natural history

Natural History

The most common site of origin of breast cancer is the upper outer
quadrant (38.5%), followed by the central area (29%), the upper inner
quadrant (14.2%), the lower outer quadrant (8.8%), and the lower inner
quadrant (5%). [ref: 305] These rates correlate with the amount of
breast tissue in the various quadrants. Cancer is somewhat more common
in the left than in the right breast; it is unusual for cancer to
appear in both breasts simultaneously (1% to 2%). Metachronous
bilateral carcinoma of the breast has been observed in 5% to 8% of
patients.

The growth rate of a tumor in the breast is thought to be constant
from the date of origin. [ref: 305] Using estimates of doubling time,
it would take an average of approximately 5 years for a tumor to reach
palpable size, and those lesions with slower doubling time would have
an even longer latent period. [ref: 305]

As the cancer grows, it travels along the ducts, eventually breaking
through the basement membrane of the duct, invading adjacent lobules,
ducts, fascial strands, and the mammary fat, spreading through the
breast lymphatics and into the peripheral lymphatics. The prognostic
and therapeutic implications of tumor multicentricity and
multifocality are discussed later in this chapter (see Prognostic
Factors). The tumor can grow through the wall of blood vessels, spread
into the deep lymphatics of the dermis, and eventually produce edema
of the skin (peau d'orange), which usually indicates that the
superficial as well as the deep lymphatics are involved. Ulceration
and infiltration of overlying skin, which may develop late in the
course of the disease, are usually preceded by fixation and localized
redness of the skin over the tumor [ref: 305] and are less frequently
seen because of current emphasis on screening and early diagnosis.

A common route taken by breast carcinoma as it metastasizes is first
through the axillary lymph nodes; the incidence of lymph node
metastasis increases with larger tumors. [ref: 168] About 20% to 40%
of newly diagnosed stage T1 and T2 breast cancers have pathologic
evidence of axillary nodal metastases, which are most frequent from
lesions of the upper outer quadrant of the breast. Table 50-1
summarizes incidence of axillary metastases according to the size of
the primary tumor.

In 263 patients with T1 unilateral invasive breast cancer, 72 patients
(27%) had nodes positive for metastasis. [ref: 102] Univariate
analysis showed that lymph node metastases were associated with tumors
larger than 1 cm (P = 0.001), moderate or poorly differentiated
nuclear grade (P = 0.005), high fraction of cells in the growth phase
(S phase) of the cell cycle (P = 0.041), presence of lymphatic
vascular invasion (P < 0.001), and age younger than 60 years (P =
0.01). The number of involved axillary lymph nodes definitely
influences prognosis and therapy outcome. [ref: 221]

In a study of 135 patients who underwent axillary lymph node
dissection in conjunction with either modified radical mastectomy or
lumpectomy (median follow-up, 6.9 years), there was no difference in
overall or disease-free survival between patients whose highest or
only level of axillary involvement was level I and those whose highest
or only level was level II. [ref: 43] Although patients whose highest
level of nodal involvement was level III had significantly worse
overall and disease-free survival rates, when patients were stratified
by the total number of positive nodes (1 to 3 versus >/= 4), there was
no difference in overall or disease-free survival rates in levels I,
II, and III.

Metastases to the internal mammary nodes are more frequent from medial
half and central lesions; these metastases occur more frequently when
there is axillary node involvement (Table 50-2). [ref: 324] The
supraclavicular lymph nodes may be the target of metastatic deposits,
usually after the high axillary or internal mammary lymph nodes are
involved by tumor, depending on the location of the primary lesion.

Vascular invasion by tumor and hematogenous metastases to the lungs,
pleura, bone, brain, eyes, liver, ovaries, and adrenal and pituitary
glands may be observed, even with small tumors. A highly significant
correlation was found between tumor size and incidence of distant
metastases. The distribution of tumor sizes and metastatic spread was
log-normal with a median diameter of 3.5 cm. The proportion of grade 1
tumors was higher in small tumors than in large ones, while the
reverse was observed for grade 3 tumors; these data suggest that,
during their growth, tumors progress toward higher grades. [ref: 779]

Patterns of Failure After Treatment

Although the frequency of recurrence is correlated with tumor stage,
the failure patterns after mastectomy are similar in patients with
various stages of disease. Valagussa and colleagues, [ref: 786] in
their study of operable breast cancer patients treated with radical
surgery, noted that "node-negative" patients had fewer failures than
"node-positive" patients, but that the proportion of locoregional and
distant metastases was essentially the same in both groups.

Fowble and associates, [ref: 257] in an analysis of node-positive
patients after mastectomy and chemotherapy who did not receive
postoperative radiation therapy, noted that isolated locoregional
recurrence correlated with the presence of four to seven positive
lymph nodes, T3 tumor stage, positive surgical margins, and high
nuclear grade. Patients with more than seven positive nodes tended to
fail systemically as well as locally, minimizing the frequency of
isolated locoregional recurrence.

DePietro and co-workers [ref: 156] found, in 800 patients with first
recurrence at various sites after mastectomy, that visceral metastases
were more frequent in patients younger than 50 years of age, whereas
local recurrence was more common in patients older than 50 years.
Survival after recurrence for patients with first metastasis confined
to the soft tissues was higher than for those with bone or visceral
metastases. A study by Hagemeister and colleagues [ref: 318] found
more tumor involvement than had been clinically suspected in 166
patients who died of breast cancer and had autopsy; most of these
patients had received treatment including chemotherapy. There were 325
unsuspected metastases; areas of tumor involvement included the
endocrine organs (40%), liver (30%), lungs (28%), cardiovascular
system (21%), and genitourinary system (21%). Major causes of death
were pulmonary insufficiency (26%), infection (24%), cardiac disease
(15%), and hepatic insufficiency (14%). The most common cause of death
was metastatic disease to various organs, accounting for 42% of all
deaths; infection was the second most common cause of death.

Fisher and associates, [ref: 218] in an analysis of patients treated
in National Surgical Adjuvant Breast Project (NSABP) Protocol B-06,
concluded that ipsilateral breast tumor recurrence was a harbinger of,
but not a cause of, distant metastases. While mastectomy or breast
irradiation after lumpectomy prevented expression of the marker
(breast relapse), neither lowered the risk of distant metastases,
which was determined by a host of prognostic factors.

The patterns of failure in intraductal, lobular in situ, and stage T1
and T2 breast cancer after breast conservation surgery are analyzed in
detail in later sections of this chapter.