Rosen's Breast Pathology Introduction

Authors: Rosen, Paul Peter

Title: Rosen's Breast Pathology, 3rd Edition

Copyright ©2009 Lippincott Williams & Wilkins

> Front of Book > Introduction

Introduction

The Pathologist as a Specialist in Breast Cancer Care

“The development and application of a concept of

localized pathology laid the groundwork for modern

specialism by providing a number of foci of interest in

the field of medicine. Each such focus of interest, that

is, a disease or the diseases of an organ or region of

the body, provided a nucleus around which could

gather the results of clinical and pathological

investigation.

On the technological side the influences represented

in specialization manifest themselves in the

multiplicity of technical skills, devices, and theories

applied to the achievement of human aims in the field

of medicine.”

--From The Specialization of Medicine by George

Rosen, M.D., 1944.

Impressive advances have been made in the past 50 years in the effort to

prevent, treat and cure breast cancer. Major milestones include the

development of mammography for early detection, the shift from

mastectomy to breast conservation therapy for many patients, advances in

chemotherapy for primary treatment and as an adjuvant modality, the

demonstration that antiestrogenic compounds can inhibit the development

and progression of breast cancer, and the introduction of sentinel lymph

node mapping for axillary staging. The growth of medical specialization in

the last half of the 20th century has had a profound influence on these

accomplishments by fostering multidisciplinary clinical practice and

research.

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Specialism in all aspects of medical care has revolutionized the role of the

surgical pathologist. Rather than fostering professional independence,

specialization in medicine has created circumstances in which the specialist

delivering a limited segment of medical care is increasingly dependent on the

assistance of colleagues who have acquired complimentary expertise. This

situation is epitomized by the multidisciplinary approach that is now

standard for treating breast diseases. Inherent in this circumstance is the

expectation that each member of the team is capable of delivering optimal

specialty care. A corollary effect is growing pressure for subspecialization in

diagnostic pathology, especially in academic centers. Breast pathology has

largely remained in the domain of generalists except for a few referral

centers. The formation of the International Society of Breast Pathology

heralds recognition of subspecialization in Breast Pathology. In 2000, a

European Society of Mastology position paper set forth guidelines for a

clinical program devoted to providing “high-quality specialist Breast Service”

included among the physicians “a lead pathologist plus usually not more than

one other nominated pathologist specializing in Breast Disease…(to be)…

responsible for all breast pathology and cytology” (1). The number of

pathologists needed to staff such a service will depend upon the number of

patients cared for. This process will be furthered by growing awareness on

the part of patients and patient advocacy organizations that accurate and

comprehensive pathology diagnosis is fundamental to effective treatment

and research in breast diseases.

Major advances that contributed to the role of the pathologist as a key

member of the breast cancer team include:

� widespread use of mammography which detects nonpalpable lesions;

� image-guided needle core biopsy procedures, which make it possible to

acquire samples from nonpalpable lesions;

� breast conservation therapy, which requires a more-detailed pathologic

assessment of breast specimens;

� the availability of histologically-based methods for detecting markers used

to assess prognosis and to plan therapy; and

� sentinel lymph node mapping and bone marrow sampling for

micrometastases.

Pathologists generate an important part of the information used for

therapeutic decisions. The complex multifactorial description of breast



pathology now considered to be standard practice has expanded the

diagnostic report from a brief one- or two-line statement to a catalogue of

data that may be several pages in length. Immunohistochemistry makes it

possible to determine the presence of prognostic and therapeutic markers by

microscopic examination, and these observations are part of the pathologist's

report. This technology is also essential for detecting micrometastases in

sentinel lymph nodes.

The expanded role of pathologists in the management of breast diseases

requires their active participation with the clinical care team. Pathologists

who diagnose breast specimens need to be aware of how various components

of their reports are relevant to treatment decisions. Optimally, there should

be a procedure for correlating imaging studies with biopsy results in regard

to nonpalpable lesions detected by mammography, ultrasound or MRI (1).

Coincidental with these medical developments has been the growing

involvement of patients in making decisions about their treatment. This, in

turn, has led to a greater public awareness of the importance of information

contained in pathology reports. For the untrained layperson to read and

interpret a pathology report, it is necessary to learn and understand a new

vocabulary. This is a daunting task—one that is even more difficult for the

patient whose name appears on the document.

Books and literature provided by medical and lay societies or associations are

helpful, as is the bottomless well of information that appears on the

Internet. The surgeon, oncologist, and radiotherapist are experts at

interpreting pathology reports for their patients and at explaining the

significance of the data. Nonetheless, a substantial number of patients with

breast diseases want an explanation from the pathologist who issued the

report or they seek out another pathologist, often with specialized expertise,

for a second opinion review. Many more patients are aware that a pathology

consultant is involved in their case. In this way, pathologists increasingly

participate in direct patient care and patient education, a vital public

service.

Consultations and Second Opinions in Breast PathologySurgical pathologists in general practice provide accurate diagnoses for the

great majority of the breast specimens they encounter without the assistance

of intramural or extramural consultation. Nonetheless, pathology

departments should have a built-in mechanism for obtaining second opinions



internally through conferencing or other quality assurance programs. In this

setting, the individual pathologist or the pathology group in a department

may seek an extramural opinion from an expert consultant. This typically

occurs when there is a difference of interpretation among pathologists in an

institution or the diagnosis is uncertain after internal review. Consultation

may also be obtained when the probable diagnosis is one with which there is

little or no experience. Another category of consultation results from

uncertainty about the diagnosis engendered by a limited or unrepresentative

sample, poor histologic preparation, or a pathologic change that appears to

be on the borderline between two or more diagnoses. As noted by Leslie et

al., “Second opinions in anatomic pathology are an integral part of quality

practice…frequent consultation between pathologists should be fostered in

all practice settings and documented as part of the quality assurance

process” (2).

Several studies have demonstrated the important contribution to patient

care of second opinion pathology consultations, generally in the context of

referrals seen at academic centers. A very positive aspect of this practice is

the high degree to which the primary diagnosis has been confirmed by the

consultant. Epstein et al. reported concordant diagnoses (cancer vs.

noncancer) in 98.7% of 535 prostatic needle biopsies diagnosed as cancer (3).

Nonetheless, the 6 diagnoses not sustained as cancer were critically

important for the 1.3% of patients. A cost analysis of these results suggested

that the saving in medical expenses for the 6 patients who did not undergo

surgery substantially exceeded the cost of reviewing all 535 biopsies. A

higher rate of discrepancies was found by Abt et al. (4) who compared the

original and second opinion diagnoses in a broad range of pathology among

777 patients referred to an academic center. Forty-five diagnostic

disagreements (6%) were regarded as clinically significant, and overall the

level of agreement was 92.1%. Perkins et al. (5) estimated that diagnoses

were inaccurate in 2% to 4% of breast cancer cases, including mistaking

benign for malignant disease or vice versa, over- or underdiagnoses of

invasive carcinoma, or misinterpretation of prognostic markers such as

HER2/neu.

It is unlikely that complete microscopic pathology samples will be routinely

converted to electronic images in the foreseeable future given the time and

cost of this undertaking and the fact that much of the information will be a

record of “normal” or nonlesional tissue. Consequently, the need to ship

glass slides for consultation is likely to be with us for some time to come.

Within the United States, several factors have contributed to the growing



number of pathology consultations. Much of the increase is generated by

patients who seek multiple clinical opinions from different physicians and

institutions. Some patients are primarily concerned with confirmation of

their diagnosis, and one or more consultations may be obtained directly from

pathologists for this reason alone. Most of the remainder of consultations are

initiated by pathologists seeking opinions from their colleagues. Surgeons,

medical oncologists, and other physicians generate some second opinion

reviews. The review of “outside” pathology slides should be mandatory

whenever a patient is referred to a physician for consultation or treatment at

an institution other than the one where the primary diagnosis was rendered

(6).

Slides sent for consultation, regardless of the reason, must be accompanied

by documents that: (a) confirm the identity of the specimen with the

patient, (b) explain why the material has been sent, (c) provide complete

information about who should receive the report, and (d) designate who will

pay for the consultation and how billing should be submitted. The

correspondence may take many forms, but it is essential that the information

cited above be provided. This must include a copy of the pathology/cytology

report for each specimen represented, clearly displaying the name of the

patient and the accession number corresponding to the slides and paraffin

blocks enclosed. It is unacceptable and substandard practice to withhold the

pathology report previously obtained from a consultant or second opinion

institution so as not to “bias” the second review.

In addition to confirming the anatomic source and patient identity of the

slides, the pathology report provides essential information such as an index

of the specific location(s) of the specimen(s) in individual slides, a

description of the gross appearance of the specimen(s), clinical information

provided with the specimen, frozen section interpretations, and details of

the pathologist's diagnosis that should be evaluated. The pathology report

must be included even if the final diagnosis has not been reached and will

depend upon the consultation. When the slides are sent directly from one

laboratory to another in relation to a clinical consultation at the recipient

institution, the correspondence should include the pathology report, the

name of the clinical physician who is being consulted, and detailed billing

instructions. When more than one consultant is involved, it is vital that all

consultants examine the same or equivalent material.

Progress and Uncertainty in Breast Pathology



Extraordinary progress has been made in linking anatomic pathology, the

study of normal and diseased tissues, to patient care throughout the

spectrum of human ailments. The 20th century has been marked by great

advances in defining the pathology of breast diseases and in relating these

observations to the development of more effective therapy tailored to the

specific type and extent of disease in the individual patient.

The stage was set in the latter half of the 19th century and first decades of

the 20th century with the flowering of classical pathology based largely on

postmortem examination of the gross and microscopic changes found in

diseased tissues. The principle objectives of these investigations were to

describe and catalogue diseases in an effort to detect clues to their

pathogenesis and to better understand their clinical manifestations. Surgical

pathology, the study of tissues from the living, emerged from classical

anatomic pathology as advances in surgery, made possible by effective

anesthesia and antisepsis, focused greater attention on a pathologic diagnosis

as a critical element in the treatment of many diseases. The study of breast

pathology has been a model of interdisciplinary investigation involving

clinical and laboratory science. Pathologists are in a unique position to meet

the challenge of developing and adapting innovative laboratory methods to

better understand and to improve the treatment of breast diseases.

Despite the perceptions of the public and some medical colleagues that

diagnostic pathology lacks ambiguity and subtlety, pathologists are

repeatedly faced with the need to deal with uncertainty. The usually blunt,

seemingly “black and white” recitation of a final pathology report actually

represents a synthesis of possibilities that constitute the “differential

diagnosis.” Pathologists strive to reduce uncertainty by constant study,

leading to the development and application of new insights or improved

techniques. Yet, each advance brings with it a new horizon of uncertainty-a

new confidence interval. One manifestation of uncertainty in the study of

breast cancer and precancerous breast disease is our limited ability to

separate “the drivers from the hitchhikers,” that is “to distinguish between

silent alterations acquired by the malignant cell and those that truly

contribute to the malignant phenotype” (7).

In the clinical arena, the phenomenon of advances creating new uncertainty

is illustrated by the procedure for axillary lymph node staging by sentinel

lymph node mapping. The coincidence of improved surgical techniques to

localize the lymph node or nodes most likely to harbor metastatic carcinoma

and the application of immunohistochemistry to the lymph nodes by the



pathologist makes it possible to determine whether axillary lymph nodes

harbor metastases by examining selected lymph nodes without the need for

more extensive axillary dissection. Sentinel lymph node staging results in

reliable information about axillary nodal status with less morbidity than

conventional axillary dissection. Nonetheless, the procedure has raised new

questions about the prognostic significance of the micrometastases so

elegantly uncovered, and uncertainty about the need for therapy based on

this finding.

Pathologists have unique opportunities in breast cancer research. Technical

advances now make it possible to apply the extraordinarily powerful

techniques of molecular and genetic analysis directly to tissues visualized

with the microscope. This is truly the intersection of the classical

microscopic pathology of the 19th and 20th centuries with the molecular

science of the 21st century. Using microdissection, the pathologist can select

small groups of cells and even individual cells from normal and abnormal

tissues that are identified and diagnosed with the microscope. DNA extracted

from these minute samples can be amplified and studied for molecular

alterations by a variety of techniques. This approach holds great promise for

furthering our understanding of precancerous and cancerous breast diseases

and for finding clues to improved prevention and therapeutic strategies.

Currently, microdissection is too costly and laborious for widespread clinical

application. It is possible that pathologists will employ microdissection and

molecular analysis in the diagnosis of breast tissues in the next 10 to 20

years. The development of robotic instrumentation will contribute

substantially to making this a clinically feasible enterprise. The ability of

pathologists to distinguish between structurally normal and abnormal tissues

will remain a fundamental step in diagnosis in the foreseeable future, but

technological advances will require greater sophistication on the part of

pathologists and continue to foster the subspeciality of Breast Pathology.

Tissue Microarrays, Gene Expression Profiles, and Breast PathologyIt is widely accepted that altered gene expression is fundamental to the

neoplastic process. The “devil is in the details” of how the exceedingly

complex system of gene actions becomes disrupted, resulting in the

phenotypic changes in cells and tissues employed by pathologists for

diagnosis and estimating prognosis. Interest in exploring and understanding

the molecular basis of breast cancer pathology has been propelled forward in

the past decade by technological advances that make it possible to



efficiently investigate very small samples from large numbers of tumors.

These studies have relied on two methodologies: high-throughput tissue

microarrays and microarray gene expression profiling. The former employs

histologic sections of small samples of multiple tumors and the latter uses

RNA extracted from diagnostic tumor tissue samples. It can be reasonably

predicted that these and related technologies will eventually have a

significant impact on the role of pathologists in breast cancer diagnosis and

treatment. The following discussion provides illustrations from the current

literature of how these studies are being used. Although largely

investigational, a few procedures, such as a recurrence score (RS) based on a

21-gene RT-PCR assay, are being employed in clinical practice for selected

patients (8,9).

Tissue MicroarraysIn 2003, Callagy et al. (10) described a classification of breast carcinoma

based on the expression of protein biomarkers detected by

immunohistochemistry in tissue microarray preparations. The inherent

efficiency of tissue microarray technology made it possible for these

investigators to study 13 biomarkers in 107 cases with only 39 histologic

slides. The authors estimated that 1,391 slides would have been needed to

obtain the same data from “conventional sections.” Two patterns of

biomarker expression were described: estrogen receptor (ER)-related (ER,

PR, bcl2, cyclin-D, p27, cytokeratin 8/18, c-myc) and proliferation-related

(Mcm2, MIB1, cyclin-E, p53, c-erbB2, cytokeratin 5/6). There was a

statistically significant association between the biomarker expression group

and the conventional prognostic markers. Tumors in the ER-related group

were more likely to have a low histologic grade and negative lymph nodes,

whereas tumors expressing proliferation-related markers were more likely to

be high grade and have nodal metastases.

A more-complex tissue microarray study published in 2005 examined the

immunohistochemical expression of 25 biomarkers in 1076 previously

characterized breast carcinomas (11). Six groups of protein expression were

found, representing 0.4% to 31.2% of the tumors. The biomarker-defined

groups were significantly related to tumor grade, tumor size, nodal status,

patient age, and prognosis. Multivariate analysis revealed that biomarker

clustering was a prognostically significant independently of grade, size, and

nodal status.

Gene Expression Profiling



In contrast to tissue microarray technology that describes gene activity in

terms of protein products that can be detected in tissue sections by

immunohistochemistry, gene expression profiling examines large numbers of

genes directly using RNA extracted from tumor tissue with the reverse

transcriptase polymerase chain reaction (RT-PCR) in DNA microarrays. These

studies have been done with frozen (12,13) or paraffin embedded (14) tissue

samples, including needle core biopsy specimens (15,16). Needle core biopsy

samples provide satisfactory material for gene expression profile analysis in

the majority of cases. Zanetti-Dallenbach et al. (17) reported 82%

concordance in the expression profiles for 60 genes obtained from core

biopsies and subsequent surgical excision biopsy specimens from 22 patients.

In four cases where gene expression profiles for the two specimens differed,

the surgical biopsy specimens exhibited a higher expression of genes

associated with tissue injury and repair that were probably activated by the

core biopsy procedure. Rody et al. (18) found greater than 90% concordance

in the gene expression profiles for estrogen and progesterone receptors and

for Her2/neu in core biopsy samples from patients undergoing neoadjuvant

chemotherapy when compared to immunostains of the same samples.

Gene profiles that were associated with prognosis, response to

chemotherapy, and patterns of metastases have been described. For

example, a recurrence score (RS) indicative of the risk of recurrence after 10

years of follow-up in node-negative, estrogen receptor-positive patients

treated with tamoxifen was based on a 21-gene RT-PCR expression profile

(19). Analysis of the 21-gene profile resulted in a quantitative assessment of

recurrence risk after treatment in this selected group of patients. Three

recurrence risk categories were defined: low risk (RS<18%), intermediate risk

(RS 19%–30%), and high risk (RS ≥ 31%). It was found that after 10 years of

follow-up, patients in the high-risk group derived a significant reduction in

recurrence from combined treatment with chemotherapy and tamoxifen (11%

recurrence) when compared to women treated with tamoxifen alone (38.3%

recurrence). Patients in the low recurrence group did not experience a

significant reduction in recurrence when chemotherapy was added to

tamoxifen (tamoxifen, 3.7% recurrence; tamoxifen plus chemotherapy, 5%

recurrence). There was a small benefit from chemotherapy in the

intermediate-risk group (tamoxifen, 17.8% recurrence; tamoxifen plus

chemotherapy, 10.1% recurrence). Histologic grade was significantly related

to RS but, when graded by more than one pathologist, 5% to 12% of

histologically low-grade tumors had a high RS and 19% to 36% of histologically

poorly differentiated carcinomas had a low RS. Lyman et al. (9) estimated a



net savings of $2,256 per patient treated when the choice between

tamoxifen alone and tamoxifen plus chemotherapy was based on the RS

derived from the 21-gene RT-PCR assay. The clinical management of a

patient whose tumor grade is at odds with the RS is an issue that needs

further investigation.

Gene expression profiling has also been applied to breast carcinoma

prognosis in other patient groups. Espinosa et al. (12) investigated a 70 gene

profile in 96 stage I and II patients. A patient was classified as having a poor

prognosis in this study if the tumor expressed more than 47% of the

previously determined poor prognosis “signature,” which featured up-

regulation of genes involved in the cell cycle, invasion and metastasis,

angiogenesis, and signal transduction (20,21). The gene profile used in this

study was significantly related to overall and relapse-free survival for the

entire group of patients, but not when patients were stratified by nodal

status.

Foekens et al. (22) used a previously validated (23) 76-gene signature to

assess prognosis in node negative patients who had not received

chemotherapy. Patients were classified as having a low or high risk for

developing a systemic recurrence. Ten-year recurrence-free survivals were

94% and 65%, respectively, in the low- and high-recurrence risk groups as

determined by the 76-gene signature. In a multivariate analysis with age at

diagnosis, tumor size, grade, and menopausal status, the 76-gene signature

was the only significant predictor of distant recurrence-free survival.

Predicting response to chemotherapy is likely to be an important application

of gene expression profiling. Mina et al. (15) identified a 22-gene signature

that significantly correlated with a pathologic complete response to

chemotherapy (doxorubicin and docetaxel) in 45 evaluable patients treated

for locally advanced breast carcinoma. Signature genes were of three types:

angiogenesis-related, proliferation-related, and invasion-related. In this

study, the expression of estrogen receptor-related genes and the RS

determined from the previously discussed 21-gene RT-PCR assay did not

correlate with a pathologic complete response. Gianni et al. (16) reported

that the expression of 86 genes correlated significantly with achieving a

pathologic complete response in women with locally advanced carcinoma

who received neoadjuvant paclitaxel and doxorubicin. A pathologic complete

response was significantly associated with a higher expression of

proliferation-related and immune-related genes and with lower expression of

estrogen receptor-related genes. A pathologic complete response was



achieved significantly more often with tumors that had a high RS based on

the 21-gene RT-PCR assay.

Gene expression profiling has also been investigated as a method for

predicting response to neoadjuvant chemotherapy in women with primary

operable breast carcinoma. One such study involved 100 women with T2-4,

N0-2, M0 breast carcinoma treated with gemcitabine, epirubicin, and

docetaxel (24). A signature of genes associated with a pathologic complete

response included prominent representation from the following categories:

TGF-β signaling, RAS-related, apoptosis-related, and DNA damage response-

related genes. Ayers et al. (25) reported that a gene expression profile had

78% predictive accuracy for identifying women who achieved a complete

pathologic response to multiagent neoadjuvant chemotherapy when

compared to a 28% overall expected response rate. Using a different gene

profile, Iwao-Koizumi et al. (26) reported 80% accuracy in predicting clinical

response to docetaxel. In a trial that compared doxorubicin-

cyclophosphamide to doxorubicin-docetaxel treatment in patients with

locally advanced carcinoma, Hammerman et al. (27) found changes in gene

expression profiles determined before and after neoadjuvant chemotherapy

in responders but not in nonresponders. However, no gene expression profile

was predictive of response to either treatment.

Evidence that gene expression profiling might detect signatures associated

with patterns of metastases has started to emerge. A study of primary tumor

tissue from 107 patients with node negative breast carcinoma identified a

panel of 69 genes that were “differentially expressed” when patients with

metastases in bone were compared to those with non-osseous metastases

(13). The genes for thyroid transcription factor 1 (TTF1) and TTF3 were found

to be most highly expressed in the 69-gene signature associated with bone

metastases. Other categories of genes associated with bone metastases were

related to cell adhesion, signaling pathways, and cell organization. Others

have also investigated gene profiles associated with breast carcinoma

metastases in bone (28,29), the lungs (30), and locoregional recurrence after

mastectomy (31). The mechanisms by which these gene profiles predisposed

to patterns of recurrence and the roles of particular genes or groups of genes

in this process have not been elucidated. Nonetheless, the ability to predict

likely sites of distant metastases could provide an opportunity to selectively

offer adjuvant therapy designed to inhibit site-specific recurrence such as

bisphosphonates for bone metastases (32) and radiotherapy for local

recurrences.



Contradictory results have been reported in attempts to find gene profiles

predictive of low and high risk for axillary nodal metastases. Weigelt et al.

(33) did not find a gene signature associated with axillary lymph node

metastases in a study of 295 tumors. In a considerably smaller series of

cases, West et al. (34) reported that gene expression profiling was predictive

of axillary nodal status. The use of gene profiling as a tool to predict the risk

for axillary lymph node metastases and to identify the genes involved in this

process, which is fundamental to breast carcinoma staging, has not yet

received the attention warranted by the clinical importance of this aspect of

the disease.

Gene expression profiles may be influenced by mutations associated with

hereditary breast carcinoma. Hedenfalk et al. (35) described a panel of 176

genes that had different expression patterns in tumors with BRCA1- and

BRCA2-associated mutations. The gene expression patterns of the BRCA-

associated carcinomas also differed from those found in sporadic carcinomas.

The strength of these results is limited by the small numbers of cases

studied.

The Future of Tissue Microarray and Gene Expression Profiling in Breast CancerThe foregoing examples offer an insight into the promise and complexity of

tissue microarray and gene expression profiling in breast carcinoma. Many

issues remain to be addressed before these techniques can be introduced

into general clinical practice. There are important technical problems

related to the use of formalin-fixed paraffin embedded tissue and the limited

availability of unfixed frozen tissue. Most breast carcinoma gene expression

profiling studies have had significant limitations that include small numbers

of tumors and/or patients, heterogeneous patient groups, and

nonstandardized treatment. There does not appear to have been an a priori

basis for selecting genes for study, and there is little understanding of how

the genes that form a particular signature are related to the outcome under

investigation (e.g., site of metastases, response to therapy or to the

histomorphology of breast proliferative lesions and carcinomas). It has been

reported that analysis of data from two different studies (21,23) identifying

prognostic gene profiles consisting, respectively, of 70 and 76 genes had only

3 genes in common (36). Disparities of a similar magnitude between other

gene signatures have also been noted (37). The predictability of gene

expression profiles can be substantially reduced when they are cross-tested

from one series of tumors to another (36,37). On the other hand, clustering



of tumor subtypes (e.g., basal, luminal, erb-b2) was reported in an analysis

of three studies (38). A re-analysis of data from a study (21) that reported a

specific 70-gene signature revealed that this gene set was not unique and

that other gene signatures also present in the data set correlated with

outcome (37).

No single gene profile has proven to be applicable to breast carcinoma

generally. At present, the 21-gene RT-PCR assay has been used clinically in

the limited subset of patients with estrogen receptor positive, lymph node-

negative tumors under treatment with tamoxifen to estimate the benefit

that would be obtained from adding chemotherapy. It is likely that other

clinically useful gene signatures will be found by analyzing subsets of

patients which are defined by established markers (e.g., ER, erb-b2) and

clinicopathologic parameters (e.g., age at diagnosis, hereditary breast

carcinoma, tumor grade). To develop assays that can be standardized for

clinical practice, larger groups of tumors need to be evaluated and gene

profiles in defined patient groups need to be cross-tested. As more studies

are performed, gene signatures associated with particular end-points can be

developed and modified when new information becomes available.

Gene expression profiling and tissue microarrays offer great promise as tools

that may revolutionize the treatment of breast carcinoma. Nonetheless, we

are certainly not on the verge of abandoning conventional prognostic

markers, and there is reason to believe that they will continue to play an

important clinical role in the foreseeable future, as suggested by Eden et al.

(39) in a provocative study titled “Good old' clinical markers have similar

power in breast cancer prognosis as microarray gene expression profiles.”

The extent to which the pathology community adapts to this new era and

incorporates these technologies into clinical practice in the pathology

laboratory will be an important factor in determining the continued primary

role of pathology in cancer classification and diagnosis.

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