The spectrum of cytologic features in nonproliferative breast lesions.

BACKGROUND: The reliability of cytologic criteria to classify nonproliferative breast lesions (NPBL) is still debated. Sampling error and heterogeneity of breast lesions complicates the histologic correlation of fine-needle aspiration results further. METHODS: To provide optimal cytohistologic correlation, two smears (one that was stained with hematoxylin and eosin and one that was stained with Diff-Quik [American Scientific Products, McGraw Park, IL]) were prepared from specific tissue sections from breast biopsies without mass lesions. The 42 cases classified as NPBL histologically were included in the current study. The cytologic features of the smears were evaluated. RESULTS: Cellularity ranged from low (40% of cases) to moderate (50% of cases) to high (7% of cases). The cells were arranged in small clusters in 79% of cases, were mixed with large sheets in 17% of cases, and were in large sheets in 2% of cases. Intact lobules were noted in 31%. The configuration of the epithelial groups was complex in 62% of cases. Myoepithelial cells in the background and within the epithelial groups were noted in all the specimens. The percentage of single epithelial cells was < 10 in 38% of cases, 10-20 in 41%, and 20-30 in 19%. Mild nuclear enlargement and overlap, micronucleoli, and mild chromatin clumping were noted in a significant number of cases. CONCLUSIONS: NPBL have been found to have a wide spectrum of cytologic appearances. At one end of the spectrum, smears are cellular with up to 30% single cells and large sheets in a complex configuration and exhibit nuclear enlargement and overlap and prominent nucleoli, features that overlap with those described in proliferative breast lesions.

Correlating Papanicolaou Smear, Colposcopic Impression, and Biopsy: Results from the Women's Interagency HIV Study.

OBJECTIVE: To determine associations among cervical cytology, colposcopy, and biopsy in HIV-seropositive women. MATERIALS AND METHODS: HIV-seropositive women and uninfected comparison women in a multicenter prospective cohort study underwent colposcopy for protocol indications. Women were eligible if they had a cervix, satisfactory cytology, and colposcopy between October 1994 and September 1999. Cytology, colposcopic impression, and biopsy were compared using equivalent categorizations. Kappa statistics with bootstrap sampling assessed strength of associations. RESULTS: Colposcopy was performed in 978/1370 HIV-seropositive women and in 154/224 seronegative women. Biopsies were performed on 603 (44%) seropositive women at least once during 1015 colposcopy visits and on 82 (37%) seronegative women at 116 visits. The positive predictive value of cytology was 72% for seropositive women and 60% for seronegative women. The positive predictive value of colposcopy was 71% for seropositive women and 55% for seronegative women. CONCLUSION: The correlation between either cervical cytology or colposcopic impression and colposcopic biopsy was poor.

Atypical glandular cells of undetermined significance: clinically significant lesions and means of patient follow-up.

BACKGROUND: The clinical significance of atypical glandular cells of undetermined significance (AGUS) remains poorly understood, and patient management is not standardized. The authors evaluated the rate, qualification, and follow-up (FU) findings of AGUS patients. METHODS: Computerized records from the authors' institution were searched from April 1992 to December 1997 for diagnoses of AGUS. Results of cytologic and histologic FU were evaluated up to 48 months of FU. Clinically significant lesions were defined as squamous intraepithelial lesion (SIL), endometrial pathology of hyperplasia or higher, adenocarcinoma in situ (AIS), or invasive adenocarcinoma. RESULTS: AGUS was diagnosed in 92 of 87,632 patients (0.11%). FU data were available from 69 patients, consisting of smears and/or surgical pathology specimens from the cervix, endometrium, or ovary. Forty patients had FU smears only, 13 had histologic FU only, and 16 had both. Seventeen patients (25%; 15 patients with unqualified AGUS and 2 patients with "favor endometrial origin" according to the Bethesda System of AGUS subclassification) had clinically significant lesions: high grade SIL (n = 8 patients), low grade SIL (n = 2 patients), endometrial lesion (n = 5 patients), AIS (n = 1 patient), and invasive cervical adenocarcinoma (n = 1 patient). It is noteworthy that 4 patients with carcinoma (3 patients with AIS and 1 patient with invasive carcinoma) were diagnosed after a long FU (36-48 months). The remaining 13 lesions were detected at first FU (1-24 months). Six lesions were detected on FU smear, whereas 15 were detected histologically (4 lesions were detected in both). CONCLUSIONS: AGUS is associated with clinically significant lesions in 25% of patients who are followed. Most of the lesions were high grade and were detected histologically. Moreover, 4 of 17 lesions were detected after a FU period ranging from 36 months to 48 months. The role of qualifying AGUS needs further study. Cancer (Cancer Cytopathol)

Cytologic features of proliferative breast disease: a study designed to minimize sampling error.

BACKGROUND: Assessment of cytologic features that allow accurate classification of proliferative breast disease has been hampered by sampling errors when fine-needle aspirations have been compared with their corresponding histologic sections. METHODS: To allow for optimal cytohistologic correlation, 2 smears (1 hematoxylin and eosin-stained and 1 Diff-Quik-stained) were prepared from each of 98 breast biopsies without mass lesions and compared with the corresponding histologic sections of the scraped area. Each smear was reviewed in a blinded fashion and assessed for cellularity, background elements, cytoarchitectural features of cell groups, and nuclear features by 2 reviewers. Smears were then classified as nonproliferative breast disease (NPBD), proliferative breast disease without atypia (PBD) or with atypia (PBDA), or DCIS, based on review of the corresponding histologic sections. RESULTS: When comparing NPBD/PBD (n = 86) with PBDA/DCIS (n = 12), smears from PBDA/DCIS were significantly (by the Fisher exact test or Wilcoxon rank sum P values with adjustment for multiple comparisons) more likely to be cellular; contain single cells and necrosis; exhibit nuclear overlap and cytoplasmic vacuoles; have large nuclei, macronucleoli, pleomorphism, clumped chromatin, and hyperchromasia; and were less likely to have complex cell groups, monolayers, swirling, cohesion, and myoepithelial cells in epithelial sheets and the smear background. When NPBD (n = 53) and PBD (n = 33) were similarly compared, smears from PBD were more likely to exhibit larger and more complex cell groups, but they were otherwise similar to smears from NPBD. CONCLUSIONS: There are many cytologic features that will allow a distinction of NPBD/PBD from PBDA/DCIS, but relatively few that can aid in separating NPBD from PBD.

Changing trends in breast fine-needle aspiration: results of the Papanicolaou Society of Cytopathology Survey.

Following the NCI-sponsored consensus conference on fine-needle aspiration of the breast, the Criteria and Nomenclature Task Force of the Papanicolaou Society of Cytopathology undertook a survey to assess the status of these issues and recommendations among practicing cytopathologists. The survey was designed to assess the impact of the changing trends in the diagnosis of breast lesions on cytopathology laboratories. It also intended to assess the impact of the recommendations of the consensus conference concerning the inclusion of a statement in breast FNA reports recommending the use of the triple test, the use of the proposed diagnostic terminology, and to evaluate criteria for specimen adequacy in breast FNAs used in different institutions. The results of this survey indicate the impact of an increasing use of core biopsies on the number of breast FNAs performed over the last several years. The recently recommended diagnostic terminology for breast FNA has quickly gained wide acceptance, as has the fundamental concept of the triple test. The issue of specimen adequacy, however, remains controversial, with some laboratories utilizing quantitative criteria, while the majority do not. Diagn. Cytopathol. 2000;22:126-130.

Current issues in breast cytopathology.

This article explores 3 aspects of breast diagnosis that are currently under investigation and about which our thinking has recently undergone considerable reshaping. The trend toward more frequent evaluation of clinically subtle lesions has suggested that it might be necessary to understand thefine-needle aspiration (FNA) presentation of proliferative breast disease. Efforts to do so, as well as our suggestions for additional studies and their potential limitations open this discussion. Following this section, the increasingly useful method of intraoperative cytology for evaluation of resected breast masses is considered in detail. In the final section, optimization of nonoperative sampling by combination of mammography, ultrasonography, fine-needle aspiration, and core biopsy is discussed and illustrated.

Interrater Variability in Diagnosis of Cervical Biopsies from Women with HIV-1: Results from the Women's Interagency HIV Study.

OBJECTIVES: To determine interrater variability in classifying cervical biopsies from women with human immunodeficiency virus (HIV). MATERIALS AND METHODS: Cervical biopsies performed on women participating in the Women's Interagency HIV Study (WIHS) were read at the six participating sites. A 10% random sample was retrieved and reviewed using standardized terminology by pathologists with a special interest in gynecologic pathology. Results were compared with kappa values and Mantel-Haentzel tests. RESULTS: Biopsies from 288 HIV-seropositive and 24 HIV-seronegative women were reviewed. The weighted kappa value of 0.67 indicated moderate to strong agreement between original and review diagnoses, with a range of 0.54 to 0.84 across sites. No cancers were identified. Significantly more specimens showing cervical intraepithelial neoplasia (CIN) grade 2 or 3 were identified by review pathologists (p = .02). CIN2 or CIN3 was graded less severely by local pathologists in 18 (51%) of 35 cases, all from HIV-seropositive women. Local pathologists' diagnoses of CIN2 or CIN3 were downgraded by reviewers in 4 of 21 cases (19%). Discrepancies were more common among women with lower CD4 lymphocyte counts. CONCLUSIONS: Although discrepancies occur, interrater correlation in the interpretation of cervical biopsies from women with HIV is moderate to strong.

Inflammatory pseudotumor of the spleen associated with a cavernous hemangioma diagnosed at intra-operative cytology: report of a case and review of literature.

This report presents a case of a 40 year old Caucasian female with a 15 cm inflammatory pseudotumor (IPT) of the spleen with associated areas of splenic hemangioma of the cavernous type. Abdominal CT showed a largely fatty splenic mass with enhancing septations, and scattered calcifications, and a small density in the liver. Grossly, the splenic lesion showed a lobulated cut surface with areas of myxoid change, necrosis, hemorrhage and cystic softening. The diagnosis of IPT was suggested at intraoperative consultation using cytologic smears and was, subsequently confirmed on permanent sections. Histologically, the lesion consisted of a densely collagenized spindle cell stroma with patchy aggregates of lymphocytes and plasma cells, and scattered foci showing hemosiderin-laden macrophages extracellular calcium deposits and osseous metaplasia. The stromal spindle cells were immuoreactive for smooth muscle actin and vimentin confirming their myofibroblastic phenotype. There were extensive areas of infarction within the mass. The patient, however, remained asymptomatic preoperatively. Histologic analysis in this case raises the possibility that low grade, perhaps repetitive, trauma to the hemangioma may have resulted in intralesional hemorrhages which, through a process of organization, may have evolved into this sizable inflammatory pseudotumor. In addition, this report reviews the current literature on the clinical significance and presentation, morphologic and immunohistochemical findings, prognosis, differential diagnosis, pathogenesis and therapy of the splenic IPT.

Interobserver variability in the classification of proliferative breast lesions by fine-needle aspiration: results of the Papanicolaou Society of Cytopathology Study.

This study evaluates the applicability of the published cytologic criteria in the categorization of proliferative breast lesions by assessing the diagnostic accuracy and interobserver reproducibility of a panel of experts. Twelve breast fine-needle aspiration (FNA) specimens of biopsy-proven nonproliferative breast lesion (NPL) (1 case), proliferative lesions without atypia (PL) (7 cases), proliferative lesion with atypia (PLA) (1 case), and low-nuclear grade ductal carcinoma in situ (DCIS) (3 cases) were selected. Six FNAs were Papanicolaou (PAP) and 6 were Diff-Quik-stained (DQ). Six expert cytopathologists classified the smears using a summary of published criteria as a guideline. All 6 participants rendered the same cytologic diagnosis in 2/12 (16%) cases. The agreement among the 6 raters was low (Kappa = 0.35). Cytohistologic correlation was achieved in 26/72 (36%) FNA diagnoses. The correlation of the PAP-stained cases was better than the DQ: 17/36 (47%) PAP and 9/36 (25%) DQ correlated. Improving the correlation was achieved by amalgamation of NPL and PL into "low risk" and PLA and DCIS into "high risk" categories: 47/72 (65%) FNA diagnoses then correlated with histology [29/36 (81%) PAP and 18/36 (50%) DQ]. We conclude that the cytologic criteria of proliferative breast lesions need to be further defined and assessed. Consideration should be given to minimizing the number of diagnostic categories and adopting a terminology that has a direct effect on patient management.

Utility of thin-layer preparations in thyroid fine-needle aspiration: diagnostic accuracy, cytomorphology, and optimal sample preparation.

BACKGROUND: The efficacy of preparing thyroid fine-needle aspirations (FNAs) as thin-layer slides has not been evaluated extensively. METHODS: To evaluate the efficacy of thin-layer cytology, the authors examined thyroid FNAs from 135 unselected palpable lesions that were aspirated using uniform procedures and prepared as air-dried, Diff-Quik-stained direct smears (DS) and Papanicolaou-stained thin-layer slides (TL). Diagnoses rendered independently on masked slides from each thyroid nodule were compared with the reported final cytologic or histologic diagnoses based on all available pathologic material. Slides were analyzed for diagnostically important cytologic features and the optimal number of TL slides per sample was assessed. RESULTS: TL diagnoses agreed with final diagnoses in 85% of cases compared with 96% for DS. All 11 neoplasms were recognized in both preparations. A final diagnosis of chronic lymphocytic thyroiditis (CLT) was missed in 10 of 26 TL (39%) compared with 2 of 26 DS (8%) (P = 0.013, McNemar's test). Cytologic features appreciated less often in TL than DS (McNemar's test) included diffuse colloid, spherules, tissue fragments, and lymphocytes. Multinucleated giant cells were identified more often in TL than DS. Two TL slides were sufficient for diagnosis in 83% of cases. CONCLUSIONS: The diagnostic accuracy of TL was 85% compared with 96% for DS. CLT was diagnosed accurately in 62% of TL compared with 92% of DS. Cytologic features in TL and DS may differ. Preparation of only two TL slides is adequate for definitive diagnosis in most cases.

The stability of estrogen and progesterone receptor expression on breast carcinoma cells stored as PreservCyt suspensions and as ThinPrep slides.

BACKGROUND: Analysis of estrogen receptor (ER) and progesterone receptor (PR) status is an important ancillary test in the evaluation of positive breast fine-needle aspirates. This study compares the detection of ER and PR in breast carcinoma cells suspended in PreservCyt with that achieved with stored ThinPrep slides (TP). METHODS: ER and PR positive mammary tumor cells (cell line ZR-75-1 spiked in PreservCyt by the American Type Culture Collection) were used to evaluate the stability of immunodetection of ER and PR under two conditions: 1) TP slides prepared immediately from PreservCyt and stored air-dried (stored TP) for up to 56 days, and 2) TP prepared from cells suspended in PreservCyt (newly prepared TP) on Days 1, 2, 5, 14, 21, 42, and 56. At each of the time periods, stored TP and newly prepared TP were analyzed for ER and PR using the same immunocytochemical staining protocol. The percentage of positive cells was calculated by counting 1000 cells/TP. RESULTS: Positivity for ER and PR was demonstrated in both stored TP and newly prepared TP on Days 1, 2, 5, 14, 21, 42, and 56. Over the 56-day period, the number of ER positive cells ranged from 41% to 57% in stored TP and from 38% to 58% in newly prepared TP. The number of PR positive cells ranged from 31% to 41% in stored TP and from 26% to 37% in newly prepared TP. Mild, nonspecific cytoplasmic and nuclear staining occurred in all newly prepared TP (PR > ER). CONCLUSIONS: ER and PR antigenicity was preserved in both stored TP and newly prepared TP of mammary tumor cells over a 56-day storage period. This demonstrates that ER and PR status can be evaluated in cytologic material from breast carcinoma using the ThinPrep technique.

Fine-needle aspiration of thyroid nodules: correlation between cytology and histology and evaluation of discrepant cases.

BACKGROUND: The purpose of this study was to evaluate the results of thyroid fine-needle aspiration (FNA) and to determine the reasons for the discrepancies between the cytologic and histologic diagnoses. METHODS: The authors evaluated the cytologic and histologic results of 133 FNAs obtained from 92 patients who underwent subsequent thyroidectomies. RESULTS: The initial cytologic results were indeterminate in 39 of 133 cases (29%) because a neoplasm could not be ruled out. These cases corresponded histologically to 9 adenomatoid nodules (ANs), 14 follicular adenomas (FAs), and 16 malignant thyroid neoplasms. The reported FNA diagnoses of the remaining 94 cases (71%) were 48 ANs, 19 follicular neoplasms (FNs), 21 papillary carcinomas (PCs), and 6 cases of Hashimoto's thyroiditis (HT). Correlation of cytology and histology showed that 69 of 94 FNA results (73%) correlated with the histologic diagnoses, whereas 25 (27%) were discrepant. The discrepancies resulted from cytodiagnostic errors in 13 cases (52%), suboptimal smears in 11 (44%), and an FNA sampling error in 1 (4%). The false-negative rate of FNA was 19% and the false-positive rate was 6%. CONCLUSIONS: Diagnostic pitfalls and indeterminate FNA diagnoses were predominantly due to overlapping cytologic criteria between ANs, FNs, and follicular variants of PCs. Rendering a definite diagnosis on suboptimal FNA samples is also a significant source of pitfalls.

Reactive cellular change: is there an increased risk for squamous intraepithelial lesions?

BACKGROUND: The aim of this study was to evaluate the rate of squamous intraepithelial lesions (SIL) in women with reactive cellular change (RCC) cervical smears and compare the results with a control group with within normal limit (WNL) smears. METHODS: The study group was comprised of 1000 women with RCC and a control group of 1000 women with WNL cervical smears diagnosed over an 8-month period. Results of the first follow-up (FU) smears were evaluated and compared between the two groups. FU smears with a diagnosis of SIL were reviewed along with the original RCC or WNL smears. RESULTS: Six hundred and thirteen women from the RCC group and 640 from the WNL group had FU smears. The mean time to FU was 11.0 and 13.8 months, respectively. FU revealed SIL in 24 of 613 smears in the RCC group (20 low grade [L] SIL and 4 high grade [H] SIL), (3.9%) and in 10 of 640 smears in the WNL group (10 LSIL and 0 HSIL) (1.6%). Fisher's exact test (two-tailed) showed statistical significance (P = 0.014). On retrospective review of the FU smears diagnosed as SIL and their corresponding original RCC or WNL smears, four RCC smears were upgraded to atypical squamous cells of undetermined significance (ASCUS). The remaining diagnoses remained unchanged. CONCLUSIONS: Women with RCC are more likely to have SIL on a FU smear compared with women with WNL smears (3.9% vs. 1.6%). It is important to emphasize that in the authors' laboratory, the rate of SIL in women with ASCUS is much higher (24%). Awareness of these rates combined with the clinical history may help clinicians determine whether women with RCC require closer FU.

Can nonproliferative breast disease and proliferative breast disease without atypia be distinguished by fine-needle aspiration cytology?

BACKGROUND: Cytologic criteria reported to be helpful in the distinction of proliferative breast disease without atypia (PBD) from nonproliferative breast disease (NPBD) have not been rigorously tested. METHODS: Fifty-one air-dried, Diff-Quik-stained fine-needle aspirates (FNA) of palpable breast lesions with biopsy-proven diagnoses of NPBD (34 cases) or PBD (17 cases) were reviewed. The smears were evaluated for the cellularity, size, and architectural arrangement of the epithelial groups; the presence of single epithelial cells and myoepithelial cells; and nuclear characteristics. RESULTS: The only cytologic feature found to be significantly different between PBD and NPBD was a swirling pattern of epithelial cells. A swirling pattern was noted in 13 of 17 PBD cases (76%) and 12 of 34 NPBD cases (35%) (P = 0.008). CONCLUSIONS: Because there is significant overlap in cytologic features between NPBD and PBD, the distinction between the two entities is difficult in cytologic sampling.

Multinucleated giant cells in thyroid neoplasms. A cytologic, histologic and immunohistochemical study.

OBJECTIVE: To evaluate the presence of multinucleated foreign body-type giant cells (MGCs) in papillary carcinoma (PC), follicular variant of papillary carcinoma (FV) and follicular adenomas (FA) and to investigate their origin by immunoperoxidase studies. STUDY DESIGN: The cytologic and histologic material of 10 PCs, 8 FVs, and 11 FAs were evaluated for the presence of MGCs. The immunohistochemical staining pattern of MGCs in paraffin-embedded tissue was studied using cytokeratin, epithelial membrane antigen, thyroglobulin, vimentin, A-1 antichymotrypsin, lysozyme and CD68. RESULTS: MGCs were demonstrated in 10/10 PCs, 5/8 FVs and 0/11 FAs. In the immunostained sections, MGCs were negative for epithelial markers and positive for histiocytic markers. CONCLUSION: These results indicate that MGCs are histiocytic and frequently present in PCs and FVs and usually absent from FAs.

Evaluation of the 5-year review of negative cervical smears in patients with high grade squamous intraepithelial lesions.

Federal regulations require laboratories to re-examine negative cervical smears from the 5 yr preceding a diagnosis of high-grade squamous intraepithelial lesion (HSIL) or carcinoma. To assess the value of this regulation as a quality assurance measure, we evaluated the previous cervical smears from 47 patients with a diagnosis of HSIL rendered during a 9-mo period. Fifteen patients had a total of 24 previous smears initially reported as squamous intraepithelial lesions (SIL). The remaining 32 patients had a total of 58 smears that carried a diagnosis lesser than SIL. Upon re-screening 22/58 (38%) smears, from 16 patients, were upgraded to SIL (8 low grade, 14 high grade). Underdiagnosed SIL was detected in seven (44%) patients with the 1-yr review, 12 (75%) with the 2-yr review, 15 (94%) with the 3-yr review, and 16 (100%) with the 5-yr review. The authors conclude that the negative smear review is a beneficial quality assurance and teaching method that may lead to quality improvement. A 3-yr retrospective review is effective and detects 94% of the undercalls.