Quantitative assessment of nuclear grooves in fine needle aspirates of the thyroid: a retrospective cytohistologic study of 94 cases.

OBJECTIVE: To quantify the association between the percentage of nuclear grooves and papillary thyroid carcinoma (PTC) in fine needle aspirates (FNAs) of the thyroid. STUDY DESIGN: All the thyroid FNA cases (n = 1,775) received at the McGill University Health Center Cytopathology Laboratory in 2003 and 2004 were retrieved. The 94 diagnostic FNAs with histologic followup were selected. The percentage of nuclear grooves was quantified manually by counting the number of grooves in 300 cells, at x400, in the areas where the nuclear grooves were most frequent. Using descriptive statistics and graphs, we evaluated the association between the percentage of nuclear grooving and 2 outcomes of surgical diagnosis. RESULTS: The mean percentage of nuclear grooves was 23.7% in PTC vs. 9.44% in non-PTC cases. We identified the cut-off of 20% nuclear grooving as having the optimal positive predictive value of 80% for presence of PTC and negative predictive value of 77% for absence of PTC. CONCLUSION: The presence of nuclear grooves in > or = 20% of cells, as counted in selective fields where grooves are the most frequent, is highly predictive of PTC.

Primary effusion lymphoma: a series of 4 cases and review of the literature with emphasis on cytomorphologic and immunocytochemical differential diagnosis.

BACKGROUND: Primary effusion lymphoma (PEL) is a human herpes virus-8 (HHV-8)-associated and very rare type of lymphoma usually confined to the body cavities and commonly observed in human immunodeficiency virus (HIV)-infected patients. A comparison was made between the cytologic and immunocytochemical features of 4 cases of PEL encountered in the authors' department with those reported to date in the literature. METHODS: A comprehensive comparison of the cytologic and immunocytochemical features of the 4 cases with those reported in the literature was conducted. RESULTS: Cytologically, the most consistent features of the 4 cases and those in the literature included large cell size, moderate to abundant cytoplasm, a single nucleus in most cells with occasional bi- or multinucleated giant cells, single to multiple prominent nucleoli, and coarse chromatin. Immunocytochemically, only 2 (50%) of the current cases were of the null-phenotype compared with 93% of cases in the literature; the other 2 cases had a T-cell phenotype. Activation markers were expressed in 50% and 78% of the current cases and the literature cases, respectively. Positivity for HHV-8 was proven in the 4 cases by immunocytochemistry. CONCLUSIONS: Cytomorphologically, PEL exhibits features bridging large cell immunoblastic and anaplastic large cell lymphoma. Although it is usually of null-phenotype, it may occasionally express B-cell or T-cell markers, rendering its distinction difficult from other lymphomatous effusions on a cytologic and immunocytochemical basis alone. Therefore, HHV-8 detection is an essential confirmatory ancillary test in suspected cases of PEL.

Testing for HER2-positive breast cancer: a systematic review and cost-effectiveness analysis.

BACKGROUND: Testing to determine HER2 status has come into focus since the approval of trastuzumab (Herceptin) for the treatment of HER2-positive breast cancer. We compared the cost-effectiveness of various strategies used to test HER2 status, an important first step toward evaluating the overall cost-effectiveness of trastuzumab therapy. METHODS: We performed a systematic review of studies that evaluated concordance between immunohistochemistry and fluorescence in situ hybridization testing to determine HER2 status. We performed a meta-analysis to estimate the distribution of immunohistochemistry scores in each category (0, 1+, 2+, 3+) and the probability of receiving a positive result of fluorescence in situ hybridization (which we assumed to be the "gold-standard" test) for each category. We calculated the accuracy and incremental cost per accurate diagnosis for each testing strategy compared with the base strategy (immunohistochemistry testing, followed by confirmation of 2+ scores by fluorescence in situ hybridization). RESULTS: The median percentage of patients in each category of immunohistochemistry score was: 0, 36.1%; 1+, 35.5%; 2+, 12.0%; and 3+, 16.2%. The median percentage of results of fluorescence in situ hybridization that were positive in each immunohistochemistry category was: 0, 1.6%; 1+, 4.9%; 2+, 29.8%; and 3+, 92.4%. The base strategy was expected to correctly determine the HER2 status of 96% of patients with breast cancer. Confirmation of the HER2 status by fluorescence in situ hybridization in cases that received a score of 3+ reduced the percentage of false-positive results to 0% and increased the percentage of accurately determined HER2 results to 97.6%. Compared with the base strategy, this strategy was associated with a median incremental cost-effectiveness ratio of $6175 per case of accurately determined HER2 status. The strategy of performing fluorescence in situ hybridization testing in all cases of breast cancer was associated with a median incremental cost-effectiveness ratio of $8401 per case of accurately determined HER2 status. INTERPRETATION: The strategy with the lowest cost-effectiveness ratio involved screening all newly diagnosed cases of breast cancer with immunohistochemistry and confirming scores of 2+ or 3+ with fluorescence in situ hybridization testing.

Loss of APAF-1 expression is associated with tumour progression and adverse prognosis in colorectal cancer.

The aim of this study was to determine the prognostic value of APAF-1 in colorectal cancer (CRC). Immunohistochemistry for APAF-1 was performed on a tissue microarray of 1015 mismatch-repair (MMR) proficient and 130 sporadic MLH1-negative CRCs. The association of APAF-1 with clinico-pathological features including 10-year survival time was analysed. Methylation specific PCR was performed on a subset of MMR-proficient and MLH1-negative CRC. Loss of APAF-1 was associated with advanced T stage (p-value=0.022), N stage (p-value=0.009), vascular invasion (p-value=0.001) and worse survival (p-value=0.017) in MMR-proficient CRC. In MLH1-negative CRC, loss of APAF-1 was associated with metastasis (p-value=0.041), worse prognosis (p-value<0.001) and independently predicted shorter survival time (p-value<0.001). No methylation was found in the selected region of APAF-1. APAF-1 is a marker of tumour progression in MMR-proficient CRC and an independent adverse prognostic factor in MLH1-negative CRC.

Gene expression signatures of morphologically normal breast tissue identify basal-like tumors.

INTRODUCTION: The role of the cellular microenvironment in breast tumorigenesis has become an important research area. However, little is known about gene expression in histologically normal tissue adjacent to breast tumor, if this is influenced by the tumor, and how this compares with non-tumor-bearing breast tissue. METHODS: To address this, we have generated gene expression profiles of morphologically normal epithelial and stromal tissue, isolated using laser capture microdissection, from patients with breast cancer or undergoing breast reduction mammoplasty (n = 44). RESULTS: Based on this data, we determined that morphologically normal epithelium and stroma exhibited distinct expression profiles, but molecular signatures that distinguished breast reduction tissue from tumor-adjacent normal tissue were absent. Stroma isolated from morphologically normal ducts adjacent to tumor tissue contained two distinct expression profiles that correlated with stromal cellularity, and shared similarities with soft tissue tumors with favorable outcome. Adjacent normal epithelium and stroma from breast cancer patients showed no significant association between expression profiles and standard clinical characteristics, but did cluster ER/PR/HER2-negative breast cancers with basal-like subtype expression profiles with poor prognosis. CONCLUSION: Our data reveal that morphologically normal tissue adjacent to breast carcinomas has not undergone significant gene expression changes when compared to breast reduction tissue, and provide an important gene expression dataset for comparative studies of tumor expression profiles.

Correlation of cytotechnologists' parameters with their performance in rapid prescreening of papanicolaou smears.

BACKGROUND: Efficient quality control is essential to ensure high sensitivity of Papanicolaou (Pap) smears. For this purpose, rescreening of 10% random negative smears is increasingly felt to be ineffective. Rapid rescreening (RR) of all negative Pap smears is more practical and has received widespread acceptance, especially in Europe, although its sensitivity is difficult to monitor and its retrospective nature may influence the vigilance of the screeners. The method of rapid prescreening (RPS) overcomes these drawbacks because rapid review of Pap smears precedes full screening. METHODS: All routine conventional Pap smears (n = 8364) over 2 months underwent RPS by 12 cytotechnologists, followed by full screening. Data were analyzed to determine correlation between the RPS sensitivity of individual cytotechnologists and both their sensitivity in full screening and their years of experience as cytotechnologists. RESULTS: There was a striking variability in sensitivity (15.4%-72.7%) among the 12 screeners with an atypical squamous cells of undetermined significance (ASCUS) threshold. There was no correlation between RPS sensitivity of individual cytotechnologists with either their sensitivity in full screening or their years of experience as cytotechnologists. CONCLUSIONS: The skills required of a cytotechnologist for achieving a high sensitivity in RPS are apparently different from those of full screening and are independent of the sensitivity of the screeners at full screening or of the years of experience as cytotechnologists.

Rapid prescreening of Papanicolaou smears: a practical and efficient quality control strategy.

BACKGROUND: Efficient quality control (QC) is essential to ensure high sensitivity of Papanicolaou (Pap) smears. For this purpose, rescreening of 10% random negative smears is ineffective. Rapid rescreening (RR) of all negative Pap smears is more practical and has received widespread acceptance, especially in Europe, although its sensitivity is difficult to monitor and its retrospective nature may influence the vigilance of the screeners. The method of rapid prescreening (RPS) overcomes these drawbacks because rapid review of Pap smears occurs before routine full screening. METHODS: All routine conventional Pap smears over 2 months underwent RPS by 12 cytotechnologists. Approximately 30 seconds were allowed to prescreen each slide. The presence of abnormal cells (atypical squamous cells of undetermined significance [ASCUS] or above), infection or endometrial cells detected on RPS was documented. All slides subsequently underwent routine full screening. Results of both screening methods were compared. RESULTS: Of a total of 8364 Pap smears, 310 (3.7%) cases were categorized as abnormal after final diagnosis. Of those, 135 were also detected on RPS (sensitivity of 43.5%). Seventeen abnormal cases were detected only on RPS: these consisted of 13 ASCUS cases, 3 low-grade squamous intraepithelial lesions, and 1 high-grade squamous intraepithelial lesion. The sensitivity of RPS for infections and endometrial cells was 51.6% and 28.3%, respectively. Implementation of RPS did not significantly impact the work flow in our laboratory. CONCLUSIONS: RPS is an efficient and practical QC tool. It is a reliable method with which to monitor sensitivity and reduce the false-negative rate, and because it is done before finalizing the case, it allows for timely corrections to the diagnosis and avoids the need to amend reports.