Introduction
xv
conventional pathologic data. The investigators developed
a scoring system or gene expression grade index based on
a 97-gene list that correlated patterns of gene expression
with histologic grade. A high gene expression grade index
was associated with 86% of grade 3 tumors, and a low index
was associated with 91% of grade 1 tumors. The contribu-
tion of the gene expression index was greatest among grade
2 carcinomas, in which a high index was associated with a
significantly greater risk for recurrence than a low index
(
p
< 0.001; hazard ratio, 3.61; CI, 2.25 to 5.78).
Finally, there are substantial parts of the world where the
technology needed to support a molecular-based descrip-
tion of breast carcinoma is unavailable. This situation is not
likely to change soon and will require the continued use of
standard morphology-based diagnostic reporting.
It would be wise to observe this rapidly evolving field with
a healthy dose of skepticism regarding the likelihood that
any of the current molecular-based classification schemes
will soon supplant standard pathologic examination as the
basis for establishing a diagnosis, estimating prognosis, and
for fundamental treatment decisions. At best, molecular
data in its current form complement pathologic observa-
tions and can “fine tune” therapeutic decisions, especially in
intermediate or ambiguous situations.
DCIS by Any Other Name Is Still
Carcinoma
Ever since it was demonstrated in the 1970s and 1980s that
mammography screening could detect clinically occult carci-
nomas of the breast and reduce breast carcinoma mortality,
concern has been expressed that screening results in “over-
diagnosis” and “overtreatment” because it identifies indolent
lesions that are unlikely to have a fatal outcome and could
be left untreated. The issue first came to a head in the late
1970s when the early results of the Breast Cancer Diagnosis
Demonstration Project (BCDDP) sponsored by the National
Cancer Institute (NCI) and the American Cancer Society
(ACS) were presented. The BCDDP program, inspired by the
breast screening initiative carried out by the Health Insur-
ance Plan of Greater New York (HIP) in the 1960s, consisted
of 29 mammography centers in 27 cities across the United
States that were created to assess the feasibility of nationwide
breast screening by this method. A total of 283,222 women
enrolled for five annual screening examinations between
1973 and 1980. The 1977 report revealed that screening on
this scale could be accomplished and that clinically occult
carcinomas were detected. The program came under fire for
leading to “overdiagnosis” and “overtreatment” as evidenced
by the large proportion of biopsies from lesions that proved
to be benign, the detection of a small number of benign
lesions that were misdiagnosed as carcinoma, and treat-
ment for “indolent” carcinomas that might not have become
clinically apparent in the patient’s lifetime. There was also
concern that radiation exposure during screening might
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. The pathology report provides
essential information such as an index of location(s) of the
specimen(s) represented by individual slides, a description
of the gross appearance of the specimen(s), clinical informa-
tion provided with the specimen, frozen section interpreta-
tions, and details of the originating pathologist’s diagnosis.
The pathology report must be included even if a final diag-
nosis had not been reached. 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 name of the clinical physician who is be-
ing consulted (if known) and detailed billing information.
When more than one consultant is involved, it is vital that
all consultants examine the same or equivalent material.
Molecular versus Morphology
for the Classification of Breast
Carcinoma: Must It Be Either/Or?
A host of new classifications of breast carcinoma have
emerged from studies using tissue microarray and gene
expression profile technology.
17–23
Some of these molecular-
based classification schemes have led to the introduction of
testing procedures that assign patients to prognostic catego-
ries and predict response to therapy, as discussed in Chapter
45. Some of these tests are being used in clinical practice
based on analysis of retrospective data. It will take many
years before they are fully validated in prospective clinical
trials. As the results of additional gene profiling studies are
reported, more classifications will no doubt be developed
and promoted for various reasons.
The exceptional speed with which the molecular study of
breast carcinoma has advanced makes it hazardous to predict
circumstances even a few years hence. Nevertheless, the cur-
rent situation was perhaps best summarized by Rakha and
Ellis
22
in their paper titled “Modern Classification of Breast
Cancer: Should We Stick with Morphology or Convert to
Molecular Profile Characteristics,” wherein they observed
that the “replacement of conventional classification seems
unfounded and incorporation of multigene molecular clas-
sifiers to conventional BC [breast carcinoma] classification
systems seems more realistic and practical to support more
effective tailoring of therapy in the future.” In a report titled
“Breast Cancer Prognostic Classification in the Molecular
Era: The Role of Histological Grade,” Rakha et al.
21
con-
cluded that “clinical acceptance of these molecular assays
will require them to be more than expensive surrogates for
established traditional factors such as histological grade.”
A study reported by Sotiriou et al.
24
illustrates how results
from gene expression profiling can be complementary to
