Interobserver variation in interpretation of serial liver biopsies from patients with chronic hepatitis C.

Reliable and accurate assessment of liver histopathology in patients with chronic hepatitis C is important for decision regarding treatment and for evaluation of therapy. However, little data on interobserver variation have been published. In this study, five specialist histopathologists evaluated 46 liver biopsies from 20 patients treated with interferon-alpha. Knodell's and Ishak's scoring systems, De Groote's classification and a four level general necro-inflammatory activity score (GNAS) were applied. Besides kappa statistics, slide by slide analysis was performed. We defined an acceptable slide by slide agreement as eight of ten observer pairs agreed on 80% of the slides. The best agreement was seen for Knodell's and Ishak's fibrosis score, De Groote's classification and GNAS (mean weighted kappa (kappa(w)) = 0.49, 0.51, 0.50 and 0.44, respectively). By condensing data from Knodell's and Ishak's scores to presence or absence of cirrhosis and piecemeal necrosis respectively, concordance was substantial concerning cirrhosis (mean kappa = 0.69 and 0.72, respectively) but only moderate concerning piecemeal necrosis (mean kappa = 0.40 and 0.39, respectively). Slide by slide analysis showed the highest agreement on Knodell's fibrosis score and GNAS; only one point of difference in score was to be accepted to obtain 'eight of ten' agreement. In contrast, five points of difference were necessary to accept in order to reach the same agreement for Knodell's total activity score. Moreover, in serial biopsies the GNAS was sufficient to detect changes in disease activity following treatment. Thus, a simple scoring system with four category scales was reproducible and sufficient for detection of therapy induced changes.

[Gastric carcinoid tumor in pernicious anemia]. / Karcinoid tumor i ventriklen ved perniciøs anaemi.

A case of a 39 year-old woman with recently diagnosed PA and a GCT is reported. Recent surveys have shown that GCTs occur far more frequently in patients with chronic atrophic gastritis type A (+/- PA) than previously noted. This may be due to an improved endoscopic technique and the use of specific immunostains, such as chromogranin A, which in our case was essential in avoiding the diagnostic pitfall of an adenocarcinoma. The pathogenesis and the management of type-1 GCT are discussed.

The soil fungus Chaetomium in the human paranasal sinuses.

Chaetomium is a soil fungus of which more than 180 species are now known. Most species cause degradation of cellulose-rich substrates, such as components in soil, straw or wood. Growth of Chaetomium globosum is often stimulated in the presence of Aspergillus fumigatus, which excretes such compounds as sugar phosphates and phospho-glyceric acid. A 73-year-old woman, with long-standing pain and secretion from her left maxillary sinus, was admitted to hospital where an infundibulectomy was performed. Histological examination showed necrotic material with hyphae of A. fumigatus and perithecia of Chaetomium sp. The latter fungus is rarely pathogenic to man.

Predicting prognosis of gastrointestinal smooth muscle tumors. Role of clinical and histologic evaluation, flow cytometry, and image cytometry.

Both flow cytometry (FCM) and morphometry have been proposed as techniques for predicting the prognosis of gastrointestinal (GI) smooth muscle tumors (SMTs). In particular, DNA aneuploidy by FCM has been associated with high histologic grade and shortened survival, whereas the DNA index determined by image cytometry has been proposed as a criterion for the diagnosis of malignancy. To further define the potential roles of these two techniques, we performed a variety of morphometric and FCM measurements on paraffin blocks from 122 patients with GI SMTs, with a median follow-up period of 6 years, together with assessments of tumor size and mitotic activity. None of the morphometric measurements (nuclear perimeter, area, form factor, longest diameter, average ferret diameter, equivalent diameter, and DNA index) was a significant prognostic factor when analyzed using a univariate Cox model. In contrast, the flow cytometric mean channel number, the fraction of cells in G2M, aneuploidy of the G0/G1 peak, aneuploidy of the G2M peak, tumor size, and mitotic activity index were statistically significant in univariate models, together with the patient age and sex, and whether or not the patient presented with metastases. In a multivariate model, > 10 mitotic figures per 50 high-power fields and metastases indicated a poor prognosis. If metastasis was not allowed to enter the model, the mitotic index and aneuploidy of the G2M peak portended a poor prognosis.

Carcinoembryonic antigen and carcinoids of the gastrointestinal tract.

We studied the prognostic significance of immunohistochemically localized carcinoembryonic antigen in 131 nonmetastasizing and 35 metastasizing gastrointestinal carcinoid tumors. The rate of positivity was lower with preabsorbed versus nonabsorbed polyclonal antiserum. Compared with generally used prognostic features (depth of invasion, tumor size, and mitotic rate) positivity for absorbed anticarcinoembryonic antigen was the most specific feature for metastatic tumors but was least sensitive. Although our results demonstrate that anticarcinoembryonic antigen, particularly when absorbed, is highly associated with metastatic disease, depth of invasion and tumor size are better predictors of behavior.

Carcinoid tumors of the duodenum. A clinicopathologic study of 99 cases.

Ninety-nine carcinoid tumors of the duodenum were studied. Seventy-seven patients were followed up for a mean period of 65 months, 20 tumors were autopsy findings, and two patients were unavailable for follow-up. Sixteen tumors (21%) produced metastases, all discovered initially; 3 patients (4%) died from metastatic disease (mean survival, 37 months postoperatively). Features associated with metastatic risk were involvement of muscularis propria, size greater than 2 cm, and the presence of mitotic figures. For 51 tumors, there was no correlation between immunohistochemical somatostatin and history of diarrhea, cholelithiasis, or diabetes mellitus (somatostatin syndrome). Five tumors were associated with Zollinger-Ellison syndrome and had immunohistochemical gastrin, but in the others there was no correlation between ulcer disease and gastrin positivity. Duodenal carcinoids are indolent, especially when small and localized to the submucosa. Immunohistochemical identification of somatostatin and gastrin has little clinical relevance.

Goblet cell carcinoids and related tumors of the vermiform appendix.

Appendiceal carcinoids with glandular differentiation pose difficulties in classification and prediction of clinical behavior. Sixty-four such cases were divided into three histologic groups on the basis of routine and immunohistochemical stains: (1) Tubular carcinoids were small and confined to the appendix, had small amounts of intraluminal mucin with few or no goblet cells, were nonargentaffin, lacked serotonin, and were diffusely positive for glucagon. All ten with follow-up (mean, 17 months) were without metastasis. (2) Goblet cell carcinoids were confined to the appendix and mesoappendix, circumferentially surrounded the appendiceal lumen, and were often not suspected grossly. Histologically, they were often mixed with small crypt-like glands and were serotonin positive. All 22 with follow-up (mean, 19 months) were without metastasis whether or not right hemicolectomy was performed. (3) Mixed carcinoid-adenocarcinomas showed spread into the cecum or adjacent viscera at the time of diagnosis and had a large carcinomatous pattern with areas of mucinous, signet-ring, or single-file structure, in addition to goblet cell or insular carcinoid. All patients had right hemicolectomies, and all but two with follow-up died of the disease (mean, 16 months). Although a histologic spectrum exists among carcinoid tumors and certain adenocarcinomas of the appendix, it is possible to delineate three biologically distinct groups. Surgical margins should be taken of all appendices because these tumors often do not form discrete masses.

Intra-abdominal fibromatosis. A pathologic analysis of 130 tumors with comparison of clinical subgroups.

We studied the clinical, gross, and histologic findings of 130 fibromatoses of the mesentery and other peritoneal sites. Seventeen patients had Gardner syndrome, 12 had prior abdominal surgery, and six had apparent estrogen elevation, including five pregnant or postpartum women and an alcoholic male with gynecomastia. The tumors were usually large and grossly circumscribed. Most often, they were located in the mesentery of the small bowel. They were multiple in 18 cases. Typical histologic features included a dense, collagenous stroma; prominent, dilated, thin-walled vessels; muscular hyperplasia of small arteries; keloidal change; myxoid change; and fibrous tissue insinuation into the muscularis propria of the bowel. Although mitoses were noted in many tumors, they were usually few in number. The gross and histologic features were similar in the clinical subgroups; however, keloidal change was seen less often in female patients. Less than half of the cases were initially correctly diagnosed. Most patients without Gardner syndrome were without recurrence at follow-up, even when the lesions had been incompletely excised.

Somatostatin-producing duodenal carcinoids in patients with von Recklinghausen's neurofibromatosis. A predilection for black patients.

Eight patients with von Recklinghausen's disease (VRD) and duodenal carcinoids are presented. Seven patients were black, and one white. Six of the eight were women. The presenting symptom was either jaundice or abdominal pain. All tumors were located in the second portion of the duodenum, and three were multiple. Associated tumors other than neurofibromas included multiple leiomyomas, meningioma, neurofibrosarcoma, and prostatic sarcoma. Seven tumors had psammoma bodies, and in three they were numerous. Somatostatin-positive cells were demonstrated in all cases. Two tumors had spread to regional lymph nodes at the time of surgery. There appears to be a predilection for black patients among those with VRD and duodenal carcinoids.

Rectal and colonic carcinoids. A clinicopathologic study of 84 cases.

Eighty-four carcinoids of the colon and rectum were studied with emphasis on prognostic features, immunohistochemical characteristics, and pitfalls in diagnosis. Follow-up data were available on 35 patients. Tumors with adenocarcinomatous components, or those resembling small cell carcinomas of the lung, were excluded. Eighty-one tumors were in the rectum and three tumors were in the distal sigmoid colon. Neuron-specific enolase, chromogranin, and Leu-7 were positive in 87%, 58%, and 53% of the tumors, respectively. Hormones were positive in the following percentages: serotonin, 45%; pancreatic polypeptide, 46%; glucagon, 10%; gastrin, 3%; somatostatin, 3%; adrenocorticotrophic hormone, 1%; cholecystokinin, 0%; calcitonin, 0%; and insulin, 0%. Many tumors elaborated more than one hormone. Fifty-five percent of the tumors were argyrophil and 28% were argentaffin. Carcinoembryonic antigen was present in 24% of the tumors; 82% of the tumors contained prostatic acid phosphatase. Three patients had liver metastases; their tumors ulcerated, invaded muscularis propria, and had more than 2 mitoses per 10 high-power fields (HPF). One patient with a 2.5-cm tumor without mitoses had regional lymph node metastases. All non-metastasizing tumors had less than one mitosis in 10 HPF. We conclude that large bowel carcinoid tumors are essentially limited to the rectum and sigmoid, that they are indolent if mitotically inactive and smaller than 2 cm, and that most show production of a selected group of endocrine markers.

Appendiceal carcinoids: correlation of histology and immunohistochemistry.

In order to compare histologic subtypes and endocrine profiles, immunohistochemical and silver stains were performed on 120 appendiceal carcinoids. Forty-three were predominantly insular; 21 were mixed insular, glandular, and trabecular; 33 were goblet cell; 17 were tubular; and five were clear cell carcinoids. Insular, mixed, and clear cell carcinoids were generally diffusely argentaffin and positive for chromogranin, neuron-specific enolase (NSE), and serotonin. Occasional tumors of insular or mixed patterns had scattered cells that stained weakly for glucagon, calcitonin, adrenocorticotrophic hormone (ACTH), somatostatin, cholecystokinin (CCK), human pancreatic polypeptide (HPP), or gastrin. Most had S-100-positive sustentacular cells. Less than half were positive for carcinoembryonic antigen (CEA). Many were cytokeratin-positive, but often focally. Goblet cell carcinoids contained few endocrine cells, but these were strongly argentaffin and positive for serotonin in nearly all, and positive for HPP in almost a third. Tubular carcinoids lacked argentaffinity and serotonin but were diffusely and strongly positive for glucagon. All goblet cell and tubular carcinoids were diffusely positive for CEA and cytokeratin. Somatostatin stained strongly in a single tumor, which had psammoma bodies and was in a patient with neurofibromatosis. In all groups, argentaffinity correlated with serotonin positivity, and argyrophilia with chromogranin positivity, although the latter was somewhat more sensitive. We conclude that among appendiceal carcinoids, the endocrine content varies according to histologic subtype.

Carcinoids of the duodenum. A histologic and immunohistochemical study of 65 tumors.

The light-microscopic and immunohistochemical characteristics of 65 duodenal carcinoids are presented. Most tumors showed a mixture of cribriform, insular, glandular, solid, and trabecular growth patterns. Eighty-five percent of the tumors were argyrophil and 15% argentaffin. The nonspecific neuroendocrine markers chromogranin, Leu-7, and neuron-specific enolase were positive in 97, 91, and 83% of tumors, respectively. Immunoreactivity for specific hormones/amines were as follows (percent positive tumors): somatostatin, 47%; N-gastrin, 56%; serotonin, 39%; calcitonin, 19%; insulin, 5%; pancreatic polypeptide, 3%; adrenal corticotropic hormone, 0%; glucagon, 0%. Sixty-eight percent had gastrin/cholecystokinin-like reactivity. Ten psammomatous tumors were located near the ampulla; eight were somatostatin positive, including two in patients with neurofibromatosis. One additional tumor in a patient with neurofibromatosis lacked psammoma bodies but elaborated somatostatin. Eight additional tumors in nonneurofibromatosis patients produced solely somatostatin. Duodenal carcinoids often elaborate more than one polypeptide hormone; those in the ampulla often elaborate somatostatin and have psammoma bodies.

Morphometry and cytophotometric assessment of DNA in smooth-muscle tumors (leiomyomas and leiomyosarcomas) of the gastrointestinal tract.

The difficulties in predicting the biologic behavior of gastrointestinal (GI) smooth-muscle tumors (leiomyomas and leiomyosarcomas) based on the usual criteria of malignancy are discussed. In order to evaluate the prognostic importance of the nuclear DNA content and nuclear dimensions, measurements were performed on Feulgen-stained sections of GI smooth-muscle tumors from 66 patients. The best discrimination between benign and malignant tumors was obtained by using DNA index and tumor size as descriptors in a linear discriminate analysis. This method separated 79% of the benign and 97% of the malignant smooth-muscle tumors. However, as with conventional criteria for malignancy, there remained a group of tumors close to the discriminating line with an indeterminate malignant potential. In an attempt to reduce the number of such indeterminate tumors, future studies will include the use of several descriptors in a multivariate analysis system and the application of flow cytometric studies to all tumors.

The effect of blood-transfusions on renal allograft survival.

The relation between previous bloodtransfusions and renal allograft survival was studied retrospectively in 88 patients, who had been transplanted for the first time. The allograft survival rate was higher in the group who had received bloodtransfusion than in the group who had not. This difference was significantly greater when considering patients who had not previously been pregnant, e.g. patients without previous stimulation of the immuno system. The material shows no difference in allograft survival between previously transfused and non transfused patients, when considering age, sex or disease of kidney. In this retrospective study it is concluded that previous transfusions improved the prognosis of the transplantation. A prospective study has yet to be done, in order to enlighten the influence of various other factors on the allograft survival rate such as length of period or uraemia and of dialysis.