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Papillary adenoma of the stomach. Pathologic and immunohistochemical study.

A total of 13 gastric papillary adenomas composed of 8 papillary and 5 papillotubular adenomas were examined pathologically and immunohistochemically. They showed a dome-like or pedunculated appearance and were located at the antrum, except for one adenoma. Histologically, the adenoma cells showed atypia in varying degree and focal adenocarcinoma was noted in seven lesions. The number of goblet cells was apparently smaller in the papillary than in the tubular portion. Lysozyme was present at the supranuclear region in most papillary adenoma cells, whereas it was concentrated in Paneth's granules in tubular adenoma cells. No difference was found in the distribution and frequency of carcinoembryonic antigen, secretory component, and carbohydrate antigen CA 19-9 between papillary and tubular adenomas. Paucity of endocrine cells also characterized gastric papillary adenoma. Different phenotypic expressions might reflect the difference in histogenesis between papillary adenoma and tubular adenoma.

Carcinoembryonic Antigen↗

The immunohistochemical diagnosis of mesothelioma. Differentiation of mesothelioma and lung adenocarcinoma.

Despite numerous histochemical, ultrastructural, and immunohistochemical studies, differentiation between malignant epithelial pleural mesothelioma and adenocarcinoma of the lung remains extremely difficult. Although there is general agreement that immunohistochemical methods can aid in this distinction, some studies have produced conflicting results with some of the proposed markers for mesothelioma. To obtain comparable and reproducible results, 19 unequivocal epithelial mesotheliomas and 23 unequivocal primary lung adenocarcinomas were studied by the avidin-biotin-peroxidase complex method on formalin-fixed, paraffin-embedded tissue specimens. Well-characterized, commercially available antibodies to carcinoembryonic antigen (CEA), a high- and low-molecular-weight keratin, vimentin, epithelial membrane antigen, human milk fat globule, Leu-M1, TAG-72 (identified by monoclonal antibody B72.3), beta 1 pregnancy-specific glycoprotein (SP1), human placental lactogen, secretory component (SC), CA19-9, and S-100 protein were used. Twenty-one adenocarcinomas (91.3%) reacted for CEA, 14 (60.9%) for Leu-M1, 14 (60.9%) for SC, nine (39.1%) for CA19-9, and eight (34.8%) for SP1; no mesotheliomas stained for any of these markers. Nineteen adenocarcinomas (82.6%) and one mesothelioma (5.3%) reacted with B72.3. Adenocarcinomas and mesotheliomas did not significantly vary in reaction to the remaining antibodies. None of the antibodies used was specific for mesothelioma, but CEA was the single most useful marker. One of the two adenocarcinomas negative for CEA was positive for TAG-72, Leu-M1, and SC, and the only B72.3-positive mesothelioma was negative for CEA, Leu-M1, SC, CA19-9, and SP1. These findings indicate that greater sensitivity in differentiating mesothelioma and adenocarcinoma can be achieved by immunostaining for both CEA and one or more of the markers TAG-72 (B72.3), Leu-M1, SC (these three have the highest sensitivity and specificity after CEA), CA19-9, and SP1.

Adenocarcinoma↗

Kinetic studies on the competition between famotidine and cimetidine in rats. Evidence of multiple renal secretory systems for organic cations.

The H2-receptor antagonists famotidine and cimetidine are both basic drugs that are predominantly eliminated by the kidneys. Cimetidine has been shown to inhibit the renal secretion of tetraethyl-ammonium bromide (TEAB) but not p-aminohippuric acid (PAH), suggesting that cimetidine is secreted by an organic cation transport system [Weiner and Roth: J. Pharmacol. Exp. Ther. 216: 516 (1981)]. The present study shows that famotidine behaves like cimetidine in that it also inhibits TEAB but not PAH excretion. Where a high concentration of cimetidine in plasma has an inhibitory effect on the renal excretion of famotidine, the reverse is not true, i.e. high plasma levels of famotidine have no effect on the excretion of cimetidine. Further evidence that additional transport systems are involved in the renal tubular secretion of cimetidine is as follows. Quinine, a potent competitor of the organic cation transport system, inhibits the secretory component of famotidine renal clearance but not that of cimetidine. Probenecid, a classic competitor for the organic anion transport system, inhibits the renal excretion of cimetidine but not famotidine. However, the effect of probenecid is minor and not sufficient to account for other components of cimetidine secretion not affected by famotidine and quinine.

Animals↗

Growth-promoting effect of gastrin on human gastric carcinoma cell line TMK-1.

A human gastric carcinoma cell line TMK-1 was established in vitro by the soft agar method from SC-6-JCK, a poorly differentiated adenocarcinoma xenotransplanted in nude mice. TMK-1 cells had a doubling time of approximately 35 hr and showed carcinoembryonic antigen (CEA), alpha 1-antitrypsin and secretory component immunoreactivity. Ultrastructurally, the tumor cells were characterized by numerous mitochondria, tubulovesicles and intracytoplasmic canaliculi filled with abundant microvilli. The growth of TMK-1 cells was promoted by 10nM human gastrin (G-17), 2 microM tetragastrin or 2 microM pentagastrin, among which human gastrin showed the most effective growth promotion. Moreover, incorporation of [3H]thymidine into TMK-1 cells was stimulated by gastrin in a dose-dependent manner. The content of cyclic adenosine 3',5'-monophosphate (cAMP) in TMK-1 cells was increased by gastrin treatment but decreased to the control level within 10 min. cAMP-dependent protein kinase was also activated by gastrin administration.

Carcinoma↗

IgD in nasopharyngeal secretions and tonsils from otitis-prone children.

Quantification of IgD was performed by ELISA in 180 plasma samples and 83 nasopharyngeal secretions (NPS) from children aged 2-162 months with varying degrees of recurrent otitis media. Furthermore, in 24 of the children the density of the IgD-immunocytes (IgD-cells) was calculated in immunoenzyme-stained cross-sections of their nasopharyngeal tonsils (NPT). Owing to a considerable variation of the IgD cell density throughout the NPT, a semi-quantitative counting system was applied. An irregular distribution of plasma IgD was observed during childhood and maximum levels were found between 48 and 72 months of age. However, an even distribution of plasma IgD was found among the four groups of children investigated. Based on calculations of the transudation of albumin from plasma to the NPS the amount of locally produced IgD in NPS (NPS-IgD (local] was estimated to 88% (range 41-99%). Significantly higher levels of NPS-IgD (local) were found in otitis-prone children than in the other groups. Moreover, a positive correlation was calculated between levels of NPS-IgD (local) and NPT-IgD cell density, indicating that NPT, being the local lymphoepithelial tissue, also functions as an important source of NPS-IgD. NPS-IgD was not found to be associated with secretory component, indicating a passive transfer of IgD through the mucosal membranes. Our results support the hypothesis of an association between the occurrence of IgD in the mucosa and secretions of the upper respiratory tract with localized inflammatory events.

Acute Disease↗

Glomerular deposition of food antigens in IgA nephropathy.

Recently, we reported on the importance of food antigens on the pathogenesis of an experimentally-induced model of, and some patients with, IgA nephropathy. In this paper, the glomerular deposition of food antigens (casein, lactalbumin, peanut protein, soy bean protein, rice protein, ovalbumin) was investigated by an immunofluorescence technique in 28 patients with IgA nephropathy and 32 controls (ten with lupus nephritis, three with Henoch-Schoenlein purpura nephritis and 19 with other glomerulonephritis). Glomerular IgA deposition was demonstrated in all IgA nephropathy and Henoch-Schoenlein purpura nephritis, and in four lupus nephritis. Positive findings of food antigens, observed as mesangial pattern, were obtained in eleven cases (39.3%) with casein, 21 (75.0%) with soy bean protein and one (3.6%) with rice protein in IgA nephropathy, even though no such findings were seen in the control group. Eleven of 28 patients with IgA nephropathy were positive with soy bean protein alone, nine were positive with soy bean protein + casein, one was positive with soy bean protein + casein + rice protein, and one was positive with casein alone. The deposition of food antigens was not observed in six cases only. Furthermore, no correlation was noted between the deposition of food antigens and the deposition of IgA1, IgA2 or J chain, in vitro binding of the secretory component, or histopathological grades. These results suggest that the exact meanings of glomerular deposition are unclear. Food antigens are postulated, however, as possibly participating strongly in the pathogenesis and as being localized in the glomerular mesangium as an antigen in some patients with IgA nephropathy.

Adolescent↗

Purification of three porcine immunoglobulin classes from the same biological source.

Porcine IgG, IgA and IgM were isolated from sow milk. They were systematically purified by a combination of gel filtration and ion exchange chromatography. The yields were 85%, 64% and 32%, respectively. These immunoglobulins were very pure, as checked by SDS-PAGE and Ouchterlony immunodiffusion. SDS-PAGE showed moreover the evidence of secretory component S in the IgA molecule and of joining piece J both in IgA and IgM molecules. The procedure can be used to purify immunoglobulin classes from other biological sources.

Animals↗

[Identification of cultured cell employing specific substance--with special references of "reserve cells" in uterine cervix].

Identification of endocervical "reserve cell", which have been regarded as the origin of squamous cell carcinoma of the uterine cervix, was attempted employing immunohistochemically specific substances. The antigenicity of keratin, squamous cell carcinoma antigen(SCC), epithelial membrane antigen(EMA), tissue polypeptide antigen(TPA), vimentin, secretory component(SC) and placental alkaline phosphatase(PLAP) was investigated in histological preparations as well as cultured cells obtained from primary culture of endocervical tissue. The immunohistochemical findings in histological preparations revealed the following: a strongly positive reaction with TPA, a slightly positive reaction with EMA, a very slightly positive with SCC and PLAP, and a negative reaction with keratin, vimentin and SC. Cultured cells were divided into 4 groups according to their morphological characteristics; among these, small rounded or polygonal cells with a centric single nucleus showed similar immunocytochemical reactions to those of "reserve cells" in histological preparations, indicating that "reserve cell" can be growing in culture. The results obtained suggest that immunohistocytochemical specific substances may be useful to identify cultured cells.

Carcinoma, Squamous Cell↗

Immunocytochemistry of the thyroid in surgical and cytologic specimens.

The value of immunocytochemistry in thyroid disease was evaluated in histologic and cytologic material derived from papillary carcinoma (25 cases), follicular carcinoma (nine cases), follicular adenoma (nine cases), Hürthle cell tumor (three cases), medullary carcinoma (two cases), nodular goiter (nine cases), and Hashimoto's thyroiditis (two cases). Thyroglobulin was positive in the follicular cells and/or colloid of all lesions (except medullary carcinoma) and two papillary carcinomas. Vimentin was positive in papillary carcinoma (17 of 25), follicular carcinoma (four of nine), follicular adenoma (four of nine), and nodular goiter (two of nine). Vimentin positivity, which was restricted to follicular cells, was strongest in those cells undergoing oncocytic transformation. Three markers of glandular/acinar secretory differentiation (lactoferrin, lactalbumin, and secretory component) were uniformly negative even in well differentiated follicular structures. In medullary carcinoma, both calcitonin and carcinoembryonic antigen were strongly positive in the parafollicular cells. The antibody panel can definitely identify histogenesis from the thyroid but is of little value in tumor classification. In histologic and cytologic preparations, vimentin positivity does not exclude thyroid follicular cell origin. The method can be successfully applied to richly cellular needle aspirates. This is best achieved with assisted needle aspirations when cellularity is ascertained by on-site microscopic examination of multiple passes.

Biopsy, Needle↗

Growth inhibition and differentiation of human salivary adenocarcinoma cells by medium conditioned with normal human fibroblasts.

The present study demonstrates that normal human fibroblasts (WI-38) exert a profound influence on the growth and differentiation of HSGc-C5, a clonal neoplastic epithelial cell line of human salivary gland origin. Coculture of HSGc-C5 with WI-38 resulted in a slowing of growth and an increase in glycosaminoglycan synthesis by an indirect effect involving a diffusible factor(s). Conditioned medium (CM) from WI-38 grown in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum affected HSGc-C5 as follows. The CM suppressed growth of monolayer cells; inhibited DNA synthesis; suppressed growth (decrease in size of colonies) in semisolid agar; stimulated glycosaminoglycan synthesis, induced expression of functional markers of the salivary gland, such as the secretory component, lactoferrin, and lysozyme; inhibited expression of alkaline phosphatase; and induced morphological alteration into elongated cells. These findings strongly suggest that WI-38 CM contains a factor(s) which inhibits growth and induces differentiation of HSGc-C5. The CM was also active on other human cancer cells as a growth inhibitor, but not on normal human fibroblasts. Partial purification and characterization of the factor(s) suggests that it may be a novel protein carrying both tumor inhibiting and differentiation inducing activities.

Adenocarcinoma↗

Plasma ferritin determination as a diagnostic tool.

Plasma ferritin is a secretory component of intracellular ferritin synthesis. In normal persons its amount reflects the size of iron stores. A decrease to less than 12 mug per liter indicates iron deficiency. Increased iron stores are associated with an increased plasma ferritin level. Various other conditions, however, can increase the plasma ferritin concentration including increased metabolism, inflammation, tissue damage and neoplastic disease. The use of the plasma ferritin determination in diagnosing iron overload depends on excluding these other causes, leaving storage iron as the only explanation for the increased plasma ferritin. It is then necessary to establish the parenchymal nature of the iron overload by showing an elevated transferrin saturation and, if elevated, the more definitive liver biopsy should be done.

Ferritins↗

Dome epithelial M cells dissociated from rabbit gut-associated lymphoid tissues.

Dome and dome epithelial cells were selectively dissociated from gut-associated lymphoid tissues of rabbits. Sequential tissue washes in dithiothreitol, EDTA, and collagenase removed the dome epithelium, without disrupting the follicles or villi, and provided a cell suspension containing 74 +/- 6% lymphocytes, 9 +/- 4% columnar epithelial cells, 10 +/- 7% tangible-body macrophages, and 4 +/- 2% M cells (follicle-associated epithelial cells). The last mentioned cells were characterized by transmission electron microscopy as large (20 to 55 microns diameter) cuboidal, round, or oval cells with eccentric nuclei and thin membranous processes surrounding empty vacuoles. The M cells were occasionally joined together by tight junctions. Histochemical and immunocytochemical analyses of M cells with the light microscope showed that they were devoid of immunoglobulins and negative for T-cell antigen and secretory component and had no detectable alkaline phosphatase or endogenous peroxidase activity. The M cells had few vacuoles with faint acid phosphatase activity; nonspecific neutral esterase was abundant. Possible uses for dome and dome epithelial cells are discussed.

Acid Phosphatase↗

[Regulation of the immunoglobulin content of the mucous membranes of the uterus: effect of estradiol on immunoglobulin A content].

A was used for the animal experimental investigations standard castration mouse model. Vaginal smears indicated no cyclic changes 14 days after the removal of the ovaries. 12.5 micrograms estradiol benzoate have been injected intramuscularly in this time. 3 days later uterus lavage fluids and tissue homogenates were used for the IgA-test, single radial immunodiffusion. The standard was prepared from mouse colostrum because S-IgA is the dominant IgA in secretions. The results were expressed as U/l selected arbitrary. Our findings of significant increased IgA concentrations in uterus lavage fluid after estradiol stimulation and, in contrary, no changed IgA concentrations in homogenates support the hypothesis, that the secretory component synthesis in the epithelial cells of the uterus is controlled by estrogens.

Animals↗

Glomerulonephritis and IgA deficiency.

A mild self-limiting mesangial proliferative glomerulonephritis is described in 3 patients with selective IgA deficiency (less than 0.05 g/l). In all cases there was irregular thickening of peripheral glomerular capillary loops and paramesangial deposits. Arteriolar hyalinosis was present in two of the three cases. By direct immunofluorescence, and immunoperoxidase techniques in one case, IgM was present in the glomeruli and C3 was present in blood vessel walls. Secretory component was not detected in the glomeruli of any of the patients. The polyethylene glycol (PEG) precipitation immune complex assay was positive for IgM and IgG immune complexes in one patient and weakly positive for IgM immune complexes alone in another. The serum of one patient contained milk precipitins. All three patients had suffered from recurrent upper respiratory tract infections. It is suggested that the glomerular IgM immune complex deposition is related to the IgA deficiency and that, although the immune complexes may be a consequence of antibodies to dietary bovine proteins, this could be due to recurrent upper respiratory tract infections. This type of glomerulonephritis appears to resemble IgM associated glomerulonephritis in some aspects. Careful appraisal is required to establish if this association constitute a specific entity.

Adult↗

Study of human T and B lymphocytes with heterologous antisera. III. Immunofluorescence studies on tonsil sections.

Lymphoid cells from human palatine tonsils were identified on tissue sections by membrane or intracellular immunofluorescence (IF) staining. Used in an indirect technique, an anti-IgM and an anti-HTLA (human T lymphocyte antigen) antiserum gave complementary patterns of membrane IF, characteristic of the follicular organization. When serial sections were stained for each of the five classes, immunoglobulin-containing cells from all classes were found. Their relative frequencies were, in decreasing order: IgG: 61.6%; IgA: 17.3%; IgM: 12%; IgE: 7.5%; IgD: 1.6%. These differed from those of the gut-associated lymphoid tissue (IgA greater than IgG greater than IgM) and of the peripheral lymph nodes (IgG greater than IgM greater than IgA), but were close to those of mesenteric nodes. The absence of secretory component in tonsil was an additional difference from gut-associated lymphoid tissue and the relatively high proportion of IgE-containing cells, in the absence of recognized atopy, is another feature in common with mesenteric lymph nodes. Finally, slight differences between these results and those obtained on tonsil cell suspensions suggest that some degree of selection probably occurs during the isolation procedure.

Adolescent↗

Metastatic adeno or undifferentiated carcinoma from an unknown primary site--natural history and guidelines for identification of treatable subsets.

Two hundred and eighty-six patients presenting with metastatic adenocarcinoma or undifferentiated carcinoma whose primary site was not identified by clinical history, physical examination and chest radiograph have been studied. Median survival from presentation was 22 weeks. Factors independently predicting improved survival were lymph node presentations, good performance status and body weight loss of less than 10 per cent. In 88 (31 per cent) patients the primary tumour site was subsequently identified, in 58 (20 per cent) during life. Lung cancer was the most frequently identified primary tumour, and in only 32 (11 per cent) of the patients was a 'treatable' primary tumour (i.e. germ cell, breast, ovarian, prostate, thyroid cancer or lymphoma) identified. Among the treatable primary tumours were those in eight out of 16 female patients presenting with axillary metastases who were subsequently shown to have primary breast cancer and four of 13 females presenting with ascites who were found to have primary ovarian cancer. Prostatic cancer was confirmed in five out of 13 men with raised serum acid phosphatase. Of 22 patients with elevated serum alphafoetoprotein (AFP) or beta-human chorionic gonadotrophin levels (beta HCG) 18 had some features of the 'atypical teratoma syndrome'. Of the total of 32 patients with treatable tumour types, 29 (90 per cent) were identified during life. Median survival for patients with treatable tumour types identified during life was 104 weeks, compared with 22 weeks for the group as a whole. Retrospective immunocytochemical staining of the original biopsy showed that prostatic specific antigen and antibodies to beta HCG and AFP were diagnostically useful, but a series of organ site non-specific markers of histogenesis or cellular differentiation (carcinoembryonic antigen, secretory component for IgA, peanut lectin binding, epithelial membrane antigen and keratin) showed no significant correlations with identified primary sites, responsiveness to empirical chemotherapy or survival. Metastatic undifferentiated carcinoma or adenocarcinoma from an unknown primary site represents 6.5 per cent of all referrals to the medical oncology unit, Royal Prince Alfred Hospital, Sydney. We offer guidelines for the rapid identification of the limited number of primary sites for which effective and specific forms of systemic treatment are available.

Adenocarcinoma↗

Polymeric IgA rheumatoid factor in idiopathic IgA mesangial nephropathy (Berger's disease).

A specific and sensitive enzyme-linked immunosorbent assay (ELISA) was used to detect IgA rheumatoid factor (RF) in sera from 88 patients with IgA nephropathy (IgA GN), a disease characterized by abnormalities of IgA production. Significantly higher levels of IgA antiglobulins were demonstrated in IgA GN patients than in normal healthy controls and patients with other forms of chronic primary glomerulonephritis (mean +/- SEM 28.4 +/- 6.6 vs 6.0 +/- 0.4 and 8.3 +/- 1.2 micrograms/ml respectively; p less than 0.002). Interestingly, in contrast to rheumatoid arthritis, IgA RF activity was not associated with IgM antiglobulins. Analysis of sera fractionated by gel chromatography at acid pH revealed that anti-IgG activity resided predominantly in the polymeric fractions of IgA as confirmed by the ability to bind "free" secretory component. Several findings in patients with IgA GN suggest that the IgA deposited in the glomeruli is polymeric, and levels of circulating macromolecular IgA are increased. Our findings confirm a general perturbation of IgA metabolism in this disease. Although the polymeric nature of the IgA RF is suggestive of a mucosal origin, additional evidence is needed to confirm this hypothesis.

Adolescent↗

Immunohistological studies of the local immune system in the reproductive tract of the mare.

The immunoperoxidase technique was adapted for the identification of free immunoglobulin and immunoglobulin producing cells in equine tissues. Staining specific for free IgG, IgA and IgM was detected at all levels of the reproductive tract, and secretory component staining was present in the uterine epithelium but not in the oviduct, cervix or vagina. Immunoglobulin producing cells were present at all levels of the tract, with IgG and IgA cells at equivalent concentrations, but with fewer IgM cells. There was no cyclical trend in free immunoglobulin staining, or plasma cell numbers. IgG and IgM plasma cell numbers declined from uterus to vagina, as did epithelial staining, and the ratio of IgG:IgA cells declined from oviduct to vagina.

Animals↗