Seminars in Diagnostic Pathology

Cover

2010-02-01

Masthead

2010-02-01

Editorial Board

2010-02-01

Topics

2010-02-01

Introduction

Ian O. Ellis, Vincenzo Eusebi, Stuart J. Schnitt — 2010-02-01

The year 2009 marks the 30th anniversary of the publication of Professor John G. Azzopardi's classical monograph, Problems in Breast Pathology. The community of breast pathologists felt that publishing a series of papers on selected topics in breast pathology to which Professor Azzopardi made significant contributions and about which he was passionate would be a fitting way to commemorate this occasion. The authors selected to write these papers have either worked directly with Professor Azzopardi or have for many years admired and have been influenced by his unique insights into various breast diseases. This issue of Seminars follows a meeting that was held in May 2006 in Malta, the native land of Professor Azzopardi, to honor him and to celebrate his accomplishments.

Preface

Juan Rosai — 2010-02-01

There are probably as many ways to perform surgical pathology as there are surgical pathologists in this world. However, if one looks carefully at the modus operandi and scientific production of the pre-eminent representatives of the specialty over the years, one begins to realize that they can be divided into 2 main models: the surgical pathologist–clinician (a primarily American phenomenon) and the surgical pathologist–morphologist–pathobiologist (a largely European species). The first type, represented by legendary people like Arthur Purdy Stout, Lauren Ackerman, Fred Stewart, Frank Foote, Malcolm Dockerty, and David Dahlin, involved professionals who were basically clinicians with a microscope. To be sure, they were also superb morphologists, with a legendary ability in the evaluation of microscopic sections. However, their heart was always with the patients and with the clinical correlates of their microscopic observations. Their overriding goal was to select the best therapy for the patient and to predict the natural history of the diseases by “being constantly and intimately in touch with surgical operations, clinical histories, clinical diagnoses, and roentgenologic findings, […] by using a microscope as if it were a stethoscope, and by becoming clinical consultants,” as advocated by W. C. MacCarty, a pioneer surgical pathologist at the Mayo Clinic. Microscopic minutiae held only a relative value for them, unless they were linked in some way with a significant clinical fact.

Epitheliosis, infiltrating epitheliosis, and radial scar

Vincenzo Eusebi, Rosemary R. Millis — 2010-02-01

The lesion termed “infiltrating epitheliosis” (IE) by Azzopardi is described using his original criteria. The differential diagnosis from radial scar (RS) is discussed. It appears that IE and RS are histologically and histogenetically different and are also associated with a different risk of carcinoma. IE can be associated with either in situ or invasive carcinoma, whereas RS being more like a process of involution is very seldom involved by a carcinoma. Therefore, whatever name is used among the several found in the literature, it should be made clear they are not interchangeable when reporting on lesions like IE and RS.

Papilloma and papillary carcinoma

Frederick Koerner — 2010-02-01

Papillomas and papillary carcinomas differ in their 3 fundamental characteristics: the geometric properties of their fronds, the amount of their stroma, and the characteristics of their epithelium. Fibrosis at the edge of papillomas often entraps glands and creates the spurious impression of invasion. The proliferation of surface epithelial cells of papillomas does not give rise to unexpected diagnostic difficulties, but glandular proliferation within the stalks of papillomas often simulates the appearance of cribriform ductal carcinoma in situ. Needle biopsies of papillomas can deposit clusters of benign cells in a distribution that resembles an invasive carcinoma. Although papillomas overrun by ductal carcinoma in situ exhibit a papillary architecture, other features differentiate them from conventional papillary carcinomas. The presence of basal carcinoma cells with clear cytoplasm (“dimorphic” cells) and the formation of short stubby fronds sometimes cause pathologists to mistake papillary carcinomas for papillomas, and the bland cytologic characteristics of solid papillary carcinomas can lead to the same error. Conventional papillary carcinomas typically invade in a blunt manner. This phenomenon complicates the recognition of invasion by many papillary carcinomas and has given rise to controversy about the nature of the lesion classically known as “intracystic papillary carcinoma.”

Clinging carcinoma: an American perspective

Stuart J. Schnitt — 2010-02-01

In 1979, Professor John Azzopardi introduced the term “clinging carcinoma” to describe what he considered to represent examples of ductal carcinoma in-situ (DCIS) characterized by “neoplastic cells…limited to the periphery of the containing structures.” He emphasized that these lesions can be easily missed “since the alteration is cytological rather than anatomical.” Two types of clinging carcinoma were described by Azzopardi. He considered the first to represent a variant of high-grade DCIS, and most pathologists concur with that view. In contrast, pathologists have been much more reluctant to accept Azzopardi's second type of clinging carcinoma as a type of DCIS, particularly in the United States. This second type is characterized by cells with low grade, monomorphic-type cytologic atypia, similar to the cells comprising low-grade DCIS with solid, cribriform, and micropapillary architectural patterns. Recent morphologic, immunophenotypic, and genetic studies have provided strong evidence that this lesion, described by Azzopardi as a type of clinging carcinoma (and now commonly referred to as flat epithelial atypia), does in fact represent a precursor to or an early stage in the development of DCIS, essentially validating the histologic observations made by Azzopardi more than 30 years ago.

Flat ductal intraepithelial neoplasia of the breast: evolution of Azzopardi's “clinging” concept

Farid Moinfar — 2010-02-01

Thirty years ago, John G. Azzopardi described a mainly cytologically defined atypical intraepithelial lesion of the breast, which he called “clinging carcinoma in situ,” a variant of “ductal carcinoma in situ.” The lesion was characterized by replacement of native epithelial cells by very few cell layers of mildly to severely atypical epithelial cells. Based on the degree of cytologic atypia, Azzopardi distinguished type 1 with highly atypical nuclei and type 2 with merely subtle cytologic (nuclear) atypia. Although this distinctive lesion remained widely unrecognized and/or ignored by many pathologists for a long period, several recent studies strongly suggest its neoplastic nature. The aim of this review is to focus on the “clinging” concept and its evolution after the first description. The diagnostic criteria, main diagnostic pitfalls, immunohistochemistry, molecular–genetic findings, and the relevance of this type of lesion for clinicians and histopathologists are discussed. Rational for adopting a more appropriate terminology and classification, namely flat ductal intraepithelial neoplasia are also discussed. It is concluded that the “clinging” or flat lesion represents one of the earliest morphologically recognizable neoplastic breast lesions. This lesion is important, if one tries to better understand the tumorigenesis of early precursor lesions of the breast. This type of breast lesion is an indicator for coexisting neoplastic lesions, such as low-grade ductal intraepithelial neoplasia (atypical ductal hyperplasia/low-grade ductal carcinoma in situ) and lobular intraepithelial neoplasia.

Lobular breast carcinoma and its variants

Emad A. Rakha, Ian O. Ellis — 2010-02-01

Lobular carcinoma is a special type of breast cancer that shows distinct clinical presentation, morphologic and molecular features, and clinical behavior, and its incidence is rising in recent years. Infiltrating lobular carcinoma (ILC) and its precursor lesions may result in diagnostic difficulties, particularly in the screening settings and their management may be problematic. Variants of lobular carcinoma, such as the pleomorphic variant, although not common, exist and some show differences in behavior warranting their recognition in view of requirements for different management strategies. Here we present a review of lobular carcinomas with particular attention to lobular in situ lesions, epidemiology, subtypes, diagnosis, molecular pathology, and grading of ILC in addition to the clinical behavior, response to therapy, and outcome of patients with ILC.

The origins of early breast carcinoma

Tibor Tot — 2010-02-01

Assessing the distribution of the in situ and invasive components of breast carcinomas and the extent of the disease represent an integrated part of our diagnostic routine. In this article, we summarize findings from 792 consecutive breast carcinoma cases, each documented in large-format histology slides. Selected cases were also analyzed in thick, large sections. Of these, 35.0% (42/120) of the purely in situ carcinomas were diffuse and occupied mostly larger ducts, whereas 37.5% (45/120) were multifocal and involved several distant terminal ductal-lobular units (TDLUs). The proportion of unifocal in situ cases involving a single TDLU or several neighboring TDLUs was 27.5% (33/120). Forty-one percent (136/332) of early (<15 mm) invasive carcinomas and 40.0% (136/340) of larger invasive tumors contained only a single invasive focus, with or without an in situ component within it. The remaining tumors were nonunifocal because of multiple invasive or multiple in situ foci or both. The proportion of extensive nonunifocal cases within purely in situ, early invasive, and more advanced invasive cases were 45.0% (54/120), 42.5% (141/332), and 42.4% (144/340), respectively. The results are discussed in the context of recent molecular genetic findings and the sick lobe theory. Elements that are congruent with the classical views of Professor Azzopardi expressed over 3 decades ago will be pointed out. Breast carcinoma seems to develop within a field of genetic alterations, often at multiple sites, and a considerable proportion of the cases comprise extensive lesions occupying a tissue space ≥40 mm in all tumor size categories.

Neuroendocrine differentiation in breast cancer: established facts and unresolved problems

Luisella Righi, Anna Sapino, Caterina Marchiò, Mauro Papotti, Gianni Bussolati — 2010-02-01

Neuroendocrine breast carcinoma (NEBC) diagnosis relies on (i) presence of morphologic neuroendocrine features, and (ii) neuroendocrine markers expressed in more than 50% of tumor cells. The World Health Organization classification describes 3 main histologic types: the solid, the small/oat cell, and the large cell variant. In addition, we have recently proposed a further categorization into 5 subgroups: the first 3 categories encompass solid lesions and include (i) solid cohesive carcinomas, (ii) alveolar carcinomas, and (iii) small cell carcinoma; the last subgroups include mucin-producing tumors which are (iv) solid papillary carcinomas and (v) cellular mucinous carcinomas. Chromogranin A and synaptophysin have been considered as the most sensitive and specific neuroendocrine markers in NEBC. At the molecular level, recent gene expression profiling studies have shown that NEBCs pertain to the luminal molecular type, being positive for hormone receptors and negative for HER2. Moreover, it has been demonstrated that mucinous and neuroendocrine carcinomas are transcriptionally distinct from conventional invasive ductal carcinomas. Following the above criteria, NEBCs constitute approximately 1% of all breast carcinomas. The clinical effect of neuroendocrine breast cancer is still a matter of debate; however, when compared with unselected breast cancers, NEBCs show a less aggressive clinical behavior.

Salivary gland-type tumors of the breast: a spectrum of benign and malignant tumors including “triple negative carcinomas” of low malignant potential

Maria P. Foschini, Thomas Krausz — 2010-02-01

Salivary gland-type neoplasms of the breast are uncommon and comprise numerous entities analogous to that more commonly seen in salivary glands. The clinicopathologic spectrum ranges from benign to malignant but there are important differences as compared with those of their salivary counterpart. In the breast, benign adenomyoepithelioma is recognized in addition to malignant one, whereas in the salivary gland a histologically similar tumor is designated as epithelial-myoepithelial carcinoma without a separate benign subgroup. Mammary adenoid cystic carcinoma is a low-grade neoplasm compared with its salivary equivalent. It is also important to appreciate that in contrast to “triple negative” conventional breast carcinomas with aggressive course, most salivary-type malignant breast neoplasms behave in a low-grade manner. Most of these tumors are capable of differentiating along both epithelial and myoepithelial lines, but the amount of each lineage-component varies from case to case, contributing to diagnostic difficulties. Well established examples of this group include pleomorphic adenoma, adenomyoepithelioma, and adenoid cystic carcinoma. Another family of salivary gland-type mammary epithelial neoplasms is devoid of myoepithelial cells. Key examples include mucoepidermoid carcinoma and acinic cell carcinoma. The number of cases of salivary gland-type mammary neoplasms in the published data is constantly increasing but some of the rarest subtypes like polymorphous low-grade adenocarcinoma and oncocytic carcinoma are “struggling” to become clinically relevant entities in line with those occurring more frequently in salivary glands.

Breast pathology: beyond morphology

Peter T. Simpson, Jorge S. Reis-Filho, Sunil R. Lakhani — 2010-02-01

Breast cancer is a heterogeneous disease and pathologists have evolved a system of classification that reflects this heterogeneity as well as provide prognostic and predictive information to manage patients. Professor Azzopardi's contribution to understanding and classifying breast disease is significant and reflected by the many articles in this issue. Nonetheless, there are limitations to the morphologic classification and new molecular methods promise to refine the biological understanding as well as provide better biomarkers for prognostication and targets for the development of novel therapeutics. The degree to which the new methods add value to the morphology remains to be seen, but there is hope that a symbiosis between morphology and molecular techniques will advance traditional histopathology and improve the care of patients with breast cancer.

Seminars in Diagnostic Pathology

Cover

Masthead

Editorial Board

Topics

Contents

Introduction

Preface

Epitheliosis, infiltrating epitheliosis, and radial scar

Papilloma and papillary carcinoma

Clinging carcinoma: an American perspective

Flat ductal intraepithelial neoplasia of the breast: evolution of Azzopardi's “clinging” concept

Lobular breast carcinoma and its variants

The origins of early breast carcinoma

Neuroendocrine differentiation in breast cancer: established facts and unresolved problems

Salivary gland-type tumors of the breast: a spectrum of benign and malignant tumors including “triple negative carcinomas” of low malignant potential

Breast pathology: beyond morphology