Nomogram to predict the presence of EGFR activating mutation in lung adenocarcinoma.

Epidermal growth factor receptor (EGFR) tumour genotyping is crucial to guide treatment decisions regarding the use of EGFR tyrosine kinase inhibitors in nonsmall cell lung cancer (NSCLC). However, some patients may not be able to obtain tumour testing, either because tissue is limited and/or tests are not routinely offered. Here, we aimed to build a model-based nomogram to allow for prediction of the presence of EGFR mutations in NSCLC. We retrospectively collected clinical and pathological data on 3,006 patients with NSCLC who had their tumours genotyped for EGFR mutations at five institutions worldwide. Variables of interest were integrated in a multivariate logistic regression model. In the 2,392 non-Asian patients with lung adenocarcinomas, the most important predictors of harbouring EGFR mutation were: lower tobacco smoking exposure (OR 0.41, 95% CI 0.37-0.46), longer time interval between smoking cessation and diagnosis (OR 2.19, 95% CI 1.71-2.80), advanced stage (OR 1.58, 95% CI 1.18-2.13), and papillary (OR 4.57, 95% CI 3.14-6.66) or bronchioloalveolar (OR 2.84, 95% CI 1.98-4.06) histologically predominant subtype. A nomogram was established and showed excellent discriminating accuracy: the concordance index on an independent validation dataset was 0.84. As clinical practices transition to incorporating genotyping as part of routine care, this nomogram could be highly useful to predict the presence of EGFR mutations in lung adenocarcinoma in non-Asian patients when mutational profiling is not available or possible.

An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors.

To address the biological heterogeneity of lung cancer, we studied 199 lung adenocarcinomas by integrating genome-wide data on copy number alterations and gene expression with full annotation for major known somatic mutations in this cancer. This showed non-random patterns of copy number alterations significantly linked to EGFR and KRAS mutation status and to distinct clinical outcomes, and led to the discovery of a striking association of EGFR mutations with underexpression of DUSP4, a gene within a broad region of frequent single-copy loss on 8p. DUSP4 is involved in negative feedback control of EGFR signaling, and we provide functional validation for its role as a growth suppressor in EGFR-mutant lung adenocarcinoma. DUSP4 loss also associates with p16/CDKN2A deletion and defines a distinct clinical subset of lung cancer patients. Another novel observation is that of a reciprocal relationship between EGFR and LKB1 mutations. These results highlight the power of integrated genomics to identify candidate driver genes within recurrent broad regions of copy number alteration and to delineate distinct oncogenetic pathways in genetically complex common epithelial cancers.

Diagnostic dilemmas in pulmonary cytology.

BACKGROUND: Diagnostic difficulties in pulmonary cytology may be compounded by other medical problems, lack of pertinent information, and the presence of rare tumors. In the current study, the authors describe six cases of lower respiratory tract cytology that presented particular diagnostic challenges or pitfalls. METHODS: Three lung fine-needle aspiration biopsies (FNAB) from three patients, four bronchoalveolar lavages from two patients, and one bronchial washing from one patient, each with histologic confirmation, were reviewed. Cytologic material included direct smears, ThinPrep slides, and cell blocks. Cytologic findings were compared with established cytologic criteria for each final diagnosis. RESULTS: Two cases with Aspergillus infection that demonstrated reactive atypical cells were misinterpreted as squamous cell carcinoma and nonsmall cell carcinoma. Two cases diagnosed as significant atypia and negative, respectively, subsequently were found to show bronchioloalveolar carcinoma (as well as lymphangioleiomyomatosis, which was suspected clinically) and bronchogenic adenocarcinoma, respectively. One lung FNAB from a patient subsequently confirmed to have bronchiolitis obliterans-organizing pneumonia (BOOP) showed reactive pneumocytes that initially were misinterpreted as being suspicious for carcinoid. These reactive pneumocytes were identified histologically in the area of BOOP. The last case was an FNAB of a well differentiated fetal-type adenocarcinoma, an unusual variant of adenocarcinoma that to the authors' knowledge rarely is described in the cytology literature. CONCLUSIONS: Cytomorphologic features of lower respiratory tract pathology combined with appropriate clinical information and diagnostic discretion usually allow accurate diagnoses and should decrease both false-positive and false-negative result rates. Clinical information and radiologic findings may be invaluable, but may not always parallel the cytologic diagnosis.

Use of thyroid transcription factor 1, PE-10, and cytokeratins 7 and 20 in discriminating between primary lung carcinomas and metastatic lesions in fine-needle aspiration biopsy specimens.

BACKGROUND: The distinction of a primary lung carcinoma from a metastatic lesion is important, because the treatment and prognosis differ for patients with these malignancies. Such a distinction can be difficult because of overlapping cytologic features. It has been shown that antibodies to thyroid transcription factor 1 (TTF-1) and PE-10 are fairly specific markers for primary lung tumors in histologic specimens. TTF-1 regulates the expression of surfactant protein production, and PE-10 is a monoclonal antibody against components of human surfactant proteins. The combination of cytokeratin 7 (CK7) and cytokeratin 20 (CK20) immunoprofiling has been helpful in the identification of the primary site of origin of lung tumors. METHODS: In the current study, the authors evaluated the utility of TTF-1 and PE-10 immunostaining and also compared the staining with expression of CK7 and CK20 in the discrimination between primary lung tumors and metastatic lesions in 55 specimens from fine-needle aspiration (FNA) biopsies of the lung. Formalin fixed, paraffin embedded cell blocks from 35 primary lung tumors (16 adenocarcinomas, 8 squamous cell carcinomas, 6 large cell undifferentiated carcinomas, and 5 small cell carcinomas) and 20 metastatic carcinomas (6 breast lesions, 6 colon lesions, 3 urinary bladder lesions, 2 kidney lesions, 1 biliary tract lesion, 1 endometrial lesion, and 1 thyroid lesion) were immunostained with monoclonal antibodies to TTF-1, PE-10, CK7, and CK 20. Positive immunostaining for CK7, CK20, and PE-10 was based on cytoplasmic staining, whereas TTF-1 positive staining was based on nuclear staining of the neoplastic cells. RESULTS: Positive immunostaining with TTF-1 and PE-10 was noted in six primary lung tumors (17%). One metastatic lesion (5%) and two metastatic lesions (10%) were positive for TTF-1 and PE-10, respectively. The CK7 positive/CK20 negative immunophenotype was noted in 30 primary lung tumors (86%) and in 11 metastatic lesions (55%). The CK7 negative/CK20 negative immunophenotype was seen in four metastatic lesions and in the remaining five primary lung tumors. The CK7 negative/CK20 positive and CK7 positive/CK20 positive immunophenotypes were seen in two and three metastatic lesions, respectively, but in none of the primary lung tumors. When a CK7 positive/CK20 negative adenocarcinoma also demonstrated either TTF-1 positive or PE-10 positive staining, it was likely that the adenocarcinoma was of pulmonary origin (P < 0.035; Fisher exact test). The specificity of such a combination for discriminating between primary and metastatic adenocarcinomas was 94%. CONCLUSIONS: The results suggest that TTF-1, PE-10, or CK7/CK20 alone did not distinguish reliably between primary pulmonary tumors carcinomas and metastatic neoplasms of the lung in FNA biopsy specimens because of low sensitivity and specificity. The use of a panel of antibodies that includes CK7/CK20, TTF-1, and PE-10 may be helpful in discriminating between primary and metastatic adenocarcinomas of the lung. An adenocarcinoma is likely a primary lung tumor when it is of the CK7 positive/CK20 negative phenotype and demonstrates either TTF-1 positive or PE-10 positive staining.

Fine-needle aspiration of epithelioid sarcoma: cytology findings in nine cases.

BACKGROUND: Epithelioid sarcoma is a rare tumor with characteristic morphologic and immunohistochemical features. It can be confused histologically and cytologically with a variety of benign and malignant lesions, including a granulomatous process, synovial sarcoma, melanoma, squamous cell carcinoma, and adenocarcinoma. The objective of this study was to define the cytologic features of this rare tumor. METHODS: The cytologic features of nine histologically confirmed epithelioid sarcomas were analyzed. The criteria evaluated included cell size and shape, cell borders, cluster organization, cytoplasmic characteristics, nuclear and nucleolar features, and background characteristics. RESULTS: In most cases, single, dispersed cells represented the predominant pattern, with only a few small clusters present. The cells were mostly round with interspersed spindle cells and mild to moderate pleomorphism. The nuclei were large and eccentrically located, with a plasmacytoid appearance. A pale zone in the perinuclear area was evident in three of nine cases. Well-defined cell borders with intercellular spaces between malignant cells were observed in eight cases. In three cases, a granuloma-like structure was identified. In two cases, the cells were mostly spindle and showed greater cellular pleomorphism. CONCLUSION: Epithelioid sarcoma is an uncommon tumor with a wide range of differential diagnoses, especially in cytology specimens. Awareness of its existence and knowledge of its cytologic features are important for a correct diagnosis.

Calcifications highly suggestive of malignancy: comparison of breast biopsy methods.

OBJECTIVE: The purpose of this study was to compare the usefulness of, and cost of diagnosing with, different breast biopsy methods for women with calcifications highly suggestive of malignancy. MATERIALS AND METHODS: One hundred thirty-nine women with calcifications highly suggestive of malignancy underwent diagnostic biopsy. Of these, 89 women had stereotactic biopsy with a 14-gauge automated needle (n = 25), 14-gauge vacuum-assisted probe (n = 17), or 11-gauge vacuum-assisted probe (n = 47); and 50 women had diagnostic surgical biopsy. Medical records were reviewed. Cost savings for stereotactic biopsy were calculated using Medicare data. RESULTS: The median number of operations was one for women who had stereotactic biopsy versus two for women who had diagnostic surgical biopsy. The likelihood of undergoing a single operation was significantly greater for women who had stereotactic rather than surgical biopsy, among all women (61/89 [68.5%] vs. 19/50 [38.0%], p < 0.001) and among women treated for breast cancer (55/77 [71.4%] vs. 6/37 [16.2%], p = 0.0000001). Stereotactic 11-gauge vacuum-assisted biopsy, as compared with 14-gauge automated core or 14-gauge vacuum-assisted biopsy, was significantly more likely to spare a surgical procedure (36/47 [76.6%] vs. 16/42 [38.1%], p = 0.0005). Stereotactic 11-gauge vacuum-assisted biopsy resulted in the greatest cost reduction, yielding savings of $315 per case compared with diagnostic surgical biopsy; for women with solitary lesions, stereotactic 11-gauge biopsy decreased the cost of diagnosis by 22.2% ($334/$1502). CONCLUSION: For women with calcifications highly suggestive of malignancy, the use of stereotactic rather than surgical biopsy decreases the number of operations. Stereotactic 11-gauge vacuum-assisted biopsy, as compared with 14-gauge automated core or 14-gauge vacuum-assisted biopsy, is significantly more likely to spare a surgical procedure and has the highest cost savings.

Chordoma: a cytologic study with histologic and radiologic correlation.

BACKGROUND: Chordoma is a rare malignant tumor of fetal notochord origin that occurs along the spinal axis. The fine-needle aspiration biopsy (FNAB) findings are described, correlated with histology and radiology, and compared with previously reported descriptions of chordoma. METHODS: Fine-needle aspiration biopsies of 12 cases of chordoma with histologic confirmation were reviewed. Imaging studies were reviewed in seven cases. Cytologic material included smears, ThinPrep, and cell blocks. Immunostains were performed on selected cytologic and histologic specimens. Multiple cytologic parameters were studied. RESULTS: Eleven specimens were from the spinal axis, and one was from a chest wall metastasis. Ten cases were diagnosed as chordoma on cytologic material, one was positive for malignancy with a differential diagnosis of chordoma and well differentiated chondrosarcoma, and one was positive for malignancy, not further classified. Most smears were moderately to highly cellular and demonstrated typical physaliphorous cells and a myxoid background. Two of the 10 cases diagnosed as chordoma showed pleomorphic physaliphorous cells, nuclear inclusions, and binucleation. Nuclear inclusions were observed in three other cases diagnosed as chordoma. Histologic follow-up of one case with pleomorphic physaliphorous cells showed conventional chordoma with focal areas of increased cellularity and pleomorphism. Pleomorphic sarcomatous cells were the predominant cell type in one case that showed dedifferentiated chordoma histologically. Mitotic figures were rarely observed in cytologic material. CONCLUSIONS: Cytomorphologic features of chordoma allow accurate diagnosis by FNAB. Features associated with dedifferentiation include increased pleomorphism of physaliphorous cells and may include nuclear inclusions, bi- or multinucleation, and rarely, mitotic figures. Cancer (Cancer Cytopathol)

Large-cell neuroendocrine carcinoma of the lung: proposed criteria for cytologic diagnosis.

The category of large-cell neuroendocrine carcinoma (LCNEC) of the lung, proposed to expand the traditional scheme of typical carcinoid, atypical carcinoid (AC), and small-cell carcinoma (SCC), based on histologic features, has not been defined in cytology. We attempt to describe LCNEC cytologically. Cytologic features in 16 histologically confirmed LCNECs in fine-needle aspiration biopsies, cell blocks, bronchial brushes, washes, and sputum specimens stained with Diff-Quik, Papanicolaou, hematoxylin-eosin, chromogranin, and synaptophysin were analyzed. Three poorly differentiated nonsmall-cell carcinomas, 4 SCCs, and 2 atypical carcinoids were studied similarly. Twenty specimens from 16 histologically confirmed cases of LCNEC with original cytologic diagnoses including high-grade neuroendocrine carcinoma, large-cell carcinoma, nonsmall-cell carcinoma, poorly differentiated carcinoma, adenocarcinoma, and SCC, were examined. Features included flattened three-dimensional clusters with peripheral palisading, moderate to large single cells with scant (alcohol-fixed) or moderate (air-dried) cytoplasm; and large, oval, or polygonal nuclei with irregular contours, thickened nuclear membranes, and finely or coarsely granular chromatin, showing some molding and crush artifact. Nucleoli were generally present, and occasionally prominent. Mitosis and necrosis were apparent. Neuroendocrine stains were applied to all specimens, with at least one marker, commonly synaptophysin, positive in 18/20 specimens. LCNEC can be diagnosed in cytologic material, using morphology confirmed by immunocytochemistry. Treatment can be offered on the basis of cytologic examination.

Palpable breast masses: is there a role for percutaneous imaging-guided core biopsy?

OBJECTIVE: The purpose of this study was to evaluate percutaneous imaging-guided core biopsy in the assessment of selected palpable breast masses. MATERIALS AND METHODS: Of 1388 consecutive breast lesions that had percutaneous imaging-guided core biopsy, 155 (11%) were palpable. Palpable masses referred for percutaneous imaging-guided core biopsy included lesions that were small, deep, mobile, vaguely palpable, or multiple. Biopsy guidance was sonography in 140 lesions (90%) and stereotaxis in 15 (10%). Surgical correlation or minimum of 2 years follow-up is available in 115 palpable masses in 107 women. Medical records, imaging studies, and histologic findings were reviewed. RESULTS: Of 115 palpable breast masses, 98 (85%) were referred by surgeons to the radiology department for percutaneous imaging-guided core biopsy and 88 (77%) had percutaneous imaging-guided core biopsy on the day of initial evaluation at our institution. Percutaneous imaging-guided core biopsy spared additional diagnostic tissue sampling in 79 (74%) of 107 women, including 57 women with carcinoma and 22 women with benign findings. Percutaneous imaging-guided core biopsy did not spare additional tissue sampling in 28 women (26%), including 15 women in whom surgical biopsy was recommended on the basis of percutaneous biopsy findings and 13 women with benign (n = 7) or malignant (n = 6) percutaneous biopsy findings who chose to undergo diagnostic surgical biopsy. CONCLUSION: Percutaneous imaging-guided core biopsy is useful in the evaluation of palpable breast masses that are small, deep, mobile, vaguely palpable, or multiple. In this study, percutaneous imaging-guided core biopsy spared additional diagnostic tissue sampling in 74% women with palpable breast masses.

Fine-needle aspiration of a follicular dendritic-cell tumor: report of a case and review of the literature.

Follicular dendritic-cell tumors (FDCT) are rare neoplasms, well-characterized in surgical pathology material. There are, however, few cytopathology reports. We describe the fine-needle aspiration (FNA) findings of a histologically confirmed FDCT. Conventional smears and a cell block showed large spindle to oval neoplastic cells admixed with small mature lymphocytes. The neoplastic cells were present mainly in small syncytial clusters. Immunostains for CD21 and CD35, performed on the cell block, were positive in the neoplastic cells. The diagnosis was fully confirmed by the presence of typical immunohistochemical and ultrastructural features on the surgically removed tumor. The differential diagnosis of FDCT is broad and includes other tumors characterized by an admixture of large neoplastic cells and small mature lymphocytes, such as thymomas, lymphoepithelioma-like carcinomas, and interdigitating dendritic-cell tumors. It may not be possible to diagnose FDCT based on FNA material without the use of immunocytochemical and electron microscopic studies. Certain cytomorphological characteristics, however, might suggest its diagnosis and allow the practicing cytopathologist to perform confirmatory studies.

Cytokeratin immunoreactivity in Ewing's sarcoma: prevalence in 50 cases confirmed by molecular diagnostic studies.

Ewing's sarcoma (ES) and primitive neuroectodermal tumor (PNET) are characterized by the presence of the specific t(11;22)(q24;q12) or variants thereof, producing diagnostic EWS fusion transcripts. Cytokeratin has been reported sporadically to be expressed in some cases of ES/PNET. However, its prevalence has not been assessed systematically in a series of cases with confirmatory molecular or cytogenetic evidence of a diagnostic translocation. We present in detail three index patients in whom strong cytokeratin immunoreactivity was a confounding factor in the diagnosis. To establish further the prevalence of cytokeratin immunoreactivity in a series of well-characterized ES/PNET, we then performed immunohistochemical studies with antibodies CAM5.2 and AE1/AE3 on 50 cases of ES/PNET diagnosed at Memorial Sloan-Kettering Cancer Center in which molecular evidence of a specific ES/PNET-associated translocation were available. Immunoreactivity to cytokeratin was present in 10 cases (20%), in five diffusely and five focally. There was no significant association between cytokeratin expression and the following parameters: patient age, sex, skeletal and extraskeletal primary site, and the type of EWS fusion transcript. Cytokeratin expression, a manifestation of epithelial differentiation, is present in as many as 20% of ES/PNET in either a diffuse or focal pattern.

Cytology of thymomas: emphasis on morphology and correlation with histologic subtypes.

BACKGROUND: Aspirates of thymomas are distinguishable from other lesions and fine-needle aspiration (FNA) is a proven method for investigating mediastinal masses. METHODS: Thirty-four cytology specimens of thymomas from 31 patients were examined. Corresponding surgical materials were available in 32 cases. Ten cases were benign and 22 were malignant. Cytologic features of these thymomas were correlated with various histologic classification systems and with biologic behavior. Dual epithelial and lymphoid populations and irregular cohesive tissue fragments of varying proportions of lymphoid and epithelial cells were characteristic of all aspirates. RESULTS: Using the Lattes-Bernatz classification, 10 cases predominately were lymphocytic, 3 cases predominately were epithelial, 3 cases predominately were spindle, 15 cases predominately were mixed, and 1 case was a thymic carcinoma. In the Muller-Hermelink classification, 3 cases were medullary, 12 were mixed, 8 predominately were cortical, 2 were cortical, 6 were well differentiated thymic carcinoma, and 1 was a poorly differentiated thymic carcinoma. In the majority of the cases the epithelial cells were round to oval. Spindle cells and a mixture of round to oval and spindle cells also were observed. No cytologic feature was found to correlate significantly with any classification scheme. Necrosis was present in 5 of the 32 aspirates, most frequently in malignant tumors. Thymomas showing predominately spindle cells frequently were encapsulated. Tumors with predominantly round to oval cells or a mixed population behaved more aggressively than those with spindle cells. Tumors that were well encapsulated and benign clinically tended to possess benign-appearing nuclei. Among the 22 invasive or malignant lesions, 8 exhibited moderate to marked cytologic atypia and 14 showed little or no atypia. No atypia was observed in benign tumors. CONCLUSIONS: The presence of cytologic atypia of epithelial cells may be helpful in predicting aggressiveness. However, the absence of atypia and necrosis may not imply a benign course. Correlation with clinical and radiographic findings should be sought.

Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase.

The blockade of epidermal growth factor receptor (EGFR) function with monoclonal antibodies has major antiproliferative effects against human tumors in vivo. Similar antiproliferative effects against some of these same tumors have also been observed with specific inhibitors of the EGFR-associated tyrosine kinase. One such inhibitor, the p.o. active ZD1839 (Iressa), has pronounced antiproliferative activity against human tumor xenografts. We now show that coadministration of ZD1839, as with anti-EGFR, will enhance the efficacy of cytotoxic agents against human vulvar (A431), lung (A549 and SK-LC-16 NSCL and LX-1), and prostate (PC-3 and TSU-PR1) tumors. Oral ZD1839 (five times daily x 2) and cytotoxic agents (i.p. every 3-4 days x 4) were given for a period of 2 weeks to mice with well-established tumors. On this schedule, the maximum tolerated dose (150 mg/kg) of ZD1839 induced partial regression of A431, a tumor that expresses high levels of EGFR, 70-80% inhibition among tumors with low but highly variable levels of EGFR expression (A549, SKLC-16, TSU-PR1, and PC-3), and 50-55% inhibition against the LX-1 tumor, which expresses very low levels of EGFR. ZD1839 was very effective in potentiating most cytotoxic agents in combination treatment against all of these tumors, irrespective of EGFR status, but dose reduction of ZD1839 below its single-agent maximum tolerated dose was required for optimum tolerance. The pronounced growth inhibitory action of the platinums, cisplatin and carboplatinum, as single agents against A431 vulvar, A549 and LX-1 lung, and TSU-PR1 and PC-3 prostate tumors was increased several-fold when ZD1839 was added, with some regression of A431 and PC-3 tumors. Although the taxanes, paclitaxel or docetaxel, as single agents markedly inhibited the growth of A431, LX-1, SK-LC-16, TSU-PR1, and PC-3, when combined with ZD1839, partial or complete regression was usually seen. Against A549, the growth inhibition of doxorubicin was increased 10-fold (>99%) with ZD1839. The folate analogue, edatrexate, was highly growth inhibitory against A549, LX-1, and TSU-PR1, whereas edatrexate combined with ZD1839 resulted in partial or complete regression in these tumors. Against the A431 tumor, paclitaxel alone either was highly growth inhibitory or induced some regression, but when combined with ZD1839, pronounced regression was obtained. Combination with gemcitabine neither added nor detracted from baseline cytotoxic efficacy, whereas ZD1839 combined with vinorelbine was poorly tolerated. Overall, these results suggest that potentiation of cytotoxic treatment with ZD1839 does not require high levels of EGFR expression in the target tumors. They also suggest significant clinical benefit from ZD1839 in combination with a variety of widely used cytotoxic agents.

Imaging-histologic discordance at percutaneous breast biopsy.

BACKGROUND: The purpose of the current study was to determine the frequency of imaging-histologic discordance at percutaneous breast biopsy and to assess the likelihood of carcinoma in these discordant lesions. METHODS: Percutaneous imaging guided breast biopsy was performed on 1785 consecutive lesions during a 7-year period under stereotactic (n = 1205) or sonographic (n = 580) guidance, using an automated needle (n = 1044) or directional vacuum-assisted probe (n = 741). Lesions were prospectively classified according to the Breast Imaging Reporting and Data System (BI-RADS) as Category 3 (probably benign), Category 4 (suspicious), or Category 5 (highly suggestive of malignancy). Imaging-histologic discordance was considered to have occurred when the percutaneous biopsy histology did not provide a sufficient explanation for the imaging features; in such cases, repeat biopsy was recommended. Medical records, imaging studies, and histologic findings were reviewed. RESULTS: Imaging-histologic discordance was present in 56 of 1785 (3.1%) lesions. The frequency of discordance was significantly higher in our first 2 years of experience with percutaneous biopsy than in later years (18 of 361 = 5.0% vs. 38 of 1424 = 2.7%; P < 0.04) and was significantly higher for lesions that were BI-RADS Category 5 rather than BI-RADS Category 4 (20 of 416 = 4.8% vs. 36 of 1366 = 2. 6%; P < 0.04). The frequency of discordance was significantly lower with the 11-gauge vacuum-assisted probe than other devices for calcifications (7 of 414 = 1.7% vs. 16 of 251 = 6.8%; P = 0.001) but not for masses (6 of 161 = 3.7% vs. 26 of 959 = 2.7%; P = 0.44). Repeat biopsy, performed in 45 discordant lesions revealed carcinoma in 11 (24.4%; 95% confidence intervals, 12.9-39.5%). The frequency of carcinoma was significantly higher among discordant BI-RADS Category 5 than discordant BI-RADS Category 4 lesions (7 of 16 = 43. 8% vs. 4 of 29 = 13.7%; P < 0.04). CONCLUSIONS: Imaging-histologic discordance occurred in 3.1% of lesions that had percutaneous breast biopsy. Imaging-histologic discordance was an indication for surgical excision because of the high (24.4%) prevalence of carcinoma in these lesions.

Complete percutaneous excision of infiltrating carcinoma at stereotactic breast biopsy: how can tumor size be assessed?

OBJECTIVE: The purpose of this study was to determine the frequency of complete excision of infiltrating carcinoma at stereotactic 11-gauge directional vacuum-assisted breast biopsy and to evaluate the feasibility of measuring tumor size in stereotactic biopsy specimens in infiltrating carcinomas that were percutaneously excised. MATERIALS AND METHODS: We performed retrospective review of 51 infiltrating carcinomas diagnosed using stereotactic 11-gauge directional vacuum-assisted biopsy that underwent subsequent surgery. For lesions yielding no residual infiltrating carcinoma at surgery, the maximal dimension of the tumor was measured in stereotactic biopsy specimens using ocular micrometry. RESULTS: In 10 (20%) (95% confidence intervals, 9.8-33.1%) of 51 infiltrating carcinomas diagnosed at stereotactic biopsy, surgery revealed no residual infiltrating carcinoma. Complete excision of infiltrating carcinoma was more frequent if 14 or more specimens were obtained (32% versus 0%, p < .004), if the mammographic lesion was removed (35% versus 7%, p < .03), and if the mammographic lesion size measured 0.7 cm or less (50% versus 16%, p = .08). Tumor size in stereotactic biopsy specimens was within 3 mm of mammographic lesion size in six (60%) of 10 lesions, including five (71%) of seven masses and one (33%) of three calcification lesions, but was smaller than the mammographic lesion size in eight (80%) of 10 lesions. CONCLUSION: Surgery revealed no residual infiltrating carcinoma in 10 (20%) of 51 infiltrating carcinomas diagnosed at stereotactic 11-gauge biopsy. Although tumor size can be assessed in stereotactic biopsy specimens in these lesions, such measurements may underestimate the maximal dimension of the tumor. Further study is needed to evaluate the usefulness of these measurements in guiding treatment decisions.

ThinPrep vs. conventional smears in fine-needle aspirations of sarcomas: A morphological and immunocytochemical study.

Very limited data exist describing the characteristics of sarcomas sampled by fine-needle aspiration (FNA) and processed by the ThinPrep (TP) method. We compared the cytopathological and immunocytochemical features of sarcoma aspirates prepared using both the conventional and TP method. We reviewed 70 sarcoma FNAs. Samples were first used to prepare conventional smears and the remainder of the specimen was rinsed in Cytolyt. The average number of slides examined per case was two for the TP method and five for the conventional technique. Immunocytochemistry for different markers was performed in a subset of cases. Sixty-five cases were positive for sarcoma both by conventional and TP methods. Five cases were positive by one method only. Cellularity was higher on conventional slides. In terms of cytoarchitecture, TP slides revealed fewer thick clusters, more single cells that were more evenly distributed, and sometimes distortion of expected cellular arrangements and architectural patterns. Cytomorphological and nuclear details were better preserved on TP slides. The background of TP slides revealed a reduction of blood but also some loss of necrosis and characteristic background tumor features. Immunocytochemical staining revealed superior results on TP slides. TP and conventional slides showed good correlation. TPs were excellent for immunocytochemistry and represent an alternative to conventional smears when expertise in slide preparation is not available. However, TPs may require additional experience in the interpretation of sarcomas, mainly related to the loss of tumor-specific background features. They are useful as an adjuvant to conventional smears in sarcoma diagnoses, particularly when special studies are needed. Diagn. Cytopathol. 1999;21:351-354.

Cytopathology of insular carcinoma of the thyroid.

BACKGROUND: Insular carcinoma of the thyroid (ICT) first was reported in 1984. To the authors' knowledge, few cytology reports have been published since that time. The authors describe the cytologic features of six tissue-proven ICTs and propose criteria that suggest its diagnosis. METHODS: Four cases were thyroid fine-needle aspiration (FNA) samples. Two cases were FNAs of metastases. All cases were found to be classic ICT on examination of primary or metastatic surgical specimens. RESULTS: Three cases originally were diagnosed as carcinoma, including two FNAs of metastatic sites and one thyroid FNA. Two additional thyroid FNAs were diagnosed as suspicious for malignancy, favor follicular neoplasm. One case was termed a neoplasm, favor follicular type. Smears showed high cellularity and scanty colloid. Three cases were found to contain some microfollicles. One case showed a few papillae. Necrosis and mitosis were rare. Cells were round with pale, poorly defined cytoplasm. Nuclei were round and monomorphic with finely granular chromatin, mild hyperchromasia, smooth nuclear membranes, and small nucleoli. Nuclear grooves and inclusions were rare. CONCLUSIONS: Three cases were diagnosed as suspicious for follicular neoplasm, the main differential diagnosis of ICT. Both tumors exhibited high cellularity and scanty colloid. However, ICT showed a predominance of single cells whereas follicular neoplasms reveal microfollicles with more nuclear atypia. There is cytologic overlap between these two neoplasms. Papillary thyroid carcinoma should be distinguished from ICT easily because the latter usually does not reveal the classic cytologic features associated with the former. ICT should be considered in the differential diagnosis of follicular neoplasms. Features favoring ICT are predominance of single cells, small loose nests of cells with few microfollicles, and little nuclear atypia. Cancer (Cancer Cytopathol)

The cytology of extraskeletal Ewing sarcoma.

BACKGROUND: Extraskeletal Ewing sarcoma (EES) shares histologic, immunohistochemical, and molecular findings with ES of bone. The authors' goal in conducting this study was to examine the cytomorphologic features of EES. In addition, immunocytostaining for CD99/O13 was performed in all cases, and cytogenetic and molecular data were available in about half of the cases. METHODS: The authors studied 20 aspiration cases, all with histopathologic confirmation, and also conducted immunohistochemistry and/or molecular studies. RESULTS: All cases had cellular smears with many single cells and focal clustering. Numerous naked nuclei and focal crush artifacts were seen. Mitosis and necrosis were rare. Four cases had cytoplasmic vacuoles. Five cases showed nuclear molding. Seventeen cases (85%) exhibited small cells with scanty cytoplasm and nuclei with fine chromatin and small nucleoli, representing the so-called typical variant. One case (5%) revealed cells with abundant cytoplasm, large nuclei, and large eosinophilic nucleoli, an example of the atypical or large cell variant. Two cases (10%) had features in between, with cells showing a fair amount of cytoplasm and medium-sized nucleoli, representing the intermediate variant. Nuclear grooves, described as common in the latter, were rare. In all cases, in either cytologic or corresponding histologic material, CD99/O13 immunocytostaining showed strong membranous reactivity. In addition, cytogenetic and/or molecular evidence of ES specific chromosomal translocation was demonstrated in histologic or cytologic material in 10 cases. CONCLUSIONS: EES shows cytologic features similar to ES of bone, with a spectrum of changes ranging from the typical appearance in a majority of cases to intermediate and atypical variants in a minority of cases. CD99/O13 immunocytostaining and/or molecular studies, particularly in the intermediate and atypical variants, may help in establishing a definitive fine-needle aspiration diagnosis, thus avoiding an open surgical biopsy.

Fine-needle aspiration biopsy of chromophobe renal cell carcinoma and oncocytoma: comparison of cytomorphologic features.

BACKGROUND: Chromophobe renal cell carcinoma (ChRCC) is a distinct tumor with a prognosis intermediate between renal oncocytoma (RO) and clear cell renal cell carcinoma. To our knowledge the cytologic features of only a limited number of ChRCC have been described to date. A retrospective review of the cytomorphologic features of ChRCC and a comparison with RO was performed. METHODS: Fine-needle aspiration biopsies (FNABs) of six cases of histopathologically proven ChRCC were reviewed. The material examined was comprised of smears, cytospins, Thin Prep Pap Test preparations, and cell block sections stained with Diff-Quik, Papanicolaou, and hematoxylin and eosin. Six FNABs of ROs were examined similarly. The cytomorphology of each tumor was studied and particular attention was paid to features differentiating the two entities. RESULTS: The characteristic cytomorphologic features of ChRCC (present in all cases) included round/oval, occasionally polygonal, moderately pleomorphic large cells present singly and in small clusters. The abundant cytoplasm was variegated, ranging from dense to flocculent to vacuolated, with prominent cytoplasmic membranes. The nuclei were large and hyperchromatic, with nuclear membrane irregularities and grooves present at least focally. Frequent binucleation was observed. Small nucleoli were present in many cells, but rarely prominent. In contrast, RO showed large cells with homogenous granular cytoplasm. The nuclei showed minimal to no nuclear membrane irregularities, tiny nucleoli, mild pleomorphism, and only an occasional large, more hyperchromatic nucleus was observed. CONCLUSIONS: ChRCC has a distinct combination of cytomorphologic features. Careful attention to cytoplasmic and nuclear features allows for the distinction between ChRCC and RO in cytologic preparations.

Anti-alpha-inhibin: marker of choice for the consistent distinction between adrenocortical carcinoma and renal cell carcinoma in fine-needle aspiration.

BACKGROUND: Anti-alpha-inhibin, an antibody directed against a peptide hormone, has been shown to be a useful diagnostic aid in surgical pathology material for the identification of sex cord-stromal neoplasms and recently has been described in adrenocortical carcinoma (ACC). The diagnosis of ACC versus renal cell carcinoma (RCC) may be difficult morphologically, particularly in fine-needle aspiration (FNA) material. To date, the immunohistochemical distinction of ACC from RCC is based on a panel of antibodies that include vimentin, cytokeratins, and epithelial membrane antigen. However, the reliability of this panel is weakened by inconsistent staining patterns. METHODS: Archival formalin fixed, paraffin embedded cell block sections from 45 FNAs of known primary and metastatic ACC and RCC as well as benign adrenocortical nodules were stained with anti-alpha-inhibin using an avidin-biotin procedure. All samples were microwave pretreated and a biotin block was performed to reduce the background stain due to the high endogenous biotin often present in these types of samples. RESULTS: All cases of ACC (n = 7; 100%) and benign adrenocortical cells (n = 15; 100%) were immunoreactive with the a-inhibin antibody, showing a diffuse cytoplasmic and granular staining pattern. The staining intensity and number of immunoreactive cells varied within each sample, with the cases of ACC having the greatest proportion of immunoreactive cells and the strongest intensity. None of the cases of RCC (n = 23; 0%) were immunoreactive with anti-alpha-inhibin. CONCLUSIONS: The morphologic distinction of ACC versus RCC in FNA material from renal, adrenal, and metastatic neoplasms is not always feasible based on cytology alone. However, due to the advent of the alpha-inhibin antibody, the reliable distinction of these entities now may be possible. The intense and specific immunostaining pattern for cells of adrenal origin, even in paucicellular samples, suggests potential for the widespread clinical utility of this marker by cytopathologists.