[Malacoplakia of the female genital tract in a woman with postmenopausal bleeding]. / Malacoplakie van de tractus genitalis bij een vrouw met postmenopauzaal bloedverlies.

A 74-year-old woman had vaginal bleeding for 6 months with no other complaints. A suspected tumour was visible on the cervix and the endometrium was slightly thickened. Histological examination revealed Michaelis-Gutmann bodies. Following antibiotic treatment, the tumour and the bleeding disappeared. Malacoplakia is a chronic inflammation which usually arises in the urinary tract of older women and, rarely, in the female genital tract. The abnormality often appears to be a malignancy, although histologically it is an inflammatory condition. Histological examination is necessary to establish the diagnosis. Treatment usually consists of antibiotics and surgical excision.

Increase of Helicobacter pylori-associated corpus gastritis during acid suppressive therapy: implications for long-term safety.

OBJECTIVES: Helicobacter pylori causes chronic active gastritis with predominant localization in the gastric antrum. This predisposes to development of mucosal atrophy, intestinal metaplasia, and eventually, gastric cancer. The effects of acid suppression on H. pylori infection and associated gastritis are unclear. However rapid development of atrophic gastritis has been consistently observed in a number of studies during low acid output. We therefore studied the histological features of antrum and corpus of the stomach before and during acid suppressive therapy. METHODS: Fifty patients with either reflux esophagitis (n = 21), benign gastric ulcer (six patients), gastric erosions (three patients), or duodenal ulcer (20 patients) were treated for 8 wk with omeprazole 40 mg o.d. Esophagogastroduodenoscopy was performed pre-entry and at 8 wk. Biopsy specimens were sampled from the antrum and corpus for histology and cultures. RESULTS: Seventeen H. pylori-negative patients had no histological signs of active gastritis, before or after therapy. Thirty-three H. pylori-positive patients showed predominant colonization and associated inflammation in the antrum before therapy. After therapy, however, the infection predominantly affected the corpus. The inflammation and bacterial colonization in the antrum significantly decreased, leading to negative antral cultures in 61% (20 of 33 patients). In contrast, the inflammation of the corpus mucosa significantly increased despite stable bacterial counts. CONCLUSIONS: We conclude 1) that H. pylori testing in patients on profound acid suppressive therapy should be performed on combined corpus and antral specimens, and 2) that omeprazole therapy leads to a strong increase in corpus gastritis, which may explain the observed development of corpus atrophy in a substantial number of patients after several years of continuous acid suppressive treatment. Therefore, we suggest that patients in need of long-term acid suppressive therapy should receive bacterial eradication therapy if they are H. pylori positive.

Long-term sequelae of Helicobacter pylori gastritis.

Chronic Helicobacter pylori gastritis has been put forward as a risk factor for development of gastric mucosal atrophy and gastric cancer. The purpose of our study was to investigate the long-term effects of H pylori gastritis on the gastric mucosa. We prospectively studied 49 subjects negative for H pylori and 58 positive subjects for a mean follow-up of 11.5 years (range 10-13 years). Serum samples were obtained at the initial and follow-up visits for determination of H pylori IgG antibodies. Gastroscopies with biopsy sampling were done in all patients at both visits. Biopsy specimens were used for assessment of H pylori infection and histology. Development of atrophic gastritis and intestinal metaplasia occurred in 2 (4%) uninfected and 16 (28%) infected subjects. Regression of atrophy was noted in 4 (7%) infected subjects. Development of atrophic gastritis and intestinal metaplasia was significantly associated with H pylori infection (p = 0.0014; odds ratio 9.0, 95% CI 1.9-41.3). The proportion of atrophic gastritis in the study population showed an annual increase of 1.15% (0.5-1.8%). We conclude that H pylori infection is a significant risk factor for development of atrophic gastritis and intestinal metaplasia. Our findings support strongly the causative role of this infection in gastric carcinogenesis.

Importance of the fiberoptic endoscope cleaning procedure for detection of Helicobacter pylori in gastric biopsy specimens by PCR.

A 16S ribosomal DNA-based PCR appeared to be a sensitive test for the detection of infection by Helicobacter pylori in 31 patients when compared with culturing and histological and serological techniques. For five patients, PCR was the only test with a positive result. H. pylori DNA was also found in gastrointestinal equipment even after standard intensive combined manual and machine cleaning. We therefore conclude that a reliable validation of PCR for the detection of H. pylori in gastric biopsy specimens is possible only when the cleaning and disinfection method used has been proven to remove all H. pylori DNA from gastrointestinal equipment. An adequate cleaning and disinfection method for the removal of H. pylori DNA from fiberoptic endoscopes is described.

MAb U36, a novel monoclonal antibody successful in immunotargeting of squamous cell carcinoma of the head and neck.

Using viable cells of a human head and neck squamous cell carcinoma (HNSCC) cell line as immunogen, we developed monoclonal antibody (MAb) U36. Immunohistochemical examination revealed distinct surface labeling of MAb U36 with normal human squamous epithelium and squamous cell carcinomas of distinct sites of origin; head and neck, lung, esophagus, cervix, and epidermis. MAb U36 shows high affinity binding (affinity constant, 3.5 x 10(10)/M) with a cell surface antigen expressed by in vitro cultured HNSCC cell lines. Similarity of the reactivity profiles of MAb U36 and MAb E48, currently the most promising antibody described for specific targeting of HNSCC in patients, warranted further comparison of these MAbs. MAb U36 recognizes a M(r) 200,000 antigen, which is different from the MAb E48 defined antigen. Furthermore, comparison of immunohistochemical staining patterns of MAb U36 and MAb E48 on a broad panel of primary HNSCC sections revealed more extensive staining for MAb U36: more tumors showed reactivity with MAb U36 and more tumor cells per tumor showed positive reaction, and staining was found to be more intense. MAb U36 does not show cross-reactivity with mouse, rat, pig, sheep, or bovine tongue epithelium. As a first approach to evaluate the suitability of MAb U36 for tumor targeting in vivo, radiolabeled MAb U36 was administered to athymic nude mice bearing human HNSCC xenografts on both flanks. Selective tumor accumulation of the radioimmunoconjugate was observed. Mean tumor uptake (in percent injected dose/g wet-weight of tissue) of MAb U36 at days 1, 2, 3, 5, 7, and 12 was 15.1, 17.9, 24.0, 21.0, 25.8, and 16.0%, respectively. The tumor to blood ratio at day 1 was 0.9 and increased up to 3.8 at day 12. The tumor uptake at day 12 was at least 10 times higher when compared to other tissues. The corollary of these findings is that MAb U36 harbors high potential for specific targeting of HNSCC.

Seroconversion for Helicobacter pylori.

The prevalence of Helicobacter pylori antibodies increases with age, but it is unknown whether this is due to a constant rate of infection in different age groups, or whether most infection occurs in childhood. Follow-up data on infection rates and the course of infection in an untreated population are scarce. We measured H pylori IgG antibody concentrations in patients who were seen at our endoscopy unit between 1979 and 1983. 115 of 164 eligible patients (70%) participated in the study. H pylori IgG antibody concentrations were measured in two serum samples taken with a mean interval of 11.5 years. 56 patients tested positive at the first visit. During follow-up, 2 patients became infected (annual infection rate 0.30%, 95% Cl 0.04-1.08%). Evidence of infection disappeared in 6 patients: after gastric surgery in 3 and due to an unknown cause in the remaining 3 patients. A non-significant decrease of infection was shown in different age cohorts during follow-up. Antibody concentrations did not increase with age. These results strongly support the concept of dominant infection rates in childhood. Elimination of infection may occur in a few patients without eradication therapy.

Prognostic value of morphometry and DNA flow-cytometry features of invasive breast cancers detected by population screening: comparison with control group of hospital patients.

Using the prognostic value of morphometric and flow-cytometric features, a group of patients with invasive breast cancers detected with population screening (PS, n = 70) has been evaluated and compared with a random control group in 2 hospitals (H group, n = 225) diagnosed in the same period. The results show that the PS patients had smaller tumors, less positive lymph nodes, better differentiated tumors with a lower mitotic activity index (MAI) and lower values of the morphometric prognostic index (MPI). Furthermore, the women more frequently had diploid tumors and tumors with small nuclei. The second purpose was to evaluate whether quantitative microscopical features, in comparison with other prognostic features such as size of primary tumor, nodal status and histologic grade, are as strong prognosticators in PS tumors as in H-detected breast cancers. In comparison with H tumors, morphometric and flow-cytometric features, as well as tumor size, had the same prognostic value for the PS tumors. In contrast, nodal status was not significant within the PS group, and the same phenomenon was found in a subgroup of H patients with similar sized tumors. Of all quantitative microscopical features (MPI, MAI, mean nuclear area (MNA) and DNA Index (DI], the MAI had the strongest prognostic value. DI showed additional prognostic value to the MAI for patients with small tumors and with small tumor-cell nuclei, because a diploid pattern in these cases (this combination occurred in 21 patients of the total group = 30%) was correlated with a 95% 10-year survival rate. Histologic grade, although significant within the large H group, was of no prognostic value within the PS group, and also not as in the H sub-group with small tumors. It is concluded from morphometric and DNA flow-cytometric criteria that these prognostic features in invasive breast cancers detected by PS were all more favorable than in randomly detected hospital breast cancers. This may account for the reported better survival rate of PS patients. Furthermore, the prognosis of patients with small invasive breast cancers detected by population screening can be more accurately deduced by quantitative microscopical features than by axillary-lymph-node status.

DNA measurement errors with a scanning microdensitometer in cytologic and histologic samples of breast cancers.

The influence of various DNA measurement errors using a commercially available scanning microdensitometer was evaluated on Feulgen-stained cytologic and histologic samples prepared from paraffin blocks containing invasive ductal breast cancers. The overall average total measurement error was 5.5% for the cytologic specimens and 10.9% for the 4 micron histologic sections. Components of the error included microscopic adjustment variation and focussing errors (3.5% and 1.1%, respectively, for both cytologic and histologic samples) and background intensity estimation errors (3.0% for the cytologic samples and 10.0% for the histologic samples). Measurements of the integrated optical density had a minimal error of 0.5% and an average error of 1.0%. Limitations due to the histologic architecture and/or heterogeneous cell population gave rise to large differences in the selection of nuclei when differently sized scanning masks were used. To improve the reproducibility, masks used should be based on the individual cell size, and background intensity values should be carefully estimated in the vicinity of the selected cells. Overall, the cytologic tumor samples were preferable to the histologic samples for static DNA measurements. It was easier to select cells suitable for measurement in the cytologic samples, and the cytologic measurements were less time consuming and produced a smaller measurement error.

The prognostic significance of selective nuclear morphometry in urinary bladder carcinoma.

Transurethral resected tumor specimens of 61 patients with a primary and untreated bladder carcinoma were studied by selective nuclear morphometry, a method recently described by us. A significant enlargement of the mean nuclear area was found with the advance of tumor grade and stage (Wilcoxon, P less than .0001 and P less than .0001). The heterogeneity of the grade 2 patient group and the additional value of morphometry were demonstrated by observing the 5-year survival rates. Patients with grade 2 carcinoma could be separated into one subgroup with small nuclei (mean nuclear area less than or equal to 95 microns2) having a favorable outcome (5-year survival rate: 100%), and into another subgroup with large nuclei (mean nuclear area greater than 95 microns2) showing a worse prognosis (5-year survival rate: 63.2%) (Mantel-Cox, P = .01). The outcome of these subgroups was not significantly different from that of the grade 1 (5-year survival rate: 93.8%) and grade 3 (5-year survival rate: 50%) patients, respectively (Mantel-Cox, P = .45 and P = .57). The value of selective nuclear morphometry, in addition to tumor staging, was indicated by the association of nuclear enlargement (mean nuclear area greater than 95 microns2) with progressive recurrence (five of 15 patients; 33%) among the patients with conservatively treated superficial carcinoma (stages Ta and Tl). The findings demonstrate the supplementary value of selective nuclear morphometry to tumor grading and staging, especially in the heterogeneous group of grade 2 carcinomas and the group of superficial tumors (stages Ta and Tl).

Further evaluation of the prognostic value of morphometric and flow cytometric parameters in breast-cancer patients with long follow-up.

The added prognostic value of cellular DNA content compared with single and combined morphometric factors and classical parameters such as tumor size, nodal status, histologic grade and estrogen receptor (ER) content was investigated in 225 consecutive breast-cancer patients with long follow-up. Of all features investigated, the MPI (multivariate prognostic index) had the strongest prognostic value [Mantel-Cox (MC) = 48.2, p less than 0.00005]. The results further showed that neither age nor ER content had significant prognostic value, but the DNA index (DI) as a single parameter had (though weak) prognostic significance (MC = 5.9, p = 0.015); a similar result was obtained with the percentage of S-phase cells (MC = 6.1, p = 0.013). The DI had (restricted) additional prognostic value to the morphometric features (MPI plus DI Mantel-Cox 53.0, p less than 0.0001). The percentage of S-phase cells had no additional prognostic value over the MPI. On the other hand, the additional value of the DI over tumor size and nodal status was much more impressive (MC = 41.0 and 40.7), although it did not reach the prognostic significance of the MPI. Prediction of disease outcome with a linear combination of quantitative microscopical parameters of the primary tumor alone [MAI (mitotic activity index), DI and mean nuclear area] was very accurate, even without considering lymph-node status (MC 30.8, p less than 0.0005). Grade had no additional value to the MPI at all (p = 0.76). This could be especially important for lymph-node-negative patients in whom the prognostic value of the MPI and the MAI are confirmed.

Reproducibility and comparison of quantitative DNA histogram features obtained with a scanning microdensitometer and a flow cytometer in breast cancers.

A pilot study compared DNA histogram features of ten invasive ductal breast cancers measured by three different techniques: in cytologic and histologic samples using a scanning densitometer and in suspensions of single nuclei using a flow cytometer. The reproducibility of measurements pertaining to quantitative ploidy factors was better for flow cytometry (FCM) than for static cytometry and was worst of all using histologic samples. The use of external reference cells for the precise determination of the diploid value in measurements of paraffin-embedded single nuclei proved to be pointless. Of all static histogram descriptors, the modal value was the most reproducible; however, this feature could not distinguish between diploid and near-diploid tumors. In contrast, using the descriptors of (1) diploid peak width, (2) coefficient of variation of the integrated optical density values and (3) percentage of cells exceeding 2.5c from histograms derived from static measurements, it was possible to distinguish between tumors that were characterized as diploid and near-diploid by FCM (chi-square P = .01). This is the more important because subjective analysis of the static histograms of these tumors failed to identify a cell population deviating from the diploid value in spite of the fact that the FCM DNA index (DI) varied from 1.12 to 1.23. Thus, quantitative histogram descriptors, as evaluated in this study, may add objective information to the measurement of DNA ploidy when using static DNA cytometry, especially in the case of near-diploid tumors. Duplicate FCM assessments of the DI showed the highest correlation of all features investigated (r = .99).

Bronchopulmonary carcinoids and regional lymph node metastases. A quantitative pathologic investigation.

Bronchopulmonary carcinoid tumors are tumors with a low malignant potential. They metastasize in 5-15% of cases. Accurate histologic preoperative prediction of the presence of regional lymph node metastases is not possible at this time. A retrospective quantitative pathologic analysis was performed to investigate the possibility of predicting the presence or absence of regional lymph node metastases in 24 patients with bronchopulmonary carcinoid tumors. The results of univariate analysis showed that large tumor size was associated significantly more frequently with regional lymph node metastases than small tumor size (P less than 0.01). The other quantitative features, ie, a larger mean nuclear area, higher standard deviation of the nuclear area and the presence of an aneuploid DNA index, were frequently associated with regional lymph node metastases, but this tendency was not significant. In multivariate analysis the combination of tumor size and mean nuclear area predicted the presence or absence of regional lymph node metastases correctly in 80 and 94% of the cases, respectively. These results indicate that the combination of tumor size and mean nuclear area may serve as a guideline to predict the presence of regional lymph node metastases.

Limited prognostic value of cellular DNA content to classical and morphometrical parameters in invasive ductal breast cancer.

This retrospective study evaluates several prognostic factors in 63 patients with invasive ductal breast cancer. Special attention is paid to the additional prognostic value of cellular DNA content to the previously developed and evaluated quantitative features mitotic activity index (MAI) and multivariate morphometric prognostic index (MPI). Follow-up was monitored for at least 50 months (median survival, 78 months) and only patients who died of distant metastases were included. The results show that the MAI is the strongest prognostic factor of all single features (Mantel-Cox, P = 0.008). Although patients with a diploid or tetraploid tumor tended to have a better prognosis than those with an aneuploid cancer, the DNA index as a single parameter was a weak prognosticator in the univariate survival analysis (Mantel-Cox, P = 0.24). Within the diploid and tetraploid tumors the MAI could distinguish patients with a favorable and unfavorable prognosis prediction (chi-square, P = 0.01). For aneuploid tumors this was not possible. Analysis of combined features revealed that the MPI has a high prognostic value (Mantel-Cox, P = 0.0015), thus confirming other studies. A linear combination of the nuclear DNA index, MAI, nodal status, and mean nuclear area showed only a slight improvement in prognosis prediction compared with the MPI (Mantel-Cox, P = 0.0005); with this rule, the classification of the patients was more in agreement with the actual outcome in 4% of the cases. The gain was in the poor prognosis group. These results suggest that the additional prognostic value of nuclear DNA content is restricted when compared with the morphometric prognostic factors. Further studies on a larger number of patients are required to confirm these findings.

Comparison of extent of disease and morphometric and DNA flow cytometric prognostic factors in invasive ductal breast cancer.

In 65 patients with primary invasive ductal breast carcinoma the relation between classic prognosticators describing the extent of disease (lymph node metastases and tumour size) and newer promising morphometric and DNA flow cytometric prognostic factors was studied. There was no relation between DNA ploidy, lymph node state, and tumour size. Tumours with a mitotic activity index of more than 10 were predominantly DNA aneuploid (61%) compared with those with a mitotic activity index of less than 10 which showed a DNA aneuploid pattern in 27%. The strongest prognosticator, the morphometric prognostic index (a multivariate combination of mitotic activity index, tumour size, and lymph node state) correlated positively with the DNA index in 63% of the cases (p = 0.038). Thus there was a discrepancy between the morphometric and DNA flow cytometric prognostic variables in 37% of the cases. These results indicate that morphometric and flow cytometric analysis may provide additional information on the prognosis in primary breast cancer.

Evaluation of the prognostic value of morphometric features and cellular DNA content in FIGO I ovarian cancer patients.

Approximately 20% to 40% of the patients with a FIGO I ovarian tumor die within five years after the diagnosis. Morphologic studies (typing and grading) of the primary tumor are prognostically important, but poorly reproducible. Therefore, the prognostic value of more objective techniques, such as morphometry and flow cytometric (FCM) DNA determinations, were evaluated in 33 adequately staged FIGO I patients with at least a five-year follow-up. The overall five-year survival in the group was 64%. Three patient categories were defined on the basis of two easily measured morphometric features, the mitotic activity index (MAI) and the volume percentage epithelium (VPE), which an earlier study had proved to be significantly associated with prognosis. The five-year survival rates were 91% for 11 patients in category A (MAI less than 30 and VPE less than 65), 67% for 9 patients in category B (MAI less than 30 and VPE greater than or equal to 65) and 38% for 13 patients in category C (MAI greater than or equal to 30). FCM showed 25 of the tumors to be diploid and 8 to be aneuploid. The cellular DNA content was also of prognostic value: the five-year survival figures for patients with diploid and aneuploid tumors were 68% and 37%, respectively. Combination of the morphometric and FCM features showed that, in diploid tumors, the morphometric features have additional prognostic value: the diploid-tumor-patient survival rates in categories A, B and C were 91%, 63% and 50%, respectively. None of the eight patients with aneuploid tumors fell in the morphometrically favorable category A while seven were in category C.(ABSTRACT TRUNCATED AT 250 WORDS)