Age: There is a steady increase in the incidence of breast cancer, as women
grow older. The age-specific incidence rate is highest in postmenopausal women.
Family history: The relative risk of breast cancer in a woman with breast
cancer in first-degree relative (mother, sister, or daughter) ranges from
1.5 to 2.5.
Reproductive factors: The younger a womans age at menarche, the higher
her risk of breast cancer. For each 2 years delay in onset of menstrual activity,
the risk is reduced by about 10%.
The earlier a woman has her first birth, the lower her lifetime risk for
breast cancer. This is independent of parity. A woman who has her first birth
after 30 years has an increased risk. A nulliparous woman has increased risk.
The later a womans age at menopause, the higher her risk of breast
cancer. Women who had their menopause after 55 years have 2 times the risk
of those who had their menopause before 45 years.
Previous cancer: Women who have had a breast cancer have a 10-fold increased
risk of developing a second primary breast cancer.
Atypical hyperplasia: See above.
Geographic factors: Breast cancer is more common in Western industrialized
countries than in developing countries.
Carcinoma of the breast is divided into noninvasive and invasive carcinomas.
This is epithelial proliferation that is still confined to the TDLU, has
not invaded beyond the basement membrane and is therefore incapable of metastasis.
There are two subtypes: 1) Ductal carcinoma in situ (DCIS) or intraductal
carcinoma and 2) Lobular carcinoma in situ. The incidence in autopsy studies
is about 20%.
Ductal carcinoma in situ (Intraduct carcinoma)
DCIS comprises a heterogeneous group of noninvasive neoplastic proliferation
with diverse morphologic appearances and risks of subsequent recurrences and
development of subsequent invasive carcinoma. The tumor distends and distorts
the ducts in the TDLU so that the terminal ducts enlarge and resemble large
ducts. Although the tumor is confined to the TDLU, neoplastic cells can spread
throughout a ductal system and produce extensive lesions involving an entire
sector of a breast. Involvement of a main lactiferous duct and thence the
nipple leads to the development of Pagets disease of the nipple (see
below). DCIS occurs throughout the age range of breast carcinoma with mean
age at diagnosis between 50 and 59 years, similar to the mean age of women
with invasive ductal carcinoma. Mammography is a very sensitive diagnostic
procedure for detecting DCIS, as a substantial proportion is not palpable.
Mammographically detected microcalcifications are found in 72 to 98% of DCIS.
The tumor is divided into two histologic types: comedo and cribriform/micropapillary
Comedocarcinoma involving multiple ducts produces a firm mass, which may
be well defined, and shows white-to-pale yellow flecks of pasty necrotic debris
which extrude from the cut surface on pressure hence the name comedocarcinoma.
Calcifications are frequent and produce a characteristic branching pattern
Histologically, comedocarcinoma grows in a solid pattern with a central area
of necrosis. Large pleomorphic tumor cells with irregular nuclei, commonly
with prominent nucleoli characterize the tumor.
The tumor spreads extensively through ducts well beyond the extent of its
visible confines. Thus excision margins frequently contain tumor and the technical
difficulties of ensuring complete excision frequently demand mastectomy.
These tumors are differentiated by their growth patterns as they form papillary
structures and small, regular fenestrations (giving a sieve-like appearance,
hence the name cribriform). The tumor cells are smaller and more uniform compared
to comedocarcinoma and lack necrosis. However, this variant of DCIS is often
admixed with the comedo type.
Cribriform DCIS. Note regular punched out fenestrations and distension of
duct, which is filled tumor cells.
Cribriform DCIS (center) surrounded by comedo-type DCIS.
The two types of DCIS differ markedly in their risk of subsequent invasive
carcinoma. Comedocarcinoma has essentially a 100% chance of becoming invasive
if left untreated. Pure cribriform/micropapillary carries only a 30% chance
of invasive carcinoma.
Lobular carcinoma in situ
Lobular carcinoma in situ (LCIS) does not form a palpable mass and cannot
be detected clinically, felt at operation or seen grossly on pathological
examination. Although LCIS may have microcalcifications, these are infrequent
and so mammography has not been useful for detecting it. The tumor presents
as a coincidental finding in breast tissue removed for other reasons. The
tumor is found in 1 to 6% of breast biopsies and forms 30 to 50% of noninvasive
carcinomas found in biopsies. The age distribution does not differ significantly
from that for invasive carcinoma ranging from 44 to 54 years. The disease
tends to be bilateral and multicentric. In biopsies about 40% of cases are
bilateral while in mastectomy cases about 67% are bilateral.
LCIS shows a proliferation of cells that fill and distend the TDLU. The cells
are larger than normal ductular cells, loosely cohesive and uniform with regular
round to oval nuclei, small nucleoli and moderate pale cytoplasm. They are
arranged in an orderly fashion and there are very few or no mitoses.
If LCIS is left untreated, about 30% of women develop an invasive cancer
within 20 years of diagnosis. The invasive cancer has a 50% chance of occurring
in the breast contralateral from the one containing the LCIS. The invasive
cancer may be ductal or lobular. LCIS is therefore a marker of increased cancer
in both breasts.
NOTE: The use of the term carcinoma for these lesions has excited
controversy. Their malignant nature has been questioned. The implication of
the term is that the lesions have the capacity to progress and invade. It
is now clear that such progression to invasive lesions does not occur clinically
in the lifetime of all patients even when not treated. It is likely that foci
of these lesions may remain dormant for years or even indefinitely. It is
possible that some may regress. There are at the present no methods to accurately
predict the likelihood of progression to invasive carcinoma and the quandary
of how to treat these lesions largely result from this. However, one thing
is certain, that these lesions place a woman at a high risk of developing
Invasive breast carcinoma is breast tumor that has extended across the basement
membrane. This permits access to lymphatics and vessels and the potential
distant metastases and thereby a lethal outcome. There are several different
types of invasive carcinoma. Invasive breast carcinoma is subdivided into:
- Invasive ductal carcinoma not otherwise specified (NOS)
- Invasive lobular carcinoma
- Medullary carcinoma
- Colloid or mucinous carcinoma
- Tubular carcinoma
There are other subtypes, which are very rare and will not be discussed.
Breast cancer. Locations and distribution.
Question: Why is the upper outer quadrant the commonest site for breast
Invasive ductal carcinoma NOS
Invasive ductal carcinoma not otherwise specified is the commonest type of
breast cancer, forming up to 80% of these cancers. Most of these tumors excite
a pronounced fibroblastic stromal reaction to the invading tumor cells producing
a palpable mass with hard consistency (hence scirrhous carcinoma), which is
the most common presentation. The tumor shows an infiltrative attachment to
the surrounding structures and may cause dimpling of the skin (due to traction
on suspensory ligaments) or nipple retraction. Cut surface is gritty and shows
irregular margins with stellate infiltration and foci of yellow, chalky streaks.
Invasive ductal carcinoma
Histologically, the tumor cells are larger than normal epithelium, and can
assume a variety of patterns such as glandular formation, cords of cells,
broad sheets of cells or a mixture of all these, usually within a dense stroma.
The tumors range from well differentiated, in which there is glandular formation,
to poorly differentiated, containing solid sheets of pleomorphic neoplastic
cells (see grading below).
Invasive ductal carcinoma. Low power view showing infiltrative margins.
Invasive ductal carcinoma showing dense fibroblastic stroma.
Invasive lobular carcinoma
Lobular carcinoma is the second most common type of invasive breast cancer
forming up to 10% of breast cancers. The tumor may occur alone or in combination
with ductal carcinoma. It tends to be bilateral more often than ductal carcinoma
The amount of stromal reaction to the tumor varies from dense desmoplasia
to little reaction and therefore the presentation varies from a discrete mass
to a subtle, diffuse indurated area.
The cancer cells are small, bland and uniform, about the size of normal ductular
epithelial cells. Classically, the cells tend to infiltrate as individual
rows (single or Indian file) and may form concentric arrays (targetoid pattern).
Occasionally, a solid pattern or cords of cells are produced. In about 10%
of cases, tumors have mixed features of invasive ductal and lobular carcinomas.
Invasive lobular carcinoma showing infiltrating single rows of cells (Indian
Invasive lobular carcinoma showing solid and single cell patterns. Note targetoid
pattern in the center of the lesion.
This subtype of breast cancer presents as a circumscribed mass. It does not
produce any fibroblastic reaction and therefore is soft and fleshy (encephaloid).
On section foci of necrosis and hemorrhage are evident.
Microscopically, the tumor is composed of solid sheets of cells forming a
syncytium with large pleomorphic nuclei, prominent nucleoli and frequent mitoses.
There is scant fibrous stroma. Moderate to large numbers of lymphocytes and
plasma cells surround the sheets of tumor cells.
Mucinous or Colloid carcinoma
Mucinous carcinoma tends to occur in older women. It is sharply circumscribed,
lacks fibrous stroma, is soft and gelatinous and has a glistening cut surface.
It may be pure in which more than 75% of the tumor is mucinous or mixed in
which it is associated with other types of invasive breast carcinoma. The
mucinous tumor is composed of small islands, occasionally forming glands,
and isolated tumor cells floating in pools of extracellular mucin.
Tubular and Cribriform carcinomas
Tubular carcinoma is composed of small glands or tubules that take variable
shapes. The distribution of the glands is haphazard and a single layer of
cells lines each gland. Cribriform carcinoma grows as rounded and angular
masses of uniform tumor cells embedded in variable amounts of fibrous stroma
with sharply outlined, round or oval glandular spaces distributed throughout
the tumor aggregates giving a sieve-like growth pattern. Both tumors may be
mixed with other types but in their pure form are locally invasive in the
breast and only a small proportion (5-10%) metastasize to lymph nodes.
Pagets disease of the nipple
Pagets disease of the nipple presents with an eczematous area of the
nipple, which may be subtle or form an obviously eroded, weeping lesion. The
underlying process is population of the epidermis of the nipple with neoplastic
cells, which are identical to a DCIS in the underlying ducts or, less commonly,
with an invasive ductal carcinoma deeper within the breast. In advanced lesions,
the process may extend to involve the areola and adjacent skin.
The histologic hallmark of Pagets disease of the nipple is the infiltration
of the epidermis by large neoplastic cells with abundant clear or pale cytoplasm
and nuclei with prominent nucleoli. The cells usually stain positively for
Question: In which other part(s) can a similar lesion occur?
The prognosis of Pagets disease depends on the prognosis of the underlying
Clinical behavior of breast cancers
The prognosis of breast cancer depends on several factors including the histologic
type of the tumor, the grade, the size of the tumor, the presence or absence
of lymph node metastases, and the presence or absence of hormone receptors.
Histologic type: Infiltrating ductal and lobular carcinomas have the
worse prognosis, medullary and mucinous have intermediate and tubular and
cribriform have the most favorable prognoses.
Stage: This is a combination of size and lymph node status. Tumor
size less than 2 cm is associated with a favorable prognosis. The single most
important prognostic indicator is the lymph node status. Negative lymph nodes
have the best prognosis. Involvement of 1 to 3 lymph nodes has an intermediate
prognosis and 4 or more positive nodes have the worse prognosis.
Grade: This is done by the pathologist. Grading separates tumors into
three categories according to the amount of well formed tubules, the degree
of nuclear pleomorphism, and the number of mitoses as follows: