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In 202 women with koilocytotic atypia in cervical smears, 136 had predominantly small condylomata of the uterine cervix, and 66 had cervical intraepithelial neoplasia (CIN) of varying degree either with koilocytosis of the neoplasia or associated with condylomata. Koilocytosis correlated well with the histological diagnosis of condylomata, but occasionally it obscured the cytological evidence of CIN. Human papilloma virus particles were found in the cells of condylomata in 10 cases and in those of CIN II with koilocytosis in two cases of 21 examined ultrastructurally. There was evidence that the condyloma of the uterine cervix is a well-defined morphological entity and also that cytopathie changes similar to those seen in condylomata are present in some cases of CIN. [ABSTRACT FROM PUBLISHER]

HER-2/neu protein expression and gene amplification were analyzed in a series of 85 consecutive breast carcinoma patients entered into an adriamicin/taxol primary chemotherapy trial followed by surgery, 45 of whom underwent pre-treatment fine needle aspirate (FNA). Dual color FISH (fluorescent in situ hybridization) assay revealed high-level HER-2/neu gene amplification in the immunocytochemistry (ICC) indicated 3+ cases and no, low or moderate amplification in the ICC 2+ group, consistent with previous findings in untreated patients series. Results obtained with the ICC assay CB 11 showed higher overall concordance with FISH than did the Herceptest ICC assay, but CB 11 was less accurate than Herceptest in terms of selecting patients suitable for Herceptin treatment, which is currently restricted to ICC 3+/FISH amplified patients. The only ICC 3+ low-level amplified case (non-amplified according the two more stringent criteria applied) was found with the CB 11 assay. Comparison between pre-treatment smears and post-treatment sections by FISH revealed no significant changes in the HER-2/neu gene profile. In the clinical setting these findings point to the usefulness of HER-2/neu assessment in chemotherapy-treated patients, when pre-treatment material is unavailable.

Diagnosis of lung cancer is reached when the disease had grown to advanced stages in its natural history. Thus, novel molecular markers for early detection and risk assessment are needed. Here we performed a longitudinal study of 20 morphological lesions occurred in the bronchial tree of high-risk patients. The lesions were subjected to LIFE (laser-induced fluorescence endoscopy) bronchoscopy and molecular follow-up over a 4 year period. The presence and the persistence of specific genetic alterations were correlated with recurrence or progression of the disease on follow-up. Molecular lesions considered as highly predictive of invasion could be prospectively used as diagnostic markers of high risk for lung cancer in exposed patients., (Copyright 2002 Elsevier Science Ireland Ltd.)

Accurate and reliable decision making in breast cancer prognosis can help in the planning of suitable surgery and therapy and, generally, optimise patient management through the different stages of the disease. In recent years, several prognostic factors have been used as indicators of disease progression in breast cancer. In this paper we investigate a fuzzy method, namely fuzzy k-nearest neighbour technique for breast cancer prognosis, and for determining the significance of prognostic markers and subsets of the markers, which include histology type, tumour grade, DNA ploidy, S-phase fraction, G0G1/G2M ratio, and minimum (start) and maximum (end) nuclear pleomorphism indices. We also compare the method with (a) logistic regression as a statistical method, and (b) multilayer feed forward backpropagation neural networks as an artificial neural network tool, the latter two techniques having been widely used for cancer prognosis. Nodal involvement and survival analyses in breast cancer are carried out for 100 women who were clinically diagnosed with breast disease in the form of carcinoma and benign conditions, and seven prognostic markers collected for each patient. For nodal involvement analysis, node positive and negative patients are predicted whereas survival analysis is carried out for two categories: whether a patient is alive or dead within 5 years of diagnosis. The results obtained show that the fuzzy method yields the highest predictive accuracy of 88% for both nodal involvement and survival analyses obtained from the subsets of [tumour grade, S-phase fraction, minimum (start) nuclear pleomorphism index] and [tumour histology type, DNA ploidy, S-phase fraction, G0G1/G2M ratio], respectively. We believe that this technique has produced more reliable prognostic factor models than those obtained using either the statistical or artificial neural networks-based methods.

Objective: To assess the performance of the AutoPap Primary Screening System (APSS) (TriPath Imaging, Inc., Burlington, North Carolina, U.S.A.) for the detection of high grade cervical squamous intraepithelial lesions and invasive cervical cancer., Study Design: A total of 14,779 consecutive conventional Pap smears were processed by the APSS. All slides designated as "Review" by the device were manually screened according to the Bethesda System. The ranking scores obtained from the device were compared with the cytologic interpretations in all cases and with the final histologic diagnoses in the cases with cytologic severe abnormalities., Results: The device classified 10,349 slides as Review (78%) and 2,912 (22%) as "No Further Review." In the 78% Review cases, the samples were ranked in descending order of potential abnormality, broken into quintiles. The correlation between the slide quintile ranks and the manual cytologic diagnosis indicated that 90% of abnormal smears were categorized by the device as in the first and second quintile rank, and the correlation between the rank report of the device and the histologic diagnosis showed that all cases of HSIL or invasive carcinoma were in the top two ranks. No significant abnormalities were observed in any of the smears categorized as No Further Review., Conclusion: This study confirmed the effectiveness of APSS for the detection of Pap smears with severe abnormalities.

Tumor suppressor protein p53 is a positive regulator of MDM2 gene expression and the mdm2 protein can bind to p53, preventing the transactivation of p53 responsive genes, thus mimicking TP53 mutation. The authors looked for alterations that could affect, directly and indirectly, p53 function in 13 patients with extrahepatic cholangiocarcinoma. Molecular analysis by single strand conformation polymorphism and DNA sequencing revealed that TP53 gene mutations occurred in only 2 of 13 cholangiocarcinomas. High levels of mdm2 protein were found, by immunohistochemical staining, in 61% of the cholangiocarcinomas and in almost all specimens (70%) displaying stabilized p53 protein in the absence and in the presence of TP53 mutations. The finding of co-overexpressed mdm2 and p53 proteins in cholangiocarcinomas indicates that they can upregulate the expression of mdm2 protein to a level sufficient for binding and accumulating p53 in a presumably inactive complexed form. The presence of TP53 mutations or upregulation of MDM2 gene expression in 9 of the 13 cholangiocarcinomas strongly supports that the impairment of the p53 pathway is an important and specific step in cholangiocarcinoma pathogenesis. At variance with other authors, no alteration of p16ink4/CDKN2 gene was observed in all 13 cholangiocarcinomas.

The hormonal milieu at time of tumor surgery seems to have a significant impact on survival in premenopausal breast cancer patients. Indeed, surgery performed during the follicular phase of the menstrual cycle was suggested to correlate with a poor prognosis. To investigate the relationship between prognosis and menstrual cycle at time of surgery, we analyzed the expression of some markers associated with tumor aggressiveness, such as the hormone receptors, HER2, p53, Bcl2, and cathepsin D in breast carcinomas obtained from 198 premenopausal women who underwent surgery during different phases of the menstrual cycle. HER2 overexpression was found to fluctuate in hormone receptor-positive tumors. In actual fact, 20% of the tumors removed during the follicular phase scored HER2-positive, versus 8% of those removed during the luteal phase. Similarly, a number of hormone receptor-positive tumor specimens, obtained from the same patients during follicular and luteal phases, were scored HER2-positive when the sample was removed during the follicular phase and HER2-negative when removed in the luteal phase. Southern blot analysis of the HER2 gene indicated that, in hormone receptor-positive cases, the overexpression of HER2 is often not associated with gene amplification. The finding that overexpression of the HER2 gene, associated with tumor aggressiveness, can fluctuate according to the hormonal milieu may explain the increased survival of patients operated during the luteal phase. It is also relevant to the selection and treatment of patients most likely to benefit from anti-HER2 antibody therapy.

Background: Percutaneous transhepatic biliary drainage (PTBD) allows ductal material to be collected for cyto-histologic examination. We evaluated the data from a large series of patients with a PTBD in whom endobiliary cyto-histologic sampling techniques were employed in order to define a strategy for their use in the diagnostic work-up., Patients and Methods: Ductal samples for cyto-histologic examination were obtained from 409 consecutive patients with a PTBD for stenosing lesions of the biliary tree. Bile aspirate cytology was performed for all patients and ductal biopsy specimens were obtained, generally after negative cytology, from 49 of them (11.9%), all candidates for a therapeutic procedure. The cyto-histologic results of intraductal sampling were compared with pathologic surgical data in 210 patients and with clinical-radiologic follow-up in 199., Results: Overall, 22 out of the 409 patients had a final diagnosis of benign stenosis and 177 had samples positive for neoplastic disease. The sensitivity of bile cytology was 43.8% while ductal biopsies showed a sensitivity of 60.4%. The combination of the two sampling techniques achieved a sensitivity of 65.1%. For both sampling methods the specificity was 100%. Hilar metastases from neoplastic lesions of the GI tract and primary lesions of the biliary ducts showed the highest sensitivity., Conclusion: Cyto-histologic assessment of stenosing lesions of the biliary ducts is mandatory when highly sophisticated interventions (e.g. wide hepatic resection or liver transplantation) or non-surgical treatments are envisaged. The collection of cyto-histologic samples from bile ducts, in patients with a percutaneous bile drainage, is an easy, safe and valuable method to obtain the diagnosis. In view of the absence of false positive results in our series and in others, intraductal biopsy serves no purpose when positive exfoliative cytology is positive for malignancy. In the presence of negative cytology it is felt that an intraductal biopsy should be mandatory when the choice of a therapeutic program depends on the result of the cyto-histologic diagnosis.

In order to improve the cytomorphologic diagnosis of malignant lymphoma on lymph node fine-needle aspiration (FNA), and to make a confident discrimination between low-grade follicular non-Hodgkin's lymphoma (NHL) and lymphoid hyperplasia, polymerase chain reaction (PCR) analysis was performed of the Ig CDR3 region and BCL2 breakpoint region in 25 nonselected cases of malignant lymphoma (17 NHL and 8 Hodgkin's disease [HD]) with histologic control, and 22 cases of lymph nodal hyperplasia with histologic and/or clinical control. Among lymphomas, IgH monoclonality was detected in 7 (77%) of 9 NHLs and BCL2 rearrangement in 3 (17.6%) of 17 NHLs, all of which were follicular centroblastic-centrocytic (FCBCC). Three BCL2/JH negative FCBCC cases were monoclonal for CDR3. Neither IgH monoclonality nor BCL2 rearrangement were found in HD. Among cytologically diagnosed lymphoid hyperplasias, one IgH polyclonal case was considered false-negative, being histologically diagnosed as lymphoplasmacytic NHL on the subsequent excisional biopsy. Another 4 cases (2 BCL2 rearranged and 2 monoclonal for IgH) were considered false-positive on the basis of histologic features or clinical control. These data indicate that the combined PCR analysis of IgH and BCL2 rearrangements can confirm a cytologic diagnosis of lymphoma in FNAs while, due to the occurrence of both false-positive and false-negative results, it is of limited value in the distinction between follicular lymphoma and lymphoid hyperplasia without morphologic or clinical support.

We describe the FNA features of five cases of malignant parotid myoepithelioma, the majority of which were thought clinically to be recurrent pleomorphic adenomas. A major finding was cell shape variation: round-oval, polygonal or spindle-shaped, with basophilic cytoplasm. Many were epithelial and plasmacytoid-like and had nuclear grooves, pseudoinclusions, and multinucleation. The true myoepithelial nature of the neoplastic cells was identified in all cases, but only two showed obvious cytological malignant features, both initially and on re-examination. FNA of malignant myoepithelioma may thus show overt features of malignancy, or may lack atypia and malignancy can only be identified on histology. The correct diagnosis can be predicted in FNA samples in certain cases, both in terms of typing and malignancy, whilst sometimes only the myoepithelial nature of the lesion can be assessed.

Two hundred eighty-five consecutive outpatients with enlarged superficial lymph node either clinically suspicious (152) or with a previous diagnosis of a malignant tumor (133) underwent fine needle aspiration (FNA) followed by excisional biopsy. Cytologic and/or cytologic-immunophenotypic diagnoses made on direct smears were compared with subsequent histologic findings. The comparison demonstrated (1) a high rate of conclusive cytologic diagnoses in the assessment of metastatic malignancies, with an overall accuracy rate of 99.1% and a typing accuracy rate of 96.5%; (2) a high rate of conclusive diagnoses in the assessment of high grade non-Hodgkin's lymphomas and Hodgkin's disease, with the exception of the lymphocytic predominance variant of the latter; and (3) significant limitations in the assessment of low grade non-Hodgkin's lymphomas because of the high rate of false-negative diagnoses in cases with a substantial nonmalignant cell component. This was particularly evident in follicular centroblastic-centrocytic lymphomas. Immunocytochemistry appeared to be of limited value in the distinction between centroblastic-centrocytic follicular lymphomas and reactive follicular hyperplasia. The results confirmed the diagnostic value of fine needle aspiration as the first step in the workup of patients with nodal enlargement suspicious for malignancy. In the area of low grade non-Hodgkin's lymphomas, morphologic and immunocytochemical methods need to be supplemented by molecular techniques in order to achieve conclusive diagnoses.

Cells from 229 pleural and peritoneal spontaneous fluids and 51 peritoneal lavage fluids from patients with neoplastic and nonneoplastic diseases were studied by indirect immunofluorescence with two monoclonal antibodies; MBr1, prepared against breast carcinoma, and MOv2, prepared against ovarian carcinoma. The results were correlated with those obtained by conventional cytologic methods. A cytologic diagnosis of metastatic carcinoma was established in about 50% of the fluids examined. Sixty percent of the cytologically malignant fluids contained tumor cells reactive with at least one of the two monoclonal antibodies tested. The specificity of the labeling was confirmed by immunoelectron microscopy. In addition, 16 fluids with a negative cytologic diagnosis contained cells strongly immunopositive with MBr1 and/or MOv2. Reactive mesothelial cells were consistently negative. These results suggest that antibodies MBr1 and MOv2 are able to identify cancer cells that do not fully meet conventional morphologic criteria for malignancy. The two reagents, when used in support of cytologic analysis, may substantially reduce the number of false negative cytologic diagnoses of fluids from patients with breast and ovarian carcinomas.

An investigation of the role of fine needle aspiration in the assessment of renal masses was carried out on 132 consecutive patients, 11 of whom were children. Selection was based on the presence of a solid or mixed solid and cystic renal mass that could not be defined by radiology, either in symptomatic patients or in patients to be submitted to embolization of the renal artery and at high surgical risk. Histologic and clinical data showed 49% of the cases to have a malignant, predominantly (45%) primary disease of the kidney and the remainder to have a nonneoplastic lesion. In five cases, the primary lesion was in the adrenal gland (three neuroblastomas and two pheochromocytomas). Sensitivity, specificity and predictive values for positive results were, respectively, 0.93, 0.96 and 0.935 because of a false-positive diagnosis in a case of multilocular cystic nephroma. Furthermore, in 43 of 65 cases (66%), consisting of 33 renal cell carcinomas, 1 transitional cell carcinoma, 3 Wilm's tumors, 1 neuroblastoma, 2 pheochromocytomas and 3 metastatic lesions, the histologic type could be ascertained on the tissue yielded by the fine needle aspiration. The findings stress the usefulness of this method for the clarification of radiologically not unequivocal space-occupying lesions of the renal area, especially when, in addition to the smears, histologic sections of paraffin-embedded tissues are available. Ultrastructural and immunohistochemical studies are cost-effective mainly in pediatric patients.

In gastric smears obtained by direct vision fiberoptic brush technique from 78 patients with carcinoma of the stomach, an attempt was made to recognize cytologically the histologic type of the tumor with reference to Lauren's classification. The cytologic diagnosis of intestinal type carcinoma was made in 36/45 positive cases on the basis of an abundant cellularity and the presence of rather large pleomorphic cohesive cells often arranged in sheets with a moderately increased N/C ratio. One case of intramucous and two of "early" invasive carcinoma revealed malignant cells which did not differ from those of the advanced cases. In these cases as well as in some of the advanced ones, atypical epithelial cells were found in addition to the malignant ones; these cells could have derived from the histologic areas of atypical hyperplasia of the gastric mucosa surrounding the carcinoma. 14/15 cases of advanced diffuse carcinoma of the stomach could be cytologically identified on the basis of a scanty cellularity and the presence of rather small, monomorphic poorly differentiated cells with a high N/C ratio. The cytologic diagnosis of the mixed-type carcinoma was made in 2/5 positive cases on the basis of the presence of an admixture of both cell types described above. In two cases of the mixed-type carcinoma, only intestinal type cells were found. In the smears of nine cases of intestinal type carcinoma, one of which was intramucous, and of one case of mixed-type carcinoma, the tumor cells could not be specified. 13/78 cases (16.7%) showed negative cytology. The overall accuracy rate was 83.3 per cent. The statistical analysis of a number of cytologic parameters indicated that morphologic differences between Type I and Type D carcinomas of the stomach do exist and that they can be evaluated for differential diagnostic purposes.

All the cytologic and histologic material pertaining to 100 patients who underwent cervical conization for advanced cervical intraepithelial neoplasia (CIN) was reviewed. The revision of the histology of the biopsies and cones showed in 56 cases the association of CIN with viral cytopathic effects (VCE) attributable to human pappiloma virus (HPV) and in 52 the coexistence of a predominantly flat condyloma. The comparison of the two groups of CIN, with and without VCE, showed that in the first the association had favored in 20% of the cases the histologic overestimation of the severity of the lesion. Of the patients with CIN III, 46% showed additional changes due to VCE. The mean age of the patients with CIN and VCE was 39.8 years and that of the patients with CIN was 48.6 (p less than 0.0001). The exocervix was significantly more often involved by CIN + VCE than by CIN alone (p less than 0.00001). Follow-up studies revealed in both groups the same percentage of residual disease and, preliminarily, a trend to a better control of CIN with VCE. New disease developed more often in the group of patients with CIN without VCE. Cytologic sensitivity for VCE in cervical smears was high (95%) in the cases of CIN II and somewhat lower (81%) in those with CIN III. Cytologic follow-up showed the persistence of VCE in 17% of the patients treated surgically for CIN and VCE. The morphologic and clinical features displayed by CIN associated with VCE warrant its recognition as a distinct variant of CIN.

The presence of malignant tumor cells in a vaginal and cervical smear of a 53-year-old female with vaginal bleeding and with subsequent negative hsitology of the scraping material could be later correlated with a leiomyosarcoma of the myometrium that produced deep local invasion and pulmonary metastases. The findings that favor the cytologic diagnosis of this neoplasm are the presence of isolated cells or the side-by-side arrangement of the tumor cells, the elongated shape of the cytoplasm, and the ovoidal cigar-shaped nuclei with sparse, coarse chromocenters. Cytologic differential diagnosis of other malignant neoplasms capable of cellular exfoliation into the vagina is discussed.