[Utility and specificity of markers of breast cancer].
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Biomarkers, Tumor↗
Biomedical subjects
J Hurlimann
Publications and source records attributed to J Hurlimann.
[The importance of immunohistochemistry in histological diagnosis].
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Antigens, Neoplasm↗
Pancreatic insuloma causing Cushing's syndrome.
The advent of new diagnostic procedures such as petrosal venous sampling and CRF testing has improved the possibilities of precise location of the site of hormonal overproduction in Cushing's syndrome. We report on a case of ectopic ACTH-dependent Cushing's syndrome in which the use of such techniques helped to locate the tumor. A 45-year-old woman with definite ACTH-dependent Cushing's syndrome was referred to our clinic for evaluation. ACTH, cortisol and urinary 17OHCS failed to suppress on high dose dexamethasone oral administration. Computerized tomography showed bilateral adrenal hyperplasia and an empty sella turcica. ACTH and cortisol did not increase after CRF administration. Staged caval system catheterism via both femoral veins up to the inferior petrosal sinuses, including after CRF administration, demonstrated no ACTH gradient between staged samples and simultaneous peripheral venous blood. This suggested a tumor drained by the portal system. An abdominal ultrasonography demonstrated a pancreatic mass, that was surgically excised and appeared as a benign islet cell tumor. Portal vein ACTH promptly decreased after tumor excision and postoperative peripheral cortisol and ACTH were normal. On immunostaining the tumor cells proved to be positive for ACTH.
ACTH Syndrome, Ectopic↗
Immunohistochemistry of dysplasias and carcinomas of the esophageal epithelium.
Two types of high grade dysplasia were associated with invasive carcinomas. The first, deeply localized, had a pagetoid appearance and a particular phenotype: the dysplastic cells had keratins of low molecular weight rarely present in the esophagus; keratins of stratified epithelia were absent. This dysplasia was probably the origin of undifferentiated invasive carcinoma with which it was often associated. The second type, transepithelial, extended through the entire thickness of the epithelium. The abnormal cells presented some differentiation and stained positive for keratins of stratified epithelia. This dysplasia was often associated with differentiated squamous cell carcinoma. An intermediate-type dysplasia shared some characteristics with both main types. Several types of dysplasia and several areas of differently differentiated carcinoma were often associated in the same case. The evolutional potential of the different dysplasias is not known.
Carcinoma↗
Immunohistology of anaplastic thyroid carcinoma. A study of 43 cases.
Forty-three cases of large cell anaplastic thyroid carcinoma were examined with various antisera. Four histological patterns were identified: spindle cell, giant cell, trabecular and squamous. In 38 cases the epithelial origin was demonstrated with various epithelial markers: 11 cases stained positively for thyroglobulin, 19 for T3 and/or T4, 35 for fat globule membrane antigens, 28 for keratin, 29 for lactoferrin, and one for calcitonin. Five cases were negative for all epithelial markers but could not be characterized further since, except for vimentin, they did not have mesenchymal markers. The immunohistochemical proof of the epithelial nature of anaplastic thyroid tumours is given by staining with anti-keratin and anti-fat globule membrane antigen. In addition the detection of lactoferrin seems useful, but not that of thyroglobulin which was present in only 4% of the spindle cell tumours and in 32-56% of the other histological types. Thirty carcinomas were positive for vimentin; the co-expression of vimentin and epithelial markers seems frequent in thyroid anaplastic carcinomas.
Aged↗
Cervical intraepithelial glandular neoplasia (adenocarcinoma in situ and glandular dysplasia). A correlative study of 23 cases with histologic grading, histochemical analysis of mucins, and immunohistochemical determination of the affinity for four lectins.
Twenty-three cases of cervical intraepithelial glandular neoplasia (CIGN)--a term encompassing adenocarcinoma in situ and glandular dysplasia of the uterine cervix--were studied histologically, histochemically for mucins (neutral mucins, sialomucins and sulfomucins), and immunohistochemically for the affinity of four lectins (WGA, PNA, RCA, UEA). For comparison, six cases of cervical invasive adenocarcinoma and ten cases of cervices without tumor were similarly studied. Criteria for histologic grading of CIGN into three degrees were proposed according to the hyperchromasia and the stratification of nuclei, number of mitoses, and amount of intracellular mucin. Two different types of CIGN were distinguished according to their histological aspect and their mucin pattern: CIGN type A, where the mucin pattern was qualitatively similar to that of normal endocervical mucosa, i.e., neutral mucins, sulfomucins and sialomucins; and CIGN type B, where the glandular cells resembled small intestinal goblet cells and the mucins consisted of neutral mucins and sialomucins with the absence of sulfomucins. Nine cases of CIGN were of type A, 2 of type B, and 12 of both type A and B. Differences in lectin binding existed between normal columnar cells, CIGN, and invasive adenocarcinomas, as well as between CIGN of type A and B. The intensity of the positive immunochemical reaction varied, as well as the type of binded lectin and its localization in the cell. There was a great heterogeneity in the same histologic group from one case to another, and even in the same case from one cell to another.
Adenocarcinoma↗
Separation, phenotyping and limiting dilution analysis of T-lymphocytes infiltrating human solid tumors.
Tumor-infiltrating lymphocytes (TIL) were obtained by a combination of mechanical release and enzymatic disaggregation from 35 human solid tumors. The number of lymphocytes in TIL-enriched suspensions varied from 1 X 10(4) to 7.6 X 10(6) per wet gram of tumor. The TIL preparations separated by differential centrifugation on Ficoll-Hypaque gradients contained 10-95% of T11+ cells (mean 50%), and tumor cells accounted for the other major cellular component. Macrophages, NK cells, B cells and granulocytes were infrequently seen. Morphologically, TIL-T were small non-activated cells. They expressed the T11 and T3 antigens but not the receptor for IL-2 (IL-2R) or HLA-DR antigens as determined by double immunofluorescence staining. Rare T11+/IL-2R+ cells were recovered only from colon and lung carcinomas. The mean T4/T8 ratio in 12 TIL preparations was 1.1 +/- 0.8. Immunohistology with monoclonal antibodies (MAbs) performed in 31/35 tumors confirmed that the T11+ cells infiltrating solid tumors rarely expressed the IL-2R and that the cell content of suspensions enriched in TIL was comparable to that determined in situ. The recovered TIL were cloned in a microculture system that permits proliferation of nearly all normal peripheral blood T lymphocytes (PBL-T). Under these culture conditions, frequencies of the proliferating T lymphocyte precursors (PTL-P) were depressed in both the TIL preparations (less than 0.01 to 0.39) and patients' PBL-T (0.05 to 0.5). These low frequencies of PTL-P were seen in patients with all tumor types, both primary and metastatic.
Antibodies, Monoclonal↗
Clonal analysis and in situ characterization of lymphocytes infiltrating human breast carcinomas.
T lymphocytes were isolated from tumor biopsies in 13 patients with breast carcinomas. Immunohistology with monoclonal antibodies confirmed the presence of mononuclear cell infiltrates composed primarily of T lymphocytes in all tumors studied. While the proportion of T lymphocytes expressing the T4 or the T8 surface marker varied from tumor to tumor as determined by morphometric analysis, T8+ cells were more numerous than T4+ cells in 8/12 breast tumors studied. Relatively few T cells (less than 10% in 11/12 tumors) were in an activated state as judged by the surface expression of HLA-DR antigens or the receptor for interleukin-2 (IL-2). In 1 case 20% of the infiltrating mononuclear cells were expressing the IL-2 receptor. The tumor infiltrating lymphocytes (TIL) recovered from 10 tumors were cloned in a microculture system that permits proliferation of nearly 100% of normal peripheral blood T lymphocytes (PBL-T). In contrast to normal and autologous PBL-T, frequencies of proliferating T lymphocyte precursors (PTL-P) were depressed (less than 0.01) in 7/10 TIL preparations indicating a decreased responsiveness of TIL to phytohemagglutinin at the single-cell level. The frequency of PTL-P was noticeably higher in 2 cases (0.03 and 0.09) and close to normal in 1 case (0.39). A total of 170 clones were expanded in vitro and analyzed for different functional capabilities. Most of these clones expressed the T4+/T8-phenotype (73%) and strikingly 53% of these T4+/T8- clones were cytolytic in a lectin-dependent assay, a functional subset which is uncommon among normal PBL-T. Some clones (10%) lysed allogeneic breast tumor cells (MCF7). Only 15% of the clones displayed natural killer activity. Among the cytolytic clones, 17 of 31 tested were also IL-2 producers irrespective of the T4 or T8 phenotype. Our results show that human mammary carcinomas contain many infiltrating T cells with cytolytic potential. Interestingly, among the proliferating cytolytic T cell clones (56% of the microcultures), many expressed the T4+/T8- phenotype. These findings may indicate that the in situ cytolytic reaction (against unknown antigens) is associated preferentially with class II antigens.
Antibodies, Monoclonal↗
Biological tissue markers in benign and malignant disease of the human prostate.
Immunoperoxidase techniques were used to study, the distribution of peanut agglutinin receptors, blood group isoantigens and several epithelial antigens in hyperplasia, adenosis, microcarcinoma and well differentiated adenocarcinoma of the prostate. Intraluminal and luminal surface PNA receptors were seen in all well differentiated carcinomas, 53% of microcarcinomas and 50% of adenosis, while no such sites could be demonstrated in benign hyperplasia. The expected blood group isoantigen was expressed in 75% of benign hyperplasias. When compared to the hyperplastic epithelium nearby, appropriate ABH expression was seen in 60% of adenosis, 47% of microcarcinomas and 25% of well differentiated carcinomas. A keratin antibody specifically labelling the basal cells in the normal prostate identified a subset of well differentiated carcinomas with preferential staining of the apical cytoplasm while microcarcinomas and adenosis were consistently negative. Our study establishes a highly ordered PNA receptor distribution in prostatic epithelia; it confirms early changes in the expression of ABH isoantigens in epithelial proliferative disorders of the prostate; it identifies a subset of keratin-positive well differentiated carcinomas, possibly of different ontogeny.
ABO Blood-Group System↗
Characterization of different amyloids with immunological techniques.
We studied 71 cases of amyloidosis from the autopsy material of our institute. 17 cases were secondary amyloidosis of which 7 had initially been diagnosed as primary amyloidosis; all cases reacted positively with an anti-substance A antibody; 13 showed a suppression and 4 a strong reduction of the Congo red staining following tissue incubation in KMnO4. 25 cases were identified as primary amyloidosis of which 7 had initially not been recognized as such. In 16 cases amyloid deposits reacted positively with antibodies specific for the light chains of the immunoglobulins (3 X kappa, 13 X lambda). A monoclonal plasmacytic cell proliferation in the bone marrow was seen in 14 cases. In all cases deposits were KMnO4 resistant, but 1 case showed a slight reduction of staining intensity. 27 cases were cardio-vascular (senile) amyloidosis; in 20 cases at least 3 organs showed deposits; 12 cases had deposits in 5 and more organs. 2 cases were heredofamilial amyloidosis. In those 29 cases deposits reacted positively with an anti-prealbumin antibody, but were negative for AA and the light chains of the immunoglobulins; the Congo red staining remained strong in all cases when previously incubated in KMnO4. KMnO4-Congo red staining and antisera specific for AA, L-chains and prealbumin proved of value for classification of amyloidosis and for its organ distribution.
Adult↗
Mononuclear cells infiltrating human mammary carcinomas: immunohistochemical analysis with monoclonal antibodies.
Breast carcinomas were examined by the immunoperoxidase technique using antisera specific for lymphocyte subsets, monocytes, NK cells and major histocompatibility antigens (HLA-A, -B, -C; Ia-like). Sixty-four per cent of the patients had a moderate or strong mononuclear cell infiltration, 77% of the patients without mononuclear cell infiltration had receptors for estrogens as compared to 51% of the patients with infiltration. The majority of the infiltrating mononuclear cells were T cells; generally the OKT8 cells were predominant. The Leu 3A/OKT8 cell ratio was not related to histological type, tumor size, age of the patient or presence of metastases. Some of the T cells had the Ia antigen and were thus probably activated. The B cells were either absent or less numerous than the T cells. There was no relation between their distribution and the various parameters studied. A few monocytes were heterogeneous according to their markers (OKM I and acid phosphatase). In 6 cases only there was a strong infiltration of mononuclear cells positive for acid phosphatase. The number of the natural killer cells was also low. Only a few mononuclear infiltrating cells had receptors for transferrin. There was a positive correlation between the inflammatory infiltration and the presence of HLA class-I antigens on tumor cells. Some of the antisera specific for lymphocyte subsets also stained the breast carcinoma cells. The great variations in the subsets of mononuclear cells in breast carcinomas may correspond to various systems of defense against neoplasm.
Acid Phosphatase↗
Adenocarcinoma in situ and invasive adenocarcinoma of the uterine cervix. An immunohistologic study with antibodies specific for several epithelial markers.
The distribution of carcinoembryonic antigen (CEA), secretory component (SC), fat globule membrane antigens ( FGMA ), and keratin was determined immunohistochemically in 22 invasive adenocarcinomas of various types and in 9 adenocarcinomas in situ of the uterine cervix. In the invasive adenocarcinomas 77% were positive for CEA, 47% for SC, 89% for keratin, and 77% for FGMA . In adenocarcinomas in situ 67% were positive for CEA, 11% for SC, and 44% for keratin. The location of the markers was variable in the cells, and the cells in a tumor were irregularly positive. For a given histologic type there were several phenotypes. No correlation was found between histologic types of invasive adenocarcinomas and the various phenotypes. It remains to be shown whether a particular phenotype has a particular biological behavior. The detection in the serum of the markers shown in histologic preparations could be useful in the postsurgical monitoring.
Adenocarcinoma↗
[Diffuse digestive ganglioneuromatosis].
Discovery of intestinal ganglioneuromatosis implies the presence of the MEN IIb syndrome or, more rarely, von Recklinghausen's neurofibromatosis. The two conditions are due to dysfunction of the neural crest. This very rare intestinal pathology is illustrated by two observations. The intestinal motility disorders, due to the diffuse proliferation of the peripheral autonomous nervous system which ganglioneuromatosis represents, may have serious implications and indeed prove fatal. The etiologic role of excessive nerve growth factor production in these two entities is mentioned. The physiopathologic implications of an increase in vasoactive intestinal polypeptide, and of possible ectopic secretion of calcitonin by ganglioneuromatosis, are discussed.
Adult↗
Autoimmune oophoritis.
A 43-year-old para 3 woman presented with a six-year history of progressive oligomenorrhea and hypomenorrhea. A total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed for the suspicion of ovarian cysts. On histologic examination, the ovaries contained lymphocytic and plasma cell infiltrates in relation to the theca interna of growing follicles, to the corpora lutea and to the endocrine hilar cells. The infiltrates increased in density with the follicular maturation and culminated against the corpora lutea. The plasma cell population was polyclonal. No antibodies to ovarian tissue components could be demonstrated in the patient's serum by means of immunohistochemistry; but antibodies to the zona glomerulosa of adrenal cortex were detected by serologic means. Although a rare disease, autoimmune oophoritis must be recognized histologically because it is a cause of ovarian failure and because it indicates that the patient is at risk of developing associated Addison's disease.
Adrenal Cortex↗
Immunohistological study of malignant diffuse mesotheliomas of the pleura.
Paraffin sections from fifteen cases of malignant diffuse mesothelioma of the pleura and five cases of bronchial adenocarcinoma infiltrating the pleura were examined with an antiserum specific for factor VIII related antigen and with antisera against various epithelial markers: keratin, carcinoembryonic antigen (CEA), fat globule membrane antigen and secretory component. In all adenocarcinomas all the epithelial markers were present whereas the factor VIII related antigen was absent. The distribution of the fat globule membrane antigens, keratin, secretory component and factor VIII related antigen varied from one mesothelioma to another. The mesotheliomas were generally negative for CEA. The three mesotheliomas which were positive for CEA were also positive for alcian blue after hyaluronidase treatment. Amongst the markers used, CEA seems the most useful for the differential diagnosis between carcinoma and mesothelioma. However, the simultaneous detection of several markers allows the characterization of various phenotypes. Some of them are close to the phenotypes of true adenocarcinoma. A relation between a given phenotype and the biological behaviour of the tumour has still to be demonstrated.
Adenocarcinoma↗
Placental site trophoblastic tumor (trophoblastic pseudotumor) of the uterus with metastases and fatal outcome. Clinical and autopsy observations of a case.
A 41-year-old woman who 5 years earlier had a hysterectomy for a placental site trophoblastic tumor (formerly called trophoblastic pseudotumor) was readmitted to the hospital with pelvic recurrence and multiple lung metastases. Despite an initial decrease in the size of the lung metastases and concomitant lowering of the serum values of human chorionic gonadotropin (beta-HCG) from 2,200 to 40 ng/ml, combined chemotherapy became ineffective. The patient died 4 months later with widespread metastases. The clinical course and the autopsy findings of this case are reported and compared with the two similar cases reported in the literature.
Adult↗
Chemical and immunochemical characterization of caseins and the major whey proteins of rabbit milk.
Caseins were separated from whey proteins by acid precipitation of skimmed rabbit milk. Whole casein was resolved by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis into three major bands with apparent relative molecular masses (Mr of 31 000, 29 000 and 25 000. On agarose/urea-gel electrophoresis whole casein gave three bands with electrophoretic mobilities alpha, beta and gamma. The three components were purified by DEAE-cellulose chromatography under denaturing and reducing conditions. Each was shown to have a different amino acid, hexose and phosphorus content, as well as non-identical peptide fragments after proteinase digestion. The 31 000 Da (dalton) protein, of alpha-electrophoretic mobility, had a high phosphorus content (4.38%, w/w); the 29 000 Da peptide, of gamma-mobility, had the highest hexose content (2.2%, w/w), contained 0.8 cysteine residue per 100 amino acid residues and was susceptible to chymosin digestion corresponding thus to kappa-casein; the 25 000 Da protein migrated to the beta-position. The rabbit casein complex is composed of at least three caseins, two of which (alpha- and kappa-caseins) are analogous to the caseins from ruminants. Although caseins are poor immunogens, specific antibodies were raised against total and purified polypeptides. The antiserum directed against whole casein recognized each polypeptide, each casein corresponding to a distinct precipitation line. The antisera directed against each casein polypeptide reacted exclusively with the corresponding casein and no antiserum cross-reaction occurred between the three polypeptides. From whey, several proteins were isolated, characterized and used as antigens to raise specific antibodies. An iron-binding protein with an apparent Mr of 80 000 was shown to be immunologically and structurally identical with serum transferrin.
Amino Acids↗
Lymphomas and pseudolymphomas of the alimentary tract. An immunohistochemical study with clinicopathologic correlations.
One hundred one lymphoproliferative lesions of the gastrointestinal tract (66 malignant lymphomas, 20 pseudolymphomas, and 5 borderline lesions) were reviewed. The pathologic features were compared to the clinical findings, with reference to differential diagnosis and prognosis. Special attention was paid to immunohistochemical features. The gross appearance was diagnostic in only a limited number of cases. Endoscopic biopsy alone was also of limited value because only a diagnosis of probability could be made in several cases. In most of them the definitive diagnosis had to be based on histologic examination of the resected specimen. Immunohistochemical examination was found to be very useful as an ancillary diagnostic technique. Malignant lymphomas displayed either cytoplasmic immunoglobulins with a monoclonal pattern (47.1 per cent) or a negative reaction, whereas the pseudolymphomas were generally characterized by polyclonal immunoglobulins. Ninety per cent of malignant lymphomas with cytoplasmic immunoglobulins contained lambda chains. The survival probability was found to be related to the size of the lesion, the depth of infiltration, and the immunohistochemical characteristics of the tumors. The histologic type of the lymphomas was of limited value as a predictor of prognosis in the present series.
Animals↗