Introduction
xix
carcinoma. We are not convinced that there is merit to the
proposed change. As noted in Chapter 12, unless otherwise
stated, the term “invasive ductal carcinoma” as used in this
book refers to invasive ductal carcinoma, NOS.
This flawed proposal does raise an important issue
about the precise microanatomical origin of various le-
sions included under the broad heading of invasive ductal
carcinoma, NOS. The ductal system is a complex series
of branching tubules extending from intralobular duct-
ules to the major lactiferous ducts that terminate in the
nipple. While the endpoint in the nipple is demarcated
histologically by a squamocolumnar junction, the point at
which terminal ductular epithelium ends and the secretory
glandular epithelium begins is less clearly defined. In fact,
this junction appears to be somewhat labile and subject to
changes induced by physiologic and/or proliferative factors.
Although it is possible that a small percentage of lesions cur-
rently categorized as invasive ductal carcinoma, NOS, arise
from epithelium that may have attributes associated with
secretory lobular epithelium, no reliable basis for distin-
guishing this subset of carcinomas has been demonstrated.
This issue is confounded by the ability of some
in situ
carcinomas that are classified as DCIS to grow into the
glandular compartment of lobules, a process referred to as
“lobular cancerization.” Conversely,
in situ
carcinomas that
arise in the glandular epithelium of lobules, LCIS, may ex-
tend into ducts either as the solid proliferation that charac-
terizes florid and pleomorphic LCIS, or as the dispersed cells
found in “pagetoid spread.” When either of these situations
is encountered, classification of the
in situ
carcinoma (and
invasive carcinoma if present) is based on the histologic
features of the lesion, not on its microanatomic distribution.
The foregoing arguments notwithstanding, the fact that
approximately 75% of mammary carcinomas are classi-
fied as invasive ductal carcinoma, NOS, is troublesome
since within this broad category are subsets of tumors with
similar histologic appearances that display diverse clinical
attributes. The genetic heterogeneity of these tumors has
become the subject of intense investigation, especially in
the past decade, leading to the identification of molecular
subtypes based of gene expression profiles for estrogen
receptor (ER), HER2, epidermal growth factor receptor
(EGFR), cytokeratins (CKs), and other markers. At pres-
ent, the subtypes based on the expression of these markers
are referred to as luminal, basal-like, HER2-rich, molecular
apocrine, and claudin-low. The complexity of this approach
to classification is manifested when a subset of invasive duc-
tal carcinomas, NOS, is classified according to more than
one molecular subtype. This is illustrated by the report by
Lu et al.,
45
who studied the expression of claudin subtypes in
high-grade invasive ductal carcinomas. Claudins are a group
of proteins that play an important role in maintaining tight
intercellular junctions. The investigators found a significant
correlation between the expression of specific claudins and
particular molecular subtypes of breast carcinomas (basal-
like, luminal, etc.). In addition, low levels of expression for
claudins 1, 3, 4, 7, and 8 were detected in 30 of 226 (14%)
of tumors (referred to as “claudin low”), 77% of which were
basal-like. When compared to patients with “non-claudin
low” basal-like carcinomas, those with “claudin-low carci-
nomas” had a significantly worse recurrence-free survival.
It is noteworthy that the attributes which define some
of these molecular subtypes among tumors classified as
invasive ductal carcinoma, NOS, are also associated with
special types of breast carcinoma that are defined by their
distinctive histologic and clinical characteristics.
46
For ex-
ample, the basal-like subtype characterized as ER(−), PR(−),
HER2(−), CK5/6(+), and EGFR(+), which is associated with
a relatively unfavorable prognosis among invasive ductal
carcinomas, NOS, is also found in prognostically favorable
adenoid cystic, medullary, and secretory carcinomas. The
relative nonspecific nature of subclassifications of invasive
ductal carcinoma, NOS, based on these gene expression
profiles is highlighted by the association of the same basal-
like attributes with clinically more aggressive metaplastic
and pleomorphic lobular special types of breast carcinoma.
Despite these overlapping patterns of gene expression
between subsets of invasive ductal carcinoma, NOS, and
some special histologic types of mammary carcinoma illus-
trated by the foregoing examples, gene expression profiling
reveals significant and distinctive genomic differences such
as the upregulation of genes involved in immune response
in medullary carcinomas
47
and the downregulation of genes
involved in cell proliferation and migration in adenoid cys-
tic carcinomas.
48
As Steensma
49
observed, “This is the age of massive ge-
nome surveys- at least for a little while longer.” Gene expres-
sion profiling is really in its infancy and will most likely lead
to important, lasting discoveries in the future. The recent
finding that carcinomas arising in different organ systems
share certain genomic alterations
50
has important thera-
peutic implications. It is reasonable to predict that genomic
studies will eventually lead to stratification of invasive ductal
carcinomas NOS, into clinically meaningful subgroups. In
the meantime, changing the name of this group of neo-
plasms without a sound scientific basis will only cause con-
fusion without improving our understanding of the disease.
With a little patience, advances in the genomics of breast
carcinoma will probably take care of the problem.
Paul P. Rosen, MD
REFERENCES
1. Roy JE, Hunt JL. Detection and classification of diagnostic discrepan-
cies (errors) in surgical pathology.
Adv Anat Pathol
2010;17:359–365.
2. Smith ML, Raab SS. Directed peer review in surgical pathology.
Adv
Anat Pathol
2012;19:331–337.
3. Raab SS, Swain J, Smith N, et al. Quality and patient safety in the di-
agnosis of breast cancer.
ClinBiochem2013
,
.
clinbiochem.2013.04.024
.
4. Renshaw AA, Gould EW. Measuring errors in surgical pathology in
real-life practice. Defining what does and does not matter.
Am J Clin
Pathol
2007;127:144–152.
