Telepathology: a diagnostic tool for the millennium?

Many developments in science have their origins in science fiction and telepathology is no exception. The concept was first illustrated in 1924 in the magazine 'Radio News'. It was not until 1980, however, that the first working telepathology system was demonstrated. Although the system was shown to work, it required special hardware, dedicated software and special microwave transmission links to be installed. Little interest was shown worldwide because of the very high cost and the inability of many people to replicate such a system. Ten years later, the personal computer (PC) was able to provide more than adequate performance at low cost for both image display quality and speed, and the development of video technology had resulted in high quality images being produced by television cameras that were now easily affordable. Microscopes were also relatively cheaper. Thus, by 1993 or 1994, all the hardware necessary to produce a telepathology system was available at reasonable cost. Telepathology can now be used for remote primary diagnosis, remote referral to a specialist pathologist, remote teaching, remote presentation of post-mortem or microscopic findings, quality assurance image circulation and feedback, and consensus diagnosis for pathological review in clinical trials. There are two residual problems. The first concerns the speed of data transmission, commonly referred to as the bandwidth. The second is that the software provided by most of the manufacturers and suppliers of these systems is not entirely suitable to the task and the systems are not interoperable. It is clear that the approach of the manufacturers is at present unlikely to produce telepathology systems which pathologists feel comfortable in using. A somewhat different approach is illustrated by the accompanying article in this issue from the Berlin group, where a relatively simple Java-based applet and the Internet are used to allow single or multiple users to view slides on a robotic microscope. This could form the basis for a truly useful system, but still needs modification for some applications.

Diagnostic difficulty arising from rectal recovery in ulcerative colitis.

AIMS: To ascertain whether the dogma that a normal rectal biopsy precludes a diagnosis of ulcerative colitis is correct. METHODS: Rectal biopsy specimens from a prospective group of 24 asymptomatic patients, with an established diagnosis of ulcerative colitis, were examined in a blinded study alongside 10 normal rectal biopsy specimens from an age and sex matched patient cohort without ulcerative colitis. Each biopsy specimen was assessed by three pathologists and ascribed to one of four categories: normal; borderline abnormality (one or more minor nonspecific abnormalities which, when combined, did not fulfil the minimal acceptable criteria for a diagnosis of ulcerative colitis); minimal features of chronic ulcerative colitis; and unequivocal ulcerative colitis. RESULTS: Two patients with ulcerative colitis had normal biopsy specimens; nine specimens were categorised as borderline abnormality, one as showing the minimal changes of chronic ulcerative colitis, and 12 as having the typical changes of chronic ulcerative colitis. Thus, 11 (46%) of the 24 patients had a rectal biopsy specimen that was devoid of the acceptable attributes on which a diagnosis is established, despite a confident previous diagnosis. Ten of these 11 cases had disease limited to the rectum. Review of all previous histological biopsy specimens (n = 164) and clinical data, including drug treatment, failed to identify any attributes that might be prognostic markers for future rectal mucosal healing. CONCLUSIONS: A normal rectal biopsy specimen, though uncommon, may occur in longstanding colitis. Moreover, in 46% of these asymptomatic but established cases the degree of healing may preclude a diagnosis of ulcerative colitis without comprehensive clinical and radiological details. Pathologists need to be aware of this minimal end of the spectrum of disease.

Histometry and the H.O.M.E. concept: an aid to the grading of intra-cervical neoplasia?

The view has been expressed that few quantitative methods are of value to the pathologist in purely diagnostic work. Quantitative systems are perceived as too large for the average reporting room, too time consuming to learn, very expensive to buy and quick to become obsolete. Further, the software supplied usually cannot provide fully automated analysis, and user interaction is often tedious. If measurement techniques have little value in diagnosis they may have a role in assessing the prognosis of tumours. High levels of inter- and intra-observer variation in tumour grading have been reported and quantitative methods have been used to reduce this and more emphasis has been placed on the measurement of changes in tissue architecture, which may help to reduce observer variation. This paper describes such a method based on cell sociology, which has been implemented on a quantitative microscope specifically designed for use in the routine diagnostic pathology environment. The results of a preliminary study on grading cervical intraepithelial neoplasia show a significant difference between all groups (P less than 1 x 10(-5)) and a linear trend for the measurement of Area Disorder (P less than 1 x 10(-5)).

The HOME tutor: a new tool for training in microscope skills.

AxioHOME is a new concept in microscope design. It is a microscope with a visual display unit mounted in the head permitting computer generated displays to be projected on to the real microscope image when viewed down the eyepieces. This allows the annotation of the microscope image with both text and graphics. The AxioHOME system was used for the construction of complex interactive tutorials for the training and assessment of students. The basis of a tutorial is that features of interest on a microscope slide are indicated to the student who is then provided with either information or questions about those features. In turn the student can also annotate the slide with comments for later discussion with the teacher. The system therefore allows a dialogue between teacher and student. The creation of tutorials is time consuming. It takes approximately 10 min of teacher time to create 1 min of student time. However since the same tutorial can be used by numerous students this releases the teacher from repetitive training. The student response to this teaching method has been very positive. The main criticism being that insufficient teaching material was available.

Zonal biochemical and morphological characteristics in BPH.

OBJECTIVE: To compare androgen, oestrogen, progesterone and epidermal growth factor receptor concentrations in the transition zone and peripheral zone of the prostate in benign prostatic hyperplasia (BPH), and to relate these findings to epithelial and stromal composition. PATIENTS AND METHODS: Tissue from both the transition and peripheral zone of the prostate was obtained from 26 patients undergoing transurethral prostatectomy for benign prostatic obstruction and used for both receptor binding studies and morphometric analysis. Androgen receptor (AR), oestrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor (EGFR) concentrations were assayed by saturation binding with a competitive inhibitor. The epithelial, stromal and luminal composition of the tissue was determined using a Zeiss AxioHOME microscope workstation. RESULTS: The epithelial content was significantly greater in the transition zone than in the peripheral zone. No overall zonal difference in AR concentration was detected; however, when values were expressed relative to the epithelial component, the AR content was significantly higher in the peripheral zone. Conversely, overall EGFR concentrations were significantly greater in the transition zone, although not when expressed per unit epithelium. Higher concentrations of oestrogen receptor were measured in the transition zone per unit stroma. No zonal difference in PR was detected. However, there was a significant correlation between AR and PR in the peripheral zone and between EGFR and AR in the transition zone. CONCLUSION: These data demonstrate that receptor concentrations should be related to tissue composition. Concentrations of AR were higher in the peripheral zone epithelium than in transition zone epithelium, suggesting greater androgen dependence. This may be important in determining its greater propensity for malignancy. Although EGFR concentrations were greater in the transition zone, there was no zonal difference after correction for the amount of epithelium. Finally, higher concentrations of ER were detected in the transition zone stroma which may reflect important zonal differences in regulating growth and provides further evidence of a role for oestrogens in BPH.

Relocation accuracy on HOME computerized microscopes.

A major practical advantage of the HOME (highly optimized microscope environment) computerized microscope is the facility for relocating cells or other microscopic objects. Features can be marked directly on the microscope image using a mouse-driven cursor, and an interactive finder can then be used to relocate the marked features. Tests on a prototype HOME microscope have shown that positions can be relocated with an accuracy of standard deviation (SD) < 7 microm. The marked features could also be relocated on a second HOME microscope, although with somewhat reduced accuracy (standard deviations of < 17 microm). The system provides a very user-friendly environment for tasks requiring relocation of microscopic objects.

Predicting the outcome of radical radiotherapy for invasive bladder cancer.

The correlation between T stage, histological grade, the presence of squamous metaplasia, and nuclear morphometry scores and response to radiotherapy and survival was investigated in 60 patients with muscle invasive transitional cell carcinomas of the bladder. Patients with T2 tumours showed a complete response significantly more often than those with T3 lesions. Multivariate analysis showed that T stage and initial response to radiotherapy were very strong predictors of survival though they were not independent variables. Histological grade, the presence of squamous metaplasia, and nuclear morphometry scores were not found to have any predictive value.

Morphometry of bladder carcinoma: morphometry and grading complement each other.

Subjective grading of bladder carcinoma is a good predictor of the clinical outcome in those patients whose tumours are grade 1 or grade 3. However, in grade 2 tumours, which account for 45% of cases, grading has little predictive value in an individual patient. We have complemented the use of subjective grading with measurement of nuclear area and used a calculation of the distribution of nuclear sizes as a predictor of the clinical course. When subjective grading was complemented by morphometry the outcome was correctly predicted in 55 of 58 cases and all cases with poor clinical outcome were identified.

Morphometry of bladder carcinoma: definition of a new variable.

In this study two measurements of nuclear size, the mean area and the size distribution curve of nuclear area, were used to differentiate between two polar groups: nuclei from non-neoplastic urothelium and nuclei from transitional cell carcinomas of bladder with a poor clinical outcome. Wide separation of these groups is necessary if a measurement is to be used to assess tumour grade where the morphometric differences are intermediate between such polar groupings. Separation between two groups was best achieved using a weighted distribution of nuclear size and this is a means of objective scoring of urothelial tumours.

Morphometry of bladder carcinoma: I. The automatic delineation of urothelial nuclei in tissue sections using an IBAS II image array processor.

Semi-automatic methods of morphometry require the boundaries of the objects under study to be drawn by hand. This is slow, tedious and does not guarantee accuracy. Complete automation, with recognition, detection and verification by computer is not yet feasible. Automatic detection of nuclear boundaries with observer verification provides a means of obtaining large amounts of data for analysis, quickly and with similar accuracy to manual tracing.

The delineation of nuclear boundaries in microscopic images.

A semiautomatic procedure for tracking the boundaries of liver nuclei in digitized microscopic images of normally prepared biopsy material is described. The operator selects the nucleus, and a guided sequential search procedure tracks edge segments, which may subsequently be linked to produce a closed or partially open boundary, which is then accepted, completed or rejected by the user.

Quantitation in inflammatory bowel disease using computerised interactive image analysis.

Objective measurements of various histological features in rectal biopsy material were made using computerised interactive image analysis. Analysis of the resulting data by forward stepwise discriminant analysis showed that biopsies from patients with ulcerative colitis and infective diarrhoea could be distinguished from each other and from normal biopsies; they could not, however, be distinguished from biopsies of patients with Crohn's disease, which behaves as a heterogeneous entity rather than a single disease. The measurements showed that the crypt atrophy described in active ulcerative colitis may be a misnomer, the appearances being due to an increase in mucosal depth and alteration in crypt configuration rather than a true atrophy. Unexpectedly, the ratio of crypt cell height to surface cell height gave the best separation of Crohn's disease from ulcerative colitis.

Shape and texture analysis of liver cell nuclei in hepatomas by computer aided microscopy.

Nuclei from non-neoplastic hepatocytes and from hepatoma cells have been examined by image analysis techniques which measure size, shape, and texture. There are significant differences in these parameters between malignant and non-neoplastic cells. When values are obtained from multiple cells in a single biopsy, discriminant programs satisfactorily separate benign and malignant tissues. Techniques of image analysis offer an opportunity to quantify the nuclear changes associated with malignancy and may provide an objective basis for tumour grading systems.

Prognostic value of tumour thickness in cutaneous malignant melanoma.

The relation between survival and histological features in 91 patients with malignant melanoma was studied and the results were analysed by Clayton's method for interpretation of censored survival data. There was a significant correlation between tumour thickness and survival. The risk of dying from malignant melanoma after 10 years of follow up was less than 15% if the primary tumour was less than 1.5 mm thick but more than 80% if the lesion was thicker than 8 mm. The type of melanoma, level of invasion, mitotic rate, and presence of ulceration also correlated with survival, but these variables are related to tumour thickness.

Measurement of striated muscle fibre diameters using interactive computer-aided microscopy.

We have measured muscle fibre diameters using two methods of interactive computer-aided microscopy. They are simple to perform, reproducible and more convenient than manual methods of measurement. The technique is of general application to histological measurement.

Morphometric study of liver cell nuclei in hepatomas using an interactive computer technique: (i) nuclear size and shape.

Liver cells from 20 normal livers and 20 hepatomas have been studied in histological sections using an interactive computer method which measures nuclear size and shape. The variables which gave best discrimination between malignant and benign nuclei were the standard deviations of nuclear shape measurements. Though the liver is an ideal tissue for computer study it is considered that such measurements may act as a model for analysis of nuclei of other tissues.