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Background. In this study the MIB-1 immunostaining pattern as an index of cellular proliferation was analyzed in smears diagnosed as borderline dyskaryosis in order to establish whether the combination of human papillomavirus testing and MIB-1 staining could resolve equivocal cytology. Methods. Conventional Pap smears of 108 women diagnosed as borderline dyskaryosis were stained with MIB-1 and the proliferation index was assessed. These women were evaluated by colposcopy, histological sampling, and human papillomavirus, semi-quantitative evaluated by hybrid Capture II test. Results. All 64 human papillomavirus- and MIB-1-negative women had no underlying high-grade cervical intraepithelial neoplasia or cervical cancer. Forty of the 104 women with normal histology or cervical intraepithelial neoplasia I were positive for human papillomavirus, compared to only one positive MIB-1 test (i.e. proliferation index of more than 35%). Conclusions. Adding a MIB-1-test in human papillomavirus-positive women with equivocal cytology might reduce the number of colposcopies needed to predict ≥ cervical intraepithelial neoplasia II. With this approach only four instead of 43 human papillomavirus-positive women would have been referred for colposcopy.

1) To assess the regression to normal cytology in women with cervical smears diagnosed as atypical squamous or glandular cells of undetermined significance (ASCUS/AGUS) and absence or clearance of human papillomavirus (HPV) infection; 2) To evaluate the association between viral load, semi-quantitatively evaluated, and cytological or histological outcome.In this cohort study HPV test and biopsy was taken in 148 women with ASCUS/AGUS cytology. After 12-18 months a HPV test and cervical smear were repeated in 121 women.Absence or clearance of HPV showed significantly more regression to normal cytology than persistent or newly acquired infected women, odds ratio 27 (95% confidence interval; 7-103). The viral load of the HPV test at enrollment was not correlated with the follow-up cytological outcome (Spearman correlation coefficient 0.2, p = 0.2). A marked association between viral load and histological outcome at enrollment was shown (Spearman correlation coefficient 0.43, p0.0001).Absence or clearance of HPV can predict regression to normal cytology. Viral load at enrollment cannot predict cytological regression. There was a marked association between viral load and the underlying CIN at enrollment. However, there was large overlapping of viral loads among the grades of CIN. Therefore, viral load is not a useful parameter to predict high-grade lesions in women with ASCUS/AGUS cytology.

The urinary bladder is lined by highly specialized epithelium, so-called urothelium or transitional cell epithelium. One specific characteristic of this urothelium is the ability to protect the human body against reabsorption of toxic elements excreted by the kidney. The constantly changing volume of urine in the bladder requires a high degree of stretching of the covering epithelium, while maintaining an intact barrier function. Unfortunately this highly specialized epithelium shows a strong tendency to develop neoplastic disease. In most industrialized parts of the world, bladder cancer constitutes an important issue in oncological health care (Rubben 1985).

To determine the degree of specificity of the cellular immune response in cervical carcinoma, that is known to be human papillomavirus-related, we investigated the exact relationship between in situ tumor-infiltrating immune cells and the monomorphic/allele-specific HLA expression on the tumor cells.Attention was focussed on the type, location and number of in situ immunocompetent cells in malignant cervical tissue (N = 30). Immune cell distribution was quantitatively assessed by morphometry for stromal and tumor tissue separately. These results were related to the degree of expression of monomorphic- and allele-specific HLA I and II antigens on the cervical tumor cells.In monomorphic HLA class I downregulated cervical tumors, a significant decrease in tumor-infiltrating CD8+ T cells was observed. However, allele-specific downregulation of respectively HLA-A2, HLA-A3, HLA-Bw4, and HLA-Bw6, did not correlate significantly with a decrease in tumor-infiltrating immune cells. For HLA class II-positive cervical tumors, HLA-DR expression significantly correlated with an increase in the presence of tumor-infiltrating CD3+/CD4+/CD8+ T cells, CD56+ natural killer cells and CD16+ macrophages. No significant correlations were found between alterations in HLA class I or II expression on the tumor cells and stromal infiltrating immune cells.Our observations provide in situ immunomorphologic evidence that in cervical carcinoma, de novo expression of HLA class II antigens on the tumor cells resulted in an increase of tumor-infiltrating immune cells. In addition, the tumor-infiltrating CD8+ T lymphocytes correlated with monomorphic HLA class I expression on the tumor cells, which stresses the existence of a HLA-restricted immune response of T lymphocytes in cervical carcinoma. These findings might have implications for the biologic behavior of this disease and have to be taken into account in strategies concerning immunotherapy of cervical carcinoma.

The case is described of a patient with fulminant hepatic failure attributed to intake of glafenine 400 mg daily for 15 days. The first symptoms appeared two weeks after discontinuation of glafenine. Other causes of hepatic necrosis could be excluded. Approximately five weeks after the onset of symptoms the patient died of hepatic failure. At autopsy massive hepatic necrosis and massive pancreatic necrosis were demonstrated.

Islet amyloid polypeptide is a recently discovered pancreatic polypeptide hormone which is produced by the B-cells of the islets of Langerhans and is co-secreted with insulin. IAPP is the formative protein in islet amyloid depositions in type-2 diabetes patients and in some non-diabetics.

The general aspects of sarcoidosis are presented, as well as some concepts derived from experimental work. Thereafter, a review of the literature on oral involvement in sarcoidosis is given, including the possible value of an oral biopsy in the case of suspected sarcoidosis. Finally, 3 patients — 2 with known sarcoidosis and 1 with unsuspected sarcoidosis — are presented as a brief illustration.

The case of a 64-year-old man with “ adenosquamous ” mesothelioma of the pleura is described. These two elements were intimately associated, which suggested that they formed an integral part of the tumor. To the authors, pluripotentiality of the mesothelium seems essential for the pathogenesis of this unusual neoplasm.

The introduction of a simple one-stage silver nitrate stain as a method of displaying nucleolar organizer regions (NOR's) in formalin-fixed tissue has made it possible to examine the significance of these structures in tumour pathology. In the current study argyrophilic proteins of the NOR's were studied in 39 consecutive patients with bladder tumours. The results indicate that the counting of silver staining particles is only of limited value in grading bladder tumours and that this method is not superior to other additional grading techniques such as histo-morphometry and flow cytometry.

The authors describe the results of the grading of bladder tumors using morphometry and then compare these with results of histologic grading of the same tumors by different pathologists. Nuclear sizes of cells obtained from superficial and deep cell layers of each carcinoma and from giant cells were measured in 27 cases in which histologic tumor grading by different pathologists was unequivocal. In cells from all three areas, nuclear area increased with higher tumor grade. However, tumors of grades I and II showed significant differences in the size only of the large cells. It is concluded that morphometry is a valuable tool in the objective grading of bladder tumors, with the exception of carcinoma in situ lining the bladder lumen.

The stromal characteristics in papillary and non-papillary tumours of the urinary bladder were investigated in an attempt to improve the accuracy of histopathological diagnosis. It appeared to be possible to differentiate true papillary tumours from pseudopapillary structures lined by carcinoma in situ. Stromal differences were not found in cases of carcinoma in situ accompanied by denuding cystitis and cystitis due to other aetiological factors. It is concluded that histopathological examination of the stroma of bladder tumours improves diagnostic accuracy.

In order to test the reproducibility of a histomorphometrical grading system of bladder tumours, 15 tumours were twice measured independently by three pathologists. The data obtained were then analysed and compared with that of histological grading only. The way in which these morphometrical results are presented to the clinician in a computerized report is described. The need for a satisfactory reliable reproducibility test of every histomorphometrical grading system before introduction in diagnostic pathology is discussed.

Thirty men and 7 women with malignant mesothelioma seen at the Free University Hospital from 1st January 1960 until 1st July 1981 were reviewed. The histological, histochemical and morphometrical findings are reported. These findings are compared with 25 cases of pleural metastatic carcinoma and 25 cases of reactive pleural lesions. Fourty-nine percent of malignant mesotheliomas produced hyaluronic acid, however all cases of pleural metastatic carcinomas failed to produce this substance. All cases of malignant mesothelioma were D-PAS negative while 15 cases of pleural metastatic carcinoma showed reactivity to D-PAS. All cases of malignant mesothelioma and 9 cases of metastases were CEA negative. To distinguish malignant mesothelioma from metastases it is advisable to perform the D-PAS staining first. If it is negative mesothelioma can be confirmed by showing hyaluronic acid activity. A positive CEA staining rules out mesothelioma. In our study it was shown that with these methods 18 of 37 mesotheliomas could be identified with certainty, and 22 of the 25 carcinoma metastases. Morphometrically the malignant mesotheliomas could not be distinguished from the metastases, however the reactive pleural lesions had smaller nuclei than the malignant cells with mean values below 30 mu2. In the malignant cases these values had a range from 36 to 101 mu2. In distinguishing between reactive pleural lesions and malignant mesothelioma the production of hyaluronic acid points to the malignant character of the lesion. Thus histochemistry and immunostaining are important in the distinction of malignant mesothelioma from metastases, while the value of morphometry lies mainly in the seperation of reactive lesions from malignant mesothelioma.

In three of 52 consecutive patients with a painful mass in the right lower quadrant, ultrasound (US) disclosed severe mural thickening of the terminal ileum and cecum and moderate mural thickening of the appendix. In all three, the tentative diagnosis of Crohn disease was subsequently confirmed. If these US features are found in a patient with a suspected appendiceal mass, the diagnosis of Crohn disease must be seriously considered, and further evaluation is imperative.

A quantitative analysis of the lipid vacuoles in benign hypertrophic and neoplastic mesothelial cells, using a size-independent distribution index, showed that computer-assisted image analysis for distribution patterns of cytoplasmic components can aid in distinguishing benign from malignant cells. Benign mesothelial cells had fewer lipid vacuoles, which were smaller and predominantly found around the nuclei. It is argued that, due to the high surface tension in the lipid vacuoles, the largest vacuoles are found in the center of the cells, which is the least flattened part of the air-dried mesothelial cells. It seems likely that the distribution pattern of rigid substructures, such as lipid vacuoles, varies between histologic and cytologic material as well as between cells processed by different cytologic methods with various cell-flattening artifacts. The study of the distribution of cytoplasmic components that differ in size was enhanced by using the defined size-independent distribution index, which incorporates the radius of the cell, the radius of the vacuoles and their respective centers of gravity.

Summary The case of a 66 year-old women with a peritoneal mesothelioma is described, which manifested itself as a tumor in the umbilical region. The clinical, cytological, histological and electron microscopical features of the tumor are reported. The diagnostic problems of this tumor are discussed.

Levamisole (1.1–3.8 mg/kg daily) or a placebo was given in a randomized, double-blind study to 211 patients undergoing curative surgery for primary lung cancer. The treatment, in a fixed dose of one tablet (containing 50 mg or a placebo) t.i.d., was given for 3 days before the operation, and such 3-day courses were repeated every 2 weeks thereafter for 2 years. A significant reduction of the cancer mortality was observed at 18 and 21 months post surgery in the levamisole group. There was also a nonsignificant increase of the disease-free interval. In patients who had received more than 2 mg/kg (or more than 80 mg/m2) daily, the crude recurrence rates had been halved and the death rates reduced to one-third. No beneficial effect could be observed in the patients who had been given a lower dose. In the former, adequately dosed patients, the beneficial effect was more marked if the tumor had been more advanced at the time of surgery. In addition, the incidence of hematogenous secondaries was significantly reduced in the same group of patients.

Cells exfoliated from primary pleural mesotheliomas differ significantly from those from primary peritoneal tumors. In a quantitative study, it was shown that the pleural cells have larger nuclei, a more pronounced anisokaryosis and a higher nuclear-cytoplasmic ratio and, therefore, appear more malignant than the peritoneal cells, which have abundant cytoplasma and small nuclei. The differences in quantitative parameters were due to a more extensive vacuolization and consequent cytoplasmic distension, combined with nuclear compression in the case of peritoneal mesotheliomas. The morphometric parameters and the vacuolization patterns of cell populations in cases with both pleural and peritoneal involvement correlated with the data of the primary tumor regardless of the fluid in which the cells were found. This finding indicates the transcoelomic metastatic properties of malignant mesothelioma.

Guinea pigs were immunized intracutaneously into the ears with sheep red blood cells (SRBC). Application of a sensitizing dose of the contact allergen dinitrochlorobenzene (DNCB) onto the same ears was shown to suppress or enhance the humoral response to SRBC depending on the time of application. When guinea pigs were sensitized to a contact allergen, application of a sensitizing dose of a non-related allergen on the same ears either had no effect or caused a clear enhancement of the development of delayed type hypersensitivity (DTH). Strongest enhancement was found when both sensitizations were performed on the same day. Further experiments on the effects of a concomitant DTH reaction elicited at the site of application of a contact allergen showed a strong potentiation of DTH when B-cell suppression was minimized by pretreatment with cyclophosphamide (CY). It was considered that CY-DTH-immunopotentiation might be a useful tool for achieving a higher level of sensitivity after epicutaneous sensitization.

In a detailed study of granulomas in lymph nodes of 19 patients with Sarcoidosis we assessed and correlated a number of features, with size, development and radiographic staging of the disease. Except with the epithelioid cells the number of constituent cells (lymphocytes, giant cells and polymorphs), size, confluency and degree of necrosis of the granulomas were found to be very variable within a single gland. This indicates that the granulomas are in different stages of activity at a given time. All the features studied showed little or no correlation with the radiographic staging, which suggests that the latter is not a good index of the extent of the disease.

In view of the discouraging results that have been obtained so far with the use of cytotoxic chemotherapy as an adjunct to surgery, a double-blind placebo-controlled evaluation of the adjuvant use of levamisole was conducted in 211 resectable lung cancer patients, following these patients for 2 years after their operation. Levamisole (or the placebo) was given for 3 days every 2 weeks and the dose level ranged 1.1--3.8 mg/kg per day (a fixed dose of 3 x 50 mg was given to all patients). It appeared that recurrences and carcinomatous deaths had occurred significantly less often in patients who had received a high dose (i.e., 2.1--3,8 mg/kg: patients weighing 70 kg or less) but not in the patients who received a lower dose. Patients who had more advanced cancers at the time of surgery seemed to have profited more from the treatment, but the results did not seem to depend upon the histologic type of the tumor or on the immune status of the patients as estimated from the skin test reactivity at the start. There was also suggestive evidence that levamisole may be more effective in preventing hematogenous dissemination than in inhibiting recurrences in the lung or the mediastinal tissues. Levamisole, if dosed adequately, appears to be a very suitable adjuvant treatment in resectable lung cancer patients as judged from its efficacy and its lack of troublesome side-effects.

Fifty-seven transurethrally resected bladder tumors were analyzed to determine whether different pathologists, using the World Health Organization grading system, graded the same bladder tumor differently (interindividual consistency) and whether the same pathologist graded a bladder tumor differently at different times (intraindividual consistency). Disturbingly high inter- and intraindividual inconsistency in the grading of bladder tumors was found. All pathologists showed essentially the same degree of intraindividual inconsistency: In almost 50 per cent of cases the tumor was graded differently at different times by the same pathologist. The inconsistencies might invalidate the usefulness of bladder tumor grading in clinical decision-making.

The histopathological diagnosis of squamous cell hyperplasia of the larynx is very subjective. Since morphometry is highly reproducible, this method was applied to routine processed slides of 45 such lesions to assess objectively the epithelial characteristics. In each case measurements of nuclei of 50 cells in the basal, intermediate, and superficial cell layers were carried out. The data were analysed statistically. The findings suggest that quantitative morphometry may be helpful for the histopathological classification of squamous cell hyperplasia of the laryngeal mucosa.

In 1926, Abrikossoff described a tumor, usually benign, which only rarely appears in the esophagus. In a 40-year-old woman, the authors found a multicentric granular cell tumor which was localized in the cervical esophagus and in the subcutaneous tissues over the right scapula; it was removed surgically. Granular cell tumors causing stenosis of the upper esophagus have been described only four times in the literature. Characteristics and treatment are discussed.

Quantitative as well as qualitative cellular parameters were investigated in 20 cases of reactive mesothelial proliferations and 40 cases of primary pleural mesotheliomas. The two groups showed statistically significant differences in the nuclear areas, cytoplasmic areas and standard deviations. In the mesotheliomas, the mean nuclear area and the mean cytoplasmic area were larger than in the reactive proliferations. Nine cases could not be properly classified with these quantitative parameters alone. Qualitative analysis revealed highly characteristic features in the mesotheliomas. Morula formation as well as irregular and coarse reticular chromatin patterns were strongly indicative of mesothelioma. The location and shape of the nucleus and the type and amount of cytoplasmic vacuolization gave additional information for distinguishing between the two groups.

Because of the rise in incidence of upper urinary tract tumors, there is a need for a simple and reliable method for diagnosing these tumors, especially in people in a "high-risk" group. This retrospective study showed the usefulness of cytology and cytomorphometry in making the diagnosis of transitional-cell carcinoma of the upper urinary tract. The study also emphasized that the methods of collection and processing are of the utmost importance: the cytologic evaluation of ureteral catheterized urine specimens gave 100% accuracy as compared with a 40% false-negative rate in the cytologic diagnosis of voided urine specimens. A higher accuracy of urinary cytology for the diagnosis of upper urinary tract lesions clearly requires selective catheterization of the ureter. Objective cytomorphologic grading of the urinary cytology specimens was shown to compare favorably with histologic grading. Cytomorphologic grading not only can offer important information in determining the prognosis and in planning treatment but can also assist in quality control of other diagnostic methods and can help to resolve apparent diagnostic discrepancies.

Several controlled studies in lung cancer have evaluated the adjuvant use of cytostatic chemotherapy. The results of these investigations, and particularly of the carefully randomized ones, have been disappointing as they range from a significant difference, to the disadvantage of chemotherapy [4], to some suggestion of benefit only [5]. In view of these data, two different attitudes can be taken in making further efforts to develop an effective adjuvant treatment modality for resectable lung cancer patients who are known to be seriously at risk of relapsing within the first few years after their operation. One research path is to continue using cytostatic chemotherapy but to more carefully select the drug(s) to be used, e.g., by relying on the known effects of these drugs in advanced cancer, and to scrutinize the intensity of the chemotherapeutic regimen to be given [7]. It seems obvious that this is a very delicate task as judged from the limited effectiveness of the wide range of available chemotherapeutic agents in advanced lung cancer, and, also, from the lack of well-established guidelines to choose a therapeutic scheme to be followed in the adjuvant setting. Moreover, if some amount of unexpected, divine intervention fails to occur, we will continuously have to deal with the sometimes very unpleasant side-effects of these drugs, even if such adverse effects may at first glance appear acceptable from the treating oncologist’s point of view: he is accustomed indeed to see more severe side-effects from more intensive treatment with the same drugs in patients with advanced malignancies.

An important question in the effective use of quantitation in cytology is how to make the link between mathematical parameters and the cytologist. As an example, an investigation is discussed in which cell images from benign mesothelial proliferations were distinguished by quantitative characteristics from those of malignant mesotheliomas originating in the pleura and peritoneum. The significant differences between the three groups in nuclear size, cytoplasmic size and nuclear-cytoplasmic (N/C) ratio could partly be explained by the vacuolation patterns of the exfoliated mesothelial cells in each. Moreover, the primary site of the tumor could be predicted by the quantitative cell parameters. The characteristics of cytologic images, once known to be important, are easily incorporated into standard diagnosis. Thus it now seems possible for the cytologist to differentiate between the three groups by using the cytomorphologic features that relate to the computed parameters. This shows the value of translating computerized parameters into cytomorphologic criteria.

The preoperative value of target ultrasonic mammography (TUSM) and cytopathology, combined with clinical examination and mammography, was studied in 146 mammographically demonstrated round-shaped breast lesions. All lesions were biopsied and histology was performed. Advantages of combining TUSM with cytology are the possibility to have a more precise puncture aspiration with TUSM and a subsequently higher predictive value, compared to each technique alone.

The results of cholecystectomy have been studied in a series of 43 patients with pain suggestive of biliary origin in the absence of gallstones. The most probable diagnosis in these cases is cholecystosis of the gallbladder usually to be ascertained by careful scrutiny of the gallbladder periphery on a good cholecystogram. Based on the present results and those reported in the literature, cholecystectomy can be advocated as treatment of patients with adenomyomatosis and other forms of cholecystosis of the gallbladder.

The qualitative features of the intracytoplasmic vacuoles occurring in the cells of pleural malignant mesothelioma and of metastatic carcinoma exfoliated in pleural fluid were studied. There were important differences in the two types of vacuoles. In mesotheliomas, the vacuoles were centrally situated, small and regular in size; these vacuoles stained positively with fat stains and always negatively with the periodic acid-Schiff stain. In routine cytology, these lipid-containing vacuoles can best be seen in air-dried May-Grünwald-Giemsa-stained smears and are almost invisible in wet-fixed Papanicolaou-stained smears. In metastatic carcinoma, the vacuoles were irregular in size, noncentral in location and often positive with mucin stains. Electron microscopy was used in one case to further elucidate the staining patterns of the vacuoles. This study proves that the analysis of the qualitative features of vacuoles of malignant cells exfoliated in pleural fluid can be of great value in the distinction between metastatic carcinoma and mesothelioma.

Only 3% of patients with T1 bladder tumours die of bladder carcinoma within 5 years (Williams, Hammonds & Saunders 1977), therefore these patients are initially treated conservatively. There would however be benefits from being able to predict which patients should be treated more aggressively. Morphometry was applied to quantitate characteristic microscopical features of the removed T1 tumours in 16 patients who had survived for five years and in seven patients dead from the tumour, in order to evaluate the prognostic value of this method. The measurements of nuclear and cytoplasmic areas were made on routine H & E sections with a graphic tablet (ASM, Leitz). Statistical analysis of the obtained data revealed that there were significant differences between the two groups. It indicated that morphometric parameters of T1 bladder tumours can have prognostic as well as therapeutic significance which will be further tested in a prospective study.

The chemotactic responsiveness of peripheral monocytes and the acid-phosphatase activity of tumor-infiltrating macrophages, as well as the ultrastructural appearance, were studied in 40 patients with squamous cell carcinoma of the head and neck. The chemotactic responsiveness was found to be decreased in carcinoma patients, and this value appeared to be positively correlated in individual patients with the number of tumor-infiltrating macrophages, as well as with the histologic grade of the tumor. Patients with poorly differentiated malignancies showed impaired monocyte chemotactic responsiveness and low numbers of tumor-infiltrating macrophages. Macrophages present in the parenchyma of the tumor showed a weak and diffuse pattern of acid phosphatase activity. The acid phosphatase activity of stromal macrophages was much stronger and distributed in foci. Electron microscopic examination of the parenchymal macrophages revealed low numbers of lysosomes and the presence of tumor cell debris in the cytoplasm of the cell, without any sign of a surrounding phagosomal membrane. Together with the weak cytochemical reactivity, this probably indicates the poor functional state of the phagocyte when infiltrated in the parenchyma of the tumor. Low molecular weight factors derived from the tumor are known to decrease chemotactic responsiveness of peripheral monocytes. The poor functional state of the macrophages infiltrated within tumor parenchyma might be explained by assuming that a high concentration of such factors in the near vicinity of malignant cells causes toxic effects in macrophages.