Should the cytologic diagnosis of "atypical squamous cells of undetermined significance" be qualified? An assessment including comparison between conventional and liquid-based technologies.

BACKGROUND: The diagnosis of atypical squamous cells of undetermined significance (ASCUS) remains an enigma for the treating physician, because it encompasses both benign, reactive, as well as preneoplastic and possibly neoplastic conditions. To address this problem, The Bethesda System recommends qualifying the ASCUS diagnosis. This study analyzes the difference in the follow-up results between the various groups of patients with an ASCUS diagnosis as outlined by the Criteria Committee: favor premalignant (ASCUS-P), favor reactive (ASCUS-R), and unqualified (ASCUS-C). The outcome, based on follow-up biopsies and/or cytologies, for both the conventional Papanicolaou smear (CS) and liquid-based (LB) methodologies is compared. METHODS: The CS and LB biopsies and/or cytologies included 590 patients and 137 patients, respectively, who had an initial diagnosis of ASCUS. The final outcome after subsequent biopsy and cytology within a 1-year period for each methodology was tabulated. Furthermore, the addition of qualifiers for each diagnosis was tabulated for both cytology and biopsy follow-up and compared between CS and LB technologies. RESULTS: For CS, 29 patients (8.6%) were found to have squamous intraepithelial lesions (SIL) on subsequent cytologic smears, and 176 patients (63.7%) had SIL on biopsy follow-up. For LB, these numbers were 17 patients (19.1%) and 56 patients (65.1%), respectively. Regardless of the qualification used in the initial CS biopsy or cytology, over 90% of the subsequent smears resulted in a benign diagnosis. Biopsy outcomes after CS diagnoses of ASCUS-P, ASCUS-R, and ASCUS-C showed SIL in 80%, 53%, and 66% of patients, respectively. For LB diagnoses, subsequent smears detected SIL in 33% of patients with a diagnosis of ASCUS-P, 22% of patients with a diagnosis of ASCUS-R, and 12% of patients with a diagnosis of ASCUS-C. Biopsy outcomes after LB diagnoses of ASCUS-P, ASCUS-R, and ASCUS-C showed SIL in 68%, 64%, and 66% of patients, respectively. CONCLUSIONS: There appears to be no statistically valid benefit from a clinical point of view in qualifying an ASCUS interpretation by either CS or LB, except for CS evaluation of patients with a diagnosis of ASCUS-P.

The expression of cyclins D1 and E in predicting short-term survival in squamous cell carcinoma of the lung.

Cyclins D1 (cD1) and E (cE) are G1 phase cyclins believed to participate in the pathogenesis of malignancy. Overexpression of cD1 has been reported to influence prognosis in squamous cell carcinomas (SCC) of the larynx, but was not significant in a limited study of non-small cell lung cancers (NSCLC). Altered expression of cE has been proposed as another potential prognostic marker in malignancy but its possible role in NSCLC has not been elucidated. In order to determine the prognostic value of cD1 and cE in NSCLC, paraffin-embedded sections of 467 NSCLC were immunostained with monoclonal antibody to cD1 (1:500, PharMingen, San Diego, CA) and 400 NSCLC with MA to cE (1:2500, PharMingen) using an enhanced sensitivity avidin-biotin complex technique. The number of tumor cells with nuclear and/or cytoplasmic immunopositivity was graded on a scale of: 0 = less than 1%, 1 = 1 to 10%, 2 = 10 to 25%, 3 = 25 to 50%, 4 = 50 to 75%, 5 = more than 75%. Results were correlated with survival by Kaplan-Meier survival plot using Stat-View software (Abacus Concepts, Berkeley, CA). Overall, 426 NSCLC with cD1 and 360 NSCLC with cE had adequate follow-up (median, 76 mo) for survival analysis. Both cyclins independently showed significance in prognosis of SCC but not other cell types. For cD1, absence of immunostaining was associated with worse prognosis than any immunopositivity for all stages of SCC (P = .025). For cE, Stage I and II SCC with less than 50% immunopositivity had a worse prognosis (P = .029). Of 70 Stage I and II SCC immunostained for both monoclonal antibodies, 55% of patients with tumors that demonstrated both absence of cD1 staining and cE immunopositivity in less than 50% of cells were dead at 5 years compared to 35% of patients with tumors that demonstrated positive staining with cD1 and cE immunopositivity in more than 50% of cells. These results strongly suggest cD1 and cE can independently predict prognosis in early stage SCC. Worse prognosis was associated with loss of expression, consistent with mechanisms other than overexpression of these cyclins in the progression of SCC.

Postatrophic hyperplasia of the prostate: lack of association with prostate cancer.

Postatrophic hyperplasia (PAH) of the prostate is a non-neoplastic glandular alteration sometimes confused with prostate carcinoma (PCa) histologically. Although atrophy had long been considered a possible precursor lesion for PCa, a theory that has been largely dismissed, the topographical relationship of PAH to PCa has not been studied systematically. Whole mount sections from 272 randomly selected radical prostatectomy (RP) specimens (T1c, 2, 3, N0, 1) and 44 cystoprostatectomy (CP) specimens (28 with incidental PCa) were assessed for the presence, location, and number of foci of PAH, and then were correlated with the presence and location of PCa foci. PAH was identified in 86 (32%) RP and in 12 (27%) CP specimens. The distribution of PAH foci: peripheral zone (91%), transition zone (8%) and central zone (1%), and apex (49%), mid (39%), and base (12%). For RP specimens, 183 foci of PAH showed no atrophy in a mirror image area of the prostate opposite the focus of PAH. Of the foci, 33% showed PCa either within or within 2 millimeters of the focus of PAH. For the mirror image area without PAH, PCa was identified either within or within 2 millimeters of the area in 40% (p = 0.19). The frequency of PAH in CP specimens and its relationship to incidental PCa was not significantly different from that of RP specimens (p = 0.60, chi square). Therefore, PAH is a relatively common lesion, most often seen in the peripheral zone of the apical third of the gland. PAH does not appear to have any association with PCa.

Metastatic carcinoma of the prostate mimicking primary carcinoid tumor of the lung and mediastinum.

Although prostatic carcinomas rarely present as intrathoracic metastases, they may occasionally exhibit clinical and radiographic findings suggestive of a primary pulmonary carcinoid, particularly when they have a cribriform pattern. This report describes three patients who presented with lung and mediastinal neoplasms initially diagnosed as primary carcinoid tumors. These tumors were later proven to be metastatic prostate carcinoma by the use of immunohistochemical studies, including stains for chromogranin, carcinoembryogenic antigen and prostate specific antigen. These findings emphasize the importance of considering metastatic prostate adenocarcinoma in the differential diagnosis of carcinoid or neuroendocrine carcinoma with a cribriform pattern.

Artificial neural networks and logistic regression as tools for prediction of survival in patients with Stages I and II non-small cell lung cancer.

The prognosis of patients with Stage I and II non-small cell lung cancer (NSCLC) can be estimated but cannot be definitively ascertained by use of current clinicopathologic criteria and tumor marker studies. The potential value of probabilistic neural networks (NNs) with genetic algorithms and multivariate logistic regression to predict the survival of NSCLC patients has not been previously evaluated. Multiple prognostic factors (age, sex, cell type, stage, tumor grade, smoking history, and immunoreactivity to c-erbB-3, bcl-2, Glut1, Glut3, retinoblastoma gene and p53 were correlated with 5-year survival in 63 patients with Stage I or II NSCLC, treated solely by surgical excision at Baylor Medical College, Houston, Texas. Several probabilistic NNs with genetic algorithm models were developed using the prognostic features as input neurons and survival at 5 years (free of disease/dead of disease) as output neurons. The probabilistic NN yielded excellent classification rates for dependent variable survival. The best model was trained with 52 cases and classified all 11 "unknown" test cases correctly. Several statistically significant logistic regression models were fitted using 50 cases to build the models and 13 cases as "hold-out" test cases. These multivariate statistical models provide various cutoff values that predict/classify the probability of survival at 5 years. In conclusion, probabilistic NNs and logistic regression models can be useful in estimating the prognosis of patients with Stage I and II NSCLC using multiple clinicopathologic and molecular variables. These multivariate predictive models need to be validated with much larger groups of patients to assess their potential clinical value.

The significance of intraluminal prostatic crystalloids in benign needle biopsies.

Intraluminal prostatic crystalloids (IPC) are more common in prostate cancer acini than in benign acini. This study was undertaken to evaluate the hypothesis that crystalloids seen in a benign biopsy may indicate an increased risk of a concomitant prostatic carcinoma. A total of 600 patients underwent more than one prostate biopsy. For 394 patients the results of the biopsy were either negative or positive for prostate cancer. After exclusion of patients whose biopsy results were considered negative but coded as high-grade prostatic intraepithelial neoplasia or were suspicious for cancer or whose slides were unavailable for review, 331 patients remained. Biopsy results for these patients were evaluated for the presence of IPC. Also, 18 completely-embedded benign prostates from cystoprostatectomy specimens from patients with bladder cancer were evaluated for the presence of IPC. Seven hundred twenty-five biopsy specimens were reviewed; 51 (7%) contained crystalloids. Thirty-two of 634 (5%) benign biopsy specimens and 19 of 91 (21%) prostatic carcinoma biopsy specimens contained crystalloids. Sixteen of 331 patients (5%) had crystalloids in the initial benign biopsy specimen; 6 patients subsequently were determined to have carcinoma (38%), and 10 continued to have negative results (62%). Three hundred fifteen initial benign biopsies did not show crystalloids; 83 (26%) patients were subsequently diagnosed as having prostatic carcinoma (p = 0.238, Fisher's Exact Test, chi-square test). The IPC were found in 5 of 18 cystoprostatectomy prostates (28%). In this study, the presence of IPC on the initial biopsy specimens was not a significant risk factor for a subsequent diagnosis of prostate cancer. The IPC were not uncommon in prostates without cancer.

Absence of prognostic significance of bcl-2 immunopositivity in non-small cell lung cancer: analysis of 427 cases.

The bcl-2 gene product inhibits apoptosis and is thought to participate in oncogenesis. Association of bcl-2 immunopositivity with improved prognosis of non-small cell lung cancers (NSCLC) is controversial. Although two studies have reported better survival in bcl-2-immunopositive NSCLCs, a third series has contradicted this finding. The authors studied a relatively larger case series involving 427 patients for whom detailed information on long-term follow-up was available to determine the prognostic significance of bcl-2 expression. The study included 252 adenocarcinomas (AC), 111 squamous cell carcinomas (SCC), and 64 large cell carcinomas (LC). After antigen retrieval, sections were immunostained using a monoclonal anti-bcl-2 antibody (1:60, Clone 124, Dako) and the avidin-biotin complex technique. Staining was scored as positive or negative and also on a semiquantitative scale as 0, low (<10%), moderate (10% to 75%), or extensive (>75%). Bcl-2 immunoreactivity was correlated with survival using the actuarial survival method, Kaplan-Meier method, and log-rank test and was not associated with statistically significant differences in survival for NSCLCs (P = .5537). Differences in survival remained insignificant even after NSCLCs were stratified for cell type, stage, or grade, singly or in combination. Therefore, using this method, bcl-2 immunopositivity does not appear to act as an independent prognostic indicator in NSCLCs.