Breast carcinoma detection in women age 35 years and younger: mammography and diagnosis by fine-needle aspiration cytology.

BACKGROUND: Delays in breast carcinoma diagnosis may occur in young women due to a low index of suspicion. Fine-needle aspiration (FNA) is an ideal method for evaluating breast lesions in younger women. Mammographic and FNA findings, including nuclear grade, were studied to determine both the utility of FNA and the presence of unique cytologic features in women age < or = 35 years with breast carcinoma. METHODS: The cytopathology files were searched from 1984 to 1996 for FNA in women age < or = 35 years with breast carcinoma. The cytologic, mammographic, and clinical findings were reviewed in the 68 FNAs identified. A nuclear grade was assigned to each FNA. RESULTS: Thirteen patients were age < 30 years and 55 were age 31-35 years (range, 22-35 years; average, 31 years). The clinical and mammographic findings were carcinoma in 45 patients (66%) and fibroadenoma/benign in 23 patients (34%). FNA diagnoses were malignant/suspicious (86%), atypical (12%), and negative (1.4%). In 23 patients with unsuspected carcinoma, the FNA diagnosed or suggested malignancy in 22 of 23 patients (96%). The cytologic findings on review were variable. Many FNAs were cellular, with enlarged nuclei and prominent nucleoli. The FNAs predominantly were nuclear Grade 2 (47%) and 3 (47%); only 4 tumors were nuclear Grade 1 (6%). CONCLUSIONS: By detecting breast carcinoma in 23 patients with unsuspected carcinoma, this study demonstrates how breast FNA in young women can help avoid delays in diagnosis. The cytologic findings are striking for an increased incidence of high grade tumors.

Fine needle aspiration of mucinous (colloid) breast carcinoma. Nuclear grading and mammographic and cytologic findings.

OBJECTIVE: The clinical, mammographic and low grade cytologic features of mucinous carcinoma can make it difficult to diagnose by fine needle aspiration (FNA). Fine needle aspirates of mucinous carcinoma were reviewed with the mammographic findings to improve the diagnostic criteria and specificity for FNA. STUDY DESIGN: All aspirates were reviewed for cytologic criteria and cellularity, atypia and single epithelial cells (SEC). A nuclear grade was assigned to each aspirate. The mammographic findings were correlated with the FNA diagnoses. RESULTS: Forty-five patients with an aspirate and confirmed diagnosis of mucinous carcinoma were identified. The clinical impressions were: benign tissue (5), fibroadenoma (6) and cancer (32). The initial cytologic diagnoses were: adenocarcinoma (32), atypical/suspicious for cancer (11), insufficient (1) and negative (1). The cytologic findings showed smears with increased cellularity (35/45 cases) and minimal atypia. SEC with eccentrically located nuclei and eosinophilic cytoplasm were numerous. The assigned nuclear grade was as follows: grade 1, 16 cases; grade 2, 20 cases; and grade 3, 6 cases. Abundant mucin was present in Papanicolaou-stained slides in 23 cases; focal mucin was observed in 14 cases. The mammograms showed a smoothly outlined to lobulated mass with only slight irregularities identified. CONCLUSION: Mucinous carcinoma has a cytologic pattern that includes increased cellularity, with numerous single cells and abundant mucin. Although the mammographic findings may mimic a benign lesion, in the most patients a specific diagnosis of mucinous carcinoma can be made by FNA.

The cost-effectiveness of fine-needle aspiration cytology and 14-gauge core needle biopsy compared with open surgical biopsy in the diagnosis of breast carcinoma.

BACKGROUND: Judicious utilization of fine-needle aspiration cytology (FNAC) and 14-gauge core needle biopsy (CB) theoretically should result in greater accuracy in breast carcinoma diagnosis and fewer unnecessary open surgical biopsies (OSBs), thus lowering health care costs. METHODS: In 1995 in Rochester, New York, the ratio of open surgical breast biopsies per each verified breast carcinoma (OSB/Ca) in a freestanding breast clinic (EWBC) was compared with the OSB/Ca ratio of all physicians in the remainder of the city. The EWBC differs from all other diagnostic facilities in Rochester in that it routinely performs FNAC and CB. RESULTS: The EWBC recommended 462 OSBs resulting in 310 verified carcinomas, for a OSB/Ca ratio of 1.5. The physicians in the remainder of the city recommended 2036 OSBs resulting in 513 verified carcinomas, for a OSB/Ca ratio of 4.0. If the EWBC OSB/Ca ratio had been identical to the remainder of the city, the number of extra OSBs recommended by the clinic would have been 778, resulting in an additional cost of $1,712,082. When the added cost of the 2594 FNACs ($256,285) and 403 CBs ($252,278) performed by the clinic was subtracted from the $1,712,082, the freestanding breast clinic cost savings was $1,203,519. The lymph node metastasis rate of 19% for the breast carcinomas diagnosed in clinic patients was identical to that of the women with breast carcinoma in the remainder of the city. CONCLUSIONS: Utilization of FNAC and CB allows radiologists to lower their OSB/Ca ratio without sacrificing early detection. In this study, these less expensive procedures result in lowered medical costs for the health care system.

Fine needle aspiration cytology of invasive micropapillary carcinoma of the breast. A report of two cases.

BACKGROUND: Invasive micropapillary carcinoma is a recently described variant of invasive breast cancer characterized by the formation of micropapillae within clear spaces separated by a fibrocollagenous stroma. Although the histologic features are well described, to the best of our knowledge, the cytologic findings have not been reported. CASES: The fine needle aspiration cytology of two cases of biopsy confirmed invasive micropapillary carcinoma are described and compared to the histologic features. In one case, an additional FNA of a subsequent metastasis is reviewed. CONCLUSION: The cytologic features of invasive micropapillary carcinoma are distinctive and correlate with the histology. Invasive micropapillary carcinoma can be suggested based on the FNA findings of numerous well-formed angular, papillary clusters along with other criteria of malignancy. The cytologic differential diagnosis of invasive micropapillary carcinoma is discussed.

Interstitial pregnancy complicated by rectal bleeding.

An interstitial pregnancy complicated by rectal bleeding is described. Despite modern imaging modalities, confounding features made preoperative diagnosis difficult. The pregnancy ruptured into the ileum. Ossified fetal skull bones and degenerated placental tissue were the only remains from the pregnancy.

The cytopathology of proliferative breast disease. Comparison with features of ductal carcinoma in situ.

Epithelial hyperplasia, a component of proliferative breast disease (PBD), is a known risk factor for the development of breast carcinoma. To determine if criteria established for tissue biopsy could be used to more precisely define cytologic criteria for diagnosis of PBD, 37 breast fine-needle aspirates with biopsy diagnoses of PBD were studied. In cases with adequate cellularity, the following findings were consistently observed: (1) three-dimensional cell clusters with outlying myoepithelial cells, swirling intralumenal masses and peripheral, slit-like, irregular sublumens (65% of cases); (2) convoluted sheets of ductal epithelium with outlying myoepithelial cells and bulbous projections tethered to the ductal lining (29%); and (3) a background of discohesive small frayed groups of ductal cells (32%). Of the 15 cases that did not meet these criteria, most were paucicellular (87%), which suggested sampling error. Other cytologic features that were observed included: moderately increased cellularity (20 cases), moderate-to-marked nuclear overlap (14 cases), minimal nuclear atypia, and few single epithelial cells. Fifteen cases of confirmed ductal carcinoma in situ were studied for comparison. In these cases, cellularity, nuclear overlap, and atypia were increased, but swirling intralumenal masses, prominent myoepithelial cells and slit-like lumens were absent. In conclusion, the features of PBD established for tissue biopsy can be applied to cytologic specimens, and may provide useful clues to the diagnosis of epithelial hyperplasia in breast fine-needle aspiration specimens.

Breast fine-needle aspiration. A comparison of thin-layer and conventional preparation.

Two hundred forty-two breast fine-needle aspirates prepared by the Cytyc ThinPrep Processor were compared with aspirates prepared by the conventional smear method. Palpable and nonpalpable mammographic breast lesions were aspirated and the first half of the aspirate was submitted for conventional smears and the second half was rinsed into a proprietary fixative and loaded on the ThinPrep Processor for monolayer slide preparation. The matched pairs were diagnosed and analyzed separately in a double-blinded manner and later paired for comparison. Diagnoses correlated exactly in 62% of cases. The diagnosis of fibroadenoma was made in only 4 of 21 cases on ThinPrep (19% correlation). Semiquantitative analysis of several cytologic features indicated potential pitfalls for accurate diagnosis using the ThinPrep Processor. These included loss of background constituents (such as stroma and adipose tissue), decreased cellularity and single ductal epithelial cells, and decreased cytologic detail including size, shape and nuclear texture. The ThinPrep Processor may play a role in breast fine-needle aspiration, but further investigation is warranted before it is used as a sole preparatory method.

Aspiration cytology of tubular carcinoma. Diagnostic features with mammographic correlation.

The detection of early, well-differentiated breast carcinoma is increasing because of mammographic screening. Because fine-needle aspiration cytology is often used as an adjunctive diagnostic tool with mammography, the authors defined the cytologic criteria for the diagnosis of this early breast carcinoma. Aspirates from 24 cases of biopsy-confirmed tubular carcinoma were studied. The majority of these carcinomas were detected by mammography and were nonpalpable masses. Mammographically, the lesions were .3-1.5 cm and were often described as ill-defined, spiculated densities. The cytologic diagnoses in these 24 cases were as follows: negative (4), fibrocystic changes (1), atypia (12), malignant (3), and fibroadenomas (4), (including 2 fibroadenomata with atypia and 1 suspicious for carcinoma). The aspiration cytology in all cases were reviewed, and the following characteristics were found in the 20 adequate smears: mild to moderate atypia, increased cellularity, angular epithelial clusters, and single epithelial cells ranging from few to numerous. Myoepithelial cells were prominent in 7 of 20 smears. The authors compared these features with aspiration cytology of 10 fibroadenomas, as this was a frequently suggested diagnosis. The fibroadenomas showed no significant atypia, minimal angular epithelial clusters, and rare single epithelial cells. Myoepithelial cells were prominent in all fibroadenomas. The authors concluded that the presence of angular epithelial groups and single epithelial cells, along with nuclear atypia, should warrant consideration of the diagnosis of tubular carcinoma.

Benign versus malignant papillary neoplasms of the breast. Diagnostic clues in fine needle aspiration cytology.

Benign and malignant papillary lesions of the breast can be difficult to distinguish in both cytologic and histologic preparations. To determine the cytologic features, we retrospectively analyzed 29 fine needle aspirates with a biopsy-confirmed diagnosis of papilloma or papillary carcinoma. They included 7 intracystic papillary carcinomas, 6 invasive papillary carcinomas and 17 intraductal papillomas. All cases were evaluated for cellularity, single epithelial cells, atypia and papillary fragments. A common pattern was increased cellularity, papillary groups and single columnar epithelial cells. Markedly increased cellularity was present in 10/12 carcinomas and 4/17 papillomas. Numerous single cells were present in 5/12 carcinomas and 2/17 papillomas. The majority of cases had only mild to moderate atypia. Papillary carcinomas displayed nuclear hyperchromasia and stratification surrounding stroma and in isolated clusters. In papillomas, nine cases had background apocrine metaplasia, foam cells and/or bipolar cells. Apocrine metaplasia was absent from all cases of papillary carcinoma. Two papillomas had marked nuclear atypia with background necrosis and inflammation. These unusual cases represented infarcted papillomas, a potential pitfall in the diagnosis of cancer. We conclude that markedly increased cellularity and numerous single cells favor a diagnosis of papillary carcinoma. More specific diagnostic clues are the cytologic findings of nuclear hyperchromasia, stratification and absence of benign background cells, such as apocrine metaplasia.

Atypia in fine needle aspiration cytology of nonpalpable and palpable mammographically detected breast lesions.

Widespread use of fine needle aspiration (FNA) in conjunction with mammography may lead to increased atypical or suspicious cytologic diagnoses. To assess the incidence and cytologic criteria of atypia in a mammographically screened population, we reviewed 220 FNA samples in this diagnostic category (5.8% incidence) from 3,798 FNAs performed in 1990-1991. The atypical category (134 cases) included 72 benign and 62 malignant confirmed cases. Common benign diagnoses were fibroadenoma and fibrocystic changes (33 cases, or 46%). Features responsible for an atypical diagnosis in benign cases were increased cellularity, single epithelial cells and "reactive nuclear atypia," the last defined as a finely granular, uniform chromatin pattern with small, prominent nucleoli. The suspicious category included 86 cases; only 10 cases (12%) were confirmed benign lesions, and the remainder were malignant. These benign cases included 3 fibroadenomas, 3 fibrocystic changes, 3 papillomas and 1 scar after radiotherapy. Two cases had prominent inflammation, a finding that should prompt caution. Malignant diagnoses in both categories included infiltrating and in situ cancers. A combination of limited cellularity, drying and/or bland nuclear features precluded a definitive diagnosis of cancer in many cases. For optimal management of mammographically screened patients, an acceptable "atypical" diagnostic rate should be defined for FNA. We conclude that a rate of less than 5% can be achieved by recognition of the following: (1) reactive atypia in the setting of fibrocystic and fibroadenomatous patterns, (2) significance of atypia in the setting of inflammation, and (3) improved sampling and sample preparation.

Presence of cytomegalovirus inclusion bodies in a recurrent ulcerative vaginal lesion.

Cytomegalovirus is present in the female lower genital tract with an incidence of 4% to 12%. Intracellular inclusion bodies, which constitute evidence of the presence of this organism, are noted on Papanicolaou smears or at direct biopsy. All previous reports regarding tissue diagnosis have involved the uterine cervix. We report an unusual case of a postmenopausal woman who was found to have recurrent symptomatic vaginal lesions; repeated biopsies of the lesion disclosed the presence of cytomegalovirus inclusion bodies.

Chromatin texture measurement by Markovian analysis. Use of nuclear models to define and select texture features.

The use of nuclear grade as a prognostic indicator in breast cancer has been limited by its poor interobserver reproducibility. Automated cell classification using digital image analysis is one approach to this problem. Nuclear chromatin distribution, an important feature used in nuclear grading, can be quantitated with texture analysis. Markovian analysis is one method of analyzing texture features that is available in a commercially available image analysis system, the CAS-100. In order to select optimal Markovian features for use in nuclear grading of breast cancer, 16 nuclear models were created with computer graphics that demonstrated specific components of nuclear chromatin pattern, such as granularity, contrast, symmetry, peripheral chromatin clumping, and number and shape of nucleoli. These models were analyzed on the CAS-100 image analysis system using software capable of measuring 22 Markovian texture features at 20 levels of pixel resolution (grain). We were able to show that Markovian analysis performed well in discriminating between degrees of chromatin granularity (finely vs. coarsely clumped), amount of contrast (vesicular change), thickness of peripheral chromatin and number of nucleoli. Of the 22 Markovian features, 10 were selected as optimal for discriminating between the above chromatin patterns. Similar optimal Markovian features were found when measurements were performed on captured images of breast cancer cells. The use of these selected Markovian texture features may allow a more rational approach to the use of image analysis for cell classification.

Recurrent stage I endometrial adenocarcinoma in the nonirradiated patient: preliminary results of surgical "staging".

Recurrent endometrial carcinoma, even when clinically confined to the vagina or pelvis, is associated with poor survival. Pelvic radiotherapy for patients with localized recurrences who have not been previously irradiated has not been highly effective. Our hypothesis was that local salvage therapy fails because a significant number of patients have occult, subclinical distant metastases at the time of relapse. In order to accurately assess disease status at the time of the recurrence, we prospectively evaluated eight patients with recurrent disease limited to the vagina/pelvis by physical examination, routine laboratory tests, and radiologic imaging. All patients underwent a "staging" procedure which included laparotomy, selective pelvic/periaortic lymphadenectomy, peritoneal biopsies, and washings. Three (37.5%) of eight patients had upper abdominal disease found at laparotomy (95% confidence interval 0.11 to 0.71). Presence of subclinical metastases was associated with larger tumor size (> or = 2 cm) and elevated serum CA 125 antigen levels. Treatment was modified in three patients according to the results of surgical staging. One patient was treated with chemotherapy while two patients received whole-abdominal radiation in addition to pelvic fields. Seven of eight patients are alive 21 to 61 months following salvage therapy. Three (43%) of seven patients treated with radiotherapy suffered nonneoplastic bowel obstruction requiring laparotomy at 3, 6, and 15 weeks following completion of radiation therapy. Since 37.5% of patients with recurrent endometrial carcinoma clinically confined to the pelvis had occult upper abdominal disease, surgical reassessment may be warranted, especially in those with elevated serum CA 125 levels or large tumors. Our limited sample size precludes any definitive conclusions regarding our data. Further research will determine the frequency of subclinical metastases and the value of serum CA 125 levels in assessing disease status.

Etiologic complexities of diaphragmatic defects: right diaphragmatic hernia, pulmonary hypoplasia/agenesis, and hydrocephalus in sibs.

Here we review the complexities of diaphragmatic defects and describe sibs with small, right diaphragmatic defects with pulmonary hypoplasia/agenesis and hydrocephalus. Despite a poor initial prognosis, the propositus has progressed remarkably well. Antenatal sonographic study detected hydrocephalus but not the diaphragmatic defect in the sib of the propositus. Because diaphragmatic defects are most commonly found in association with other anomalies and may occur in association with chromosome anomalies careful workup of all affected infants is crucial for accurate genetic counseling.

Nuclear grading of breast carcinoma by image analysis. Classification by multivariate and neural network analysis.

The use of nuclear grade as a prognostic indicator for breast carcinoma has been limited by interobserver variability. Advances in image analysis and automated cell classification offer one approach to this problem. The authors used the CAS-100 (Cell Analysis System. Elmhurst, IL) system to measure and analyze nuclear morphometric and texture features of cytologic preparations from 35 breast carcinomas (well, moderate, and poorly differentiated) as well as benign lesions. Morphometric and Markovian texture feature data from breast cancer nuclei of various grades comprised a training set, which was then used to establish classification criteria by multivariate (Bayesian) analysis and to train a neural network system. Both systems were tested for the ability to classify the nuclear grade of individual nuclei. There was good agreement between computer classification and the grade assigned by human observer to individual nuclei using either Bayesian or neural network analysis. Thirty-one unknown cases, which were assigned an overall grade by an observer, were then analyzed by computer, and an overall grade assigned based on the grade of nucleus most frequently present. Using this method, both classification systems were able to assign a "correct" grade to low-grade lesions (approximately 70% correct) more often than to high-grade tumors (approximately 20%). Difficulty in computer assignment of high-grade tumors was explained by nuclear heterogeneity in these tumors (i.e., although the percentage of high-grade nuclei was increased compared with that of low-grade tumors, high-grade nuclei frequently did not predominate). The authors present this study to demonstrate the feasibility of using image analysis as an objective means of nuclear grading. Further studies will be needed to establish criteria for assigning overall nuclear grade based on computer analysis of imaging data.

Comparative assessment of proliferation and DNA content in breast carcinoma by image analysis and flow cytometry.

Although tumor DNA content and proliferation are usually determined by flow cytometry (FCM), quantitative microscopic image analysis is a viable alternative technique that also provides important histologic correlations. To compare these methods, we measured DNA content and proliferation in 54 consecutive breast cancers and 15 benign breast lesions by FCM and IA. DNA content determination was concordant in 49 of 54 cancers measured by FCM and IA. Four of the discordant cases were aneuploid by IA and diploid by FCM. There was good correlation between the DNA index (DI) measured by FCM and IA (r = 0.89, P less than 0.0001). Proliferation was assessed by IA quantitation of Ki-67 and PCNA/Cyclin antibody staining, as well as by flow cytometric S-phase fraction (SPF). Ki-67 positivity was greater in breast cancer than in benign controls (21.6% +/- 13.1% vs. 7.9% +/- 5.6% [P less than 0.0001]), as was PCNA/Cyclin positivity (10.2 +/- 6.7% vs. 2.7 +/- 2.5% [P less than 0.0001]). S-phase fraction measured by FCM was 7.9% +/- 5.7% for carcinomas and 3.17% +/- 2.1% for benign controls (P less than 0.003). Ki-67 and Cyclin staining, as well as SPF, were significantly increased in aneuploid compared to diploid tumors, and increased staining was associated with worsening nuclear grade. There were significant correlations between SPF and Ki-67 staining (r = 0.48, P less than 0.0001) and SPF and Cyclin staining (r = 0.48, P less than 0.0001). We conclude that FCM and IA provide comparable measurements of DNA content, although occasional discrepancies occur. Image analysis provides a valuable alternative method for assessing tumor cell proliferation and may offer certain advantages over FCM.