Diagnostic accuracy of fine-needle aspiration biopsy is determined by physician training in sampling technique.

BACKGROUND: Fine-needle aspiration biopsy (FNAB) has been used with variable success as a diagnostic test for benign and malignant breast lesions. The goal of this study was to examine the effects of training physicians in the fine-needle aspiration sampling-technique on the diagnostic accuracy of FNAB of palpable breast masses. The settings for this study were private physicians' offices and university clinics of primary care physicians, surgeons, and cytopathologists. METHODS: We reviewed 1043 consecutive FNAB specimens of the breast obtained during 1 year (1992): 729 FNABs were performed by formally trained physicians (at least 150 FNABs performed previously under supervision during fellowship training or the equivalent) who had done at least 100 FNABs during the year; 314 FNABs were performed by physicians without formal training who had done a median of only 2 FNABs during the year (range, 1-43 FNABs). All FNAB specimens were reviewed microscopically and evaluated for cellularity and type of material present, for diagnostic accuracy, and for the rate of surgical intervention. A minimum of 2 years of follow-up was obtained by matching all cases to the population-based Northern California Cancer Registry. FNAB specimens were correlated with histologic specimens when they were available. RESULTS: Using FNAB, the formally trained physicians missed 2% of cancers, whereas the physicians without formal training missed 25%. Among the patients with benign lesions seen by the formally trained physicians, 8% went on to surgery, whereas 30% of those seen by physicians without formal training did so. Specimens obtained by the formally trained physicians were significantly more cellular and were significantly less likely to be nondiagnostic. CONCLUSIONS: FNAB, when performed by physicians who are well trained in the technique, is a highly accurate, cost-effective diagnostic method that carries minimal morbidity and could replace a large number of surgical biopsies. When performed by physicians without adequate training, FNAB is often misleading and potentially harmful.

The prognostic value of proliferation indices: a study with in vivo bromodeoxyuridine and Ki-67.

Proliferation indices are intended to help patients and clinicians make treatment decisions. We have previously demonstrated that a proliferation index based on in vivo labeling of S-phase cells with bromodeoxyuridine (BrdUrd) correlates with Ki-67 labeling index (LI). We now compare the prognostic value of these indices. With written consent, we gave 129 women with biopsy confirmed breast cancer 200 mg/M2 BrdUrd during 30 min immediately preceding surgery. We used IU-4 anti BrdUrd antibody to count the immunohistochemical labeling index (LI) of DNA-incorporated BrdUrd in 2,000 cells and MIB-1 to count Ki-67 (118 cases). Patients received standard surgical and adjuvant treatment. No patients were lost to follow-up and patients were followed a minimum of 2 (median 5.1) years. We compared survival and recurrence in tumors with high vs low labeling indices. We found that women in the low BrdUrd LI group had better disease free survival (92% vs 67% 5-yr DFS p = 0.001) and overall survival (94% vs 70% 5-yr OS, p = 0.0001) than those with a high LI. In comparison, a low Ki-67 index predicted better OS (87% vs 80% 5-yr OS, p = 0.020) and a trend for better DFS (84% vs 72% DFS p = 0.055). The apparent superiority of BrdUrd LI over Ki-67 LI is likely due to chance (p = 0.18). In multivariate survival analyses we found that BrdUrd LI proliferative index significantly improves prediction of DFS or OS even when node status, age or tumor size is in the model. We conclude that markers of proliferation are useful adjuncts in predicting patient prognosis.

The functional relationship between in vivo bromodeoxyuridine labeling index and Ki-67 proliferation index in human breast cancer.

Proliferation indices are used, along with other parameters, to estimate the risk of recurrence of breast cancer for individual patients. Because it is unlikely one index will be practical for all patients, it is important to understand the relationship between various indices of proliferation. For this reason, we compared a proliferation index based on in vivo labeling of S-phase tumor cells with the thymidine analog bromodeoxyuridine (BrdUrd), to a proliferation index based on an estimate of the growth fraction with the MIB-1 antibody to the Ki-67 antigen. With informed consent, we gave 145 patients 200 mg/m2 BrdUrd intravenously just prior to surgical removal of breast cancer. On histology sections, we visually counted S-phase cells which had incorporated BrdUrd using the Br-3 antibody which is specific to DNA-incorporated BrdUrd, and we counted cells in the growth fraction using the MIB-1 antibody to the Ki-67 antigen. We found that both indices were positively correlated with tumor size, number of positive nodes, and tumor grade, and both were negatively correlated with age and estrogen-progesterone receptor positivity. Using a linear functional relationship model, we found that the best (i.e. the maximal) fit between the two indices (correlation coefficient 0.79; p < 0.0001) occurred when each index was square root transformed, as is appropriate when counts follow a Poisson distribution. When we used the median as a cutpoint for each index, the classification of 19 percent of data pairs changed depending upon which index was used. We also estimated that the Ki-67 intercept (1.02 +/- 0.25) was significantly greater than zero. We conclude that the BrdUrd index of DNA synthesis in S-phase correlates highly with the MIB-1 index of the growth fraction, and both indices correlate well with other parameters of tumor aggressiveness. Because this correlation is driven by concordance of the extremes of high and low counts, clinical comparison will be necessary to determine which is the better prognostic marker for human breast cancer.

Wound tissue oxygen tension predicts the risk of wound infection in surgical patients.

OBJECTIVE: To test the hypothesis that subcutaneous wound oxygen tension (PsqO2) has a predictive relation to the development of wound infection in surgical patients. DESIGN: A noninterventional, prospective study. SETTING: A university department of surgery. PATIENTS: One hundred thirty operative general surgical patients at notable risk of infection as predicted by an anticipated Study on the Effect of Nosocomial Infection Control (SENIC) score of 1 or greater. OUTCOME MEASURES: PsqO2 was measured perioperatively. Its relation to the subsequent incidence of surgical wound infection was then determined and compared with the SENIC score as a criterion standard. RESULTS: Although the SENIC score and PsqO2 are inversely correlated, PsqO2 is the stronger predictor of infection. Low PsqO2 identified patients at risk and concentrated them in a cohort that was about half the size of that identified by the SENIC score. CONCLUSIONS: Subcutaneous perfusion and oxygenation are important components of immunity to wound infections. The SENIC score identifies systemic physiological variables that are important to the development of wound infection. Nevertheless, PsqO2 is the more powerful predictor of wound infection. Moreover, PsqO2 can be manipulated by available clinical means, and thus may direct interventions to prevent infection.

Genetic alterations in primary breast cancers and their metastases: direct comparison using modified comparative genomic hybridization.

Breast tumor development and progression are thought to be driven by an accumulation of genetic alterations, but little is known about the specific changes that occur during the metastatic process. We analyzed pairs of primary breast cancers and their matched lymph node metastases from 11 patients, pairs of primaries and distant metastases from three patients, and pairs of primaries, and local recurrences from two patients by using comparative genomic hybridization (CGH). Simultaneous hybridization analysis of primary versus matched lesion DNAs from 11 patients was also performed (modified CGH). This modified approach was useful not only for confirming CGH results but also for demonstrating quantitative differences between aberrations present at both sites. Frequent chromosomal changes present at both sites (> 35% of 16 cases) were 1q, 8q, and 17q gains and 6q, 8p, 9q, 13q, 16q, 17p, and Xp losses. The total number of aberrations detected exclusively in the lymph nodes or distant metastases was higher than that in the primary tumors (2.5 vs. 0.7, P < 0.05). We found high-level amplifications in four metastases (two lymph nodes and two distant metastases), but none in any primary tumor. These findings suggest that progression from primary breast cancer to metastasis may be associated with the acquisition of further genetic changes. Although further investigations are required, it was of interest that 3 of 11 patients (27%) showed 18q loss solely in their lymph node metastases.

Pathologic prognostic factors for patients with breast carcinoma. Which factors are important.

Current technologies can identify subsets of patients who are at greater risk for developing recurrent carcinoma. This article presents conventional and generally accepted pathologic features of breast carcinoma that allow breast carcinoma patients to be placed into low-risk or high-risk categories for recurrence-free or overall survival. Also, the role of flow cytometry, estrogen-progesterone receptor measurement, tumor angiogenesis, and selection oncoprotein expression, such as c-erbB2, are reviewed.

Clinical breast examination.

An astute clinician has an appreciation of the wide variation possible in normal breasts, but anticipates that the palpation of the breasts of an individual woman will be determined by basic facts concerning typical relative distribution of gland tissue, breast symmetry, the influence of life history, and possibly previous surgery. If the findings of a CBE are not as anticipated, the clinician must find out why this is so. This is a different frame of reference from asking whether a given lump or area should be considered suspicious for cancer. The basic questions are whether the findings of a CBE are consistent with typical breast structure and anatomy and in the context of the woman's life history. If these questions can be answered in the affirmative, the examination is complete; if not, further evaluation is necessary.

Axillary lymphadenectomy for breast cancer without axillary drainage.

OBJECTIVE: To evaluate axillary lymph node dissection done without closed drainage in conjunction with breast conservation cancer surgery. DESIGN: Prospective clinical study. SETTING: Two university hospitals. PATIENTS: Eighty-one women undergoing wide local excision of breast cancer with simultaneous or subsequent axillary lymph node dissection. INTERVENTIONS: No axillary drain was placed following axillary lymphadenectomy. MAIN OUTCOME MEASURES: The development and resorption of axillary seroma fluid as measured by clinical aspiration and serial sonographic examination. RESULTS: Thirty-four (42%) of the 81 women required axillary seroma aspiration even though axillary fluid was present in 92% (22/24) of those studied sonographically. The seromas accumulated over the first 2 weeks following axillary dissection and resorbed over the next 2 weeks, as assessed by both clinical and sonographic examination. The complication rate was 2% (2/81). The surgery was performed safely on an outpatient or short-stay basis in 99% (80/81) of patients. All patients except one were discharged within 23 hours of surgery, and 56 patients were discharged directly after anesthesia. CONCLUSION: Axillary lymph node dissection done in conjunction with breast conservation surgery can be performed in an ambulatory or short-stay setting without axillary drainage. Postoperative seromas will resolve within 1 month, and fewer than half will require aspiration. Lymphadenectomy without drainage reduces morbidity and allows the patient greater personal comfort.

Effects of dynamic exercise on subcutaneous oxygen tension and temperature.

Exercise influences blood flow distribution and may thereby influence tissue oxygen. Given that experimental evidence suggests exercise improves wound healing, this study was undertaken to determine the effect of exercise on subcutaneous tissue oxygen tension (PscO2). Subjects performed a treadmill test to maximum oxygen consumption (VO2) while PscO2 and subcutaneous temperature (Tsc) were measured using a tonometer and optode/thermocouple system. There were no significant differences in PscO2 between measurement points. Mean Tsc had increased 4.8% at maximum VO2, and 6.3% as the cool-down period ended and differed significantly across the exercise period. Changes in PscO2 and Tsc were not correlated. Oxygen availability was neither enhanced nor significantly reduced by exercise. However, PscO2 did not increase as expected in relation to increases in Tsc. Further study will determine the purported beneficial effects of exercise and the mechanism by which it may affect wound healing.

Starch powder contamination of surgical wounds.

OBJECTIVES: To determine if (1) lubricating starch glove powder contaminates surgical wounds even after powdered gloves have been washed and/or wiped: (2) starch powder can be eliminated from surgical wounds when the surgical team wears only powderless gloves; and (3) starch powder introduced into surgical wounds may increase scar formation. DESIGN AND OUTCOME MEASURES: Human surgical wounds were irrigated at the end of operations in which various combinations of powdered and powderless gloves were used. Team members who wore powdered gloves washed them in a saline solution and wiped them on surgical towels. The starch particles in the irrigant were counted. In addition, two series of breast biopsies were performed, one in which the surgeon wore powdered gloves and the other, powderless gloves. Pathologic specimens from reexcisions (for carcinoma) were examined for starch granules and inflammation. RESULTS: Starch granules were found in proportion to the number of surgical team members who wore powdered gloves and to the proximity of the wearer(s) to the operative site. Exclusive use of powderless gloves eliminated the presence of starch powder. Starch-containing phagocytes in tissue were surrounded by an inflammatory reaction, and in one patient the inflammation and scarring were severe. CONCLUSIONS: Starch powder is introduced into wounds by the use of powdered gloves despite glove washing and wiping. It can be eliminated by the exclusive use of powderless gloves. The inflammatory reaction to starch is variable and can be severe.

Cell proliferation in hyperplastic and in situ carcinoma lesions of the breast estimated by in vivo labeling with bromodeoxyuridine.

The proliferative activity of normal, benign proliferative, and carcinoma in situ (CIS) breast lesions was studied by in vivo labeling with 5-bromodeoxyuridine (BrdU) in 35 patients with concurrent breast carcinoma. The BrdU-labeled cells were identified on histologic sections by an anti-BrdU monoclonal antibody and an immunoperoxidase reaction. The percentage of BrdU-labeled cells in nonatypical hyperplasia (NAH) was higher (1.15 +/- 1.14%) than normal epithelial cells (0.67 +/- 0.56%, p = 0.066, borderline significance). This difference was very significant in postmenopausal women and disappeared in premenopausal women. No significant difference was found in the fraction of proliferating cells between NAH and atypical hyperplasia (AH): 1.15 +/- 1.14% for NAH versus 1.26 +/- 1.19% for AH. In CIS and in invasive carcinoma (ICA), a significant increase in the percent of BrdU-labeled cells was observed when compared to the normal epithelial cells or NAH (p < 0.001). No significant difference was found in the values of BrdU-labeled cells between CIS and ICA (p = 0.29). The percent of BrdU-labeled cells in benign breast lesions, including fibroadenoma, papilloma, and sclerosing adenosis, did not differ from those of the normal epithelial cells. The menopausal status of the patients did not affect the proliferative activity in NAH or CIS. No correlation was found in the fraction of BrdU-labeled cells between the normal and hyperplastic epithelial cells (r2 = 0.012) or between NAH and CIS (r2 = 0.406) or between CIS and ICA (r2 = 0.429).

The effects of activity and bed rest on tissue oxygen tension, perfusion, and plasma volume.

An experimental study with a crossover design was used to compare the effects of activity and bed rest on subcutaneous oxygen (PscO2), perfusion (BFsc), and plasma volume, and to explore the relationship of cardiovascular fitness to these variables. Fifteen healthy males were randomized to bed rest or activity and later completed the remaining protocol. Exercise prescription for the activity protocol and cardiovascular fitness were based on a treadmill performance test. Repeated measurements were made of subcutaneous oxygen and temperature using an optode in upper arm subcutaneous tonometers. Perfusion and PscO2 were greater during bed rest (p < .05). Post hoc analysis revealed a trend toward higher heart rates and diastolic blood pressure during the activity protocol. Change in plasma volume did not differ between protocols, and cardiovascular fitness was unrelated to PscO2 or BFsc. Findings suggest that in uninjured individuals, higher levels of activity intensity reduce oxygen levels and blood flow in peripheral tissues.

Correlation of bromodeoxyuridine (BRDU) labeling of breast carcinoma cells with mitotic figure content and tumor grade.

Tumor proliferation is inversely associated with survival in patients with breast carcinoma. Labeling of tumor cells with bromodeoxyuridine (BRDU) correlates highly with that seen with [3H]thymidine, the current "gold standard" for measuring tumor S-phase. However, the relationship of BRDU labeling to mitotic figure content and tumor grade remains incompletely defined. To determine this, we labeled 55 breast carcinomas with BRDU in vivo and correlated the results with mitotic figure content. The BRDU labeling index was the number of BRDU-positive cells/2,000 tumor cells, the mitotic figure index was the number of mitotic figures per 1,000 tumor cells, and the mitotic figure count was the number of mitotic figures per 10 high-powered fields. BRDU labeling was also correlated with tumor grade (Scarff-Bloom-Richardson). The BRDU labeling index correlated highly with the mitotic figure index (r = 0.814, p = 7.0 x 10(-14)), mitotic figure count (r = 0.725, p = 6.0 x 10(-10)), and tumor grade (r = 0.68, p = 1.1 x 10(-8)). The correlation of BRDU labeling with mitotic figure content was strong enough to suggest that a very carefully measured mitotic figure index provides an estimate of tumor growth fraction equivalent to the BRDU labeling index. Also, analysis of variance showed that the mitotic figure index was twice as precise as the mitotic figure count in estimating BRDU labeling, and thus was a more accurate measure of tumor proliferation. Moreover, measurements made by the mitotic figure index were as precise as those made by BRDU labeling. However, which method is optimal for estimating tumor proliferation rate remains unclear. Further studies are indicated.

Tumor labeling indices of primary breast cancers and their regional lymph node metastases.

BACKGROUND: Tumor labeling index has emerged as a strong predictor of the clinical course of women with breast cancer. This study investigated whether labeling index of primary tumors correlates with labeling indices of concurrent regional node metastases. METHODS: With appropriate written consent, preoperative in vivo infusion of the thymidine analogue 5-bromodeoxyuridine (BrdUrd) was used to label 109 human breast cancers. Labeled S-phase cells were identified immunohistochemically with an antibody specific to DNA-incorporated BrdUrd. Labeling index was the fraction of labeled nuclei in 2000 tumor nuclei. For 30 women, there was sufficient cancer in axillary lymph nodes to compare labeling indices in primary breast cancer and regional lymph node metastases. RESULTS: The 30 women were from 25 to 82 years of age. Tumors were from 1 to 12 cm in size and there were from 1 to 26 positive nodes. Tumor labeling index ranged from 0.1% to 34%, (mean, 11.1%; median, 10.3%) and axillary lymph node metastasis labeling index ranged from 0.1% to 27.7% (mean, 10.8%; median, 10.0%). There was strong correlation between primary tumor labeling index and regional lymph node metastases labeling index (r = 0.82, with 95% confidence interval 0.65-0.91). The correlation persisted within subgroups according to age, tumor size, number of positive nodes, and hormone receptor status. Primary tumor and lymph node metastases labeling indices also had statistically similar relationships with age, level of hormone receptors, tumor size, and number of positive nodes. CONCLUSIONS: Primary tumor and regional node labeling indices correlate strongly; the relationship is not influenced by age, level of hormone receptors, tumor size, or number of positive nodes.

Physician-patient sexual contact. Prevalence and problems.

To document the current prevalence of physician-patient sexual contact and to estimate its effect on involved patients, 10,000 family practitioners, internists, obstetrician-gynecologists, and surgeons were surveyed. Of the 1,891 respondents, 9% acknowledged sexual contact with 1 or more patients. Even in the unlikely case that none of the nonrespondents had sexual contact with patients, its prevalence among all 10,000 physicians surveyed would still be 2%. Of respondents, 23% had at least 1 patient who reported sexual contact with another physician; 63% thought this contact was "always harmful" to the patients. Almost all (94%) responding physicians opposed sexual contact with current patients; 37% also opposed sexual contact with former patients. More than half of respondents (56%) indicated that physician-patient sexual contact had never been addressed in their training; only 3% had participated in a continuing education course focusing on this issue. Clear and enforceable medical ethics codes concerning physician-patient sexual contact are needed, as well as preventive educational programs for medical schools and residency programs.

Tissue oxygenation, anemia, and perfusion in relation to wound healing in surgical patients.

Oxygen tension and collagen deposition were measured in standardized, subcutaneous wounds in 33 postoperative surgical patients. Pertinent clinical and wound parameters were analyzed by Pearson's correlation test and sequential linear regression analysis. Collagen deposition was directly and significantly proportional to wound oxygen tension and measures of perfusion. There were no significant correlations with hematocrit, estimated blood loss, length of operation, smoking, age, weight, sex, or urine output. This study in humans confirms animal experiments showing that collagen deposition and tensile strength in wounds are limited by perfusion and tissue oxygen tension. It appears unnecessary to maintain hemoglobin at normal levels to support repair, provided that peripheral perfusion can be maintained at a high level in compensation for anemia. These circumstances reflect the fact that although oxygen is essential to many aspects of healing, and must be delivered at adequate partial pressures, reparative tissue consumes relatively little of it.

In vivo measurement of breast cancer growth rate.

S-phase cells of 66 primary breast cancers were labeled in vivo by preoperative infusion of the thymidine analogue bromodeoxyuridine. A monoclonal antibody specific for DNA-incorporated bromodeoxyuridine was used to identify positive cells and compute a labeling index on histologic sections. The labeling index (the percentage of cells in S-phase) ranged from 0.1% to 23.9%; it correlated positively with poorly differentiated cancer, higher mitotic counts on routine histologic examination, and tumor size; and it correlated inversely with estrogen and progesterone receptors. The labeling index did not correlate with nodal involvement or ploidy. Of the 15 patients with a labeling index greater than 12%, three died and one had systemic disease after a median follow-up of 19 months. No other patients had recurrences. There were no clinical complications of bromodeoxyuridine infusion.

Cigarette smoking decreases tissue oxygen.

Subcutaneous wound-tissue oxygen (PsqO2) tension in eight volunteers fell rapidly and significantly in response to smoking, and remained low for 30 to 50 minutes. Sham "smoking" had no effect. These data suggest that a typical "pack-per-day" smoker experiences tissue hypoxia during a significant portion of each day. The degree of hypoxia found in these subjects has been associated with poor wound healing in animal and human studies. The onset and duration of tissue hypoxia paralleled the well-established plasma pharmacokinetics of nicotine. This suggests that peripheral vasoconstriction, induced by the adrenergic effects of nicotine, may contribute to the observed decrease in PsqO2.