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Background: In the evaluation of PD-L1 expression to select patients for anti-PD-1/PD-L1 treatment, uniform guidelines that account for different immunohistochemistry assays, different cell types and different cutoff values across tumor types are lacking. Data on how different scoring methods compare in breast cancer are scant., Methods: Using FDA-approved 22C3 diagnostic immunohistochemistry assay, we retrospectively evaluated PD-L1 expression in 496 primary invasive breast tumors that were not exposed to anti-PD-1/PD-L1 treatment and compared three scoring methods (TC: invasive tumor cells; IC: tumor-infiltrating immune cells; TCIC: a combination of tumor cells and immune cells) in expression frequency and association with clinicopathologic factors., Results: In the entire cohort, positive PD-L1 expression was observed in 20% of patients by TCIC, 16% by IC, and 10% by TC, with a concordance of 87% between the three methods. In the triple-negative breast cancer patients, positive PD-L1 expression was observed in 35% by TCIC, 31% by IC, and 16% by TC, with a concordance of 76%. Associations between PD-L1 and clinicopathologic factors were investigated according to receptor groups and whether the patients had received neoadjuvant chemotherapy. The three scoring methods showed differences in their associations with clinicopathologic factors in all subgroups studied. Positive PD-L1 expression by IC was significantly associated with worse overall survival in patients with neoadjuvant chemotherapy and showed a trend for worse overall survival and distant metastasis-free survival in triple-negative patients with neoadjuvant chemotherapy. Positive PD-L1 expression by TCIC and TC also showed trends for worse survival in different subgroups., Conclusions: Our findings indicate that the three scoring methods with a 1% cutoff are different in their sensitivity for PD-L1 expression and their associations with clinicopathologic factors. Scoring by TCIC is the most sensitive way to identify PD-L1-positive breast cancer by immunohistochemistry. As a prognostic marker, our study suggests that PD-L1 is associated with worse clinical outcome, most often shown by the IC score; however, the other scores may also have clinical implications in some subgroups. Large clinical trials are needed to test the similarities and differences of these scoring methods for their predictive values in anti-PD-1/PD-L1 therapy.

Objective: Different molecular subtypes of triple-negative breast cancer (TNBC) have previously been identified through analysis of gene expression profiles. The luminal androgen receptor (LAR) subtype has been shown to have a lower rate of pathologic complete response to neoadjuvant chemotherapy than other TNBC subtypes. The purpose of this study was to determine if the imaging features of TNBCs differ by AR (androgen receptor) status, which is a surrogate immunohistochemical (IHC) marker for the chemoresistant LAR subtype of TNBC., Materials and Methods: This sub-study was part of a clinical trial in patients with stage I-III TNBC who were prospectively monitored for response while receiving neoadjuvant systemic therapy (NAST) at a single comprehensive cancer center. This interim imaging analysis included 144 patients with known AR status measured by IHC. AR-positive (AR+) tumors were defined as those in which at least 10% of tumor cells had positive nuclear AR staining. Two experienced, fellowship-trained breast radiologists who were blinded to the IHC results retrospectively reviewed and reached consensus on all imaging studies for the index lesion (i.e., mammogram, ultrasound, and breast magnetic resonance imaging). The index lesion for each patient was reviewed and described according to the fifth edition of the Breast Imaging Reporting and Data System lexicon. Logistic regression modeling was used to identify imaging features predictive of AR status. p ≤ 0.05 was considered statistically significant., Results: Univariate logistic regression models for AR status showed that AR+ TNBC was significantly associated with heterogeneously dense breast composition on mammography (p = 0.02), mass with calcifications (p = 0.05), irregular mass shape on mammography (p = 0.03), and irregular mass shape on sonography (p = 0.003). Multivariate logistic regression models for AR status showed that AR+ TNBC was significantly associated with heterogeneously dense breast composition on mammography (p = 0.01), high mass density on mammography (p = 0.003), and irregular mass shape on sonography (p = 0.0004)., Conclusion: The imaging features of TNBCs differ by AR status. Multimodality breast imaging may help identify the LAR subtype of TNBC, which has been shown to be a subtype that is relatively resistant to neoadjuvant chemotherapy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Metaplastic breast cancer is one of the most therapeutically challenging forms of breast cancer because of its highly heterogeneous and chemoresistant nature. We have previously demonstrated that ribosomal protein L39 (RPL39) and its gain-of-function mutation A14V have oncogenic activity in triple-negative breast cancer and this activity may be mediated through inducible nitric oxide synthase (iNOS). The function of RPL39 and A14V in other breast cancer subtypes is currently unknown. The objective of this study was to determine the role and mechanism of action of RPL39 in metaplastic breast cancer., Methods: Both competitive allele-specific and droplet digital polymerase chain reaction were used to determine the RPL39 A14V mutation rate in metaplastic breast cancer patient samples. The impact of RPL39 and iNOS expression on patient overall survival was estimated using the Kaplan-Meier method. Co-immunoprecipitation and immunoblot analyses were used for mechanistic evaluation of RPL39., Results: The RPL39 A14V mutation rate was 97.5% (39/40 tumor samples). High RPL39 (hazard ratio = 0.71, 95% confidence interval = 0.55 to 0.91, P = 006) and iNOS expression (P = 003) were associated with reduced patient overall survival. iNOS inhibition with the pan-NOS inhibitor N G -methyl-L-arginine acetate decreased in vitro proliferation and migration, in vivo tumor growth in both BCM-4664 and BCM-3807 patient-derived xenograft models (P = 04 and P = 02, respectively), and in vitro and in vivo chemoresistance. Mechanistically, RPL39 mediated its cancer-promoting actions through iNOS signaling, which was driven by the RNA editing enzyme adenosine deaminase acting on RNA 1., Conclusion: NOS inhibitors and RNA editing modulators may offer novel treatment options for metaplastic breast cancer., (© The Author 2016. Published by Oxford University Press.)

Radioactive seed localization is a new procedure for localizing breast lesions that has several advantages over the standard wire-localization procedure. It is reported to be safe for both patients and medical personnel. Although it is theoretically possible to transect the titanium-encapsulated seed while processing the breast specimen in the pathology laboratory, the likelihood of such an event is thought to be exceedingly low. In fact, there are no previous reports of such an event in the literature to date. We recently encountered 2 cases in which a radioactive seed was inadvertently transected while slicing a breast specimen at the grossing bench. In this report, we describe each case and offer recommendations for minimizing radioactive exposure to personnel and for preventing radioactive contamination of laboratory equipment.

Background: Galectin-3 (Gal3) plays diverse roles in cancer initiation, progression, and drug resistance depending on tumor type characteristics that are also associated with cancer stem cells (CSCs). Recurrence of breast carcinomas may be attributed to the presence of breast CSCs (BCSCs). BCSCs exist in mesenchymal-like or epithelial-like states and the transition between these states endows BCSCs with the capacity for tumor progression. The discovery of a feedback loop with galectins during epithelial-to-mesenchymal transition (EMT) prompted us to investigate its role in breast cancer stemness., Method: To elucidate the role of Gal3 in BCSCs, we performed various in vitro and in vivo studies such as sphere-formation assays, Western blotting, flow cytometric apoptosis assays, and limited dilution xenotransplant models. Histological staining for Gal3 in tissue microarrays of breast cancer patients was performed to analyze the relationship of clinical outcome and Gal3 expression., Results: Here, we show in a cohort of 87 node-positive breast cancer patients treated with doxorubicin-based chemotherapy that low Gal3 was associated with increased lymphovascular invasion and reduced overall survival. Analysis of in vitro BCSC models demonstrated that Gal3 knockdown by small hairpin RNA (shRNA) interference in epithelial-like mammary spheres leads to EMT, increased sphere-formation ability, drug-resistance, and heightened aldefluor activity. Furthermore, Gal3 negative BCSCs were associated with enhanced tumorigenicity in orthotopic mouse models., Conclusions: Thus, in at least some breast cancers, loss of Gal3 might be associated with EMT and cancer stemness-associated traits, predicts poor response to chemotherapy, and poor prognosis.

Purpose: Placing clips in nodes with biopsy-confirmed metastasis before initiating neoadjuvant therapy allows for evaluation of response in breast cancer. Our goal was to determine if pathologic changes in clipped nodes reflect the status of the nodal basin and if targeted axillary dissection (TAD), which includes sentinel lymph node dissection (SLND) and selective localization and removal of clipped nodes, improves the false-negative rate (FNR) compared with SLND alone., Methods: A prospective study of patients with biopsy-confirmed nodal metastases with a clip placed in the sampled node was performed. After neoadjuvant therapy, patients underwent axillary surgery and the pathology of the clipped node was compared with other nodes. Patients undergoing TAD had SLND and selective removal of the clipped node using iodine-125 seed localization. The FNR was determined in patients undergoing complete axillary lymphadenectomy (ALND)., Results: Of 208 patients enrolled in this study, 191 underwent ALND, with residual disease identified in 120 (63%). The clipped node revealed metastases in 115 patients, resulting in an FNR of 4.2% (95% CI, 1.4 to 9.5) for the clipped node. In patients undergoing SLND and ALND (n = 118), the FNR was 10.1% (95% CI, 4.2 to 19.8), which included seven false-negative events in 69 patients with residual disease. Adding evaluation of the clipped node reduced the FNR to 1.4% (95% CI, 0.03 to 7.3; P = .03). The clipped node was not retrieved as an SLN in 23% (31 of 134) of patients, including six with negative SLNs but metastasis in the clipped node. TAD followed by ALND was performed in 85 patients, with an FNR of 2.0% (1 of 50; 95% CI, 0.05 to 10.7)., Conclusion: Marking nodes with biopsy-confirmed metastatic disease allows for selective removal and improves pathologic evaluation for residual nodal disease after chemotherapy., (© 2016 by American Society of Clinical Oncology.)

Aims: We have demonstrated previously that gross cystic disease fluid protein-15 (GCDFP-15) and mammaglobin A (MAM) are of limited utility in triple-negative breast cancer (TNBC). GATA-binding protein 3 (GATA-3) is an emerging breast-associated immunohistochemical (IHC) marker with limited data in TNBC. Here, we examined GATA-3 expression in TNBC in comparison with GCDFP-15 and MAM., Methods and Results: We studied GATA-3, GCDFP-15 and MAM IHC expression in 62 primary and 68 metastatic TNBCs. In primary TNBCs, GATA-3 staining was observed in 25 cases (40%), including 16 cases that were negative for GCDFP-15 and MAM. In metastatic TNBCs, GATA-3 staining was observed in 30 cases (44%), including 16 cases that were negative for GCDFP-15 and MAM. The expression frequency of any of the markers was 56% in primary and 62% in metastatic TNBCs. However, when focal staining was excluded, the expression frequency of any marker dropped to 31% and 44%, respectively., Conclusion: GATA-3 is expressed at a higher frequency by IHC in TNBC compared to GCDFP-15 and MAM, although the tissue specificity of the latter markers may be superior. When evaluating a triple-negative tumour, including GATA-3 in a panel of markers may increase the diagnostic accuracy for tissue origin in the appropriate clinical setting., (© 2015 John Wiley & Sons Ltd.)

Background: The management of benign papilloma (BP) without atypia identified on breast core needle biopsy (CNB) is controversial. In this study, we determined the upgrade rate to malignancy for BPs without atypia diagnosed on CNB and whether there are factors associated with upgrade., Methods: Through our pathology database search, we studied 80 BPs without atypia identified on CNB from 80 patients from 1997 to 2010, including 30 lesions that had undergone excision and 50 lesions that had undergone ≥ 2 years of radiologic follow-up. Associations between surgery or upgrade to malignancy and clinical, radiologic, and pathologic features were analyzed., Results: Mass lesions, lesions sampled by ultrasound-guided CNB, and palpable lesions were associated with surgical excision. All 3 upgraded cases were mass lesions sampled by ultrasound-guided CNB. None of the lesions with radiologic follow-up only were upgraded to malignancy. The overall upgrade rate was 3.8%. None of the clinical, radiologic, or histologic features were predictive of upgrade., Conclusion: Because the majority of patients can be safely managed with radiologic surveillance, a selective approach for surgical excision is recommended. Our proposed criteria for excision include pathologic/radiologic discordance or sampling by ultrasound-guided CNB without vacuum assistance when the patient is symptomatic or lesion size is ≥ 1.5 cm., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Studies evaluating the biological behavior of primary squamous cell carcinoma (SCC) of the breast have yielded inconsistent results, perhaps in part because most studies have not taken into consideration specific histologic subtypes. We identified 21 cases of primary SCC of the breast diagnosed between the years 1985 and 2010 and analyzed the association between particular histologic features and disease outcome. Most tumors (17/21) were moderately or poorly differentiated, and most had a high nuclear grade (15/21). Five-year locoregional recurrence-free survival (LRRFS) for all patients was 54%±12%, and 5-year overall survival (OS) was 51%±13%. The only statistically significant feature associated with LRRFS was the presence of a spindle cell component in the tumor. Patients with >10% spindle cell component had decreased LRRFS (log rank; P=0.006). The only statistically significant features associated with OS were patient age and tumor keratinization. Patients more than 60 years of age had decreased OS (log rank; P=0.035), and patients with tumors having at least focal keratinization had improved OS (log rank; P=0.027). Lymph node status, mitotic rate, tumor necrosis, cystic degeneration, clear cell change, and the presence of a pleomorphic component or associated ductal carcinoma in situ were not associated with either LRRFS or OS. In summary, primary SCC of the breast tends to be aggressive, particularly in patients more than 60 years of age and those with tumors having >10% spindle cell component. The presence of at least focal keratinization, however, is associated with significantly improved OS.

Aims:   In addition to oestrogen and progesterone receptors, gross cystic disease fluid protein-15 (GCDFP-15) and mammaglobin A (MAM) are the most common markers used to identify breast origin by immunohistochemistry. GCDFP-15 expression has been reported in approximately 60% of breast carcinomas and MAM expression in approximately 80%. Data on their expression in triple-negative breast cancer (TNBC) are very limited. The aim of this study was to examine the expression of these markers in TNBC to determine their utility in pathological diagnosis., Methods and Results:   We studied the immunohistochemical (IHC) expression of GCDFP-15 and MAM in 63 primary and 118 metastatic TNBCs. GCDFP-15 staining was present in 14% of primary and 21% of metastatic TNBCs. MAM staining was present in 25% of primary and 41% of metastatic TNBCs. The frequency of expression of GCDFP-15 and/or MAM was 30% in primary and 43% in metastatic TNBCs, and many positive tumours had only focal staining., Conclusions:   Staining for GCDFP-15 and/or MAM in triple-negative carcinomas helps to confirm breast origin, but most tumours in this subgroup of breast carcinomas lack expression of either marker., (© 2012 Blackwell Publishing Limited.)

BRCA testing of patients with breast cancer considered at high risk for having a germ-line BRCA mutation usually consists of comprehensive mutational analysis of both BRCA1 and BRCA2. A more cost-effective strategy of triaging patients for analysis of a single gene could be adopted if tissue-based predictors indicated a high risk specifically for either BRCA1 or BRCA2. To identify potentially useful tissue-based predictors of BRCA mutation status in breast cancer, we evaluated multiple histopathologic features of invasive breast carcinoma on archival tissue sections from 196 high-risk patients who had undergone BRCA testing, and we analyzed which individual or combination of features was most associated with BRCA mutations. Of the 196 patients with invasive breast carcinoma, there were 44 (22%) with a deleterious BRCA1 mutation and 27 (14%) with a deleterious BRCA2 mutation. For patients with available untreated surgical resection specimens for evaluation (n=172), estrogen receptor-positive phenotype was inversely associated with the presence of a BRCA1 mutation (odds ratio, 0.243; 95% confidence interval, 0.070-0.840; P=.025), and high mitotic activity (≥25 mitotic figures per 10 high-power fields) was directly associated with the presence of a BRCA1 mutation (odds ratio, 4.222; 95% confidence interval, 1.353-13.18; P=.013). The combination of estrogen receptor-negative phenotype and high mitotic rate had high specificity (99%; 95% confidence interval, 95%-100%) but low sensitivity (43%; 95% confidence interval, 26%-61%) for identifying a deleterious BRCA1 mutation. In patients with breast cancer at high risk for carrying a BRCA mutation, those with estrogen receptor-negative phenotype and high mitotic rate could be triaged specifically for BRCA1 testing instead of initially performing mutational analysis for both BRCA1 and BRCA2., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Mammary Paget disease (MPD) is considered an intraepidermal manifestation of an underlying mammary carcinoma. In contrast to extramammary Paget disease, invasion of mammary Paget cells into the dermis (invMPD) has not been reported, except for 2 cases described in Rosen's textbook. Our study was designed to identify the presence of dermal invasion of mammary Paget cells and characterize the associated clinicopathologic features. Slides from 146 MPD patients were retrieved. Six cases of invMPD were identified. One case of invMPD was not associated with an underlying breast cancer, 1 was associated with invasive ductal carcinoma (IDC), 1 with ductal carcinoma in situ (DCIS) with microinvasion, and 3 with DCIS only. The underlying breast carcinomas was separate from the area of invMPD. The depth of invasion, measured from the dermal-epidermal junction to the focus of deepest invasion, ranged from 0.02 to 0.9 mm. The horizontal extent ranged from 0.01 to 4.0 mm. Lymph node with isolated tumor clusters was present in case 1, which had no underlying carcinoma but had the greatest extent of invasion, and in case 3, which had DCIS with microinvasion. One patient (case 1) died of unrelated causes 2 years later, and the remaining patients were alive without disease at last follow-up. In summary, we describe 6 cases of MPD with invasion of Paget cells into the dermis and provide histopathologic criteria for the diagnosis of this rare and underrecognized entity. Further studies are required to determine whether invasion in MPD has clinical significance.

Objective: This purpose of this study is to describe the imaging findings in patients who presented with a diagnosis of primary breast sarcoma., Materials and Methods: A search was performed of the pathology database at a single institution for patients with a histopathologic diagnosis of primary breast sarcoma or pure sarcomatoid carcinoma and who underwent preoperative mammography, sonography, or MRI. Patients with malignant phyllodes tumors were excluded. The imaging studies were retrospectively reviewed using the American College of Radiology BI-RADS lexicon. We documented clinical presentation, histopathologic characteristics, axillary nodal status, and the presence of distant metastases., Results: Twenty-four women were included in the study; their mean age was 56 years (range, 21-86 years), and the mean tumor size was 6.1 cm (range, 0.9-15 cm). Only one tumor was identified in each patient. The predominant mammographic finding was a noncalcified oval mass with indistinct (9/14 [64%]) margins. Sonography most commonly revealed an oval (19/22 [86%]) solid mass with indistinct margins (17/22 [77%]). The masses were frequently hypoechoic (18/21 [86%]) and hypervascular (17/20 [85%]) and had posterior acoustic enhancement (13/21 [62%]). MRI showed a round or oval T2-hyperintense mass with irregular margins in four of five (80%) patients, and inhomogeneous enhancement was most common (3/4 [75%])., Conclusion: Primary breast sarcoma has imaging features that are not typically seen in infiltrating ductal carcinoma. A large oval hypervascular mass with indistinct margins should raise the suspicion for a primary breast sarcoma and prompt biopsy.

Metaplastic sarcomatoid carcinoma (MSC) of the breast is usually triple receptor (ER, PR, and HER2) negative and is not currently recognized as being more aggressive than other triple receptor-negative breast cancers. We reviewed archival tissue sections from surgical resection specimens of 47 patients with MSC of the breast and evaluated the association between various clinicopathologic features and patient survival. We also evaluated the clinical outcome of MSC patients compared to a control group of patients with triple receptor-negative invasive breast carcinoma matched for patient age, clinical stage, tumor grade, treatment with chemotherapy, and treatment with radiation therapy. Factors independently associated with decreased disease-free survival among patients with stage I-III MSC of the breast were patient age > 50 years (P = 0.029) and the presence of nodal macrometastases (P = 0.003). In early-stage (stage I-II) MSC, decreased disease-free survival was observed for patients with a sarcomatoid component comprising ≥ 95% of the tumor (P = 0.032), but tumor size was the only independent adverse prognostic factor in early-stage patients (P = 0.043). Compared to a control group of triple receptor-negative patients, patients with stage I-III MSC had decreased disease-free survival (two-sided log rank, P = 0.018). Five-year disease-free survival was 44 ± 8% versus 74 ± 7% for patients with MSC versus triple receptor-negative breast cancer, respectively. We conclude that MSC of the breast appears more aggressive than other triple receptor-negative breast cancers.

Myofibroblastoma of the breast is an unusual benign spindle cell tumor composed of cells with histologic, immunohistochemical, and ultrastructural features of myofibroblasts. In addition to the classic form, a few variants of myofibroblastoma have been described. Recognition of these variants is important to prevent overdiagnosis of a malignant lesion, especially on core biopsy. Three variants that can cause particular confusion on core biopsy are the lipomatous, infiltrative, and epithelioid variants of myofibroblastoma. Thus far, there have been only a few reports of these variants in the English literature. We report a rare case of a lipomatous variant of myofibroblastoma with an epithelioid cell component and discuss the differential diagnosis and potential diagnostic pitfalls., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Aims: The aim of this study was to review the clinicopathological characteristics of neuroendocrine tumours (NETs) metastasizing to the breast, in order to identify features that could be useful in distinguishing these metastatic lesions from primary breast neoplasms., Methods and Results: Eighteen metastatic NETs in the breast were identified from two large hospitals over a 15-year period. Eleven (62%) tumours originated in the gastrointestinal tract, 5 (28%) originated in the lung, and the other two were of indeterminate origin. Eight (44%) cases were initially misdiagnosed as primary mammary carcinomas. In retrospect, all metastatic tumours exhibited architectural and cytological features that would suggest neuroendocrine differentiation. Immunohistochemistry can further aid in the distinction between metastatic neuroendocrine and primary mammary carcinoma. All 11 tumours from the gastrointestinal tract expressed CDX-2, 3 (60%) of five tumours from the lung expressed thyroid transcription factor-1, and only 2 (11%) of 18 showed weak oestrogen receptor positivity. Additionally, unlike primary carcinomas, the majority (82%) of metastatic NETs were negative for cytokeratin 7, and all were negative for gross cystic disease fluid protein 15 and mammoglobin., Conclusions: There is a high propensity for metastatic NETs to mimic primary breast carcinomas. Careful attention to cytological and architectural features can help to identify cases that require further immunophenotypic workup with a panel of tissue-specific antibodies. However, clinical history is paramount for optimal diagnosis., (2011 Blackwell Publishing Limited.)

Invasive mammary carcinoma with neuroendocrine differentiation has been controversial in terms of its definition and clinical outcome. In 2003, the World Health Organization histologic classification of tumors designated this entity as neuroendocrine carcinoma of the breast and defined mammary neuroendocrine carcinoma as expression of neuroendocrine markers in more than 50% of tumor cells. It is an uncommon neoplasm. Our recent study showed that it is a unique clinicopathologic entity and has a poor clinical outcome compared with invasive mammary carcinoma with similar pathologic stage. Other investigators have also demonstrated a different molecular profile in this type of tumor from that of invasive ductal carcinoma. It is unknown whether the current prognostic markers for invasive mammary carcinoma are also applicable for neuroendocrine carcinoma of the breast. In the current study, we reviewed the clinicopathologic features and outcome data in 74 cases of mammary neuroendocrine carcinoma from the surgical pathology files at The University of Texas, MD Anderson Cancer Center, to identify relevant prognostic markers for this tumor type. As shown previously by univariate analysis, large tumor size, high nuclear grade, and presence of regional lymph node metastasis are adverse prognostic factors for overall survival and distant recurrence-free survival. In the current study, multivariate analysis revealed that overall survival was predicted by tumor size, lymph node status, and proliferation rate as judged by Ki-67 immunohistochemistry. Only nodal status proved to be a significant independent prognostic factor for distant recurrence-free survival. Neither mitosis score nor histologic grade predicted survival in mammary neuroendocrine carcinoma. Our data suggest that routine evaluation of Ki-67 proliferation index in these unusual tumors may provide more valuable information than mitotic count alone., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Aims: The aim of this study was to review the histomorphological features of primary neuroendocrine carcinomas (NEC) of the breast, in order to identify features useful in recognition of this entity for appropriate classification., Methods and Results: 2003 World Health Organization (WHO) classification of tumors of the breast and female genital organs defined NEC of the breast as a subtype of invasive mammary carcinoma in which >50% of the tumor cells express neuroendocrine markers. Seventy-four cases that fulfilled the WHO diagnostic criteria for NEC of the breast, excluding small cell carcinoma and low-grade solid papillary carcinoma with a predominant in-situ component, were identified between 1984 and 2008 from MD Anderson Cancer Center, and were included in the study. NECs of the breast had variable histomorphological features. The most common histologic patterns were papillary (80%) and nested (64%). Mixed growth patterns were common (59%), including admixed ductal component. The tumor cells could be polygonal, round, plasmacytoid, spindled, or with signet ring cell features. The cytoplasm could be granular, eosinophilic, clear, or finely vacuolated. These tumors frequently mimicked invasive or in situ ductal carcinoma, or invasive lobular carcinoma., Conclusions: NEC of the breast is underrecognized. Careful attention to cytologic and architectural features can help to identify cases that require further immunophenotypic confirmation for correct tumor classification., (© 2011 Blackwell Publishing Limited.)

Aim: The objective of this study is to review the imaging features and percutaneous biopsy findings of mucocele-like lesions (MLLs) of the breast and correlate these with histopathology at surgical excision (SE), where available, to determine whether all MLLs of the breast require surgery for management., Materials and Methods: A search of two pathology databases was performed to identify 44 patients who had been diagnosed with MLL of the breast and who had corresponding imaging findings available for review. These patients' medical records were reviewed to determine patient age at diagnosis, site of disease/affected breast, symptoms at diagnosis, mammographic and sonographic findings and methods used for histopathologic diagnosis (percutaneous biopsy and/or SE)., Results: The mean age of all patients was 56 years (range, 35-76 years). Sixteen patients had MLLs diagnosed by core needle biopsy (CNB) or fine needle aspiration biopsy followed by SE. Eighteen patients had CNB without SE and had clinical and imaging follow-up. Ten patients had MLL diagnosed at SE without prior percutaneous biopsy. In total, 29 patients (66%) had MLLs without atypia, while 10 patients had MLLs associated with atypical ductal hyperplasia (ADH) (23%) and five patients had MLLs associated with ductal carcinoma in situ (DCIS) (11%). Findings were upgraded at SE following the percutaneous biopsy from ADH to DCIS in 19% (3/16) of patients., Conclusion: Surgical excision following the identification of MLL is warranted to exclude coexisting in situ carcinoma in specific situations where CNB detects the presence of associated ADH or where a mass with indistinct or irregular margins is shown by mammography or sonography., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: A wide range of false-negative rates has been reported for sentinel lymph node (SLN) biopsy after preoperative chemotherapy. The purpose of this study was to determine whether histologic findings in negative SLNs after preoperative chemotherapy are helpful in assessing the accuracy of SLN biopsy in patients with confirmed lymph node-positive disease before treatment., Methods: Eighty-six patients with confirmed lymph node-positive disease at presentation underwent successful SLN biopsy and axillary dissection after preoperative chemotherapy at a single institution between 1994 and 2007. Available hematoxylin and eosin-stained sections from patients with negative SLNs were reviewed, and associations between histologic findings in the negative SLNs and SLN status (true negative vs false negative) were evaluated., Results: Forty-seven (55%) patients had at least 1 positive SLN, and 39 (45%) patients had negative SLNs. The false-negative rate was 22%, and the negative predictive value was 67%. The negative SLNs from 17 of 34 patients with available slides had focal areas of fibrosis, some with associated foamy parenchymal histiocytes, fat necrosis, or calcification. These histologic findings occurred in 15 (65%) of 23 patients with true-negative SLNs and in only 2 (18%) of 11 patients with false-negative SLNs (P = .03, Fisher exact test, 2-tailed). The lack of these histologic changes had a sensitivity and specificity for identifying a false-negative SLN of 82% and 65%, respectively., Conclusions: Absence of treatment effect in SLNs after chemotherapy in patients with lymph node-positive disease at initial presentation has good sensitivity but low specificity for identifying a false-negative SLN.

The World Health Organization classification of tumors of the breast includes a rare variant of invasive ductal carcinoma termed pleomorphic carcinoma. This variant has marked nuclear pleomorphism (>6-fold variation in nuclear size by definition, but often>10-fold) and characteristically contains multinucleated tumor giant cells. Approximately one-third of the cases in the initial series contained a focal spindle cell metaplastic component. The tumors are reported to have an aggressive behavior, but because some contain a spindle cell metaplastic component, it is unclear whether the metaplastic component or other clinicopathologic features account for the poor clinical outcome. We identified 37 cases of pleomorphic carcinoma of the breast and evaluated the association between clinical outcome and multiple clinicopathologic features. Patients with invasive pleomorphic lobular carcinoma and those without at least a tissue biopsy before chemotherapy were excluded. Patients ranged in age from 23 to 78 years (median, 49 y). Tumor size was >5 cm in 12 cases and <5 cm in 22. A focal spindle cell component (<25% of the tumor) was present in 14 tumors (38%). Clinical follow-up was available for 36 patients (median, 17 mo). In multivariate analysis, when the 2 stage-IV patients were excluded, the presence of a spindle cell component and tumor size >5 cm were each independently associated with decreased overall survival. The actuarial 5-year overall survival for patients with and without a metaplastic spindle cell component was 38%+/-15% and 89%+/-7%, respectively. Poor clinical outcome, therefore, is associated with the subset of pleomorphic carcinomas with a spindle cell metaplastic component. As the morphologic features of pleomorphic carcinoma can be seen in primary tumors from other sites, it is important to recognize this tumor as a rare variant of invasive breast carcinoma.

Rosai-Dorfman disease (also known as sinus histiocytosis with massive lymphadenopathy) is an uncommon, idiopathic, benign histiocytic lesion. It usually involves the cervical lymph nodes and, less commonly, extranodal sites. Involvement of the breast is rare, with only 17 cases reported in the English literature to date. Here we describe 3 new patients with extranodal Rosai-Dorfman disease in the breast. All 3 patients-aged 45, 53, and 54 years-presented with solid breast lesions that were detected on screening mammography and had no clinical history of Rosai-Dorfman disease or radiographic evidence of extramammary involvement. Initial diagnoses were accomplished by needle core biopsy in the one case and excisional biopsy in the other two. We present the histopathologic findings and follow-up of each patient and conduct a literature review of mammary Rosai-Dorfman disease with emphasis on its differential diagnosis. Because Rosai-Dorfman disease frequently mimics invasive breast carcinoma in its clinical presentation and radiographic appearance-and can mimic other benign or malignant histiocytic lesions microscopically-awareness and appropriate diagnosis of this entity are essential for proper treatment., (Copyright 2010 Elsevier Inc. All rights reserved.)

Pleomorphic stromal giant cells are occasionally found as an incidental finding in breast tissue but are only rarely seen in fibroepithelial lesions. In this report, we describe 4 fibroadenoma-like lesions of the breast with pleomorphic stromal giant cells. Two cases had focal stromal hypercellularity, one of which was with architectural features borderline between a fibroadenoma and a phyllodes tumor, but none was considered diagnostic of phyllodes tumor. One lesion had up to 4 mitotic figures per 10 high-power fields, including rare atypical mitotic figures. The remaining 3 cases lacked mitotic activity. Follow-up for 3 cases at 16 to 59 months revealed no evidence of tumor recurrence. The fourth case was lost to follow-up. It appears that the presence of pleomorphic stromal giant cells in an otherwise benign fibroepithelial lesion has no adverse clinical significance. The clinicopathologic features of each case are discussed, and a review of the literature is provided.

Background: The alpha6beta4 integrin is overexpressed in the basal subtype of breast cancer and plays an important role in tumor cell motility and invasion. EGFR is also overexpressed in the basal subtype of breast cancer, and crosstalk between alpha6beta4 integrin and EGFR appears to be important in tumor progression., Methods: We evaluated the effects of alpha6beta4 crosslinking on the distribution and function of EGFR in breast carcinoma cell line MDA-MB-231. Receptor distribution was evaluated by fluorescence microscopy and multispectral imaging flow cytometry, and ligand-mediated EGFR signaling was evaluated using Western blots and a Rho pull-down assay., Results: Antibody-mediated crosslinking of alpha6beta4 integrin was sufficient to induce cell-surface clustering of not only alpha6beta4 but also EGFR in nonadherent cells. The induced clustering of EGFR was observed minimally after 5 min of integrin crosslinking but was more prominent after 15 min. EGFR clustering had minimal effect on the phosphorylation of Akt or Erk1,2 in response to EGF in suspended cells or in response to HB-EGF in adherent cells. However, EGFR clustering induced by crosslinking alpha6beta4 had a marked effect on Rho activation in response to EGF., Conclusion: Crosslinking alpha6beta4 integrin in breast carcinoma cells induces EGFR clustering and preferentially promotes Rho activation in response to EGF. We hypothesize that this integrin-EGFR crosstalk may facilitate tumor cell cytoskeletal rearrangements important for tumor progression.

Metaplastic breast cancers (MBC) are aggressive, chemoresistant tumors characterized by lineage plasticity. To advance understanding of their pathogenesis and relatedness to other breast cancer subtypes, 28 MBCs were compared with common breast cancers using comparative genomic hybridization, transcriptional profiling, and reverse-phase protein arrays and by sequencing for common breast cancer mutations. MBCs showed unique DNA copy number aberrations compared with common breast cancers. PIK3CA mutations were detected in 9 of 19 MBCs (47.4%) versus 80 of 232 hormone receptor-positive cancers (34.5%; P = 0.32), 17 of 75 HER-2-positive samples (22.7%; P = 0.04), 20 of 240 basal-like cancers (8.3%; P < 0.0001), and 0 of 14 claudin-low tumors (P = 0.004). Of 7 phosphatidylinositol 3-kinase/AKT pathway phosphorylation sites, 6 were more highly phosphorylated in MBCs than in other breast tumor subtypes. The majority of MBCs displayed mRNA profiles different from those of the most common, including basal-like cancers. By transcriptional profiling, MBCs and the recently identified claudin-low breast cancer subset constitute related receptor-negative subgroups characterized by low expression of GATA3-regulated genes and of genes responsible for cell-cell adhesion with enrichment for markers linked to stem cell function and epithelial-to-mesenchymal transition (EMT). In contrast to other breast cancers, claudin-low tumors and most MBCs showed a significant similarity to a "tumorigenic" signature defined using CD44(+)/CD24(-) breast tumor-initiating stem cell-like cells. MBCs and claudin-low tumors are thus enriched in EMT and stem cell-like features, and may arise from an earlier, more chemoresistant breast epithelial precursor than basal-like or luminal cancers. PIK3CA mutations, EMT, and stem cell-like characteristics likely contribute to the poor outcomes of MBC and suggest novel therapeutic targets.

HER2 is an important predictive marker for response to trastuzumab and lapatinib in breast cancer. It is also a powerful prognostic marker in node-positive patients. Although standardized assays are used to help select patients for anti-HER2 therapy, there are no standardized criteria for assessing HER2 as a prognostic marker. Recent data using quantitative image analysis suggest that both high and low HER2 expression are associated with poor clinical outcome. Using the immunohistochemical scoring criteria currently recommended by the College of American Pathologists and American Society of Clinical Oncology to help select patients for trastuzumab, we evaluated HER2 protein expression in tumor tissue microarrays of 91 node-positive patients with invasive breast carcinoma treated with mastectomy and doxorubicin-based chemotherapy without trastuzumab and without irradiation with a median follow-up of 12.5 years. A wide range of HER2 expression (HER2 >or=1+) in the primary tumor was significantly associated with decreased locoregional recurrence-free survival (P=0.014), decreased disease-specific survival (P=0.001), and decreased overall survival (P=0.001). Even in the subset considered HER2 negative by current College of American Pathologists and American Society of Clinical Oncology guidelines, HER2=1+ was associated with worse outcome than HER2=0 in this patient cohort. The association between HER2 >or=1+ and worse outcome had the greatest statistical significance in the hormone receptor-positive subset of patients. These findings support the hypothesis that low-level HER2 expression may have significant clinical implications. Although the assessment of HER2 expression is most important for predicting response to anti-HER2 therapy, detection of low-level HER2 expression might also be useful in helping to select a more aggressive treatment regimen for patients ineligible for anti-HER2 therapy.

Matrix-producing carcinoma (MPC) of the breast is a subtype of metaplastic carcinoma defined as an invasive breast carcinoma with a direct transition of carcinoma to cartilaginous or osseous matrix without an intervening spindle cell component. Our aims were (1) to evaluate specific histologic characteristics of MPC and correlate these with disease recurrence; and (2) to determine whether rates of locoregional and distant recurrence for MPC are significantly different from those of invasive ductal carcinoma. Thirty-two cases of MPC were identified. Fourteen patients (44%) were < or =50 years of age; 10 (31%) had tumors of size < or =2 cm, and 6 (19%) had tumors > or =5 cm. In this series, all tumors contained chondromyxoid or chondroid matrix, and 1 (3.1%) also contained focal (<5%) osseous matrix. High-grade matrix was present in 9 cases (28%), and low-grade matrix was present in 23 (72%). Matrix comprised < or =10% of the tumor in 14 cases (44%), >10% but <40% in 9 (28%), and > or =40% in 9 (28%). The carcinomatous component was high grade in 30 cases (94%), and 19 tumors (59%) had central necrosis. Seven patients (22%) had positive axillary lymph nodes, and 8 (25%) had lymphovascular space invasion (LVSI). LVSI was the only factor independently associated with locoregional recurrence-free survival in multivariate analysis (P=0.043). Although > or =40% matrix was associated with improved distant recurrence-free (DFS) survival in univariate analysis (P=0.044), only LVSI and tumor stage were independently associated with DFS survival in multivariate analysis (P=0.027 and P=0.001, respectively). Compared with matched controls with invasive ductal carcinoma, patients with MPC had decreased locoregional recurrence-free survival (P=0.001) and decreased DRF survival (P=0.001). In summary, MPC is an aggressive subtype of metaplastic carcinoma with a worse clinical outcome than invasive ductal carcinoma.

Metastasis to the breast from extramammary malignancies is rare. Nevertheless, its recognition is important because the prognosis and treatment differ from that of primary breast cancer. We report a unique case of primary peritoneal serous carcinoma that initially presented as inflammatory breast cancer. The patient received neoadjuvant chemotherapy for breast cancer and subsequently underwent bilateral total mastectomy and bilateral sentinel lymph node biopsy. She was found to have extensive intralymphatic carcinoma in both breasts, with only focal minimal breast parenchymal involvement, and residual metastatic carcinoma in bilateral sentinel lymph nodes. Further work-up revealed pelvic ascites and omental nodularities. The patient underwent laparoscopic bilateral salpingo-oophorectomy, which revealed high-grade serous carcinoma involving both ovaries and fallopian tubes. Molecular testing of tumor from the ovary and axillary lymph node showed an identical pattern of allelic loss, confirming a common origin for both tumors. To our knowledge, this is the first reported case of an extramammary primary malignancy that not only presented as inflammatory breast cancer but also was diagnosed and initially treated as such.

Preclinical data indicate that alpha6beta4 integrin signaling through Ras homolog gene family, member A, plays an important role in tumor cell motility. The objective of this study was to determine whether the combined expression of alpha6beta4 integrin and neuroepithelioma transforming gene 1 (Net1), a guanine nucleotide exchange factor specific for Ras homolog gene family member A, is associated with adverse clinical outcome in breast cancer patients. Immunohistochemical expression of each protein was evaluated in a tumor tissue microarray prepared from the primary tumors of 94 node-positive patients with invasive breast carcinoma treated with total mastectomy and doxorubicin-based chemotherapy without radiation with a median follow-up of 12.5 years. Associations between staining results and multiple clinicopathologic variables were investigated. Although there was no significant association between alpha6beta4 integrin or Net1 expression and clinical outcome when each marker was considered individually, coexpression of alpha6beta4 and Net1 was associated with decreased distant metastasis-free survival (P = 0.030). In the subset of patients with hormone receptor-positive tumors, coexpression of alpha6beta4 and Net1 was associated with a decrease in distant metastasis-free and overall survival (P < 0.001 and P = 0.006, respectively). Although an association between human epidermal growth factor receptor 2 expression and coexpression of alpha6beta4 and Net1 (P = 0.008) was observed, coexpression of alpha6beta4 and Net1 (hazard ratio, 1.63; P = 0.02) and lymphovascular invasion (hazard ratio, 2.35; P = 0.02) were the only factors independently associated with the development of distant metastasis in multivariate analysis. These findings suggest that coexpression of alpha6beta4 integrin and Net1 could be a useful biomarker for aggressive disease in node-positive breast cancer patients.

Background: : It remains unclear how many sentinel lymph nodes (SLNs) must be removed to accurately predict lymph node status during SLN dissection in breast cancer. The objective of this study was to determine how many SLNs need to be removed for accurate lymph node staging and which patient and tumor characteristics influence this number., Methods: : The authors reviewed data for all patients in their prospective database with clinical tumor, lymph node, metastasis (TNM) T1 through T3, N0, M0 breast cancer who underwent lymphatic mapping at their institution during the years 1994 through 2006. There were 777 patients who had at least 1 SLN that was positive for cancer. Simple and multiple quantile regression analyses were used to determine which patient and tumor characteristics were associated with the number of positive SLNs. The baseline number of SLNs that needed to be dissected for detection of 99% of positive SLNs in the total group of patients also was determined., Results: : The mean number of SLNs removed in the 777 lymph node-positive patients was 2.9 (range, 1-13 SLNs). Greater than 99% of positive SLNs were identified in the first 5 lymph nodes removed. On univariate analysis, tumor histology, patient race, tumor location, and tumor size significantly affected the number of SLNs that needed to be removed to identify 99% of all positive SLNs. On multivariate analysis, mixed ductal and lobular histology, Caucasian race, inner quadrant tumor location, and T1 tumor classification significantly increased the number of SLNs that needed to be removed to achieve 99% recovery of all positive SLNs., Conclusions: : In general, the removal of a maximum of 5 SLNs at surgery allowed for the recovery of >99% of positive SLNs in patients with breast cancer. The current findings indicated that tumor histology, patient race, and tumor size and location may influence this number., ((Copyright) 2008 American Cancer Society.)

Objective: The purpose of this study was to compare the imaging features of metaplastic breast carcinoma with those of invasive ductal carcinoma., Materials and Methods: Women diagnosed on preoperative mammography or sonography with metaplastic breast carcinoma and T-stage matched invasive ductal carcinoma of the breast from a single pathology database were included in the study. Clinical and pathologic information on all metaplastic cancers was documented. Mammography and sonography variables were recorded using the BI-RADS lexicon. Groups were compared using Fisher's exact test, the chi-square test, or Wilcoxon's rank sum test, as appropriate., Results: Forty-three patients diagnosed with metaplastic carcinoma were matched to 43 patients with ductal carcinoma by tumor T stage. Patients with metaplastic carcinoma were younger (median, 46 vs 53 years, p = 0.048) than those with ductal carcinoma. Mammographically, metaplastic carcinomas were less frequently irregular in shape (16% vs 74%, p < 0.0001) and less frequently showed microlobulated or spiculated margins (19% vs 56%, p = 0.0008) and calcifications (25% vs 51%, p = 0.02) when compared with ductal carcinomas. Sonographically, metaplastic carcinomas were less frequently irregular in shape (27% vs 69%, p = 0.001) and less frequently showed angular margins (9% vs 49%) and posterior acoustic shadowing (9% vs 49%, p < 0.0001)., Conclusion: Characteristic malignant imaging features, including irregular shape, spiculated margins, segmentally distributed pleomorphic calcifications, and posterior acoustic shadowing, are uncommon in metaplastic carcinomas. These carcinomas tend to show more benign imaging features, such as round or oval shape with circumscribed margins, when compared with ductal carcinomas.

A 63-year-old Japanese woman was diagnosed with metastatic well-differentiated neuroendocrine carcinoma presenting as a perianal mass without an obvious primary site. Two years later, she presented with a breast mass determined on histologic examination to be the primary neuroendocrine carcinoma. The tumor was weakly positive for estrogen receptor and clearly originated in multifocal ductal carcinoma in situ. At the same time, she was found to have multiple metastases in bone and liver and, later, heart. Most studies report a relatively poor prognosis and limited treatment responsiveness for neuroendocrine breast carcinoma. Better understanding of the cellular origin and molecular pathogenesis of this relatively enigmatic rare disease is required.

Aims: Reports on the frequency of myoepithelial loss in solid papillary carcinoma (SPC) of the breast, an unusual variant of papillary carcinoma with a solid pattern of expansile growth, have been strikingly contradictory. The aim was to clarify the frequency of myoepithelial loss in cases of SPC diagnosed at our institution., Methods and Results: Eleven cases of SPC with available blocks or unstained slides were retrieved from the M. D. Anderson archives or obtained from outside contributors. Immunohistochemistry for smooth muscle actin (SMA) and p63 was evaluated on the circumscribed nests that appeared to be non-invasive by haematoxylin and eosin morphology. Three of the 11 cases (27%) were positive for both SMA and p63 at the periphery of all such foci, whereas eight cases (73%) lacked staining for both myoepithelial markers in at least one focus. Of these eight cases, one was diagnosed with only microinvasion, yet metastatic tumour resembling the circumscribed primary SPC was identified in two ipsilateral axillary lymph nodes., Conclusions: SPC of the breast frequently lacks myoepithelial markers at the tumour-stromal interface in spite of a circumscribed non-invasive appearance. Metastases from such tumours are infrequent, but can occur in cases that lack myoepithelial marker expression by immunohistochemistry.

Galectin-3 (GAL3), a beta-galactoside-binding lectin, confers chemoresistance to a wide variety of cancer cell types. It may exhibit anti- or pro-apoptotic activity depending on the nature of the stimulus. We report here that introducing phosphorylated galectin-3 (P-GAL3) into GAL3-null, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant human breast carcinoma cells promotes TRAIL-induced apoptotic cell death by stimulating the phosphorylation/inactivation of the pro-apoptotic molecule Bad resulting in the inhibition of mitochondrial depolarization and the release of cytochrome c. Exposure of the transfectant cells to TRAIL leads to the recruitment of the initiator capase-8 followed by activation of the effector caspase-9, independent of cytochrome c, and subsequently the processing of the executioner caspase-3. P-GAL3 and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) were coordinately expressed, with concomitant dephosphorylation of Akt in TRAIL-sensitive cells. In contrast, overexpression of phospho-mutant GAL3 (incapable of phosphorylation) failed to elicit similar responses. Depletion of PTEN using small interference RNAs reinstated Akt phosphorylation and conferred TRAIL resistance. In addition phosphatidylinositol 3-kinase inhibitors rendered the phospho-mutant GAL3-resistant cells sensitive to TRAIL. These findings suggest a pivotal role for P-GAL3 in promoting TRAIL sensitivity through activation of a nonclassic apoptotic pathway and identify P-GAL3 as a novel regulator of PTEN.

Background: The feasibility and accuracy of sentinel lymph node (SLN) biopsy in patients with breast cancer after preoperative chemotherapy has been demonstrated in a number of large, single-institution studies. However, a relative contraindication to SLN biopsy after preoperative chemotherapy is the presence of axillary metastases at initial diagnosis. The objective of this study was to determine the feasibility and accuracy of SLN biopsy after preoperative chemotherapy in patients with documented axillary metastases at presentation., Methods: Between 1994 and 2002, 69 patients who had axillary metastases identified by ultrasound-guided, fine-needle aspiration underwent SLN biopsy after treatment on prospective, preoperative chemotherapy protocols. All but 8 patients underwent axillary lymph node dissection (ALND). Those 8 patients either declined additional surgery or were offered enrollment in other institutional protocols., Results: The median patient age was 49 years, and the median primary tumor size was 4 cm. The SLN identification rate was 92.8%. Thirty-one of 64 patients (48.4%) had successfully mapped, positive SLNs. Sixty-one patients underwent ALND, including 5 patients who did not have an SLN identified. In the 56 patients in whom a SLN was identified and an ALND was performed, 10 patients had a false-negative SLN (25%)., Conclusions: SLN biopsy was feasible after preoperative chemotherapy, even in patients who initially presented with cytologically proven, lymph node-positive disease. However, the false-negative rate of SLN biopsy in this group of patients was much higher than that observed in clinically lymph node-negative patients. Based on the current results, the status of the SLN cannot be used as a reliable indicator of the presence or absence of residual disease in the axilla in this patient population., ((c) 2007 American Cancer Society.)

Although most cells of adult mammals express multiple different integrins, particular types of cells have a characteristic repertoire of integrin expression. Benign and malignant epithelial cells use specific integrins to allow the epithelial microenvironment to modulate a wide variety of cell functions, including cell survival, proliferation, morphogenesis, differentiation, motility, invasion and metastasis. An important concept emerging from the data on integrin signal transduction is that integrin signaling impinges on pathways downstream of other receptors, creating elaborate intracellular signaling networks. This review highlights signal transduction functions of epithelial integrins, with particular emphasis on signaling pathways underlying some of the most important functions of epithelium.

Nodal staging is the most important prognostic factor in the management of patients with breast cancer. Sentinel lymph node (SLN) procedure enables selective targeting of the first lymph node that drains the tumor when the initial metastases occur. A negative sentinel node predicts the absence of tumor mestastases in the other regional lymph nodes with high accuracy. Thorough histopathological evaluation of SLNs important for accurate assessment. In this chapter, we discuss the histopathological evaluation of SLNs.

Metaplastic carcinomas of the breast are a heterogeneous group of neoplasms ranging from tumors with a predominant component of overt carcinoma and focal mesenchymal differentiation to keratin-positive tumors with pure sarcomatoid morphology. We examined the clinicopathologic features of 22 patients previously diagnosed at M.D. Anderson Cancer Center with metaplastic carcinoma of the breast with pure or almost pure sarcomatoid morphology. Patients were included in the study if their tumors had sarcomatoid morphology and: 1) an invasive carcinomatous component identifiable on hematoxylin and eosin stains comprising less than 5% of the invasive tumor; or 2) associated ductal carcinoma in situ; or 3) immunohistochemical expression of keratin in the sarcomatoid areas. Patients with low-grade fibromatosis-like metaplastic tumors and those who received neoadjuvant chemotherapy were excluded. Axillary lymph node dissection or limited axillary node excision was performed in 17 patients, including 1 patient who had a sentinel lymph node biopsy. Lymph node involvement occurred in only 1 patient and consisted of a single 3.5-mm metastasis. Clinical follow-up was available for 21 patients and ranged from 4 months to 155 months (median follow-up, 35 months). Ten patients experienced local relapse, including 7 of 11 patients treated with breast-conserving surgery, and 9 developed distant metastases, most frequently to the lungs. These findings suggest that metaplastic sarcomatoid carcinomas that lack or have only a minimal overt invasive carcinomatous component have a biologic behavior similar to that of sarcomas. In addition to systemic treatment, early aggressive local therapy is recommended, as these patients have a high rate of local relapse.

Purpose: To retrospectively identify radiographic characteristics of stage I non-small cell lung cancer (NSCLC) that may correlate with epidermal growth factor receptor (EGFR) or HER2 expression or with prognosis., Materials and Methods: This study was approved by the institutional review board, with waiver of informed consent, and was in compliance with HIPAA regulations. Findings of chest computed tomography (CT) were retrospectively evaluated in 72 patients who underwent resection of pathologic stage I NSCLC; tumor diameter, presence of calcifications, type of contour, type of margins, attenuation of the nodule, presence of a halo, presence of cavitation, and tumor location were documented. Immunohistochemical studies were performed in surgical specimens. Imaging and molecular data were correlated with patient outcome. Cox proportional hazards regression models were used to correlate biologic and radiographic variates with clinical outcome., Results: There were 38 men (53%) and 34 women (47%) (median age, 65.5 years). Median follow-up was 56.3 months; median overall survival, 76.3 months. A strong correlation was found between tumor diameter measured by radiologists and that measured by pathologists (P < .001; Pearson correlation coefficient, 0.81). EGFR overexpression was found in 48 (67%) tumors; significantly more was found in squamous cell carcinomas than was found in adenocarcinomas (P = .028), and more was found in T2 tumors than was found in T1 tumors (P = .001). HER2 overexpression was found in 13 (18%) tumors; cavitation, in 16 (22%) tumors. Cavitary lesions were significantly more common in squamous cell carcinomas than were in adenocarcinomas (P = .013) and in EGFR-overexpressing tumors (P = .012) than in tumors that did not overexpress EGFR. Cavitary lesions were significantly associated with shorter disease-free survival time (P = .01) and shorter overall survival time (P < .007)., Conclusion: Patients who have stage I NSCLC with cavitary lesions have an adverse prognosis and are likely to have tumor EGFR overexpression., (RSNA, 2005)

In vitro data support a role for the alpha6beta4 integrin in tumor cell migration and invasion, particularly in breast carcinoma cells, but clinical data on this potentially important integrin are limited. The beta4 integrin subunit has been shown to cluster with genes characteristic of basal/myoepithelial cells in cDNA microarray analyses of breast cancer, and the subset of breast cancers with increased expression of genes characteristic of basal/myoepithelial cells appears to be particularly aggressive. The purpose of this study was to determine whether alpha6beta4 integrin expression correlates with aggressive clinicopathologic features of breast cancer and whether expression of this integrin has prognostic significance in early breast cancer. We evaluated tumor expression of the beta4 integrin subunit gene in a cohort of patients with early invasive breast carcinoma by in situ hybridization and correlated expression levels with multiple clinicopathologic characteristics. We also evaluated expression of laminin-5 protein, the principal ligand of alpha6beta4, in this patient cohort. Although we observed a slight trend towards decreased disease-free survival for patients whose tumors had high beta4 gene expression and coexpression of laminin-5, this did not reach statistical significance (P=0.11). However, we did observe a correlation between beta4 mRNA expression and both tumor size (P=0.01) and tumor nuclear grade (P<0.01). These results do not demonstrate prognostic significance for beta4 gene expression and/or laminin-5 protein expression in early breast cancer, but increased beta4 gene expression in larger tumors and in higher grade tumors does support a potential role for the alpha6beta4 integrin in tumor progression.