymphocytes may undergo activation/maturation and acquire the CD45RO phenotype.     

Fibrous connective tissue between Müller's muscle and the palpebral conjunctiva as a reinforcement structure and a natural barrier for the upper eyelid

This study was performed to illustrate and discuss the significance of fibrous connective tissue between the Müller's muscle and the palpebral conjunctiva. Nine upper eyelids of 6 Oriental cadavers were microscopically examined; ages at death ranged from 72 to 91 years. Tissue of the posterior lamella of the upper eyelid was removed without the orbital septum and orbital fat. Removed eyelids were incised perpendicularly at the center of the eyelid. After pretreatment, sliced sections were stained with Hematoxylin and Eosin and examined microscopically. A thick fibrous connective tissue was found to exist between the Müller's muscle and the palpebral conjunctiva. The connective tissue continued proximally to the intermuscular transverse ligament and was distally attached to the posterior site of the upper aspect of the tarsus. All cases showed infiltration of lymphocytes from the conjunctiva; however, these were completely blocked by the fibrous connective tissue and never reached Müller's muscle. This connective tissue supports eyelid traction and is a natural barrier for the Muller's muscle against conjunctivitis.     

The morphology of the lymph node in the macroglobulinaemia of Waldenström

In 16 cases of Waldenström''s macroglobulinaemia the following findings were sufficiently frequent to justify a provisional diagnosis: a modestly enlarged node with lymphocytic infiltration through the capsule into the adjacent connective tissue, retention of the sinus and medullary reticulin pattern, few or no peripheral follicles, sinuses marked out by pale histiocytes, scanty mitoses, numerous plasma cells, and dark staining of plasma in blood vessels. Mast cells were not more frequent than in reactive nodes, but were more frequent than in lymphomas. Periodic acid-Schiff-positive inclusions were found in every case, but were usually very scanty. Similar inclusions can rarely be found in other cases.     

Left ventriculotomy of the heart: tissue repair and localization of collagen types I,II, III,IV, V,VI and fibronectin

Summary The reparative process following left ventriculotomy was investigated immunohistochemically using anti-type I, II, III, IV, V and VI collagen antibodies, and anti-fibronectin antibody. Wound healing began with proliferation of young fibroblasts positive for type I, III and V collagens at the wound margin; vascular granulation tissue then grew into the injured myocardium followed by deposition of fibrous components immunoreactive with type I and III. At 30 days after operation when almost the entire thickness of the myocardium at the wound was replaced by fibrosing granulation tissue, a small cluster of adipocytes appeared around capillaries at the wound margin. The granulation tissue was gradually replaced by the adipose tissue with establishment of a fibrous union at the subendocardium by 90 days. In addition to type I and III collagens, type VI collagen was detected in a fine fibrillary pattern along thick collagen fibre bundles in the fibrous tissue and around the adipocytes. Fibronectin was distributed diffusely in the granulation tissue and gradually decreased with increase of the fibrous components. These results indicate that the ventriculotomy was finally repaired in the form of a fibrous scar, particularly in the endocardium. There was marked infiltration of adipose tissue in the damaged myocardium. Presumably type VI collagen, as well as type I and type III collagens, plays an important role in wound union.     

Murine Experimental Autoimmune Oophoritis Develops Independently of Gonadotropin Stimulation and is Primarily Localized in the Stroma and Theca

PROBLEM : Neonatal thymectomy performed on day 3 of life (NTX3) induces experimental autoimmune oophoritis in certain strains of mice. The disease has its onset around the time of the first estrous, suggesting the process may be gonadotropin dependent. Furthermore, one study reported that gonadotropin stimulation exacerbated the ovarian lymphocytic infiltration in NTX3 mice. Here we examine the possibility that gonadotropin stimulation of the ovary plays a role in the development of post-thymectomy autoimmune oophoritis. METHOD : Using immunohistochemistry we defined the time course and histologic distribution of the post-thymectomy ovarian lymphocytic infiltration that develops in B6A mice ([C57BL6 × A/J]F₁). We detected ovarian leukocytes using a monoclonal antibody against mouse CD45/T200 and counted those positive staining cells that had the morphologic appearance of lymphocytes. We then treated NTX3 mice to determine if gonadotropin stimulation could exacerbate the disease or cause the disease to appear earlier. We also treated NTX3 mice to determine if gonadotropin suppression could reduce the severity of the disease. RESULTS : Ovarian lymphocytic infiltration was observed as early as 3 weeks after thymectomy, and, during the course of the disease, was primarily located in the stroma and theca. Gonadotropin stimulation did not exacerbate existing disease or induce an earlier onset of severe disease. Furthermore, gonadotropin suppression did not reduce the degree of lymphocytic infiltration or oocyte destruction. CONCLUSIONS : Our findings suggest that murine experimental autoimmune oophoritis develops independently of gonadotropin stimulation of the ovary.     

Biologic characterization of human bone tumors IX. Occurrence of macrophages

Fifty bone tumors were investigated using immunohistological methods for an assessment of the amount and nature of macrophage infiltration. Polyclonal antibodies against lysozyme, alpha 1-antichymotrypsin, and alpha 1-antitrypsin were used as markers, besides certain monoclonal antibodies against blood monocytes and mature tissue macrophages. Particularly high macrophage infiltration was found in malignant fibrous histiocytomas, giant cell-containing osteosarcomas, giant cell tumors of bone, and aneurysmal bone cysts. Moderate infiltrates were seen in some highly malignant osteosarcomas, in fibrosarcoma, and in chondroblastoma. A low macrophage content was observed in some osteosarcomas, in Ewing's sarcomas, chordomas, fibrous dysplasias, aggressive fibromatoses, and cartilage tumors. Osteoclast-like giant cells showed distinctly positive reactions with the monoclonal antibody against mature tissue macrophages. In fibrohistiocytic tumors (MFH, giant cell tumor, non-ossifying fibroma) only macrophages gave positive reactions with those antibodies, whereas the reaction of spindle-shaped tumor cells was always negative. These results strongly indicate that the macrophages found in bone tumors (including those of fibrohistiocytic type) result from reactive infiltration. The autochthonous tumor cells are most probably derived from local mesenchymal cells, and are thus cytogenetically unrelated to the infiltrating macrophages.     

Immunohistological studies of fibrous pseudotumor of the testicular tunica vaginalis

A fibrous pseudotumor of the testis from a 46-year-old man was examined histologically and immunohistochemically. The tumor, situated in the tunica vaginalis, appeared as multiple round nodules up to 2 cm in diameter, and was composed largely of fibrous tissue with scanty inflammatory cell infiltration. Besides mesothelial cells covering part of the tumor, foci of piled-up cells were found among the fibrous tumor tissue. The cells in the foci were spindle and polygonal in shape, and contained oval nuclei. Immunohistochemically, these cells were positive for vimentin and keratin, but negative for CEA. Similar features have been found in pleural mesothelioma, supporting the concept that testicular fibrous pseudotumor could represent neoplastic growth of the mesothelium of the tunica vaginalis.     

An investigation of the cytotoxicity and histocompatibility of in situ forming lactic acid based orthopedic biomaterials

The cytotoxicity and biocompatibility of polymer networks prefabricated from multifunctional lactic acid based oligomers that are being developed for orthopedic applications were assessed through in vitro cytotoxicity analysis and subcutaneous implantation. After 7 and 14 days, no significant difference was observed in the relative viability or alkaline phosphatase activity of primary rat calvarial osteoblasts cultured in the presence or absence of degrading polymer networks, indicating that the degradation products had no detrimental effect on the function or activity of the cultured cells. The tissue response to preformed lactic acid networks implanted in rats consisted of a mild inflammatory response with an increase in fibrous capsule thickness and inflammation correlating with faster degrading polymer compositions. This relatively neutral response is indicative of a biocompatible, degradable polymer that has potential medical applications. Finally, porous scaffolds were implanted subcutaneously in rats, and vascularized fibrous tissue infiltration was highly dependent on the scaffold porosity and architecture. This finding indicates that an in situ forming porous scaffold of this composition may support the infiltration of surrounding vascularized tissue, and thus be applicable to orthopedic treatments of large bone defects.     

Green tea polyphenols reduce autoimmune symptoms in a murine model for human Sjogren's syndrome and protect human salivary acinar cells from TNF-α-induced cytotoxicity

Sjogren's syndrome (SS) is a relatively common autoimmune disorder. A key feature of SS is lymphocytic infiltration of the salivary and lacrimal glands, associated with the destruction of secretory functions of these glands. Current treatment of SS targets the symptoms but is unable to reduce or prevent the damage to the glands. We reported previously that the major green tea polyphenol (GTP) epigallocatechin-3-gallate (EGCG) inhibits autoantigen expression in normal human keratinocytes and immortalized normal human salivary acinar cells (Hsu et al. 2005). However, it is not known whether GTPs have this effect in vivo, if they can reduce lymphocytic infiltration, or protect salivary acinar cells from tumor necrosis factor-α (TNF-α)-induced cytotoxicity. Here, we demonstrate that in the NOD mouse, a model for human SS, oral administration of green tea extract reduced the serum total autoantibody levels and the autoimmune-induced lymphocytic infiltration of the submandibular glands. Further, we show that EGCG protected normal human salivary acinar cells from TNF-α-induced cytotoxicity. This protection was associated with specific phosphorylation of p38 MAPK, and inhibitors of the p38 MAPK pathway blocked the protective effect. In conclusion, GTPs may provide a degree of protection against autoimmune-induced tissue damage in SS, mediated in part through activation of MAPK elements.