Gianmario Mariuzzi

The Perivascular Epithelioid Cell and Related Lesions

Summary A family of lesions composed of a newly characterized and distictive cell type, called perivascular epithelioid cell (PEC), has been identified. This cell type characteristically shows immunoreactivity with the melanogenesis-marker HMB45. In this review, we summarize the rapidly growing data on this cell type and its related lesions. These lesions can occur in many different organs, are closely related lo the tuberous sclerosis complex, and can show loss of heterozygosity in TSC1 or TSC2 regions. These lesions include: angiomyolipoma (AML) and its monotypic variants (leiomyoma-like AML, lipoma-like AML, oncocyloma-like AML, monolypic epithelioid AML), pulmonary and extrapulmonary clear cell “sugar” tumor, lymphangiomyoma, lymphangioleiomyomatosis, and renal capsuloma

Quantitative Study of Ductal Breast Cancer Progression: Morphometric Evaluation of Phenotypical Changes Occurring in Benign and Preinvasive Epithelial Lesions

Fifty-nine cases of Breast Epithelial Proliferative Lesions (BEPL) and Ductal Carcinoma in Situ (DCIS), were studied by image analysis, to evaluate the nuclear changes occurring in the conventional diagnostic categories of ductal hyperplasia, atypical ductal hyperplasia and DCIS with quantitative methods. Diagnosis reproducibility is the main practical problem of these breast lesions. In fact, with subjective methods, the reproducibility appears to be very low and precarious especially for clinical demands. The objective, quantitative evaluation of cell phenotypical changes should be the method for both practical diagnostic problems and study of ductal cancer progression. The distribution pattern of the data in the feature, obtained with quantitative analysis, strongly suggests a continuum of changes, indicating an evolutionary process of Breast Ductal Carcinoma (BDC) progression in its preinvasive stage. Each observed case may be characterised by its own cellular, objective alterations and a progressive trend toward BDC can be stated. Since the actual changes of the proliferative phenotypes can be measured, and the values are reproducible, karyometric measurement may allow an objective grading of individual cases.

Quantitative Study of Breast Cancer Progression: Different Pathways for Various In Situ Cancers

The chromatin pattern in nuclei from breast ductal proliferative lesions was quantitatively evaluated with the objective of deriving measures of tumor progression. A total of 110 cases were analyzed. There were 38 cases of normal tissue or benign proliferative lesions, 41 cases of ductal carcinoma in situ (DCIS), and 31 cases of microinfiltrating DCIS and of infiltrating cancer. A total of 9424 nuclei were analyzed. High-resolution images were digitally recorded. For each nucleus, 93 karyometric features descriptive of the spatial and statistical distribution of the nuclear chromatin were computed. Data analysis included establishing a profile of relative deviations of each feature from “normal,” called the nuclear signature, and of lesion signatures as well as of trends of lesion progression. Two trends of evolution could be discerned: one from normal to hyperplasia, atypical hyperplasia, and comedo DCIS as representative of high-grade lesions; and the other from normal to hyperplasia to cribriform DCIS, solid DCIS, and infiltrating cancer, representing lower grade lesions. The nuclei in microinfiltrating foci are distinctly different from nuclei in high-grade comedo DCIS. The nuclei in microinfiltrating foci have a statistically significantly lower nuclear abnormality. They may represent outgrowing clones.

Quantitative study of ductal breast cancer--patient targeted prognosis: an exploration of case base reasoning.

Current analytic methodologies allow the extraction, even from small tumor masses, of extensive information on the biologic characteristics of malignant lesions, such as tumor aggressivity, metastatic potential, drug resistance, and host interactions. Clinical practice now offers a wide range of therapeutic strategies. Information technological advances offer the opportunity to refer to very large data bases of patient anamnestic data, response to treatment and clinical outcome. There is a need to formulate therapy and prognosis for each individual case. Case based reasoning is a knowledge based methodology where the outcome for complex situations can be predicted by referring to a large data base of cases of known outcomes. The preliminary data obtained from this study suggest that case based reasoning may offer a promising approach to individual targeted prognosis.

Automated reasoning system in histopathologic diagnosis and prognosis of prostate cancer and its precursors.

OBJECTIVE This article presents the rationale and options offered to diagnostic and prognostic decision support systems for prostate pathology by automated reasoning capabilities. METHODS The symbolic information used in diagnostic decision-making is systematically ordered, compared, numerically assessed in its probability, and combined such that a conclusion can be drawn. The framework for the processing of such symbolic information may be an expert system, an inference network or a case-based reasoning system. Automated reasoning is implemented by the use of a rule base and information flow control modules. RESULTS Automated reasoning allows decision support systems to follow highly adaptive decision sequences, capable of handling contradictory evidence, exceptions in diagnostic clue expression, and nonmonotonic decision-making. CONCLUSIONS Automated reasoning capability in diagnostic and prognostic decision support systems allows highly flexible decision development, very close to human decision procedures.

Quantitative Evaluation of Recurrent Meningiomas

Clinical, histological and karyometric parameters, nuclear DNA content and the number of nucleolar organizer regions were investigated in 9 recurrent meningiomas and 10 meningiomas which had not recurred within a 10-year period. There were no significant differences between the two groups as to age, sex, site of the tumours and most of the histological parameters scored. Recurrent tumours showed a higher number of mitotic figures and the nucleolus was visible in most of the cells. Cell density, nuclear area, perimeter and nuclear DNA content had values with no statistically significant differences between the two groups. However, significant differences were found in the distribution of the nuclei in the different ploidy regions. Most of the nuclei in the non recurrent cases were in the diploid range, whereas in recurrent tumours there was a reduction in the number of diploid cells associated with an increase in 2c--4c and 4c components. Recurrent tumours also showed a higher number of nucleolar organizer regions positively stained using an argyrophil method. The mitotic count and the nucleolar organizer regions appeared to be the best predictors for recurrence.

Evolutionary somatic cell changes in cervical tumour progression quantitatively evaluated with morphological, histochemical and kinetic parameters.

The somatic cell changes which characterise malignancy evolution in human cervical preneoplastic and neoplastic lesions have been assessed on histological sections by means of a computerised image analyser. Many features have been simultaneously measured on each cell of the lesions studied, and the following results have been obtained: Some features, mainly kinetic, show continuously increasing values which express changes correlated to the increasing malignancy; other features, especially related to nuclear atypia, cellular heterogeneity and the degree of aneuploidy, have values dropping at the level of early stromal infiltration, which can be morphometrically characterised as composed of relatively homogeneous phenotypes; these features seem to express the degree of genetic instability and relate to the evolutionary somatic cell changes; tumour progression evolves through sequential discontinuous steps, each of them characterised by specific phenotypical features of the neoplastic cell population; the neoplastic cells in the foci of early stromal infiltration and vascular invasion, phenotypically more homogeneous than the parent cell populations of carcinoma in situ and infiltrating carcinoma, seem to possess a greater genetic stability.

Prognostic value of computerized DNA analysis in noninvasive papillary carcinomas of the urinary bladder.

DNA parameters and a DNA status index were calculated in cases of noninvasive urothelial papillary carcinomas and apparently normal urothelium. DNA feature analysis included the measurement of basic parameters as well as those related to DNA deviation. Normal urothelium had a diploid content with a few values between 2c and 4c. The papillary lesions in the three grades showed a progressive decrease in diploid nuclei and steadily increasing percentages of tetraploid ones. One case of grade 1 papillary carcinoma and some of grade 2 showed a small proportion of aneuploid cells; the proportion quintupled in grade 3. The values of parameters related to DNA deviation increased progressively in the three grades, numerically expressing the shift from diploidy. The DNA status index is a multiparameter classification in which a single number, ranging from 0.5 to 3.7, expresses the degree of DNA deviation from a non-proliferating diploid population. The cases of normal urothelium and of grade 1 had the lowest values, from 0.5 to 1.9, whereas grade 3 cases had the highest, from 2.2 to 3.7. The index values of grade 2 cases were partly intermediate and partly in the range of the neighboring grades. The DNA status index has a prognostic significance. In fact, associated lesions and recurrences were only observed in cases with index values over 2.0.

Sources and Nature of Variation in DNA Analysis of Follicular Thyroid Adenoma

We investigated the sources and nature of variation that may occur in the DNA analysis of thyroid adenomas from cytological and histological samples. Imprints and smears gave identical results. However, the nuclear area was higher in smears where the optical density of the nuclei was lower. In measuring imprints, the interactive selection of nuclei was preferred to the automatic, because the risk of measuring nuclear fragments or undesired objects was thus avoided. The reproducibility and the variation of the DNA measurements depended on the degree of observer training in quantitative pathology, the method of field selection, and the type of instrumentation. Biological variation in the spatial distribution of nuclei with different ploidy values in some adenomas seemed to hide the influence of section thickness on measurements. Our data seem to suggest that it is best to apply a constant section thickness and 5 micron sections seem acceptable.