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ABSTRACT: Ductal carcinoma in situ (DCIS) is an established precursor of invasive breast carcinoma. Immunoperoxidase stains for selected markers can assist pathologists in the diagnosis of challenging ductal epithelial proliferations, but they cannot replace morphologic evaluation as the primary and critical assessment of this disease. Molecular studies provide further insight into how DCIS progresses to invasive carcinoma and also confirm the heterogeneity of this lesion. Morphology-based knowledge, immunohistochemistry, and molecular advances in DCIS are the subjects of this review.
Advances in anatomic pathology 07/2013; 20(4):205-16. · 3.22 Impact Factor
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ABSTRACT: We previously demonstrated a high specificity of immunohistochemistry using epidermal growth factor receptor (EGFR) mutation-specific antibodies in lung adenocarcinoma and correlation with EGFR mutation analysis. In this study, we assessed EGFR mutation status by immunohistochemistry in a variety of extrapulmonary malignancies, especially those that frequently show EGFR overexpression. Tissue microarrays containing triplicate cores of breast carcinomas (n=300), colorectal carcinomas (n=65), pancreatic adenocarcinoma (n=145), and uterine carcinosarcoma or malignant mixed müllerian tumors (n=25) were included in the study. Tissue microarray of lung adenocarcinoma with known EGFR mutation status was used as reference. Immunohistochemistry was performed using antibodies specific for the E746-A750del and L858R mutations. In pulmonary adenocarcinoma, a staining intensity of 2+ or 3+ correlates with mutation status and is therefore considered as positive. Out of 300 breast carcinomas, 293 (98%) scored 0, 5 (2%) had 1+ staining, 2 (1%) were 2+ for the L858R antibody. All breast carcinomas scored 0 with the E746-A750 antibody. All the colorectal, pancreatic carcinomas and malignant mixed müllerian tumors were negative (0) for both antibodies. Molecular analysis of the breast carcinomas that scored 2+ for L858R showed no mutation. Our results show that EGFR mutation-specific antibodies could be an additional tool distinguishing primary versus metastatic carcinomas in the lung. False-positivity can be seen in breast carcinoma but is extremely rare (1%).Modern Pathology advance online publication, 19 April 2013; doi:10.1038/modpathol.2013.53.
Modern Pathology 04/2013; · 4.79 Impact Factor
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ABSTRACT: Focal extravasated mucin (EM) with benign or atypical epithelium is a rare finding at breast core needle biopsy (CNB) and usually prompts surgical excision to rule out mucin-producing carcinoma. In the largest detailed series to date, we assessed surgical outcomes in lesions yielding EM with atypical or nonatypical epithelium at CNB. With IRB approval, we retrospectively reviewed 28 consecutive atypical and nonatypical CNBs with EM that underwent surgical excision at our center over a 22-year period. CNB imaging and pathologic findings were concordant if pathology sufficiently explained the radiologic features of the lesions. Pathologic findings in CNB and excision specimens were correlated. Statistical analysis was performed. CNBs sampled mammographic calcifications in 25/28 (89%) women and a mass in 3/28 (11%). All cases had concordant pathologic and imaging findings. At CNB, the epithelium associated with EM was atypical in 18/28 (64%) lesions and nonatypical in 10 (36%). Cancer (one mucinous carcinoma; three ductal carcinoma in situ) was present in 4/28 excision specimens (14%; 95% confidence intervals [CI], 4%-33%). All carcinomas were in lesions with epithelial atypia at CNB (4/18; 22%; 95% CI, 6%-48%) versus none (0/10; 0%; 95% CI, 0%-31%) in nonatypical lesions at CNB; this difference was not statistically significant (p = 0.3). Surgery is warranted for lesions yielding EM with atypia at CNB due to the high (22%) prevalence of cancer. Our data suggest that surgical excision of lesions yielding EM without epithelial atypia at CNB may not be necessary provided that imaging and pathologic findings are concordant.
The Breast Journal 03/2013; · 1.64 Impact Factor
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ABSTRACT: Non-mammary metastases to the breast and axilla are rare occurrences. However, they are important diagnostic considerations as their treatment and prognosis differ significantly from primary breast cancer. Between 1990 and 2010, we identified a total of 85 patients, 72 women and 13 men, with non-mammary malignancies involving the breast, axilla, or both. The tumor types consisted of carcinoma (58%), melanoma (22%) and sarcoma (20%). Ovary was the most common site of origin for carcinoma, and metastatic high-grade ovarian serous carcinoma was most frequently misdiagnosed as a primary breast carcinoma. Melanoma was the single most common non-carcinomatous tumor type to involve the breast and/or axilla, and uterine leiomyosarcoma was the most common type of sarcoma. Most patients (77%) had other metastases at the time of diagnosis of the tumor, but in 11% the breast or axillary lesion was the first presentation. Without a clinical history, non-mammary metastases were difficult to diagnose because the majority of cases presented with a solitary nodule and lacked pathognomonic pathologic features. There were, however, certain recurrent histological findings identified, such as the often relatively well-circumscribed growth pattern of the metastatic lesion surrounded by a fibrous pseudocapsule, and the absence of an in situ carcinoma. Overall, these patients had poor survival; 96% of patients with follow-up available are dead of disease, with a median survival of 15 months after the diagnosis of the breast or axillary lesion. This finding emphasizes the need to accurately identify these tumors as metastases in order to avoid unnecessary procedures and treatments in these patients.Modern Pathology advance online publication, 23 November 2012; doi:10.1038/modpathol.2012.191.
Modern Pathology 11/2012; · 4.79 Impact Factor
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ABSTRACT: BACKGROUND: No consensus exists on the need to excise breast lesions that yield classic lobular carcinoma in situ (LCIS) or atypical lobular hyperplasia (ALH) (known together as classic lobular neoplasia [LN]) as the highest risk lesion at percutaneous core-needle biopsy (CNB). Here, the authors report findings from 72 consecutive lesions with LN at CNB and prospective surgical excision (EXB). METHODS: Lesions that yielded LN at CNB at the authors' center have been referred for EXB since June 2004, regardless of imaging-histologic concordance. A lesion was "concordant" if histologic findings provided sufficient explanation for imaging. An upgrade consisted of ductal carcinoma in situ and/or invasive carcinoma at EXB. Statistical analysis, including 95% confidence intervals (CIs), was performed. RESULTS: Between June 2004 and May 2009, CNB of 85 consecutive lesions yielded LN without other high-risk histologies. Eighty of 85 lesions (94%) underwent prospective EXB. Seventy-two of 85 lesions (90%; 42 LCIS, 30 ALH) had concordant imaging-histologic findings. EXB yielded low-grade carcinoma in 2 of 72 cases (3%; 95% CI, 0%-9%). In both patients, stereotactic, 11-gauge, vacuum-assisted biopsy of calcifications yielded calcifications in benign parenchyma and ALH. CNB results were discordant in 8 of 80 lesions (10%; 4 LCIS, 4 ALH), and EXB yielded cancer in 3 of those 8 lesions (38%; 95% CI, 9%-76%). The upgrade rate was significantly higher for discordant lesions versus concordant lesions (38% vs 3%; P < .01). CONCLUSIONS: Prospective excision of LN identified carcinoma in 3% (95% CI, 0%-9%) of concordant cases versus 38% (95% CI, 9%-76%) of discordant cases. The current data provide an unbiased assessment of the upgrade rate of LN diagnosed at CNB. Cancer 2012. © 2012 American Cancer Society.
Cancer 11/2012; · 4.77 Impact Factor
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ABSTRACT: The objective of our study was to determine the frequency of cancer at surgery in breast lesions yielding papilloma at MRI-guided 9-gauge vacuum-assisted biopsy (VAB) and to determine whether any features are associated with cancer upgrade.
For this study, 1487 MRI-guided vacuum-assisted biopsies performed from January 2004 to March 2011 were reviewed. Lesions yielding papilloma were identified and classified as papilloma with or without atypia. Surgical findings were reviewed to determine the cancer rate. Statistical analysis was performed and 95% CIs were calculated.
Papilloma was identified in 75 of the 1487 MRI-guided vacuum-assisted biopsies (5%). These 75 papillomas occurred in 73 women with a median age of 49 years (age range, 27-70 years). Of the 75 papillomas, 25 (33%) had atypia and 50 (67%) did not on core needle biopsy. Subsequent surgery of 67 of the 75 papillomas (89%) yielded ductal carcinoma in situ (DCIS) in four (6%; 95% CI, 2-15%). Surgery yielded DCIS in two of 23 papillomas with atypia (9%; 95% CI, 1-28%) at MRI-guided VAB and in two of 44 papillomas without atypia (5%; 95% CI, 0.4-16%) at MRI-guided VAB; these cancer rates did not differ significantly (p = 0.6). Postmenopausal status (p = 0.04) and histologic size of less than 0.2 cm (p = 0.04) had a significant association with the cancer upgrade rate.
Papilloma with or without atypia was found in 5% of patients who underwent MRI-guided VAB during the study period. Surgery revealed cancer in 6%. DCIS was found at surgery in 9% of lesions yielding papilloma with atypia versus 5% of lesions yielding papilloma without atypia. For lesions yielding papilloma with or without atypia at MRI-guided VAB, surgical excision is warranted.
American Journal of Roentgenology 10/2012; 199(4):W512-9. · 2.78 Impact Factor
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ABSTRACT: Recent studies have suggested that breast cancer is part of the tumor spectrum in Lynch syndrome (LS). However, the frequency and significance of DNA mismatch repair (MMR) deficiency in breast carcinoma in general is unclear. Some triple-negative breast carcinomas (TNBCs) have morphologic features similar to those described in LS-associated colorectal carcinomas; therefore, we hypothesized that TNBCs might be more likely to have MMR deficiency. In this study, we tested our hypothesis in a series of 226 TNBCs along with a control series of 90 non-triple-negative tumors, utilizing DNA MMR protein immunohistochemistry followed by PCR microsatellite instability testing and MLH1 promoter methylation testing. By immunohistochemistry, we identified 4 triple-negative carcinomas (4/226, 1.8%) showing loss of MMR proteins (3 lost MLH1 and PMS2, and 1 lost MSH2 and MSH6); whereas none of the 90 non-triple-negative carcinomas showed loss of protein. Further testing of the 3 MLH1/PMS2 protein-deficient carcinomas identified 1 tumor showing high-frequency microsatellite instability and MLH1 promoter hypermethylation. All 4 MMR protein-deficient carcinomas were ductal type with high histologic and nuclear grades. Prominent lymphocytic infiltration was noted in 2 tumors. The clinical characteristics and survival outcome varied widely among the 4 patients. In conclusion, our results suggest that DNA MMR deficiency is rare in breast carcinoma, and as such, testing of breast carcinoma for the detection of LS may best be restricted to high-risk individuals only. Our data also suggest that not all MMR protein-deficient breast tumors show microsatellite instability, and MLH1 promoter methylation is the molecular basis for at least a subset of microsatellite instable breast tumors. Although MMR-deficient breast carcinomas share certain morphologic features with the more typical types of LS-associated tumors, better characterization, and a better understanding of their clinical behavior await further analysis with a larger sample size.
The American journal of surgical pathology 09/2012; 36(11):1700-8. · 4.06 Impact Factor
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ABSTRACT: BACKGROUND: In a previous study of the relationship between breast density and primary tumor features, we observed a higher mastectomy rate in patients with extremely dense breasts. Here we examine possible reasons for this finding. METHODS: Data were obtained from a prospectively maintained database of 1,056 invasive breast cancer patients from January 2005 to June 2007. Mammographic density was assigned by Breast Imaging-Reporting and Data System (BI-RADS) classification. Initial and final surgical procedures, and patient and tumor variables were recorded. RESULTS: Breast-conserving surgery (BCS) was attempted in 758 patients (72 %), 385 (51 %) of whom had preoperative magnetic resonance imaging (MRI). Initial BCS was less common among patients with the highest (BI-RADS 4) breast density compared to patients with less-dense breasts (52 vs. 74 %; p < 0.0001), but MRI use was more common (65 vs. 33 %; p < 0.0001). Adjusting for clinical and pathologic variables, patients with the highest breast density had 1.94-times (95 % confidence interval 1.44-2.62; p < 0.0001) the odds of initial mastectomy compared to patients with less-dense breasts. After initial BCS, 387 patients (51 %) had positive shaved margins, 96 (25 %) of whom converted to mastectomy. MRI did not correlate with the rate of positive margins overall or among those with dense breasts. Adjusting for clinical and pathologic variables, density did not predict margin status or conversion to mastectomy. In a multivariate model, age, histologic grade, extensive intraductal component, and multicentricity/multifocality were independently associated with conversion to mastectomy. CONCLUSIONS: Density alone seems to influence the decision to proceed with initial mastectomy. When BCS was attempted, breast density was not associated with positive margins or conversion to mastectomy. A benefit of MRI in decreasing positive margins was not observed. These data do not support the use of breast density as a selection criterion for BCS.
Annals of Surgical Oncology 09/2012; · 4.17 Impact Factor
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Swarnali Acharyya,
Thordur Oskarsson,
Sakari Vanharanta,
Srinivas Malladi,
Juliet Kim,
Patrick G Morris,
Katia Manova-Todorova,
Margaret Leversha,
Nancy Hogg,
Venkatraman E Seshan,
Larry Norton, Edi Brogi,
Joan Massagué
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ABSTRACT: Metastasis and chemoresistance in cancer are linked phenomena, but the molecular basis for this link is unknown. We uncovered a network of paracrine signals between carcinoma, myeloid, and endothelial cells that drives both processes in breast cancer. Cancer cells that overexpress CXCL1 and 2 by transcriptional hyperactivation or 4q21 amplification are primed for survival in metastatic sites. CXCL1/2 attract CD11b(+)Gr1(+) myeloid cells into the tumor, which produce chemokines including S100A8/9 that enhance cancer cell survival. Although chemotherapeutic agents kill cancer cells, these treatments trigger a parallel stromal reaction leading to TNF-α production by endothelial and other stromal cells. TNF-α via NF-kB heightens the CXCL1/2 expression in cancer cells, thus amplifying the CXCL1/2-S100A8/9 loop and causing chemoresistance. CXCR2 blockers break this cycle, augmenting the efficacy of chemotherapy against breast tumors and particularly against metastasis. This network of endothelial-carcinoma-myeloid signaling interactions provides a mechanism linking chemoresistance and metastasis, with opportunities for intervention.
Cell 07/2012; 150(1):165-78. · 32.40 Impact Factor
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ABSTRACT: BRCA1 germline mutation carriers usually develop ER, PR and HER2 negative breast carcinoma. Somatic BRCA1 mutations are rare in sporadic breast cancers, but other mechanisms could impair BRCA1 functions in these tumors, particularly in triple-negative breast carcinomas (TNBCs). Id4, a helix-loop-helix DNA binding factor, blocks BRCA1 gene transcription in vitro and could downregulate BRCA1 in vivo. We compared Id4 immunoreactivity in 101 TNBCs versus 113 non-TNBCs, and correlated the results with tumor morphology and immunoreactivity for CK5/6, CK14, EGFR, and androgen receptor (AR). Id4 was present in 76 out of 101 (75 %) TNBCs: 40 (40 %) TNBCs displayed Id4 positivity in >50 % of neoplastic cells, 23 (23 %) in 5-50 %, and 13 (13 %) in <5 %. In contrast, only 6 (5 %) of 113 non-TNBCs showed focal Id4 positivity, limited to fewer than 5 % of the tumor (p < 0.0001). Id4 expression significantly associated with high histologic grade (p = 0.0002) and mitotic rate (p = 0.006). Id4 decorated all 12 TNBCs with large central acellular zone of necrosis in our series, with positive staining in 10-90 % of the cells. Id4 signal strongly correlated with cytokeratin CK14 reactivity (p < 0.0001), but not with CK5/6 and EGFR. All apocrine carcinomas in our series were positive for AR and most for EGFR, but they were negative for CK5/6, CK14, and Id4, with only two exceptions. Our results document substantial expression of Id4 in most TNBCs, which could result in functional downregulation of BRCA1 pathways in these tumors.
Breast Cancer Research and Treatment 04/2012; 135(1):93-102. · 4.43 Impact Factor
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Alice Y Ho,
Gaorav Gupta,
Tari A King,
Carmen A Perez,
Sujata M Patil,
Katherine H Rogers,
Yong Hannah Wen, Edi Brogi,
Monica Morrow,
Clifford A Hudis,
Tiffany Traina,
Beryl McCormick,
Simon N Powell,
Mark E Robson
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ABSTRACT: The authors evaluated the clinical characteristics, natural history, and outcomes of patients who had ≤1 cm, lymph node-negative, triple-negative breast cancer (TNBC).
After excluding patients who had received neoadjuvant therapy, 1022 patients with TNBC who underwent definitive breast surgery during 1999 to 2006 were identified from an institutional database. In total, 194 who had lymph node-negative tumors that measured ≤1 cm comprised the study population. Clinical data were abstracted, and survival outcomes were analyzed.
The median follow-up was 73 months (range, 5-143 months). The median age at diagnosis was 55.5 years (range, 27-84 years). Tumor (T) classification was microscopic (T1mic) in 16 patients (8.2%), T1a in 49 patients (25.3%), and T1b in 129 patients (66.5%). Most tumors were poorly differentiated (n = 142; 73%), lacked lymphovascular invasion (n = 170; 87.6%), and were detected by screening (n = 134; 69%). In total, 129 patients (66.5%) underwent breast-conserving surgery, and 65 patients (33.5%) underwent mastectomy. One hundred thirteen patients (58%) received adjuvant chemotherapy, and 123 patients (63%) received whole-breast radiation. The patients who received chemotherapy had more adverse clinical and disease features (younger age, T1b tumor, poor tumor grade; all P < .05). Results from testing for the breast cancer (BRCA) susceptibility gene were available for 49 women: 19 women had BRCA1 mutations, 7 women had BRCA2 mutations, and 23 women had no mutations. For the entire group, the 5-year local recurrence-free survival rate was 95%, and the 5-year distant metastasis-free survival rate was 95%. There was no difference between patients with T1mic/T1a tumors and patients with T1b tumors in the distant recurrence rate (94.5% vs 95.5%, respectively; P = .81) or in the receipt of chemotherapy (95.9% vs 94.5%, respectively; P = .63).
Excellent 5-year locoregional and distant control rates were achievable in patients with TNBC who had tumors ≤1.0 cm, 58% of whom received chemotherapy. These results identified a group of patients with TNBC who had favorable outcomes after early detection and multimodality treatment. Cancer 2012. © 2012 American Cancer Society.
Cancer 03/2012; 118(20):4944-52. · 4.77 Impact Factor
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ABSTRACT: E-cadherin (E-CD) inactivation with loss of E-CD-mediated cell adhesion is the hallmark of lesions of the lobular phenotype. E-CD is typically absent by immunohistochemistry in both lobular carcinoma in situ (LCIS) and invasive lobular lesions, suggesting it occurs early in the neoplastic process. In laboratory models, downstream post-transcriptional modifiers such as TWIST and SNAIL contribute to the dissociation of the intracellular component of the cadherin-catenin complex (CCC), resulting in tumor progression and invasion. We hypothesized that complete CCC dissociation may play a role in lobular neoplasia progression. Here we explore the relationship between loss of E-CD and dissociation of the CCC in pure LCIS and LCIS associated with invasive cancer. Fresh-frozen tissues were obtained from 36 patients undergoing mastectomy for pure LCIS (n = 11), LCIS with ILC (n = 18) or LCIS with IDC (n = 7). Individual lesions were subject to laser-capture microdissection and gene-expression analysis (Affymetrix HG-U133A 2.0). Immunohistochemistry for ER,PR,HER2, E-CD,N-CD,α-,β-, and phosphoβ-catenin, TWIST, and SNAIL were evaluated in normal, in situ, and invasive components from matched formalin-fixed paraffin-embedded samples (n = 36). CCC-dissociation was defined as negative membranous E-CD, α- and β-catenin expression. E-CD was negative in all LCIS and ILC lesions, and positive in all normal and IDC lesions. Membranous α and β-catenin expressions decreased with the transition from LCIS to ILC (pure LCIS 82%; LCIS w/ILC 28%; ILC 0%), while TWIST expression increased (pure LCIS low; LCIS w/ILC moderate; ILC high). Gene expression paralleled IHC-staining patterns with a stepwise downregulation of E-CD, α and β-catenins from normal to LCIS to invasive lesions, and increasing expression of TWIST from normal to LCIS to ILC. Loss of E-CD expression is an early event in lobular neoplasia. Decreasing membranous catenin expression in tandem with increasing levels of TWIST across the spectrum of lobular lesions suggests that CCC dissociation is a progressive process.
Breast Cancer Research and Treatment 11/2011; 132(2):641-52. · 4.43 Impact Factor
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ABSTRACT: The increasingly widespread use of immunohistochemistry in the detection of DNA mismatch repair proteins has led to the observation of various unusual tumor types that occur in Lynch syndrome and exhibit mismatch repair protein deficiency. Understanding the clinical significance of such unusual tumors has become increasingly desirable. Here, we report a case of 2 synchronous breast cancers occurring in a 74-year-old woman who carried a deleterious germline mutation in MSH2 and who survived an endometrial and a colonic carcinoma. Both breast cancers were of lobular type with similar expression patterns for estrogen receptor, progesterone receptor, and Her2/neu. However, the 2 cancers differed in other characteristics. One tumor showed a solid alveolar histologic pattern with prominent tumor-infiltrating lymphocytes and loss of MSH2 and MSH6 protein on immunohistochemical staining. In contrast, the other tumor was of classic type with no apparent lymphocytic infiltration and no loss of mismatch repair protein. Such a case carries practical implications as it suggests that certain breast cancers may serve as tissue samples for the detection of mismatch repair deficiency in families at high risk for Lynch syndrome, thus expanding the test sample repertoire for genetic workup in these families. Furthermore, the case exemplifies the complexity of tumorigenesis in Lynch syndrome patients. The observation that, of the 2 breast cancers, increased tumor-infiltrating lymphocytes were present only in the tumor that showed mismatch repair protein abnormality is in keeping with what has been observed in the colon and other sites. Such persistent genotype-phenotype correlation across different organs affords the promise that molecular classification may allow identification of biologically distinct tumor subsets beyond the confines of the tumor's primary anatomic location.
The American journal of surgical pathology 11/2011; 35(11):1743-8. · 4.06 Impact Factor
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ABSTRACT: We report that breast cancer cells that infiltrate the lungs support their own metastasis-initiating ability by expressing tenascin C (TNC). We find that the expression of TNC, an extracellular matrix protein of stem cell niches, is associated with the aggressiveness of pulmonary metastasis. Cancer cell-derived TNC promotes the survival and outgrowth of pulmonary micrometastases. TNC enhances the expression of stem cell signaling components, musashi homolog 1 (MSI1) and leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5). MSI1 is a positive regulator of NOTCH signaling, whereas LGR5 is a target gene of the WNT pathway. TNC modulation of stem cell signaling occurs without affecting the expression of transcriptional enforcers of the stem cell phenotype and pluripotency, namely nanog homeobox (NANOG), POU class 5 homeobox 1 (POU5F1), also known as OCT4, and SRY-box 2 (SOX2). TNC protects MSI1-dependent NOTCH signaling from inhibition by signal transducer and activator of transcription 5 (STAT5), and selectively enhances the expression of LGR5 as a WNT target gene. Cancer cell-derived TNC remains essential for metastasis outgrowth until the tumor stroma takes over as a source of TNC. These findings link TNC to pathways that support the fitness of metastasis-initiating breast cancer cells and highlight the relevance of TNC as an extracellular matrix component of the metastatic niche.
Nature medicine 06/2011; 17(7):867-74. · 27.14 Impact Factor
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ABSTRACT: Perioperative window trials provide an opportunity to obtain intact tumor samples at two different time-points for evaluation of potential surrogate biomarkers. We report results of a pilot trial designed to determine if treatment-mediated changes in gene expression can be detected in formalin-fixed paraffin-embedded (FFPE) samples after 10-d exposure to anastrozole in estrogen receptor (ER)-positive breast cancer compared with untreated controls.
Paired tumor samples (biopsy, surgical) were obtained from 26 postmenopausal women with ER-positive breast cancer. Patients were assigned anastrozole (1 mg/d) for 10 d immediately prior to surgery (13 cases) or no treatment (13 controls). Five hundred two cancer-related genes were examined by the Illumina cDNA-mediated annealing, selection, extension, and ligation, FFPE cDNA array (moderated t-test, P ≤ 0.005). Surrogate biomarkers reflecting changes in gene expression were examined by immunohistochemistry (Wilcoxon rank-based test, P < 0.05).
Sufficient RNA was available from 19 paired samples (8 controls, 11 cases). Frozen tissue and FFPE showed good correlation (r = 0.82). Within each group, 18 genes, reflecting roles in proliferation, angiogenesis, and apoptosis, showed differential expression from biopsy to surgery (P < 0.005). Estrogen-related genes were dysregulated in the treated group only. A reduction in Ki-67 was observed in 7 (54%) treated cases and in 1 (7.7%) control patient.
10-d exposure to anastrozole resulted in dysregulation of 18/502 cancer-related genes, and Ki-67 was reduced in 54% of cases. FFPE samples demonstrated good correlation with frozen samples. However, changes in gene expression and increased Ki-67 in the control group suggest local effects of wound healing may represent a confounding factor in the interpretation of perioperative window trials.
Journal of Surgical Research 06/2011; 176(1):121-32. · 2.25 Impact Factor
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Patrick G Morris,
Clifford A Hudis,
Dilip Giri,
Monica Morrow,
Domenick J Falcone,
Xi Kathy Zhou,
Baoheng Du, Edi Brogi,
Carolyn B Crawford,
Levy Kopelovich,
Kotha Subbaramaiah,
Andrew J Dannenberg
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ABSTRACT: Obesity is a risk factor for the development of hormone receptor-positive breast cancer in postmenopausal women and has been associated with an increased risk of recurrence and reduced survival. In humans, obesity causes subclinical inflammation in visceral and subcutaneous adipose tissue, characterized by necrotic adipocytes surrounded by macrophages forming crown-like structures (CLS). Recently, we found increased numbers of CLS, activation of the NF-κB transcription factor, and elevated aromatase levels and activity in the mammary glands of obese mice. These preclinical findings raised the possibility that the obesity → inflammation axis is important for the development and progression of breast cancer. Here, our main objective was to determine if the findings in mouse models of obesity translated to women. Breast tissue was obtained from 30 women who underwent breast surgery. CLS of the breast (CLS-B) was found in nearly 50% (14 of 30) of patient samples. The severity of breast inflammation, defined as the CLS-B index, correlated with both body mass index (P < 0.001) and adipocyte size (P = 0.01). Increased NF-κB binding activity and elevated aromatase expression and activity were found in the inflamed breast tissue of overweight and obese women. Collectively, our results suggest that the obesity → inflammation → aromatase axis is present in the breast tissue of most overweight and obese women. The presence of CLS-B may be a biomarker of increased breast cancer risk or poor prognosis.
Cancer Prevention Research 06/2011; 4(7):1021-9. · 4.91 Impact Factor
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ABSTRACT: Intracystic papillary carcinoma (IPC) is regarded as an intraductal neoplasm, but recent evidence suggests that it could be invasive, as it often lacks myoepithelial lining. We evaluated myoepithelial cells and collagen IV, a basement membrane component, in 40 IPCs from 39 (35 female and 4 male) patients and assessed their clinical management and follow-up. The mean patient age at diagnosis was 68 years, and the mean tumor size was 1.8 cm. Thirteen cases were pure IPC, 8 cases were IPC with or without microinvasion, and 19 cases were IPC with invasive carcinoma (IPC+IC), including 1 mucinous and 1 cribriform carcinoma. Ductal carcinoma in situ associated more often with IPC+IC (84.2%) than with pure IPC (61.5%) or IPC with or without microinvasion (62.5%). Myoepithelial cells were completely absent in 33 of 40 (82.5%) IPCs, and only focal in the remaining 7 of 40 cases (17.5%). Collagen IV lining was discontinuous in most cases (89%). All tumors were estrogen receptor positive and HER2 negative; most were progesterone receptor positive (93%). Eleven patients underwent mastectomy and 28 lumpectomy; 3 of 27 (11%) patients had lymph node involvement. Fourteen of all patients treated with breast conservation received radiation, 10 hormonal treatment, and none chemotherapy. Four patients treated conservatively (3 with pure IPC and 1 with IPC+IC) recurred locally, including one who later developed bone metastasis. We conclude that IPC constitutes a spectrum of intraductal and IC, with predominance of the latter. IPC rarely involves lymph nodes and carries very good prognosis, but can recur locally. This type of tumor is strongly estrogen receptor positive and hormonal therapy should be pursued for its management, whereas the benefit of radiation after lumpectomy remains unclear.
The American journal of surgical pathology 11/2010; 35(1):1-14. · 4.06 Impact Factor
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ABSTRACT: Knowledge of estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor-2 (HER2) status is necessary for determining the optimal treatment of breast cancer patients. At the same time, the discordance between marker profiles (ER/PR and HER2) of primary and metastatic breast cancer is well documented. Whether discordant cases are secondary to "clonal selection" in the face of targeted anti-estrogen or anti-HER2 therapy or whether they are a laboratory artifact is still debated; both scenarios are likely. This article outlines current modalities for ER, PR, and HER2 testing in primary breast carcinoma and its metastases and reviews prospective and retrospective studies that have addressed these issues, as well as recent advances in the field.
Current Oncology Reports 10/2010; 13(1):17-25. · 2.55 Impact Factor
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ABSTRACT: While the mortality associated with ductal carcinoma in situ (DCIS) is minimal, the risk of ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery (BCS) is relatively high. Radiation therapy (RT) and antiestrogen agents reduce the risk of IBTR and are considered standard treatment options after BCS. However, they have never been proven to improve survival, and in themselves carry rare but serious risks. Individualized estimation of IBTR risk would assist in decision making regarding the various treatment options for women with DCIS.
From 1991 to 2006, 1,868 consecutive patients treated with BCS for DCIS were identified. A multivariate Cox proportional hazards model was constructed using the 1,681 in whom data were complete. Ten clinical, pathologic, and treatment variables were built into a nomogram estimating probability of IBTR at 5 and 10 years after BCS. The model was validated for discrimination and calibration using bootstrap resampling.
The DCIS nomogram for prediction of 5- and 10-year IBTR probabilities demonstrated good calibration and discrimination, with a concordance index of 0.704 (bootstrap corrected, 0.688) and a concordance probability estimate of 0.686. Factors with the greatest influence on risk of IBTR in the model included adjuvant RT or endocrine therapy, age, margin status, number of excisions, and treatment time period.
The DCIS nomogram integrates 10 clinicopathologic variables to provide an individualized risk estimate of IBTR in a woman with DCIS treated with BCS. This tool may assist in individual decision making regarding various treatment options and help avoid over- and undertreatment of noninvasive breast cancer.
Journal of Clinical Oncology 08/2010; 28(23):3762-9. · 18.37 Impact Factor
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ABSTRACT: The occurrence of benign epithelial inclusions in lymph nodes is well documented and can sometimes mimic metastatic carcinoma. Benign müllerian inclusions, such as endometriosis and endosalpingiosis, are common in pelvic and para-aortic lymph nodes, but their presence in supradiaphragmatic lymph nodes is a rare event. We report our experience with 3 patients found to have endosalpingiosis in axillary sentinel lymph nodes obtained for staging of breast carcinoma. All patients were postmenopausal women, with age ranging between 65 and 75 years. Endosalpingiosis involved a single lymph node in 1 patient, and 2 nodes in each of the other 2; it was present in the lymph node capsule in all the 3 cases, with few glands scattered within the lymph node parenchyma in 2 of the patients. The glands contained ciliated and intercalated peg cells, had no periglandular endometrial-type stroma, and showed no atypia or mitotic activity. The epithelium demonstrated positive nuclear immunoreactivity for WT1 and PAX8, and was devoid of myoepithelium or basement membrane. Endosalpingiosis had been misinterpreted as metastatic carcinoma at another hospital in 1 of the 3 patients, with subsequent dissection of 19 additional benign axillary lymph nodes. We conclude that endosalpingiosis can involve axillary lymph nodes and closely simulate metastatic mammary carcinoma. Morphologic identification of ciliated cells and "peg" cells is most helpful to recognize this benign inclusion, and positive immunoreactivity for WT1 and/or PAX8 can be used to support the diagnosis.
The American journal of surgical pathology 08/2010; 34(8):1211-6. · 4.06 Impact Factor
