Pediatric thyroid nodules: disease demographics and clinical management as determined by fine needle aspiration biopsy.

OBJECTIVE: The prevalence of thyroid nodularity in children has been estimated to be 1.8%. The reported prevalence of specific diseases which comprise these nodules is conflicting as evidenced by a reported range of malignancy of 2 to 50% in solitary nodules. In order to better classify pediatric (< 18 years old) thyroid disease and evaluate the utility of fine needle aspiration biopsy (FNAB) in this patient population, we retrospectively reviewed 66 FNABs from 64 thyroid nodules and 2 perithyroid lymph nodes from 57 patients. PATIENTS: The study was composed of 8 males and 49 females who ranged in age from 1 to 18 years old (mean = 13.1). DESIGN: Surgical and/or clinical follow-up was obtained in all patients. The 66 FNAB diagnoses were initially classified into specific diseases. However, for the purpose of this review, the cases were classified as: 3 insufficient, 51 benign, 8 suspicious, and 4 malignant. RESULTS: There were no "false positives" and one "false negative" (a papillary carcinoma was misdiagnosed as a benign nodule). Overall, 10 patients (18%) had malignant thyroid lesions, including 8 papillary carcinomas and 2 follicular carcinomas. Benign diagnoses included benign nodule, cyst, lymphocytic thyroiditis, granulomatous thyroiditis, hyperplasia, and abscess. CONCLUSIONS: The prevalence of malignancy in pediatric patients with thyroid nodules was 18%. We conclude that, because of its high diagnostic accuracy and minimal invasiveness, FNAB is useful in the management of pediatric thyroid nodules.

p53 protein overexpression in smooth muscle tumors of the uterus.

p53 is a nuclear phosphoprotein whose overexpression may portend a poor prognosis in a variety of neoplasms. In this immunohistochemical study we examined p53 overexpression in a variety of uterine smooth muscle tumors (34 leiomyosarcomas, 18 leiomyomas, and six smooth muscle tumors of uncertain malignant potential [STUMPs]). p53 immunoreactivity was observed in none of 18 (0%) leiomyomas, one of six (17%) STUMPs, and 16 of 34 (47%) leiomyosarcomas. Reactivity was not observed in the surrounding nonneoplastic uterine smooth muscle. Strong p53 overexpression in the leiomyosarcomas was significantly associated with high grade morphology (P = .013) and a high stage at the time of presentation (P = .021). In 25 leiomyosarcoma patients with clinical follow-up, p53 overexpression was associated with shorter length of survival (P = 0.024). However, this effect was not independent of tumor stage or grade. A regression analysis showed that tumor stage was the only independent predictor of length of survival. Our study size is small, and further studies are warranted to determine the significance and replicability of these findings.

The effect of a patient's risk-taking attitude on the cost effectiveness of testing strategies in the evaluation of pulmonary lesions.

STUDY OBJECTIVES: To assess the health and cost effects of a patient's risk-taking attitudes about diagnostic tests. DESIGN: Cost-effectiveness analysis. SETTING: Diagnostic testing strategies used in the evaluation of a patient with a radiographically detected lung lesion were evaluated. Strategies included combinations of sputum, fine-needle aspiration, bronchoscopy, thoracoscopy, and expectant management. PATIENTS: Patient data were obtained from the Survival Epidemiology and End Results Program, MEDLINE search, National Center for Health Statistics, and the Universities of Iowa and Stanford, and Kaiser Permanente Hospital. INTERVENTIONS: Different patient risk-taking attitudes were simulated using decision analysis. MEASUREMENTS: Lifetime cost of medical care, life expectancy, and cost effectiveness. RESULTS: The cost effectiveness of competing strategies depended on patient attitudes about taking risks. For a patient averse to expectantly waiting without definitive knowledge of whether cancer was or was not present, testing strategies using invasive procedures, such as thoracoscopy, were more cost effective. In contrast, for a patient who was identical except that he or she was averse to tests with higher morbidity and mortality, strategies that involved expectantly waiting, instead of more invasive tests, were more cost effective. Small changes in some risk-taking attitudes resulted in large changes in cost effectiveness. CONCLUSIONS: Risk-taking attitudes influenced the cost effectiveness of testing strategies. Consideration of patient risk-taking attitudes in diagnostic testing appears warranted in setting clinical policies and making individual decisions.

The importance of sputum cytology in the diagnosis of lung cancer: a cost-effectiveness analysis.

STUDY OBJECTIVE: To assess the potential health and cost effects of initial testing with sputum cytology to diagnose lung cancer. DESIGN: Cost-effectiveness analysis. DATA SOURCES: Surveillance Epidemiology and End Results (SEER) program; cost data from Northern California Kaiser Permanente Hospitals and Universities of Stanford and Iowa; National Center for Health Statistics; and a MEDLINE search. INTERVENTIONS: The use of sputum cytologies preceding other tests (ie, fine-needle aspiration, bronchoscopy, thoracoscopy) in patients with suspected lung cancer. MAIN OUTCOME MEASURES: Mortality associated with testing and initial surgical treatment (eg, performance of thoracoscopy to remove a local-stage, centrally located cancer), cost of testing and initial treatment, life expectancy, lifetime cost of medical care, and cost-effectiveness. RESULTS: In central lesions, sputum cytology as the first test was the dominant strategy because it both lowers medical-care costs ($2,516 per patient) and lowers the mortality risk (19 deaths in 100,000 patients) of the evaluation without adversely affecting long-term survival. In peripheral lesions, sputum cytology costs less then $25,000 per year of life saved if the pretest probability of cancer exceeds 50%. The estimated annual savings of adopting sputum cytology as the first test for diagnosing lung cancer in the United States is at least $30 million. CONCLUSIONS: Experience in regional centers indicates that sputum cytologic testing is infrequently ordered before implementing invasive diagnostic techniques, even in patients with central lung masses. The study findings suggest that sputum cytology as the first test in suspected lung cancer is likely to be cost saving without adversely affecting patient outcomes.

The cost-effectiveness of cervical-vaginal rescreening.

Although most laboratories practice 10% manual rescreening, the cost-effectiveness of this and other rescreening strategies rarely has been evaluated. Using data obtained from the medical literature, a decision model was created in which rescreening strategies were compared with nonrescreening strategies for the number of false-negative and false-positive diagnoses, cancers, life expectancy, and cost-effectiveness. The strategy of 10% rescreening with a repeated cervical-vaginal smear yielded almost no gain in life expectancy compared with an equivalent strategy with no rescreening. With 100% rescreening, the gain in life expectancy was only 0.24 days per patient. A 100% rescreening strategy generally was more cost-effective than a no-rescreening strategy at costs of rescreening varying from $2 to $10 per patient. A 10% rescreening strategy has limited utility. In addition, 100% rescreening strategies are more cost-effective than nonrescreening strategies, but only if the rescreening cost is low.

The cost-effectiveness of routine histologic examination.

Although the histologic examination of routine tissues, such as hernia sacs and intervertebral disks, has shown a low incidence of detecting clinically significant unsuspected disease, the cost-effectiveness of histologic examination has not been determined. By using a theoretical model that assumed variable costs and gains in life expectancy secondary to detecting clinically significant disease, a threshold incidence of disease detection at which histologic examination is cost-effective was determined. By using the University of lowa (Iowa City) cost of examination (approximately $25), at least 1 of every 2,000 examinations would have to show clinically significant disease for histologic examination to be cost-effective. This threshold incidence decreases as production costs decrease or life-year values increase. Before definitive policy conclusions can be made, additional studies are needed to better define the trade-off between cost and the value of information and the incidence of detecting clinically significant disease.

The cytologic diagnosis of low-grade transitional cell carcinoma.

Current theory suggests that transitional cell carcinoma (TCC) occurs as either of 2 disease processes, each of which has a distinct cytologic appearance and clinical course: low-grade and high-grade TCC. Urinary cytology has become a mainstay technique for monitoring disease recurrence in patients with TCC. Most cases of high-grade TCC can be diagnosed accurately in urinary cytology specimens. However, the cytologic diagnosis of low-grade TCC is difficult; these tumors exhibit subtle cytomorphologic alterations that are difficult to distinguish from benign or reactive processes. The cytologic criteria most useful for diagnosing low-grade TCC in urinary cytology specimens are reviewed. Additionally, the discussion includes some of the new ancillary tests that are emerging as possible diagnostic aids for the detection of low-grade urothelial neoplasms.

Fine-needle aspiration biopsy of pulmonary coccidiodomycosis. Spectrum of cytologic findings in 73 patients.

Coccidioides immitis, the causal agent of coccidiodomycosis, is endemic in the arid desert regions of Mexico and the southwestern United States. Individuals may acquire the disease through the inhalation of conidia. The majority of infected patients are asymptomatic or exhibit flu-like symptoms. Two percent of infected individuals ultimately demonstrate a solitary pulmonary nodule that may be radiographically indistinguishable from neoplasms or other infectious lesions. This report describes the spectrum of cytologic findings in 73 patients who were diagnosed with pulmonary coccidiodomycosis by fine-needle aspiration (FNA) biopsy. The patients ranged in age from 30 to 92 years. Ten had a previous history of malignancy. The smears were characterized by a large amount of granular, eosinophilic debris with a paucity of acute or chronic inflammation. Granulomatous inflammation was present in only three cases. The diagnosis was confirmed by the cytologic observation of C. immitis spherules that ranged in size from approximately 20 to 200 microns. Many of these spherules had a crushed or fractured appearance, and occasional calcified forms were seen. Endospores were observed in intact spherules and were rarely observed outside these spherules. Mycelial elements occasionally were present. C. immitis were cultured in 9 of 44 cases in which fungal cultures were obtained. The cytologic differential diagnosis, which includes contaminant, other infectious diseases and malignancies, is discussed.

Cost effectiveness of rescreening cervicovaginal smears.

Although cytology laboratories are mandated to rescreen at least 10% of cervicovaginal smears, there is no uniform national rescreening practice. Follow-up data for 16,188 rescreened cervicovaginal smears were studied and decision analysis was performed to determine an optimal rescreening strategy. High-grade dysplasia was detected in 0.40% of women with a history of cervical disease and in 0.04% without a history of cervical disease. Compared with 0% rescreening of smears, with 15% rescreening the cost to gain a year of discounted life expectancy was $386,890 for women without a history of cervical disease, and $2,980 for women with a history of cervical disease. We conclude that rescreening only smears from women with a history of cervical disease could save US laboratories more than $11.2 million annually without seriously compromising care.

Long-term outcome and relative risk in women with atypical squamous cells of undetermined significance.

Few studies have compared long-term follow-up and risk for invasive cancer in women with atypical squamous cells of undetermined significance (ASCUS). We conducted a 6-year review of pathology files for 651 women in whom ASCUS had been diagnosed in 1992. Data collected included patient demographics, follow-up diagnoses, time between follow-up examinations, and procedures performed. At follow-up, high-grade squamous intraepithelial lesions (HSIL) had developed in 9.0% of the women, and invasive cancer in none. Previous cervical history did not affect risk for an HSIL. Although the average time to first follow-up was 6.18 months, in 20.9% of the women the diagnosis of HSIL was not established until after 2.0 years. For individual pathologists, the percentage of HSILs ranged from 0% to 18.8%. Thus women with ASCUS who are followed up regularly are at low risk for development of invasive cancer.

The usefulness of pathologists' assistants.

The usefulness of pathologists' assistants (PAs) has not been assessed rigorously. Data from a time-motion self-report log generated by an Allegheny General Hospital (Pittsburgh, PA) PA and from the corresponding surgical specimen logs were reviewed to determine the daily distribution of PA time and multiple parameters of practice for gross examination of specimens. Using these data in specific scenarios, PA and non-PA practices were compared. The majority of the PA's time (56.5%) was spent performing gross examination of surgical biopsy specimens. The average cost of gross examination per specimen for a PA and a pathologist was $4.37 and $15.19, respectively. In this practice setting, $91,970.00 is saved per year by the use of a PA. The use of PAs instead of pathologists results in considerable practice cost savings ($560,000 in a practice of 50,000 specimens) or saves pathologists time to perform other necessary functions. PAs are highly useful in an era of cost containment.

The cost-effectiveness of the cytology laboratory and new cytology technologies in cervical cancer prevention.

The effect of changes in cytology laboratory costs, including the costs of new technologies, on the cost-effectiveness of cervical cancer prevention has not been studied. Using University of Iowa laboratory detection rates and costs, a decision model determined the cost-effectiveness of the laboratory with and without new technologies. Compared with not performing a cervicovaginal smear, the cost to increase the discounted life expectancy per patient by 1 year was $2,805 for the laboratory component alone and $19,655 for the entire cervical cancer prevention strategy. In moderate- to high-risk women, cervical cancer screening was cost-effective even at high cytology laboratory costs (eg, $75 per smear). New technologies were cost-effective only if they resulted in a substantial increase in the detection of high-grade squamous intraepithelial lesions (eg, an additional 236 high-grade squamous intraepithelial lesions per 10,000 women). New technologies have not demonstrated these increased detection rates.

Cytologic features useful for distinguishing small cell from non-small cell carcinoma in bronchial brush and wash specimens.

One blinded observer (C.D.S.) retrospectively reviewed 76 previously diagnosed and biopsy-confirmed malignant bronchial brush and wash specimens, 46 non-small cell and 30 small cell carcinomas, obtained from 55 patients. Each case was scored for the presence or absence of 36 standard criteria (architectural, cytoplasmic, and nuclear). Logistic regression analysis was used to determine which criteria were most useful for separating small cell from non-small cell lesions. Although no single criterion displayed 100% sensitivity and specificity for small cell cancer, univariate statistical analysis indicated that 3 individual criteria (nuclear molding, finely granular or "salt and pepper" chromatin, and scant delicate cytoplasm) were more than 90% sensitive and specific in cases of small cell carcinoma. The presence of nuclear molding alone provided the best fit for the logistic regression model. When nuclear molding was present, the odds of a small cell diagnosis increased more than 300-fold. Nuclear molding, finely granular or salt and pepper chromatin, and scant, delicate cytoplasm are the 3 most sensitive and specific cytomorphologic features traditionally used to separate small cell from non-small cell carcinoma. Nuclear molding alone represents the most significant cytomorphologic feature for distinguishing between these malignant lesions.

Adenocarcinoma in the lung in patients with breast cancer. A prospective analysis of the discriminatory value of immunohistology.

In some patients with a history of breast cancer who also have masses in the lung, making a clinical distinction between primary pulmonary neoplasia and pulmonary metastasis of mammary carcinoma may be impossible. To ascertain whether immunohistologic studies could contribute to resolving this problem, the authors undertook a prospective study of 30 cases showing synchronous or metachronous adenocarcinomas in these two sites. A predefined panel of antibodies--as derived from published antigenic catalogs for breast and lung cancer--was applied to each case. Tumors were interpreted as metastases if they were positive for gross cystic disease fluid protein-15, estrogen receptor protein, or S-100 protein. Conversely, primary adenocarcinomas of the lung were defined by their expression of carcinoembryonic antigen and a lack of the other three determinants. Using these criteria, 15 lesions were classified as metastatic; 11 were categorized as primary pulmonary adenocarcinomas; and 4 cases were indeterminate in origin. Responses to corresponding therapeutic protocols generally supported the validity of the immunohistologic diagnoses; 8 of 15 patients treated for metastatic breast cancer were well at least contact, as were 5 of 11 patients who received therapy for primary carcinoma of the lung. These data suggest that immunohistology plays a useful role in distinguishing mammary from pulmonary adenocarcinomas.

Value-based pathology: a cost-benefit analysis of the examination of routine and nonroutine tonsil and adenoid specimens.

To study the cost-effectiveness of the histologic examination of tonsil and adenoid specimens, the histologic diagnoses for all routine (2,700) and nonroutine (71) tonsil and adenoid specimens during a 10-year period were reviewed. There were 27 routine cases (1%) and 56 nonroutine cases (79%) with a diagnosis other than normal, tonsillitis, or hyperplasia. Twelve of the 27 routine cases did not have a significant clinical history, and a potentially significant pathologic diagnosis was made in only 6 cases; in none of these cases did the pathologic diagnosis affect patient care. In all nonroutine cases, the pathologic diagnosis affected patient care. The average charge per case to detect potentially significant disease in routine and nonroutine cases was $64,718 and $525, respectively. We conclude that histologic examination of nonroutine cases is cost-effective, whereas in most routine cases with adequate clinical history, histologic examination is not cost-effective.

Interobserver variability of a Papanicolaou smear diagnosis of atypical glandular cells of undetermined significance.

The interobserver variability of a Papanicolaou smear diagnosis of atypical glandular cells of undetermined significance (AGUS) has not been measured. Four expert cytopathologists retrospectively reclassified 100 smears originally diagnosed as AGUS; on follow-up examination, 54 had a clinically significant lesion and 46 had a benign lesion. The mean sensitivity and specificity of reclassification were 86% and 21%, respectively. The kappa statistic for pairwise cytopathologist comparison varied from 0.16 to 0.27. In 45% of cases the cytopathologists all used different Bethesda System diagnoses, and in no case did all the cytopathologists use the same diagnosis. There was little agreement on which cytologic criteria were important in separating clinically significant and benign lesions. We conclude the following: interobserver agreement in reclassifying AGUS lesions is very poor; the AGUS category is poorly understood, and there is no agreement on diagnostic cytologic criteria; and when reclassifying slides, cytopathologists make a number of false-negative diagnoses.

Histopathologic practices for esophageal biopsy specimens: survey results and implications for surveillance in patients with Barrett's esophagus.

A clinically valuable interpretation of esophageal biopsy specimens begins with well-prepared histologic sections. This may be especially true for reflux esophagitis and Barrett's glandular dysplasia. To determine exactly which histologic procedures are used by experts in gastrointestinal pathology, a checklist survey was mailed to 50 members of the Gastrointestinal Pathology Society. Responses were received from 42 (84%). Formalin, used 80% of the time, is overwhelmingly the most popular fixative. Orientation of biopsy material before further processing is performed in 36% of the institutions, most often (53%) by an endoscopy technician. The most frequently used (60%) substrate for orientation is filter material. The most common (83%) routine procedure uses only H&E staining. Others routinely add a mucin reaction to the H&E. Eleven different practices for sectioning are used; the most common (43%) is serial step sectioning at 3 levels. One third of the responders had a formal surveillance program for patients with Barrett's esophagus. For esophageal biopsy specimens, a broad spectrum of histologic practices exists. Trends for the more complex histotechnologic procedures to be used by those involved in screening for dysplastic Barrett's epithelium are evident.

The diagnosis and significance of visceral pleural invasion in lung carcinoma. Histologic predictors and the role of elastic stains.

Invasion of the visceral pleura is an important component of lung carcinoma staging, and in some studies is an independent prognostic indicator. Evaluation of invasion by H&E may be indeterminate. Elastic stains can be helpful but are performed rarely. We reviewed all lung carcinoma resections from 1993 for 13 histologic features potentially predictive of pleural invasion. Of 57 resections, 20 were indeterminate by H&E. Verhoeff-Van Gieson (VVG) stain revealed invasion in 8 cases, increasing the pathologic stage in 1. VVG stain was negative in 12 cases, 2 of which had been falsely reported as positive, decreasing the stage in 1. Angiolymphatic invasion and single-cell spread were significant predictors of invasion. Absence of both or the presence of intervening aerated parenchyma predicted lack of involvement in all cases. Elastic stains can provide prognostically important information, changing the pathologic stage in 4% of lung carcinoma resections overall and in 10% of cases indeterminate by H&E for pleural invasion.

Clinical perception of disease probability associated with Bethesda System diagnoses.

The degree to which clinical perceptions of Papanicolaou smear sensitivity contribute to patient mismanagement is uncertain. A voluntary, anonymous questionnaire was mailed to 350 obstetricians/gynecologists (OGYNs) and 350 other primary care providers (PCPs) located in Pennsylvania or Ohio. The clinicians estimated the probability of no disease, dysplasia, and invasive carcinoma for 1 of 7 Bethesda System diagnoses. Differences in probability estimates between provider types and between the clinicians and medical literature data were measured. The response rate was 22.7%. Compared with published values, clinicians estimated similar disease probabilities for many diagnoses. However, for some diagnoses, the probability estimates differed considerably from published values (e.g., overestimation of dysplasia and invasive carcinoma for benign diagnoses and underestimation of dysplasia for some dysplasia diagnoses), and such errors could contribute to patient mismanagement. OGYNs generally were more accurate in probability estimates than PCPs. Methods to convey more accurately these diagnostic disease probabilities should be examined.

Pathologists' assistants practice: a measurement of performance.

Despite their widespread utilization, little is known about the quality of pathologists' assistants' services. Pathologists' assistants' performance was compared with pathology residents' performance using the metrics of lymph node retrieval and tissue resubmission rates. Lymph node retrieval was calculated by retrospective review of surgical pathology reports from a sample of axillary dissection, mastectomy, and colorectal specimens. Tissue resubmission rates were calculated by retrospective review of a sample of general surgical pathology reports. Pathologists' assistants retrieved a significantly greater total number of lymph nodes compared with pathology residents; however, there was no difference in the total number of positive lymph nodes retrieved. Cases for which pathologists' assistants performed the gross examination had a significantly decreased resubmission rate compared with those performed by residents. In this setting, the gross examination performance of pathologists' assistants was equivalent to or superior to that of pathology residents. These results provide the first information available relating to pathologists' assistants' performance in surgical pathology.