Publications by authors named "Adriana Corben"

41 Publications

Pathophysiology of SARS-CoV-2: the Mount Sinai COVID-19 autopsy experience.

Mod Pathol 2021 Apr 1. Epub 2021 Apr 1.

Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated clinical syndrome COVID-19 are causing overwhelming morbidity and mortality around the globe and disproportionately affected New York City between March and May 2020. Here, we report on the first 100 COVID-19-positive autopsies performed at the Mount Sinai Hospital in New York City. Autopsies revealed large pulmonary emboli in six cases. Diffuse alveolar damage was present in over 90% of cases. We also report microthrombi in multiple organ systems including the brain, as well as hemophagocytosis. We additionally provide electron microscopic evidence of the presence of the virus in our samples. Laboratory results of our COVID-19 cohort disclose elevated inflammatory markers, abnormal coagulation values, and elevated cytokines IL-6, IL-8, and TNFα. Our autopsy series of COVID-19-positive patients reveals that this disease, often conceptualized as a primarily respiratory viral illness, has widespread effects in the body including hypercoagulability, a hyperinflammatory state, and endothelial dysfunction. Targeting of these multisystemic pathways could lead to new treatment avenues as well as combination therapies against SARS-CoV-2 infection.
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http://dx.doi.org/10.1038/s41379-021-00793-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015313PMC
April 2021

Measuring Invasive Breast Carcinoma on Core Biopsy: Is it Necessary?: An Analysis of Ultrasound, Mammotome, and Magnetic Resonance Imaging-Guided Core Biopsies.

Arch Pathol Lab Med 2021 Jan 27. Epub 2021 Jan 27.

From the Department of Pathology, Mount Sinai Medical Center, New York, New York (Liang, Corben, Zeizafoun, Alexander, Jaffer).

Context.—: Pathologic tumor size is significant in the treatment of breast carcinoma and is routinely measured on excision.

Objective.—: To analyze the need for measuring size of invasive mammary carcinoma on biopsy.

Design.—: Nine hundred twenty-two cases of invasive carcinoma whose size was measured (greatest linear measurement) on biopsy and excision was correlated, including imaging when available (110 cases).

Results.—: Patient mean age was 62 years. Most (90%; 830 of 922) carcinomas were ductal and sampled by ultrasound and graded as follows: well, 13% (113 of 922); moderately, 58% (532 of 922), and poorly differentiated, 28% (258 of 922); 19 microinvasive not graded. Tumor mean size was 7.5 mm on biopsy and 14.4 mm on excision. Biopsy modality was as follows: ultrasound, 7.8 mm (92%, 844 of 922); mammotome, 3.3 mm (7%, 65 of 922); and magnetic resonance imaging, 5.9 mm (1%, 13 of 922). Size comparison on biopsy versus excision was biopsy > excision: 8% (72 of 922), biopsy = excision: 10% (95 of 922), and biopsy < excision: 82% (755 of 922). Half (36 of 72) of the biopsy > excision tumors were less than 5 mm, 96% (726 of 755) of biopsy < excision tumors were greater than 5 mm, while those equal on both were predominantly (88%, 84 of 95) less than 10 mm, 20% (19 of 95) of which were microinvasive. Stage changed in 600 cases, staging based on excision in 581 (63%), and staging based on biopsy in 19 (2%). Radiologic-pathologic correlation (n = 110) showed perfect concordance in 11 (10%), 83 (75%) were ±1 to 2 mm and 16 (15%) were ± more than 3 mm. Difference between the biopsy and excision ranged from a lower limit of 1.3 mm for T1a tumors to 18 mm for T2.

Conclusions.—: While most carcinomas are larger on excision, 18% (167 of 922) are larger or equal on biopsy. Factors predictive of biopsy > excision tumors include stage 1 tumors (P < .001), especially less than 5 mm, and sampled by mammotome. We recommend measuring invasive carcinoma on biopsy and excision.
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http://dx.doi.org/10.5858/arpa.2020-0287-OADOI Listing
January 2021

Response in breast vs axilla after neoadjuvant treatment and implications for nonoperative management of invasive breast cancer.

Breast J 2021 Feb 3;27(2):120-125. Epub 2021 Jan 3.

Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Improved imaging and neoadjuvant chemotherapy (NAT) have led to higher pathologic complete response rates (pCR) in patients with invasive breast cancer. This has questioned the necessity of surgery and axillary lymph node (ALN) dissection in these patients. Prospective clinical trials are implementing extensive core biopsies of the tumor bed of patients with clinical complete response as a means to identify and spare them breast surgery. In addition, it is anticipated that patients with pCR are most likely going to have no or minimal disease in ALN as well. To verify the feasibility of these trials, we performed a pathologic analysis of all our patients who have undergone NAT from 2009 to present. Using pathology data base, we identified 362 patients treated with neoadjuvant chemotherapy followed by surgery. Clinical and pathologic information including gross and microscopic descriptions as well as biomarker status was collected. pCR was 50% for patients with negative ALN pretreatment but only 28% for patients with positive ALN at diagnosis. Despite achieving pCR in the breast, up to 10% of patients with positive ALN and 1% with negative ALN had persistent disease. Eight percent of patients that were presumed to have no ALN disease either clinically and or by imaging were found to have metastatic carcinoma in ALN. The metastases were predominantly (80%) <5 mm, and not palpable on physical examination and or due to biopsy sampling error. pCR in breast and ALN directly correlated with tumor size, ALN disease, and Her2 positive and triple negative receptor phenotype. In breast cancer patients who are node positive at time of diagnosis with pCR in the breast after neoadjuvant chemotherapy, residual lymph node disease was very uncommon. Further study is warranted to select patients who may avoid breast and axillary surgery post neoadjuvant chemotherapy.
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http://dx.doi.org/10.1111/tbj.14125DOI Listing
February 2021

Molecular Stressors Engender Protein Connectivity Dysfunction through Aberrant N-Glycosylation of a Chaperone.

Cell Rep 2020 06;31(13):107840

Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Stresses associated with disease may pathologically remodel the proteome by both increasing interaction strength and altering interaction partners, resulting in proteome-wide connectivity dysfunctions. Chaperones play an important role in these alterations, but how these changes are executed remains largely unknown. Our study unveils a specific N-glycosylation pattern used by a chaperone, Glucose-regulated protein 94 (GRP94), to alter its conformational fitness and stabilize a state most permissive for stable interactions with proteins at the plasma membrane. This "protein assembly mutation' remodels protein networks and properties of the cell. We show in cells, human specimens, and mouse xenografts that proteome connectivity is restorable by inhibition of the N-glycosylated GRP94 variant. In summary, we provide biochemical evidence for stressor-induced chaperone-mediated protein mis-assemblies and demonstrate how these alterations are actionable in disease.
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http://dx.doi.org/10.1016/j.celrep.2020.107840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372946PMC
June 2020

Paradigms for Precision Medicine in Epichaperome Cancer Therapy.

Cancer Cell 2019 11 24;36(5):559-573.e7. Epub 2019 Oct 24.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Program in Molecular Pharmacology, Sloan Kettering Institute, New York, NY 10065, USA.

Alterations in protein-protein interaction networks are at the core of malignant transformation but have yet to be translated into appropriate diagnostic tools. We make use of the kinetic selectivity properties of an imaging probe to visualize and measure the epichaperome, a pathologic protein-protein interaction network. We are able to assay and image epichaperome networks in cancer and their engagement by inhibitor in patients' tumors at single-lesion resolution in real time, and demonstrate that quantitative evaluation at the level of individual tumors can be used to optimize dose and schedule selection. We thus provide preclinical and clinical evidence in the use of this theranostic platform for precision medicine targeting of the aberrant properties of protein networks.
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http://dx.doi.org/10.1016/j.ccell.2019.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996250PMC
November 2019

Evaluation of surgically excised breast tissue microstructure using wide-field optical coherence tomography.

Breast J 2020 05 14;26(5):917-923. Epub 2019 Oct 14.

Dubin Breast Center of the Tisch Cancer Institute, Mount Sinai Hospital, New York, New York.

Background: Currently, positive margins at lumpectomy contribute to health care cost, patient anxiety, and treatment delay. Multiple technology solutions are being explored with the aim of lowering re-excision rates for breast-conserving surgery (BCS). We examined wide-field optical coherence tomography (WF-OCT), an innovative adjunct intraoperative imaging tool for tissue visualization of margins.

Methods: This IRB-approved pilot study included women with invasive or in situ carcinoma scheduled for primary BCS. Lumpectomy specimens and any final/revised margins were imaged by optical coherence tomography immediately prior to standard histological processing. The optical coherence tomography used provided two-dimensional, cross-sectional, real-time depth visualization of the margin widths around excised specimens. A volume of images was captured for 10 × 10 cm tissue surface at high resolution (sub-30 μm) to a depth of 2 mm. Integrated interpretation was performed incorporating final pathology linked with the optical image data for correlation.

Results: Wide-field optical coherence tomography was performed on 185 tissue samples (50 lumpectomy specimens and 135 additional margin shaves) in 50 subjects. Initial diagnosis was invasive ductal carcinoma (IDC) in 10, ductal carcinoma in situ (DCIS) in 14, IDC/DCIS in 22, invasive lobular carcinoma (ILC) in 2, ILC/DCIS in 1, and sarcoma in 1. Optical coherence tomography was concordant with final pathology in 178/185 tissue samples for overall accuracy of 86% and 96.2% (main specimen alone and main specimen + shave margins). Of seven samples that were discordant, 57% (4/7) were considered close (DCIS < 2 mm from margin) per final pathology.

Conclusion: Wide-field optical coherence tomography demonstrated concordance with histology at tissue margins, supporting its potential for use as a real-time adjunct intraoperative imaging tool for margin assessment. Further studies are needed for comprehensive evaluation in the intraoperative setting.
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http://dx.doi.org/10.1111/tbj.13663DOI Listing
May 2020

Chaperome heterogeneity and its implications for cancer study and treatment.

J Biol Chem 2019 02 8;294(6):2162-2179. Epub 2018 Nov 8.

From the Chemical Biology Program and

The chaperome is the collection of proteins in the cell that carry out molecular chaperoning functions. Changes in the interaction strength between chaperome proteins lead to an assembly that is functionally and structurally distinct from each constituent member. In this review, we discuss the epichaperome, the cellular network that forms when the chaperome components of distinct chaperome machineries come together as stable, functionally integrated, multimeric complexes. In tumors, maintenance of the epichaperome network is vital for tumor survival, rendering them vulnerable to therapeutic interventions that target critical epichaperome network components. We discuss how the epichaperome empowers an approach for precision medicine cancer trials where a new target, biomarker, and relevant drug candidates can be correlated and integrated. We introduce chemical biology methods to investigate the heterogeneity of the chaperome in a given cellular context. Lastly, we discuss how ligand-protein binding kinetics are more appropriate than equilibrium binding parameters to characterize and unravel chaperome targeting in cancer and to gauge the selectivity of ligands for specific tumor-associated chaperome pools.
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http://dx.doi.org/10.1074/jbc.REV118.002811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369301PMC
February 2019

Histopathologic characteristics of background parenchymal enhancement (BPE) on breast MRI.

Breast Cancer Res Treat 2018 Nov 23;172(2):487-496. Epub 2018 Aug 23.

Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, 485 Lexington Avenue, Room 2061, New York, NY, 10017, USA.

Purpose: Breast fibroglandular tissue (FGT), as visualized on a mammogram (mammographic density, MD), is one of the strongest known risk factors for breast cancer. FGT is also visible on breast MRI, and increased background parenchymal enhancement (BPE) in the FGT has been identified as potentially a major breast cancer risk factor. The aim of this exploratory study was to examine the biologic basis of BPE.

Methods: We examined the unaffected contra-lateral breast of 80 breast cancer patients undergoing a prophylactic mastectomy before any treatment other than surgery of their breast cancer. BPE was classified on the BI-RADS scale (minimal/mild/moderate/marked). Slides were stained for microvessel density (MVD), CD34 (another measure of endothelial density), glandular tissue within the FGT and VEGF. Spearman correlations were used to evaluate the associations between BPE and these pathologic variables.

Results: In pre-menopausal patients, BPE was highly correlated with MVD, CD34 and glandular concentration within the FGT, and the pathologic variables were themselves highly correlated. The expression of VEGF was effectively confined to terminal duct lobular unit (TDLU) epithelium. The same relationships of the four pathologic variables with BPE were seen in post-menopausal patients, but the relationships were much weaker and not statistically significant.

Conclusion: The strong correlation of BPE and MVD together with the high correlation of MVD with glandular concentration seen in pre-menopausal patients indicates that increased breast cancer risk associated with BPE in pre-menopausal women is likely to result from its association with increased concentration of glandular tissue in the FGT. The effective confinement of VEGF expression to the TDLUs shows that the signal for MVD growth arises directly from the glandular tissue. Further studies are needed to understand the basis of BPE in post-menopausal women.
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http://dx.doi.org/10.1007/s10549-018-4916-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697118PMC
November 2018

Prospective Clinical Trial of F-Fluciclovine PET/CT for Determining the Response to Neoadjuvant Therapy in Invasive Ductal and Invasive Lobular Breast Cancers.

J Nucl Med 2017 07 17;58(7):1037-1042. Epub 2016 Nov 17.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

F-labeled 1-amino-3-fluorocyclobutane-1-carboxylic acid (F-fluciclovine) is a leucine analog radiotracer that depicts amino acid transport into cells. F-fluciclovine PET/CT visualizes malignancy, including prostate cancer, invasive ductal breast cancer, and invasive lobular breast cancer. Whether changes in F-fluciclovine avidity reflect changes in tumor burden resulting from treatment has not been shown. In this prospective clinical trial (clinical trials.gov: NCT01864083), changes in F-fluciclovine avidity after neoadjuvant therapy were compared to breast cancer therapy response, as determined by residual tumor burden on pathology, were evaluated. Twenty-four women with a new diagnosis of locally advanced invasive ductal breast cancer ( = 18) or invasive lobular breast cancer ( = 6) underwent F-fluciclovine PET/CT before and after the completion of neoadjuvant systemic therapy. SUV, SUV, metabolic tumor volume, and total lesion avidity were obtained for the primary breast tumor, axillary lymph nodes, and extraaxillary lymph nodes on each examination and corrected for background F-fluciclovine avidity. The relationship between changes in F-fluciclovine avidity and the percentage of reduction of tumor on pathology was assessed with the Spearman rank correlation. The median decrease in the corrected SUV of the primary breast lesions was 99% (range, 33%-100%). The median reduction of tumor on pathology was 92% (range, 10%-100%). Changes in F-fluciclovine avidity were strongly correlated with the percentage of reduction of tumor on pathology (Spearman ρ, 0.79; 95% CI, 0.56-0.90; < 0.001). Changes in F-fluciclovine avidity strongly correlated with the tumor response on pathology in this pilot study.
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http://dx.doi.org/10.2967/jnumed.116.183335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944156PMC
July 2017

The epichaperome is an integrated chaperome network that facilitates tumour survival.

Nature 2016 Oct 5;538(7625):397-401. Epub 2016 Oct 5.

Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.

Transient, multi-protein complexes are important facilitators of cellular functions. This includes the chaperome, an abundant protein family comprising chaperones, co-chaperones, adaptors, and folding enzymes-dynamic complexes of which regulate cellular homeostasis together with the protein degradation machinery. Numerous studies have addressed the role of chaperome members in isolation, yet little is known about their relationships regarding how they interact and function together in malignancy. As function is probably highly dependent on endogenous conditions found in native tumours, chaperomes have resisted investigation, mainly due to the limitations of methods needed to disrupt or engineer the cellular environment to facilitate analysis. Such limitations have led to a bottleneck in our understanding of chaperome-related disease biology and in the development of chaperome-targeted cancer treatment. Here we examined the chaperome complexes in a large set of tumour specimens. The methods used maintained the endogenous native state of tumours and we exploited this to investigate the molecular characteristics and composition of the chaperome in cancer, the molecular factors that drive chaperome networks to crosstalk in tumours, the distinguishing factors of the chaperome in tumours sensitive to pharmacologic inhibition, and the characteristics of tumours that may benefit from chaperome therapy. We find that under conditions of stress, such as malignant transformation fuelled by MYC, the chaperome becomes biochemically 'rewired' to form a network of stable, survival-facilitating, high-molecular-weight complexes. The chaperones heat shock protein 90 (HSP90) and heat shock cognate protein 70 (HSC70) are nucleating sites for these physically and functionally integrated complexes. The results indicate that these tightly integrated chaperome units, here termed the epichaperome, can function as a network to enhance cellular survival, irrespective of tissue of origin or genetic background. The epichaperome, present in over half of all cancers tested, has implications for diagnostics and also provides potential vulnerability as a target for drug intervention.
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http://dx.doi.org/10.1038/nature19807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5283383PMC
October 2016

Breast intraductal papillomas without atypia in radiologic-pathologic concordant core-needle biopsies: Rate of upgrade to carcinoma at excision.

Cancer 2016 09 17;122(18):2819-27. Epub 2016 Jun 17.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: The surgical management of mammary intraductal papilloma without atypia (IDP) identified at core-needle biopsy (CNB) is controversial. This study assessed the rate of upgrade to carcinoma at surgical excision (EXC).

Methods: This study identified women with a CNB diagnosis of intraductal papilloma without atypia or carcinoma at a cancer center between 2003 and 2013. Radiologic-pathologic concordance was assessed for all cases, and discordant cases were excluded. The radiologic and clinicopathologic features of patients with a CNB diagnosis of IDP were correlated with an upgrade to carcinoma at EXC.

Results: The study population consists of 189 women with 196 IDPs; 166 women (171 IDPs) underwent EXC. The upgrade rate was 2.3% (4 of 171). The upgraded lesions were 2 invasive lobular carcinomas and 2 cases of ductal carcinoma in situ (DCIS). One case of DCIS involved the residual IDP, whereas the other 3 carcinomas were ≥ 8 mm away. Twenty-four women (25 IDPs) did not undergo EXC and had stable imaging on follow-up (median, 23.5 months).

Conclusions: The upgrade rate at EXC for IDPs diagnosed at CNB with radiologic-pathologic concordance was 2.3%. These findings suggest that observation is appropriate for patients with radiologic-pathologic concordant CNB yielding IDP, regardless of its size. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2819-2827. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014573PMC
September 2016

Detection of HER2-Positive Metastases in Patients with HER2-Negative Primary Breast Cancer Using 89Zr-Trastuzumab PET/CT.

J Nucl Med 2016 Oct 5;57(10):1523-1528. Epub 2016 May 5.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York Department of Radiology, Weill Cornell Medical College, New York, New York.

Our objective was to determine whether imaging with a human epidermal growth factor receptor 2 (HER2)-targeted PET tracer can detect HER2-positive metastases in patients with HER2-negative primary breast cancer.

Methods: Patients with HER2-negative primary breast cancer and evidence of distant metastases were enrolled in an Institutional Review Board-approved prospective clinical trial. Archived pathologic samples from the patient's primary breast cancer were retested to confirm HER2-negative disease. Patients with confirmed HER2-negative primary breast cancer underwent Zr-trastuzumab PET/CT to screen for Zr-trastuzumab metastases. Metastases avid for Zr-trastuzumab by PET/CT were biopsied and pathologically examined to define HER2 status. Patients with pathologically proven HER2-positive metastases subsequently received off-protocol HER2-targeted therapy to evaluate treatment response.

Results: Nine patients were enrolled, all of whom had pathologic retesting that confirmed HER2-negative primary breast cancer. Five demonstrated suggestive foci on Zr-trastuzumab PET/CT. Of these 5 patients, 2 had biopsy-proven HER2-positive metastases and went on to benefit from HER2-targeted therapy. In the other 3 patients, biopsy showed no evidence of HER2-positive disease, and their foci on Zr-trastuzumab PET were considered false-positive.

Conclusion: In this proof-of-concept study, we demonstrated that Zr-trastuzmab PET/CT detects unsuspected HER2-positive metastases in patients with HER2-negative primary breast cancer. Although these are only initial results in a small sample, they are a proof of the concept that HER2-targeted imaging can identify additional candidates for HER2-targeted therapy. More specific HER2-targeted agents will be needed for clinical use.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5050126PMC
http://dx.doi.org/10.2967/jnumed.115.172031DOI Listing
October 2016

Acinic cell carcinoma of breast: morphologic and immunohistochemical review of a rare breast cancer subtype.

Hum Pathol 2016 May 7;51:16-24. Epub 2016 Jan 7.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065.

Acinic cell carcinoma of breast is a rare subtype of triple-negative breast carcinoma and demonstrates extensive morphologic overlap with acinic cell carcinoma of the salivary gland. In this study, we perform a detailed morphologic and immunohistochemical description of 2 cases of this rare entity and undertake a comprehensive review of all reported cases of breast acinic cell carcinoma in the English language literature to date. One-third of reported cases of breast acinic cell carcinoma have been associated with the presence of a ductal carcinoma not otherwise specified component, which is frequently poorly differentiated. Breast acinic cell carcinoma can demonstrate focal morphologic features similar to microglandular adenosis; these areas are frequently negative for collagen IV and laminin on immunohistochemistry. The true relationship between these 2 entities remains unclear, but we advocate that microglandular adenosis-like areas at the periphery of a breast acinic cell carcinoma should be considered part of the carcinomatous process and re-excised if this process extends to the initial surgical margins.
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http://dx.doi.org/10.1016/j.humpath.2015.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027139PMC
May 2016

Breast Carcinoma in Young Women: No Evidence of Increasing Rates of Metastatic Breast Carcinoma in a Single Tertiary Center Review.

Breast J 2016 May 29;22(3):287-92. Epub 2016 Feb 29.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

Breast carcinoma in young women aged less than 40 years attracts a high level of mainstream media coverage, and there is a gap between societal perceptions of the disease as a growing problem and epidemiological trends. Several population studies have reported that the overall incidence of breast carcinoma in young women is stable, while one recent article suggested that the relative proportion of breast carcinoma in young women that is metastatic at diagnosis is growing. We sought to establish whether these trends were apparent at our institution. In this study, the clinical database at a breast carcinoma tertiary center was reviewed in terms of clinicopathologic data on patient age, diagnosis, clinical and pathologic stage, hormone receptor status, and HER-2 overexpression status for the period 2000-2011. Over the study period, young patients represented a decreasing proportion of all breast carcinoma cases (10.8% [2000-2003] to 8.7% [2008-2011]; p < 0.0001) treated at our institution. Young patients were more likely than patients aged 40 years or older to present with metastatic (M1) disease (5.4% versus 4.4%; p = 0.009), to be triple negative (21.6% versus 13%; p < 0.001), or to be HER-2 positive (24.3% versus 14.8%; p < 0.01). Young patients with HER-2-positive cancers were significantly more likely to present with metastatic disease (8.3% versus 4.8%; p = 0.004). This study showed no demonstrable increase in the relative proportion of breast cancer occurring in patients aged <40 years over the 12-year period 2000-2011 and no increase in the proportion of young patients presenting with metastatic disease.
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http://dx.doi.org/10.1111/tbj.12575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558606PMC
May 2016

Biomarkers That Predict Sensitivity to Heat Shock Protein 90 Inhibitors.

Clin Breast Cancer 2016 08 19;16(4):276-83. Epub 2015 Nov 19.

Memorial Sloan Kettering Cancer Center, New York, NY.

Introduction: Heat shock protein (HSP) 90, a viable target for cancer treatment, mediates the maturation and stabilization of client oncoproteins. HSP90 inhibitors (HSP90i) are potentially active in a variety of tumors, but therapeutic benefit is confirmed in only a small subset. We explored potential biomarkers across multiple studies of HSP90i in advanced solid tumors.

Patients And Methods: Archived tumor specimens from patients treated with HSP90i in 7 different phase I/II trials at Memorial Sloan Kettering Cancer Center were identified. Tumor tissue was tested using immunohistochemistry; estrogen, progesterone, and androgen receptors ≥ 1% positive and < 1% negative; HSP90 and HSP70: 0, 1 + negative, and 2+, 3 + positive; phosphatase and tensin homolog: 0 negative, 1 reduced, and 2 positive; HER2: 0, 1 + negative, 2 + equivocal, 3 + positive; and epidermal growth factor receptor: 0 negative, and 1+, 2+, 3 + positive. The expression of the biomarker panel was correlated with clinical benefit (CB) (defined by overall response [ORR] or CB by the "8-week" scan) using Fisher exact test.

Results: Adequate tissue was available for 51 of 158 patients (32%), including 10 different solid tumors. Of these, 71% (36 of 51) and 51% (26 of 51) patients met the criteria to assess CB by best ORR or by the "8-week scan" assessment, respectively. Breast was the most frequent tumor. The mean duration of HSP90i therapy was 55 days (range, 16-411 days). There were 16 responses (4 partial response; 12 stable disease); 13 of 16 responses strongly correlated with HER2-positive status (P = .001).

Conclusion: Our findings suggest HER2 as a sensitive client and perhaps the only effective biomarker for sensitivity to these HSP90i.
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http://dx.doi.org/10.1016/j.clbc.2015.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242238PMC
August 2016

Spontaneously-forming spheroids as an in vitro cancer cell model for anticancer drug screening.

Oncotarget 2015 Aug;6(25):21255-67

Department of Chemistry and Biochemistry, University of California - San Diego, La Jolla, CA, USA.

The limited translational value in clinic of analyses performed on 2-D cell cultures has prompted a shift toward the generation of 3-dimensional (3-D) multicellular systems. Here we present a spontaneously-forming in vitro cancer spheroid model, referred to as spheroids(MARY-X), that precisely reflects the pathophysiological features commonly found in tumor tissues and the lymphovascular embolus. In addition, we have developed a rapid, inexpensive means to evaluate response following drug treatment where spheroid dissolution indices from brightfield image analyses are used to construct dose-response curves resulting in relevant IC50 values. Using the spheroids(MARY-X) model, we demonstrate the unique ability of a new class of molecules, containing the caged Garcinia xanthone (CGX) motif, to induce spheroidal dissolution and apoptosis at IC50 values of 0.42 +/-0.02 μM for gambogic acid and 0.66 +/-0.02 μM for MAD28. On the other hand, treatment of spheroids(MARY-X) with various currently approved chemotherapeutics of solid and blood-borne cancer types failed to induce any response as indicated by high dissolution indices and subsequent poor IC50 values, such as 7.8 +/-3.1 μM for paclitaxel. Our studies highlight the significance of the spheroids(MARY-X) model in drug screening and underscore the potential of the CGX motif as a promising anticancer pharmacophore.
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http://dx.doi.org/10.18632/oncotarget.4013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673263PMC
August 2015

Appearance of untreated bone metastases from breast cancer on FDG PET/CT: importance of histologic subtype.

Eur J Nucl Med Mol Imaging 2015 Oct 14;42(11):1666-1673. Epub 2015 May 14.

Department of Radiology, Weill Cornell Medical College, New York, NY, USA.

Purpose: To determine if the histology of a breast malignancy influences the appearance of untreated osseous metastases on FDG PET/CT.

Methods: This retrospective study was performed under IRB waiver. Our Hospital Information System was screened for breast cancer patients who presented with osseous metastases, who underwent FDG PET/CT prior to systemic therapy or radiotherapy from 2009 to 2012. Patients with invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), or mixed ductal/lobular (MDL) histology were included. Patients with a history of other malignancies were excluded. PET/CT was evaluated, blinded to histology, to classify osseous metastases on a per-patient basis as sclerotic, lytic, mixed lytic/sclerotic, or occult on CT, and to record SUVmax for osseous metastases on PET.

Results: Following screening, 95 patients who met the inclusion criteria (74 IDC, 13 ILC, and 8 MDL) were included. ILC osseous metastases were more commonly sclerotic and demonstrated lower SUVmax than IDC metastases. In all IDC and MDL patients with osseous metastases, at least one was FDG-avid. For ILC, all patients with lytic or mixed osseous metastases demonstrated at least one FDG-avid metastasis; however, in only three of seven patients were sclerotic osseous metastases apparent on FDG PET.

Conclusion: The histologic subtype of breast cancer affects the appearance of untreated osseous metastases on FDG PET/CT. In particular, non-FDG-avid sclerotic osseous metastases were more common in patients with ILC than in patients with IDC. Breast cancer histology should be considered when interpreting non-FDG-avid sclerotic osseous lesions on PET/CT, which may be more suspicious for metastases (rather than benign lesions) in patients with ILC.
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http://dx.doi.org/10.1007/s00259-015-3080-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558334PMC
October 2015

Radial Scar at Image-guided Needle Biopsy: Is Excision Necessary?

Am J Surg Pathol 2015 Jun;39(6):779-85

Departments of *Pathology †Radiology, Memorial Sloan Kettering Cancer Center, New York, NY.

Optimal management of a lesion yielding radial scar (RS) without epithelial atypia on breast biopsy is controversial. In this single-institution study spanning 17 years, 53 patients with this biopsy diagnosis were evaluated in terms of clinical, radiologic, and pathologic features and outcomes. RSs were categorized as either "incidental" or as the "targeted" lesion according to defined criteria. Of 48 patients who underwent surgical excision after a diagnosis of RS on biopsy, only 1 had an "upgrade" diagnosis of malignancy (2%). No "incidental" RS was associated with the presence of malignancy on surgical excision. Meta-analysis of 20 RS excision studies demonstrated an overall upgrade rate of 10.4%, with a higher rate in patients with a diagnosis of RS with atypia (26%). The upgrade rate for RS without atypia was 7.5% overall. The lower rate of upgrade to malignancy in this study (2%) is likely related to the thorough radiologic-pathologic review undertaken. In the setting of multidisciplinary agreement and careful radiologic-pathologic correlation, it may be appropriate for patients with a biopsy diagnosis of RS without atypia to forego surgical excision in favor of imaging follow-up.
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http://dx.doi.org/10.1097/PAS.0000000000000393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012304PMC
June 2015

Ex vivo treatment response of primary tumors and/or associated metastases for preclinical and clinical development of therapeutics.

J Vis Exp 2014 Oct 2(92):e52157. Epub 2014 Oct 2.

Department of Surgery, Memorial Sloan Kettering Cancer Center;

The molecular analysis of established cancer cell lines has been the mainstay of cancer research for the past several decades. Cell culture provides both direct and rapid analysis of therapeutic sensitivity and resistance. However, recent evidence suggests that therapeutic response is not exclusive to the inherent molecular composition of cancer cells but rather is greatly influenced by the tumor cell microenvironment, a feature that cannot be recapitulated by traditional culturing methods. Even implementation of tumor xenografts, though providing a wealth of information on drug delivery/efficacy, cannot capture the tumor cell/microenvironment crosstalk (i.e., soluble factors) that occurs within human tumors and greatly impacts tumor response. To this extent, we have developed an ex vivo (fresh tissue sectioning) technique which allows for the direct assessment of treatment response for preclinical and clinical therapeutics development. This technique maintains tissue integrity and cellular architecture within the tumor cell/microenvironment context throughout treatment response providing a more precise means to assess drug efficacy.
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http://dx.doi.org/10.3791/52157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315621PMC
October 2014

The extent of extracapsular extension may influence the need for axillary lymph node dissection in patients with T1-T2 breast cancer.

Ann Surg Oncol 2014 Sep 29;21(9):2897-903. Epub 2014 Apr 29.

Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Whether extracapsular extension (ECE) of tumor in the sentinel lymph node (SLN) is an indication for axillary lymph node dissection (ALND) in patients managed by American College of Surgeons Oncology Group Z0011 criteria is controversial. Here we examine the correlation between ECE in the SLN and disease burden in the axilla.

Methods: Patients meeting Z0011 clinicopathologic criteria (pT1-2, cN0 with <3 positive SLNs) were selected from a prospectively maintained database (2006-2013). Chart review documented the presence and extent of ECE. Neoadjuvant chemotherapy patients were excluded. Comparisons were made by presence and extent (≤2 vs. >2 mm) of ECE.

Results: Of 11,730 patients, 778 were pT1-2, cN0 with <3 positive SLNs without ECE, and 331 (2.8 %) had ECE. Of these, 180 had ≤2 mm and 151 had >2 mm of ECE. Patients with ECE were older (57 vs. 54 years; p = 0.001) and had larger (2.0 vs. 1.7 cm; p < 0.0001), multifocal (p = 0.006), hormone receptor-positive tumors (p = 0.0164) with lymphovascular invasion (p < 0.0001). Presence and extent of ECE were associated with greater axillary disease burden; 20 and 3 % of patients with and without ECE, respectively, had ≥4 additional positive nodes at completion ALND (p < 0.0001), and 33 % of patients with >2 mm ECE had ≥4 additional positive nodes at completion ALND, compared with 9 % in the <2 mm group (p < 0.0001). On multivariate analysis, >2 mm of ECE was the strongest predictor of ≥4 positive nodes at completion ALND (odds ratio 14.2).

Conclusions: Presence and extent of ECE were significantly correlated with nodal tumor burden at completion ALND, thus suggesting that >2 mm of ECE may be an indication for ALND or radiotherapy when applying Z0011 criteria to patients with metastases in <3 SLNs. ECE reporting should be standardized to facilitate future studies.
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http://dx.doi.org/10.1245/s10434-014-3752-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346337PMC
September 2014

Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions.

Expert Opin Investig Drugs 2014 May 26;23(5):611-28. Epub 2014 Mar 26.

New York University Cancer Institute, NYU Clinical Cancer Center, Division of Hematology/Medical Oncology , NY , USA.

Introduction: Heat shock protein 90 (HSP90) serves as a critical facilitator for oncogene addiction. There has been augmenting enthusiasm in pursuing HSP90 as an anticancer strategy. In fact, since the initial serendipitous discovery that geldanamycin (GM) inhibits HSP90, the field has rapidly moved from proof-of-concept clinical studies with GM derivatives to novel second-generation inhibitors.

Areas Covered: The authors highlight the current status of the second-generation HSP90 inhibitors in clinical development. Herein, the authors note the lessons learned from the completed clinical trials of first- and second-generation inhibitors and describe various assays attempting to serve for a more rational implementation of these agents to cancer treatment. Finally, the authors discuss the future perspectives for this promising class of agents.

Expert Opinion: The knowledge gained thus far provides perhaps only a glimpse at the potential of HSP90 for which there is still much work to be done. Lessons from the clinical trials suggest that HSP90 therapy would advance at a faster pace if patient selection and tumor pharmacokinetics of these drugs were better understood and applied to their clinical development. It is also evident that combining HSP90 inhibitors with other potent anticancer therapies holds great promise not only due to synergistic antitumor activity but also due to the potential of prolonging or preventing the development of drug resistance.
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http://dx.doi.org/10.1517/13543784.2014.902442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161020PMC
May 2014

Time to change the way we diagnose mucinous carcinomas of breast--reply.

Hum Pathol 2014 Feb 21;45(2):435. Epub 2013 Nov 21.

Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA.

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http://dx.doi.org/10.1016/j.humpath.2013.09.021DOI Listing
February 2014

Reversed MUC1/EMA polarity in both mucinous and micropapillary breast carcinoma--reply.

Hum Pathol 2014 Feb 7;45(2):434. Epub 2013 Nov 7.

Department of Pathology Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

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http://dx.doi.org/10.1016/j.humpath.2013.08.025DOI Listing
February 2014

Surgical margins in breast conservation.

Int J Surg 2013 ;11 Suppl 1:S69-72

Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.

Breast cancer is the most common tumor affecting women worldwide. Breast-conserving therapy (BCT) followed by irradiation nowadays is the treatment of choice for early-stage disease; there is no difference in long-term survival between mastectomy and BCT combined with external radiotherapy. A positive margin is associated with increased risk of local recurrences after BCT for invasive breast cancer and ductal carcinoma in situ. The exact definition of an adequate surgical margin after breast cancer resection has long been debated among physicians and represents an area of considerable variation in clinical practice. There is a lack of standardization in the pathology methods of margin evaluation, which yields little consensus regarding what constitutes an adequate negative margin. As a consequence, patient management varies widely based on the threshold that surgeons accept for adequate margins and the subsequent need for re-excision. We analyze and discuss recent literature about this topic both from the pathological and from the surgical point of view.
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http://dx.doi.org/10.1016/S1743-9191(13)60021-7DOI Listing
October 2014

Management of breast cancer during pregnancy.

Int J Surg 2013 ;11 Suppl 1:S64-8

Unit of General Surgery, Circolo Teaching Hospital, University of Insubria, Varese, Italy.

Introduction: Pregnancy-associated breast cancer (PABC) is one of the most common malignancies during pregnancy. Since maternal age at the time of pregnancy is increasing, PABC rate is expected to increase. Diagnostic delays are common.

Methods: Retrospective observational study analysing twelve pregnant patients with breast cancer who underwent surgical treatment during the period of February 2006 to June 2013 at the Department of Surgery I, University of Insubria Varese.

Results: The median age of pregnant patients was 34 y (range 28-44 y). Three patients were affected by BRCA1 mutation. In six patients diagnosis was made during gestation, in the other six patients breast cancer was discovered during breastfeeding. Ten patients underwent breast-conserving surgery. Sentinel lymph node biopsy was performed in six patients; in one of them it was positive so axillary dissection was simultaneuosly performed. Six patients underwent axillary dissection ab initio. In all cases the histological type was invasive ductal carcinoma; grade 3 in ten patients and grade 2 in two patients. Eleven of twelve patients received adjuvant chemotherapy, one patient both adjuvant and neoadjuvant. In three cases also radiation therapy was performed after delivery. In all cases healthy babies were born. Nine of twelve patients are still alive and disease free, after a median follow-up of 20 months (range 3-52 months). Three patients died from systemic progression of the disease.

Conclusion: There are no significant series of patients in worldwide literature to develop standard protocols. Pregnant women must be followed by a multidisciplinary team.
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http://dx.doi.org/10.1016/S1743-9191(13)60020-5DOI Listing
October 2014

Pathologic response and long-term follow-up in breast cancer patients treated with neoadjuvant chemotherapy: a comparison between classifications and their practical application.

Arch Pathol Lab Med 2013 Aug;137(8):1074-82

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Context: Breast cancer is increasingly treated with neoadjuvant chemotherapy to improve surgical resectability and evaluate tumor response, which is assessed histopathologically. Several histopathologic classification systems have been previously described for assessment of treatment response.

Objectives: To test performance in a side-by-side comparison of several histopathologic classification systems after neoadjuvant chemotherapy with clinical outcome.

Design: Sixty-two patients were enrolled in a randomized trial receiving sequential neoadjuvant chemotherapy with doxorubicin and paclitaxel. Histologic sections from the patients' tumors sampled before (core biopsy) and after treatment (excision or mastectomy) were reviewed. Histologic response was assessed following National Surgical Adjuvant Breast and Bowel Project protocol B18, Miller-Payne grading, Sataloff tumor and nodes, Residual Cancer Burden (RCB), and Residual Disease in Breast and Nodes (RDBN). Pathologic classification results were correlated with survival using Kaplan-Meier and Cox hazards regression with a median follow-up of 93 months.

Results: RDBN was associated with distant disease-free survival by univariate and multivariate analysis (P = .01 and .004, respectively), as were lymph node metastases (P = .02 and .01, respectively). Five patients (8%) had complete pathologic response after neoadjuvant chemotherapy, and none of them relapsed during the study period. Survival was shorter among patients with higher Residual Cancer Burden scores, but the associations were not significant. Miller-Payne grading and Sataloff tumor scores were not correlated with survival.

Conclusions: Evaluation of breast specimens after neoadjuvant chemotherapy by the composite index RDBN correlates with long-term outcome. The residual disease in breast and nodes system is suitable for routinely processed pathology cases. This study confirms the importance of lymph node status after neoadjuvant chemotherapy and favorable outcome in patients with pathologic complete response.
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http://dx.doi.org/10.5858/arpa.2012-0290-OADOI Listing
August 2013

Focal extravasated mucin in breast core needle biopsies: is surgical excision always necessary?

Breast J 2013 May-Jun;19(3):302-9. Epub 2013 Mar 28.

Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York City, NY, USA.

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.
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http://dx.doi.org/10.1111/tbj.12104DOI Listing
November 2013

Mucinous micropapillary carcinoma of the breast: an aggressive counterpart to conventional pure mucinous tumors.

Hum Pathol 2013 Aug 19;44(8):1577-85. Epub 2013 Mar 19.

Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

Mucinous micropapillary carcinoma of the breast, also described as "pure mucinous carcinoma with micropapillary pattern," has recently come to attention as an unusual form of invasive breast cancer exhibiting dual mucinous and micropapillary differentiation. Despite increasing awareness of this morphologic variant, its clinical significance has not yet been elucidated. Here, we present 15 additional examples of these rare tumors to highlight some important differences between mucinous micropapillary carcinoma of the breast and ordinary pure mucinous carcinomas. The key features of mucinous micropapillary carcinoma of the breast included (a) largely or entirely mucinous appearance (>90% mucinous morphology), (b) distinctive micropapillary arrangement of the neoplastic cells, (c) intermediate to high nuclear grade, (d) "hobnail" cells, and (e) frequent psammomatous calcifications. In contrast to ordinary pure mucinous carcinomas, 20% of mucinous micropapillary carcinomas of the breast were characterized by human epidermal growth factor receptor 2 positivity, and 23% were p53 positive. More than half of mucinous micropapillary carcinomas of the breast (60%) demonstrated lymphovascular invasion, sometimes extensive. Synchronous axillary lymph node metastases were detected in 33% of patients and, on 2 occasions, involved more than 10 nodes. With a median follow-up of 4.5 years, we identified 1 patient (7%) with chest wall recurrence of mucinous micropapillary carcinoma of the breast after mastectomy. We conclude that mucinous micropapillary carcinomas of the breast constitute a clinically aggressive subset of mucin-producing breast carcinomas characterized by an increased capacity for lymphatic invasion and regional lymph node metastasis, reflective of their dual phenotype. Recognition of the morphologic and biologic heterogeneity within breast cancer subtypes should allow for a more accurate classification of the individual tumors and better patient stratification for treatment.
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http://dx.doi.org/10.1016/j.humpath.2013.01.003DOI Listing
August 2013

Pathology of invasive breast disease.

Authors:
Adriana D Corben

Surg Clin North Am 2013 Apr 13;93(2):363-92. Epub 2013 Feb 13.

Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

Invasive breast cancers constitute a heterogeneous group of lesions. Although the most common types are ductal and lobular, this distinction is not meant to indicate the site of origin within the mammary ductal system. The main purpose of the identification of specific types of invasive breast carcinoma is to refine the prediction of likely behavior and response to treatment also offered by the other major prognostic factors, including lymph node stage, histologic grade, tumor size, and lymphovascular invasion.
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http://dx.doi.org/10.1016/j.suc.2013.01.003DOI Listing
April 2013

Non-mammary metastases to the breast and axilla: a study of 85 cases.

Mod Pathol 2013 Mar 23;26(3):343-9. Epub 2012 Nov 23.

Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

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.
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http://dx.doi.org/10.1038/modpathol.2012.191DOI Listing
March 2013