It is our great privilege to write the editorial for the second special section of the Princeton Integrated Pathology Symposium for Archives of Pathology & Laboratory Medicine. The following 8 review articles are derived from lectures presented at the Second Princeton Integrated Pathology Symposium: Breast Pathology, which attracted more than 120 attendees to our venue at the University Medical Center of Princeton, Plainsboro, New Jersey, on February 8, 2015. In line with our previous special section published in the December 2015 issue, we again focus on both “bread-and-butter” and “zebra” topics.

The 4 articles making up part 1 share diagnostic pearls and pitfalls of common yet challenging breast lesions.

Histologic classification of papillary lesions of the breast is often diagnostically difficult. Wei discusses the histologic, immunohistochemical, and prognostic features of papillary lesions, including the intraductal papilloma, papilloma harboring atypical ductal hyperplasia and ductal carcinoma in situ (DCIS), intraductal papillary carcinoma (papillary DCIS), encapsulated papillary carcinoma, solid papillary carcinoma, and invasive papillary carcinoma. The epithelial displacement phenomenon, not infrequently encountered after needling procedures of papillary lesions, is highlighted as a potential pitfall in its histologic mimicry of invasive disease. How best to stage encapsulated papillary carcinoma is still debatable, though current recommendation is for classification as in situ disease unless an invasive component is identified, which is then graded and staged separately. As solid papillary carcinoma may encompass both in situ and invasive categories, its diagnosis should be accompanied by clarification of its noninvasive or invasive nature.1 

Secretory and mucinous lesions of the breast consist of a spectrum of pathologic changes and may be diagnostically challenging. Toll et al categorize these lesions into 4 groups according to their biological nature (nonneoplastic versus neoplastic) and location of the secretions/mucin (intraluminal versus extravasated), an approach that appears practical and effective. The authors also highlight useful histologic, immunohistochemical, and molecular characteristics that can assist in differentiating lesions, such as pseudolactational changes, cystic hypersecretory hyperplasia, cystic hypersecretory carcinoma, and secretory carcinoma.

Ginter et al review the differential diagnoses and interpretative pitfalls of small glandular proliferations with absent or attenuated immunohistochemical reactivity for myoepithelial markers. In particular, nonmalignant lesions that may mimic invasive carcinoma because of their lack of myoepithelial cells deserve attention. Microglandular adenosis, with its permeative pattern of small glands and absence of myoepithelial cells, is a major diagnostic hazard, especially on limited core biopsy samples. It is characterized by positive S100, negative estrogen receptor (ER), and negative progesterone receptor (PR) immunohistochemical stains and positive basement membrane stains such as collagen type IV and laminin, contrasting with tubular carcinoma, for which it is often mistaken. Epithelial displacement, which may or may not be accompanied by immunohistochemically identified myoepithelial cells, can be recognized by its out-of-place epithelial/glandular clusters, reactive granulation tissue–like stroma, biopsy site changes, and a history of recent or concurrent surgery/biopsy. The authors also note that the benign radial scar may disclose glands in its center that have diminished or no myoepithelial cells. Finally, the syringomatous adenoma (referred to as syringomatous tumor by the World Health Organization Working Group),2  commonly located in the nipple and superficial subareolar region, comprises infiltrating tadpole- or comma-shaped nests of cells that can have variable results on immunohistochemical staining for myoepithelial cells.

Phyllodes tumors are an uncommon group of fibroepithelial neoplasms that are graded into benign, borderline, and malignant categories. Zhang and Kleer summarize the commonly used diagnostic criteria for grading, namely stromal cellularity, stromal atypia, mitotic activity (<5, 5–9, and >9 mitoses per 10 high-power fields as the cutoffs), stromal overgrowth, and nature of the tumor borders. The recent discovery of recurrent MED12 mutations in both fibroadenomas and phyllodes tumors has given new insights into their molecular pathogenesis. Additionally, epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF1R) amplifications and tumor protein p53 (TP53), retinoblastoma 1 (Rb1), and neurofibromin 1 (NF1) mutations are present in borderline and malignant phyllodes tumors, but are absent in benign phyllodes tumors and fibroadenomas. These molecular signatures may be helpful for distinguishing the different fibroepithelial neoplasms.

Part 2 of this special section, which will appear in the August 2016 issue, consists of 4 articles focusing on the classification and management of breast carcinomas (BCs).

Maguire and Brogi present a systematic review of recent clinical and pathologic studies of sentinel lymph nodes that have led to a paradigm shift in axillary management practices for invasive BC. The 4 clinical trials included in their analysis agree that addition of axillary lymph node dissection (ALND) does not offer better overall or disease-free survivals for patients with T1/T2 and clinical N0 tumors than sentinel lymph node biopsy alone in those treated by a combination of breast conservation surgery, whole-breast irradiation, and systemic therapy. A useful algorithm is also provided to illustrate their approach to managing patients with T1/T2 disease who are clinically node negative. Given the considerable morbidity associated with ALND and no significant survival benefits, it is timely to consider omitting ALND in selected patients within a multidisciplinary management setting.

Yang and Fu provide an update on invasive micropapillary carcinoma (IMPC) of the breast, which confers a dismal prognosis and is accompanied by a high frequency of lymphovascular invasion and lymph node metastasis. These tumors are characterized by morule-like nests of malignant cells rimmed by clear spaces around the tumor clusters. They also have a unique inside-out immunohistochemical staining pattern of epithelial membrane antigen (EMA)/mucin 1 (MUC1) and sialyl Lewis X. Cellular and molecular mechanisms of metastatic behavior of IMPC are summarized, which may promote better understanding and treatment of this unusual subtype of BC.

Tang and Tse describe immunohistochemical surrogates for the intrinsic molecular subtypes of BC using ER, PR, HER2/neu, Ki67, CK5, and EGFR, with androgen receptor and p53 being more recently added to the list of markers for molecular stratification. Relevant clinical correlations of these molecular subtypes, as well as the limitations of using immunohistochemical surrogates, are discussed, with a call for continued efforts toward standardization of terminologies, immunohistochemical panels, and cutoffs.

Routine testing for ER, PR, and human epidermal growth factor receptor 2 (HER2/neu or ERBB2) is critical for invasive BC prognostication and management. In this article, Hagemann expands on the indications, test platforms, and data interpretation of various available and emerging molecular tests. Advantages and disadvantages of tumor profiling using next-generation sequencing are discussed. Next-generation sequencing, a high-throughput modality, is able to detect all 4 canonical classes of genetic variations and sequence multiple genes in a single test. Next-generation sequencing could be both cost and time effective but it has not yet been validated for clinical use. On the other hand, multianalyte assays with algorithmic analysis (MAAAs) have been applied for routine clinical care for years. Benefits and limitations of the 3 major platforms, MammaPrint, Oncotype DX, and Prosigna, are discussed in detail. The article also addresses the potential reimbursement issue of MAAAs, which may be interesting and relevant to practicing pathologists and laboratory managers. Finally, germline testing for hereditary BC is pertinent for affected patients and their relatives. These topics are comprehensively reviewed.

In summary, this special section discusses diagnostic issues concerning papillary lesions, secretory and mucinous lesions, small glandular proliferations, and phyllodes tumors of the breast, as well as provide timely updates on sentinel lymph node evaluation of BC, IMPC, immunohistochemical surrogates for molecular classification of BC, and molecular testing of BC. It is hoped that our readers will use these articles, particularly their informative tables and figures, as a handy reference in their daily practice.

We wish to thank Archives Editor in Chief, Philip T. Cagle, MD; the advisory committee members of the Princeton Integrated Pathology Symposium; authors; and reviewers for their time and efforts. We are also grateful to Patrick H. Kearns, Katie Giesen, and Hilary Price at the editorial office of Archives of Pathology & Laboratory Medicine, and James Demetriades, BS, MBA, Elliot A. Krauss, MD, and Rachel P. Dultz, MD, at Princeton HealthCare System (Plainsboro, New Jersey). The exceptional team made the production of this special section possible.

1
Tan
PH,
Schnitt
SJ,
van de Vijver
MJ,
Ellis
IO,
Lakhani
SR.
Papillary and neuroendocrine breast lesions: the WHO stance
.
Histopathology
.
2015
;
66
(
6
):
761
770
.
2
Eusebi
V,
Lester
S.
Syringomatous tumor
.
In
:
Lakhani
SR,
Ellis
IO,
Schnitt
SJ,
Tan
PH,
van de Vijver
MJ,
eds
.
WHO Classification of Tumours of the Breast
.
Lyon, France
:
IARC;
2012
:
151. World Health Organization Classification of Tumours; vol 4.

Puay Hoon Tan, MD

 Puay Hoon Tan, MD, is senior consultant histopathologist and head, Department of Pathology, Singapore General Hospital, and chair of the Pathology Academic Clinical Program, SingHealth-Duke-NUS Academic Medical Center, Singapore. She has active interests in breast, urologic, and renal pathology, and was a volume editor of the 2012 WHO Classification of Tumours of the Breast. She sits on the editorial boards of Modern Pathology, Breast Cancer Research, Journal of Clinical Pathology, Pathology, Seminars in Diagnostic Pathology, and Analytical and Quantitative Cytology and Histology. She is associate editor of Histopathology and the Singapore Medical Journal. Apart from a busy service largely focused on subspecialty surgical sign-outs, she and her collaborators are recipients of several research grants related to translational studies of breast and prostate cancer. She is the author of close to 400 publications, and participates regularly in regional and international meetings.

 Dr Tan's research interests in breast pathology center around the classification of breast fibroepithelial lesions and their molecular pathogenesis, triple-negative breast cancers, and ductal carcinoma in situ. In urologic pathology, she is engaged in prostate and renal cancer studies and is a contributor to the 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs.

 She is the immediate past president of the International Society of Breast Pathology, and was Councilor for Asia of the International Society of Urological Pathology until 2015.

Puay Hoon Tan, MD

 Puay Hoon Tan, MD, is senior consultant histopathologist and head, Department of Pathology, Singapore General Hospital, and chair of the Pathology Academic Clinical Program, SingHealth-Duke-NUS Academic Medical Center, Singapore. She has active interests in breast, urologic, and renal pathology, and was a volume editor of the 2012 WHO Classification of Tumours of the Breast. She sits on the editorial boards of Modern Pathology, Breast Cancer Research, Journal of Clinical Pathology, Pathology, Seminars in Diagnostic Pathology, and Analytical and Quantitative Cytology and Histology. She is associate editor of Histopathology and the Singapore Medical Journal. Apart from a busy service largely focused on subspecialty surgical sign-outs, she and her collaborators are recipients of several research grants related to translational studies of breast and prostate cancer. She is the author of close to 400 publications, and participates regularly in regional and international meetings.

 Dr Tan's research interests in breast pathology center around the classification of breast fibroepithelial lesions and their molecular pathogenesis, triple-negative breast cancers, and ductal carcinoma in situ. In urologic pathology, she is engaged in prostate and renal cancer studies and is a contributor to the 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs.

 She is the immediate past president of the International Society of Breast Pathology, and was Councilor for Asia of the International Society of Urological Pathology until 2015.

Lanjing Zhang, MD, MS

 Lanjing “L.J.” Zhang, MD, MS, is the gastrointestinal and liver pathology director at University Medical Center of Princeton at Plainsboro, New Jersey, an associate member of Rutgers Cancer Institute of New Jersey, and a clinical assistant professor of pathology and laboratory medicine at Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey. He also regularly teaches cancer molecular biology at Princeton University, Princeton, New Jersey, and mentors graduate students from Rutgers School of Public Health, Piscataway, New Jersey.

 His research and clinical interest is focused on gastrointestinal and breast pathology, particularly the clinical epidemiology and carcinogenesis of colorectal and breast cancers. Given the ever-changing reimbursement environment, his recent work also concerns the economics of pathology and laboratory services. Dr Zhang has published more than 30 peer-reviewed articles, has mentored more than 7 undergraduate and graduate students, and is a co–principal investigator of a Rutgers University Initiative for Multidisciplinary Research Teams grant. He was a recipient of a resident subspecialty grant from the American Society of Clinical Pathology and several unrestricted educational grants. His editorial experiences include serving as executive editor-in-chief of American Journal of Digestive Disease, associate editor of Journal of Clinical and Translational Hepatology, section editor of Stem Cell Investigation, and academic editor of PLoS One, and editorial board membership on Medicine, Scientific Reports, Experimental Hematology and Oncology, Gastrointestinal Endoscopy, and North American Journal of Medicine and Science. He serves on the International Expert Panel of National Medical Research Council of Singapore after having been an ad hoc grant reviewer with them for 8 years. He has also reviewed grant proposals for the Center for the Advancement of Science in Space (National Aeronautics and Space Administration) and for the National Science Foundation of China. Dr Zhang serves as an associate editor for the Archives of Pathology & Laboratory Medicine.

Lanjing Zhang, MD, MS

 Lanjing “L.J.” Zhang, MD, MS, is the gastrointestinal and liver pathology director at University Medical Center of Princeton at Plainsboro, New Jersey, an associate member of Rutgers Cancer Institute of New Jersey, and a clinical assistant professor of pathology and laboratory medicine at Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey. He also regularly teaches cancer molecular biology at Princeton University, Princeton, New Jersey, and mentors graduate students from Rutgers School of Public Health, Piscataway, New Jersey.

 His research and clinical interest is focused on gastrointestinal and breast pathology, particularly the clinical epidemiology and carcinogenesis of colorectal and breast cancers. Given the ever-changing reimbursement environment, his recent work also concerns the economics of pathology and laboratory services. Dr Zhang has published more than 30 peer-reviewed articles, has mentored more than 7 undergraduate and graduate students, and is a co–principal investigator of a Rutgers University Initiative for Multidisciplinary Research Teams grant. He was a recipient of a resident subspecialty grant from the American Society of Clinical Pathology and several unrestricted educational grants. His editorial experiences include serving as executive editor-in-chief of American Journal of Digestive Disease, associate editor of Journal of Clinical and Translational Hepatology, section editor of Stem Cell Investigation, and academic editor of PLoS One, and editorial board membership on Medicine, Scientific Reports, Experimental Hematology and Oncology, Gastrointestinal Endoscopy, and North American Journal of Medicine and Science. He serves on the International Expert Panel of National Medical Research Council of Singapore after having been an ad hoc grant reviewer with them for 8 years. He has also reviewed grant proposals for the Center for the Advancement of Science in Space (National Aeronautics and Space Administration) and for the National Science Foundation of China. Dr Zhang serves as an associate editor for the Archives of Pathology & Laboratory Medicine.

Author notes

The authors have no relevant financial interests in the products or companies described in this article.