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Aarti Mathur,
Julie Weng,
Willieford Moses,
Seth M Steinberg,
Reza Rahbari,
Reza Rahabari,
Mio Kitano,
Elham Khanafshar, Britt-Marie Ljung,
Quan-Yang Duh,
Orlo H Clark,
Electron Kebebew
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ABSTRACT: Approximately 30% of fine needle aspiration biopsies of the thyroid have inconclusive results. We conducted a prospective trial to determine whether clinical and molecular markers could be used in combination to improve the accuracy of thyroid fine needle aspiration biopsy.
Clinical, tumor genotyping for common somatic mutations (BRAF V600E, NRAS, KRAS, RET/PTC1, RET/PTC3, and NTRK1), and the gene expression levels of 6 candidate diagnostic markers were analyzed by univariate and multivariate methods in 341 patients to determine whether they could distinguish reliably benign from malignant thyroid neoplasms, and a scoring model was derived.
By a multivariate analysis, fine needle aspiration biopsy cytology classification, the presence of a NRAS mutation, and the tissue inhibitor of metalloproteinase 1 expression level were associated jointly with malignancy. The overall accuracy of the scoring model, including these 3 variables, to distinguish benign from malignant thyroid tumors was 91%, including 67% for the indeterminate and 77% for the suspicious FNA subgroups.
Fine needle aspiration biopsy cytology classification, the presence of NRAS mutation, and tissue inhibitor of metalloproteinase 1 messenger RNA expression levels in combination provide a greater diagnostic accuracy than fine needle aspiration biopsy cytology alone to allow selection of more definitive initial operative treatment. The sensitivity of the scoring model, however, was too low to avoid the need for diagnostic thyroidectomies for indeterminate fine needle aspiration biopsy findings.
Surgery 12/2010; 148(6):1170-6; discussion 1176-7. · 3.10 Impact Factor
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ABSTRACT: Thyroid fine-needle aspiration (FNA) biopsy is indeterminate or suspicious in up to 30% of cases and these patients are commonly subjected to at least a diagnostic hemithyroidectomy. If malignant on histology, a completion thyroidectomy is usually performed, which may be associated with higher morbidity. To determine the clinical utility of genetic testing in thyroid FNA biopsy, we conducted a prospective clinical trial.
Four hundred seventeen patients with 455 thyroid nodules were enrolled and had genetic testing for common somatic mutations (BRAF, NRAS, KRAS) and gene rearrangements (RET/PTC1, RET/PTC3, RAS, TRK1) by PCR and direct sequencing and by nested PCR, respectively. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of genetic testing in thyroid FNA biopsy were determined based on the histologic diagnosis.
One hundred twenty-five of 455 thyroid nodule FNA biopsies were indeterminate or suspicious on cytologic examination. Overall, 50 mutations were identified (23 BRAF, 4 RET/PTC1, 2 RET/PTC3, 21 NRAS) in the thyroid FNA biopsies. There were significantly more mutations detected in malignant thyroid nodules than in benign (P = 0.0001). For thyroid FNA biopsies that were indeterminate or suspicious, genetic testing had a sensitivity of 12%, specificity of 98%, PPV of 38%, and NPV of 65%.
Genetic testing for somatic mutations in thyroid FNA biopsy samples is feasible and identifies a subset of malignant thyroid neoplasms that are indeterminate or suspicious on FNA biopsy. Genetic testing for common somatic genetic alterations thus could allow for more definitive initial thyroidectomy in those with positive results.
World Journal of Surgery 11/2010; 34(11):2589-94. · 2.36 Impact Factor
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Karla Kerlikowske,
Annette M Molinaro,
Mona L Gauthier,
Hal K Berman,
Fred Waldman,
James Bennington,
Henry Sanchez,
Cynthia Jimenez,
Kim Stewart,
Karen Chew, Britt-Marie Ljung,
Thea D Tlsty
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ABSTRACT: Studies have failed to identify characteristics of women who have been diagnosed with ductal carcinoma in situ (DCIS) and have a high or low risk of subsequent invasive cancer.
We conducted a nested case-control study in a population-based cohort of 1162 women who were diagnosed with DCIS and treated by lumpectomy alone from 1983 to 1994. We collected clinical characteristics and information on subsequent tumors, defined as invasive breast cancer or DCIS diagnosed in the ipsilateral breast containing the initial DCIS lesion or at a regional or distant site greater than 6 months after initial treatment of DCIS (N = 324). We also conducted standardized pathology reviews and immunohistochemical staining for the estrogen receptor (ER), progesterone receptor, Ki67 antigen, p53, p16, epidermal growth factor receptor-2 (ERBB2, HER2/neu oncoprotein), and cyclooxygenase-2 (COX-2) on the initial paraffin-embedded DCIS tissue. Competing risk models were used to determine factors associated with risk of subsequent invasive cancer vs DCIS, and cumulative incidence survival functions were used to estimate 8-year risk.
Factors associated with subsequent invasive cancer differed from those associated with subsequent DCIS. Eight-year risk of subsequent invasive cancer was statistically significantly (P = .018) higher for women with initial DCIS lesions that were detected by palpation or that were p16, COX-2, and Ki67 triple positive (p16(+)COX-2(+)Ki67(+)) (19.6%, 95% confidence interval [CI] = 18.0% to 21.3%) than for women with initial lesions that were detected by mammography and were p16, COX-2, and Ki67 triple negative (p16(-)COX-2(-)Ki67(-)) (4.1%, 95% CI = 3.4% to 5.0%). In a multivariable model, DCIS lesions that were p16(+)COX-2(+)Ki67(+) or those detected by palpation were statistically significantly associated with subsequent invasive cancer, but nuclear grade was not. Eight-year risk of subsequent DCIS was highest for women with DCIS lesions that had disease-free margins of 1 mm or greater combined with either ER(-)ERBB2(+)Ki67(+) or p16(+)COX-2(-)Ki67(+) status (23.6%, 95% CI = 18.1% to 34.0%).
Biomarkers can identify which women who were initially diagnosed with DCIS are at high or low risk of subsequent invasive cancer, whereas histopathology information cannot.
CancerSpectrum Knowledge Environment 05/2010; 102(9):627-37. · 14.07 Impact Factor
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Britt-Marie Ljung
Cancer 07/2008; 114(3):144-8. · 4.77 Impact Factor
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ABSTRACT: Routine secondary cytologic review of thyroid gland fine-needle aspiration (FNA) specimens in patients referred from other institutions has been the recommended practice at some medical centers. We sought to determine the concordance rates between FNA interpretations at referring institutions and our center to determine if they alter surgical management.
All thyroid gland FNAs referred to our center for cytopathologic opinion from June 2000 to August 2004 were reviewed. Patients in whom FNA biopsies were performed for thyroid cancer recurrences or core biopsies and patients in whom only a cytopathologic opinion was requested without a clinical consultation were excluded from the study. FNA results were divided into benign, indeterminate, suspicious, malignant, and nondiagnostic categories. FNA interpretations at our medical center and the referring institutions were compared with final histology results in patients who underwent operations.
One hundred forty-seven patients had secondary review of their thyroid gland FNA specimens. The overall concordance was 82%, with the highest concordance rate in the malignant category (95%) and the lowest in the suspicious category (62%, p<0.001). The sensitivity (94% versus 92%), specificity (76% versus 56%), and positive (93% versus 87%) and negative (79% versus 69%) predictive values were all higher on secondary review. Twenty-seven patients were found to have discordant FNA interpretations. As a result of the discordant FNA result, four patients had their surgical management decisions changed. Another four patients had appropriate oncologic thyroid resection as a result of the secondary review.
Our results suggest that routine secondary cytopathologic review of FNA specimens from referring institutions changes surgical management in some patients with thyroid neoplasms. We recommend this practice be widely used at other centers, especially for suspicious results.
Journal of the American College of Surgeons 08/2007; 205(1):8-12. · 4.55 Impact Factor
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ABSTRACT: Ductal lavage (DL) does not routinely identify cytologically malignant cells. For this study, the authors asked whether molecular analyses of DL specimens from women with cancer would identify abnormal cells, even if they appeared cytologically normal.
DL was performed and yielded fluid in 29 of 45 consenting women who were undergoing breast cancer surgery. Array comparative genomic hybridization (CGH) was performed on the corresponding tumor tissue from 14 women. There was no single, common alteration; thus, bacterial artificial chromosome-specific fluorescence in situ hybridization (FISH) probes were selected based on CGH alterations.
FISH copy number changes were detected in tumor sections in 9 women. In the corresponding 9 DL samples, 1 sample was clearly malignant on cytology, 1 showed marked atypia, 1 showed mild atypia, and the rest were benign. Five of the 9 DL samples had epithelial cells that showed genetic changes identical to those observed in the tumor by FISH. The remaining 4 of 9 DL samples that did not show molecular changes were probably (N = 1) or possibly (N = 3) from the same duct as the tumor.
Although only 11% of the DL samples were identified as malignant cytologically, 55% showed molecular changes that were identical to those observed in the tumor. FISH was more sensitive for finding tumor in DL specimens than cytology. However, the ductal system in which the tumor was located did not always yield fluid, limiting the sensitivity of DL. The results from this study showed that genetic changes can be detected in the absence of morphologic changes in cytologically benign cells, but the application will be limited without a better approach for acquiring cells and a common set of probes for detecting molecular abnormalities that are found in breast malignancies.
Cancer 07/2007; 111(3):185-91. · 4.77 Impact Factor
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Koei Chin,
Sandy DeVries,
Jane Fridlyand,
Paul T Spellman,
Ritu Roydasgupta,
Wen-Lin Kuo,
Anna Lapuk,
Richard M Neve,
Zuwei Qian,
Tom Ryder, [......],
Shanaz Dairkee,
Zhenhang Meng,
Karen Chew,
Daniel Pinkel,
Ajay Jain, Britt Marie Ljung,
Laura Esserman,
Donna G Albertson,
Frederic M Waldman,
Joe W Gray
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ABSTRACT: This study explores the roles of genome copy number abnormalities (CNAs) in breast cancer pathophysiology by identifying associations between recurrent CNAs, gene expression, and clinical outcome in a set of aggressively treated early-stage breast tumors. It shows that the recurrent CNAs differ between tumor subtypes defined by expression pattern and that stratification of patients according to outcome can be improved by measuring both expression and copy number, especially high-level amplification. Sixty-six genes deregulated by the high-level amplifications are potential therapeutic targets. Nine of these (FGFR1, IKBKB, ERBB2, PROCC, ADAM9, FNTA, ACACA, PNMT, and NR1D1) are considered druggable. Low-level CNAs appear to contribute to cancer progression by altering RNA and cellular metabolism.
Cancer Cell 01/2007; 10(6):529-41. · 26.57 Impact Factor
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ABSTRACT: A 50-year-old man presented with progressive gastrointestinal symptoms. An abdominal computed tomography scan demonstrated a 12 x 12-cm pancreatic mass involving the greater curvature of the stomach and multiple hypervascular hepatic metastases. An initial fine needle aspiration of the pancreatic mass was nondiagnostic, and a subsequent fine needle aspiration of a liver mass was read as metastatic acinar cell carcinoma. The patient underwent a palliative resection for tumor-associated pain and gastrointestinal hemorrhage that revealed a large pancreatic tumor invading through the full thickness of the colon at the splenic flexure and adherent to the posterior gastric wall. The pathology from the distal pancreatectomy, splenectomy, partial gastrectomy, partial colectomy, and cholecystectomy unexpectedly supported a diagnosis of pancreatoblastoma with evidence for squamoid corpuscles as well as areas of acinar formation. Despite multiple chemotherapy regimens, the patient's disease continued to progress in the liver and the lungs. During the course of his therapy, the patient's serum alpha-fetoprotein levels and serum lipase levels rose concurrently, suggesting tumor-associated production of both of these factors. Seventeen months after the diagnosis of metastatic pancreatoblastoma, the patient died from his disease. Our case illustrates the fact that pancreatoblastomas are extremely difficult to diagnosis preoperatively. In addition, our case demonstrates that pancreatoblastomas can be alpha-fetoprotein producing, hormone producing, and enzyme producing when it occurs in adults.
Journal of Gastrointestinal Surgery 07/2006; 10(6):829-36. · 2.83 Impact Factor
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Jane Fridlyand,
Antoine M Snijders,
Bauke Ylstra,
Hua Li,
Adam Olshen,
Richard Segraves,
Shanaz Dairkee,
Taku Tokuyasu, Britt Marie Ljung,
Ajay N Jain,
Jane McLennan,
John Ziegler,
Koei Chin,
Sandy Devries,
Heidi Feiler,
Joe W Gray,
Frederic Waldman,
Daniel Pinkel,
Donna G Albertson
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ABSTRACT: Genomic DNA copy number aberrations are frequent in solid tumors, although the underlying causes of chromosomal instability in tumors remain obscure. Genes likely to have genomic instability phenotypes when mutated (e.g. those involved in mitosis, replication, repair, and telomeres) are rarely mutated in chromosomally unstable sporadic tumors, even though such mutations are associated with some heritable cancer prone syndromes.
We applied array comparative genomic hybridization (CGH) to the analysis of breast tumors. The variation in the levels of genomic instability amongst tumors prompted us to investigate whether alterations in processes/genes involved in maintenance and/or manipulation of the genome were associated with particular types of genomic instability.
We discriminated three breast tumor subtypes based on genomic DNA copy number alterations. The subtypes varied with respect to level of genomic instability. We find that shorter telomeres and altered telomere related gene expression are associated with amplification, implicating telomere attrition as a promoter of this type of aberration in breast cancer. On the other hand, the numbers of chromosomal alterations, particularly low level changes, are associated with altered expression of genes in other functional classes (mitosis, cell cycle, DNA replication and repair). Further, although loss of function instability phenotypes have been demonstrated for many of the genes in model systems, we observed enhanced expression of most genes in tumors, indicating that over expression, rather than deficiency underlies instability.
Many of the genes associated with higher frequency of copy number aberrations are direct targets of E2F, supporting the hypothesis that deregulation of the Rb pathway is a major contributor to chromosomal instability in breast tumors. These observations are consistent with failure to find mutations in sporadic tumors in genes that have roles in maintenance or manipulation of the genome.
BMC Cancer 02/2006; 6:96. · 3.01 Impact Factor
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ABSTRACT: Ductal lavage (DL) is a new procedure for sampling of the mammary epithelium, but experience with this technique remains limited. We compared the findings in paired DL and fine-needle aspiration (FNA) specimens obtained from patients with breast carcinoma. Four reviewers evaluated all DL samples. Two reviewers also examined the FNA material and compared cellular composition and morphologic findings in paired samples. DL and FNA samples from six patients were satisfactory for evaluation. Two DL samples showed marked atypia, one showed mild atypia, and two were benign; there was no agreement in one case (mild atypia vs. benign). Overall, the atypical cells in DL samples resembled those in the paired FNA material, but low degree of cytologic atypia and relative paucity of atypical cells limited their correct identification. The interpretation of DL samples is more challenging than that of FNA material, but similar criteria apply. To increase the sensitivity of DL, the number of epithelial cells required for a satisfactory sample should be higher than previously set.
Diagnostic Cytopathology 01/2006; 33(6):370-5. · 1.16 Impact Factor
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ABSTRACT: To investigate the dysregulating effect of excess oxidative stress on mammary gland development, mammary anlage from newborn female mice with normal (+/+) or absent (null, -/-) manganese superoxide dismutase (SOD2) were excised and implanted under the renal capsule of normal host female nude mice with/without concurrent estrogen supplementation. After 30 days the transplanted glands were excised for wholemount, microscopic and immunohistochemical evaluation. In contrast to the normal growth and maturation of transplanted SOD2+/+ glands, SOD2-/- glands showed arrested development, reduced ductal outgrowth and branching, and absent lumen. These hypomorphic SOD2-/- ducts contained hyperplastic epithelium with increased Ki-67 labelling, loss of E-cadherin expression, and disorganized p63 and cytokeratin (K)-14 expressing basal and myoepithelial components. Estrogen treatment failed to upregulate progesterone receptor or normalize development. These findings suggest that excess oxidative stress from loss of SOD2 function can arrest mammary gland maturation and induce hyperplastic epithelium with early premalignant features.
The Breast 09/2005; 14(4):256-63. · 2.49 Impact Factor
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ABSTRACT: Antiestrogens reduce the risk of estrogen receptor-positive (ER+) but not ER-negative (ER-) breast cancer. Women at high risk of ER+ cancer would be the most likely to benefit from these treatments, but the best approach to predicting ER+ cancer is uncertain.
We prospectively assessed putative risk factors for breast cancer and archived serum at -190 degrees C from a community-based cohort of 7,676 women ages > or =65 years who had no history of breast cancer. Follow-up for breast cancer over 10.5 years was 99% complete. Using a case-cohort design, we measured baseline levels of estradiol and testosterone in 196 cases of invasive ER+ cancer and 378 randomly selected controls.
Women whose testosterone level in highest two quintiles had a 4-fold increased risk of ER+ breast cancer (P < 0.0001). High estradiol concentration also indicated an increased risk but was not a significant predictor after adjustment for testosterone. Women with >16 years of education had a 2.1 times increased risk (P = 0.03) of ER+ cancer, but no other risk factors were significantly related to an increased risk of ER+ cancer. Women with a family history of breast cancer had a 2.9-fold increased risk of ER- cancer (P = 0.002) but no increased risk of ER+ cancer (relative hazard = 1.2, 0.8-1.8).
High serum testosterone and advanced education predicted ER+ breast cancer. If confirmed, high testosterone level may be more accurate than family history of breast cancer and other conventional risk factors for identifying older women who are most likely to benefit from antiestrogen chemoprevention.
Cancer Epidemiology Biomarkers & Prevention 06/2005; 14(5):1047-51. · 4.12 Impact Factor
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Christopher Haqq,
Mehdi Nosrati,
Daniel Sudilovsky,
Julia Crothers,
Daniel Khodabakhsh,
Brian L Pulliam,
Scot Federman,
James R Miller,
Robert E Allen,
Mark I Singer,
Stanley P L Leong, Britt-Marie Ljung,
Richard W Sagebiel,
Mohammed Kashani-Sabet
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ABSTRACT: Because of the paucity of available tissue, little information has previously been available regarding the gene expression profiles of primary melanomas. To understand the molecular basis of melanoma progression, we compared the gene expression profiles of a series of nevi, primary melanomas, and melanoma metastases. We found that metastatic melanomas exhibit two dichotomous patterns of gene expression, which unexpectedly reflect gene expression differences already apparent in comparing laser-capture microdissected radial and vertical phases of a large primary melanoma. Unsupervised hierarchical clustering accurately separated nevi and primary melanomas. Multiclass significance analysis of microarrays comparing normal skin, nevi, primary melanomas, and the two types of metastatic melanoma identified 2,602 transcripts that significantly correlated with sample class. These results suggest that melanoma pathogenesis can be understood as a series of distinct molecular events. The gene expression signatures identified here provide the basis for developing new diagnostics and targeting therapies for patients with malignant melanoma.
Proceedings of the National Academy of Sciences 05/2005; 102(17):6092-7. · 9.68 Impact Factor
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ABSTRACT: In the search for early deletion targets in sporadic breast cancer, the analysis of TP53, BRCA1, BRCA2, and ATM revealed loss of heterozygosity (LOH) in tumor cells at 1 or more genes in 18 of 24 cases examined. Notably, in more than 60% of such tumors, LOH was detectable in morphologically normal terminal ductal lobular units (TDLUs) adjacent to carcinoma (LOHint). At BRCA2 and ATM, LOHint was most frequent, particularly in TDLUs of women <or= 50 years old (7 of 10). In a novel preneoplastic model system, declining expression levels observed with increasing passage in culture supported the postulate that during the acquisition of continuous growth, elimination of these genes at an early stage confers a distinct selective advantage. The intimate role of these genes in DNA repair and their early deletion has implications for the possible transforming effects of DNA-damaging agents on unexcised breast tissue harboring LOHint within breast cancer patients.
Genes Chromosomes and Cancer 12/2004; 41(3):214-22. · 3.31 Impact Factor
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Koei Chin,
Carlos Ortiz de Solorzano,
David Knowles,
Arthur Jones,
William Chou,
Enrique Garcia Rodriguez,
Wen-Lin Kuo, Britt-Marie Ljung,
Karen Chew,
Kenneth Myambo,
Monica Miranda,
Sheryl Krig,
James Garbe,
Martha Stampfer,
Paul Yaswen,
Joe W Gray,
Stephen J Lockett
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ABSTRACT: Transition through telomere crisis is thought to be a crucial event in the development of most breast carcinomas. Our goal in this study was to determine where this occurs in the context of histologically defined breast cancer progression. To this end, we assessed genome instability (using fluorescence in situ hybridization) and other features associated with telomere crisis in normal ductal epithelium, usual ductal hyperplasia, ductal carcinoma in situ and invasive cancer. We modeled this process in vitro by measuring these same features in human mammary epithelial cell cultures during ZNF217-mediated transition through telomere crisis and immortalization. Taken together, the data suggest that transition through telomere crisis and immortalization in breast cancer occurs during progression from usual ductal hyperplasia to ductal carcinoma in situ.
Nature Genetics 10/2004; 36(9):984-8. · 35.53 Impact Factor
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ABSTRACT: Ductal carcinoma in situ (DCIS) is thought to be a nonobligate precursor of invasive cancer. Genomic changes specific to pure DCIS versus invasive cancer, as well as alterations unique to individual DCIS subtypes, have not been fully defined.
Chromosomal copy number alterations were examined by comparative genomic hybridization in 34 cases of pure DCIS and compared with 12 cases of paired synchronous DCIS and invasive ductal cancer, as well as to 146 additional cases of invasive breast cancer of ductal or lobular histology. Genomic differences between high-grade and low/intermediate-grade DCIS, as well as between pure DCIS and invasive cancer, were identified.
Pure DCIS showed almost the same degree of chromosomal instability as invasive ductal cancers. A higher proportion of low/intermediate-grade versus high-grade DCIS had loss of 16q (65 versus 12%, respectively; P = 0.002). When compared with lower grade DCIS, high-grade DCIS exhibited more frequent gain of 17q (65 versus 41%; P = 0.15) and higher frequency loss of 8p (77 versus 41%; P = 0.04). Chromosomal alterations in those cases with synchronous DCIS and invasive ductal cancer showed a high degree of shared changes within the two components.
DCIS is genetically advanced, showing a similar degree of chromosomal alterations as invasive ductal cancer. The pattern of alterations differed between high- and low/intermediate-grade DCIS, supporting a model in which different histological grades of DCIS are associated with distinct genomic changes. These regions of chromosomal alterations may be potential targets for treatment and/or markers of prognosis.
Clinical Cancer Research 09/2004; 10(15):5160-7. · 7.74 Impact Factor
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ABSTRACT: The cytologic evaluation of nipple aspirate fluids has been shown to identify women at increased risk for developing breast cancer. One limitation of this assay is the often scant cellularity of the specimen. An improved technique, ductal lavage, utilizes a microcatheter inserted into individual breast ducts to collect large numbers of cells for cytologic evaluation. Epithelial cells in ductal lavage fluids can be categorized as benign, malignant, or showing mildly or markedly atypical changes. The cell characteristics which were most helpful in identifying abnormal cells were related to cell arrangement, cell size, nuclear size, and size variation, nuclear membrane irregularity, chromatin granularity, and the presence of large nucleoli. Cell size, nuclear size variation, and large nucleoli were the most robust features, as determined by agreement between two pathologists. Moderate cell enlargement and the presence of large nucleoli were the features selected by structured tree analysis for classifying the specimens into the diagnostic groups. The similarity of the cytology of ductal lavage fluid to nipple aspirate fluid strongly suggests that these specimens will also be useful for predicting breast cancer risk.
Diagnostic Cytopathology 04/2004; 30(3):143-50. · 1.16 Impact Factor
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ABSTRACT: Ductal lavage (DL) is a new method for the sampling of breast epithelium. Data regarding its sensitivity in the detection of epithelial abnormalities, including carcinoma in situ (CIS), remains limited.
DL was performed in the affected breasts of 26 women undergoing mastectomy for mammary carcinoma and in the clinically normal breast of 4 additional women undergoing risk-reducing mastectomy. After surgery, dye was injected through the microcatheter used for DL. Three cytopathologists independently reviewed all DL slides and the data reflect consensus by at least two reviewers. Interobserver agreement was assessed. The findings in DL samples were correlated with the features of CIS in the mastectomy specimens.
Four (14%) of 29 DL samples satisfactory for evaluation showed marked atypia, 10 (34%) showed mild atypia, and 15 (52%) were benign. No DL sample was clearly malignant. Interobserver agreement was good (average kappa = 0.52). Of the DL samples satisfactory for evaluation, 27 had been obtained from 24 breasts containing CIS, which included 18 ductal CIS (DCIS), 3 lobular CIS (LCIS), 2 DCIS and LCIS, and 1 solid CIS with mixed ductal and lobular features. Invasive carcinoma was present in 20 samples. Two DL samples from breasts with extensive LCIS showed mild atypia and injected dye was identified in ducts and lobules involved by LCIS.
DL had low sensitivity for CIS in breasts that also contained invasive carcinoma. The use of DL remains investigational, and close follow-up should be continued for all patients undergoing DL, including those with benign diagnoses.
Cancer 12/2003; 98(10):2170-6. · 4.77 Impact Factor
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ABSTRACT: Clinical and histopathologic characteristics that may predict risks of recurrence in women with ductal carcinoma in situ (DCIS) have not been consistently identified. We identified factors associated with recurrence as DCIS versus invasive breast cancer and determined the 5-year absolute risks of recurrence as a function of these factors.
We conducted a population-based cohort study among 1036 women in the San Francisco Bay Area who were aged 40 years or older when diagnosed with DCIS and treated by lumpectomy alone from January 1983 through December 1994. Standardized pathology reviews were conducted to determine disease recurrence, defined as DCIS or invasive breast cancer diagnosed in the ipsilateral breast containing the initial DCIS lesion or at a distant site more than 6 months after the initial diagnosis and treatment of DCIS. Conditional logistic regression models were used to determine factors associated with recurrence. All statistical significance tests were two-sided.
During a median follow-up of 77.9 months, 209 women (20.2%) experienced a recurrence. Overall, the 5-year risks of recurrence as invasive cancer and as DCIS were 8.2% (95% confidence interval [CI] = 6.6% to 9.8%) and 11.7% (95% CI = 9.9% to 13.3%), respectively. The 5-year risks of recurrence as invasive cancer and as DCIS were 4.8% (95% CI = 3.7% to 6.8%) and 4.8% (95% CI = 3.8% to 5.8%), respectively, for women with low-nuclear-grade DCIS; 11.8% (95% CI = 9.9% to 14.1%) and 17.1% (95% CI = 15.5% to 18.7%), respectively, for women with high-nuclear-grade DCIS; 11.6% (95% CI = 11.3% to 12.0%) and 8.6% (95% CI = 7.1% to 10.2%), respectively, for women whose initial DCIS lesion was detected by palpation; and 6.6% (95% CI = 6.2% to 7.1%) and 14.1% (95% CI = 11.4% to 17.8%), respectively, for women with DCIS detected by mammography alone. High- (versus low-) nuclear-grade DCIS lesions and detection of the initial DCIS lesion by palpation (versus mammography) were associated with recurrence as invasive cancer. High- (versus low-) nuclear-grade lesions; resection margins that were positive, uncertain, or less than 10 mm disease-free (versus > or = 10 mm disease-free); and age 40-49 years at diagnosis (versus > or =50 years) were associated with recurrence as DCIS.
Nuclear grade is strongly associated with recurrence but not with the type of recurrence. Women with high-nuclear-grade DCIS or DCIS detected by palpation who are treated by lumpectomy alone are at relatively high risk of having an invasive breast cancer recurrence, compared with women with low-nuclear-grade or mammographically detected DCIS, and may be appropriate candidates for additional treatment.
CancerSpectrum Knowledge Environment 12/2003; 95(22):1692-702. · 14.07 Impact Factor
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ABSTRACT: Women who metabolize a large proportion of their estrogen via the 16alpha hydroxylation pathway could be at a higher risk of breast cancer. The objective of this study was to test the hypothesis that serum concentrations of 2-hydroxyestrone (2-OHE1) and 16alpha-hydroxyestrone (16alpha-OHE1), as well as their ratio, predict the risk of breast cancer in older women.
We performed a case-cohort study of 272 women with confirmed incident breast cancer and 291 controls chosen randomly from the cohort. Estrogen metabolites were measured in serum collected at the baseline examination and stored at -120 degrees C. Incident breast cancers were confirmed by medical records and pathology reports during an average follow-up of 8.7 years.
Mean concentrations of 2-OHE1 and 16alpha-OHE1, adjusted for age and body mass index, were 3% to 4% higher in cases compared with controls: 2-OHE1 was 176 pg/mL and 169 pg/mL and 16alpha-OHE1 was 233 pg/mL and 226 pg/mL in cases and controls, respectively. There was, however, no difference in the ratio of 2-OHE1 to 16alpha-OHE1. The risk of breast cancer in women with the highest quartile of this ratio compared with those in the lowest quartile was 1.17 (95% confidence interval = 0.73-1.87).
The study results do not support the hypothesis that the ratio of 2-OHE1 to 16alpha-OHE1 predicts breast cancer risk.
Epidemiology 11/2003; 14(6):740-4. · 5.57 Impact Factor
