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Table of contents :
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from the breast
(mass effect on hypothalamus or compression of hypothalamic root)
secretion
(increased TRH,
which is also a releasing factor for PRL)
therapy
incretion,
breast bandage
gene may be potential candidate for lactation insufficiencies.
(ulceration in primary syphilis; acute mastitis in secondary syphilis;
gum in tertiary syphilis requires differential diagnosis with carcinoma)
or streptococcal bacteria and usually affecting lactating women; it may
be),
not associated with cigarette smoke; dilatation of of subareolar ducts
=> deposition of cellular debris and lipids => cronic interstitial granulomatous
inflammation.
Women, usually age 40-59 years. Associated with pituitary adenomas, increased
prolactin levels. Not associated with smoking; not related to fibrocystic
changes. Gross: skin retraction from fibrosis may mimic cancer; nipple
discharge in 20%. Micro: duct dilation, inspissation of secretions (cheesy),
periductal and interstitial granulomatous inflammation (granulomatous mastitis)
or plasma cells (plasma cell mastitis); ducts contain foamy macrophages;
increased elastic fibers in duct wall, calcification; no squamous metaplasia
of nipple ducts; no epithelial hyperplasia
(mainly large B cell lymphoma).
Associated with mild increased risk of carcinoma, especially with ductal
hyperplasia or family history of breast carcinoma. Malignant transformation
occurs in < 0.1%, usually DCIS. Infarction associated with pregnancy,
lactation, fine needle aspirationref.
Gross: sharply circumscribed, freely movable, spherical nodule, usually
3 cm or less; often in upper outer quadrant, gray-white, bulging cut surface;
20% multifocal. Micro: overgrowth of fibrous and glandular tissue; intralobular
stroma (delicate, cellular, myxoid or fibrotic) encloses glandular spaces;
may infarct, become inflammed, calcify; 15% have apocrine metaplasia; no
necrosis, no elastic tissue. Pericanalicular: open glandular spaces vs
intracanalicular: compression of glandular spaces [no clinical significance
to this distinction]. Glands composed of cuboidal/low columnar epithelium
without atypia, adjacent myepithelium. Rarely benign but pleomorphic, bizarre
multinucleated giant cellsref,
metaplastic cartilage, smooth muscle or adipose tissue; myxoid change (suggests
Carney’s syndrome of endocrine hyperactivity, cardiac myxoma and cutaneous
hyperpigmentation), fibrocystic features, sclerosing adenosis, squamous
metaplasia. Positive stains: PR. Negative stains: ER. DD: phylloides tumor
(cellular stroma), papillary carcinoma at FNAref
mutations, the possibility to develop breast cancer by age 50 may be as
high as 60%. Those who also have relatives with breast or ovarian cancer
have an 80% chance of developing breast cancer, compared with 10% in the
general population : the risk is also close to 80% for women with BRCA
mutations but no affected family member. Lifestyle is also important :
heterozygous women born after 1940 have a 67% risk of developing breast
cancer by the age of 50. For those born before 1940, the risk is only 24%.
Exercising and staying slim as a teenager tend to delay the age at which
women with mutations develop cancer by several years.,
with slight increases for those with...
have a RR = 2 : use of CHRT for 10 years is estimated to result in 19 extra
breast cancers per 1,000 users. Women using estrogen-only
replacement therapy (ERT)
have RR = 1.3, but ERT has been linked to a slightly increased risk of
developing endometrial adenocarcinoma
- which is why it tends to be given to those women who have undergone hysterectomy.
Users of HRT are more likely than newer users to develop breast cancer
(RR = 1.66) and die from it (RR = 1.22) : the risk begins to increase within
1-2 years of starting HRT. Interestingly, past users are not at increased
risk of developing or dying from breast cancer.
in postmenopausal women (obese women have about 3 times the circulating
estrogen
levels as lean women and also leptin
is a breast growth factor)
in underarm cosmetics (deodorants, ...) are transdermally absorbed : they
are found unmodified in 90% of breast tumor tissues with a mean concentration
of 20.6+/-4.2 ng/ g tissue = 1 part per 48m (comparison of individual parabens
showed that methylparaben was present at the highest level (with a mean
value of 12.8 +/- 2.2 ng/g tissue) and represents 62% of the total paraben
recovered in the extractions), but there is still no scientific evidence
of a causal link. The strongest supporting evidence comes from unexplained
clinical observations showing a disproportionately high incidence of breast
cancer in the upper outer quadrant of the breast, just the local area to
which these cosmetics are appliedref1,
ref2.
An earlier age (> 15 years younger) of breast cancer diagnosis is related
to more frequent use of antiperspirants/deodorants and underarm shaving
(> 2 times a week) : consistet with previous studies no link is found between
younger age of breast cancer diagnosis when either shaving or deodorant
is used aloneref.,
contained in many hard plastics which can leach into food after heating
and also appearing in some dental fillings and the linings of tin cans.
Industry began using bisphenol A in the 1950s, but in recent years scientists
have documented how it mimics the hormone oestrogen. Some scientists worry
that because oestrogen plays such a crucial role in the development of
a fetus's reproductive system and other organs, exposure to bisphenol A
in the womb could cause problems. A recent study of mice exposed in this
way found that the artificial compound caused abnormally high levels of
growth in the male animals' prostate glands. Now, another team of researchers
has investigated the effects of this chemical on female miceref.
The scientists hypothesized that bisphenol A could make breast tissue more
sensitive to the effects of oestrogen. So they exposed mouse fetuses to
a daily dose of 250 ng/kg of their body weight, < 1% the amount deemed
safe for humans in the USA. 4 days after birth, the scientists stopped
administering the chemical to the mice. They then waited until the animals
reached puberty at 30 days of age, and removed their ovaries. This allowed
them to deliver the mice's oestrogen themselves, so that they could measure
its influence in a controlled way. The mice exposed to bisphenol A while
in the womb developed significantly more tissue in parts of their mammary
glands than their control counterparts. The exposed mice had a 4-fold increase
in gland structures known as terminal end buds. This is important because
increased breast tissue density in humans is an established risk factor
for breast cancer. It's an important study because it's the first time
someone's showed that prenatal exposure to bisphenol A causes alterations
in mammary gland development. Although the findings focus on laboratory
animals, they may have implications for people. Testing the effects of
the chemical in humans would be difficult, as the study would have to monitor
exposure over 50 years from birth to the age at which breast cancer more
commonly occurs. Lawmakers in California are currently considering legislation
that would ban bisphenol A from children's toys.,
and CE-3,4-Q by conjugation with glutathione (GSH) or by reduction to CE,
catalyzed by quinone reductase and/or cytochrome P450 reductase. Females
homozygous for hypoactive forms of the catechol-inactivating enzyme COMT
are more susceptible to side effects of HRT.
: women who took antibiotics for > 500 days or had > 25 prescriptions for
antibiotics, over an average of 17 yrs, had twice the risk of breast cancer
as women who had taken no antibiotics. The association with breast cancer
risk might be mediated throgh the effects of the antibiotics on immune
and inflammatory factors, and disruption of phytochemical and estrogen
metabolism by intestinal microfloraref
intake : older women with a history of at least 30 grams of ethanol
abuse a day (roughly the equivalent of 2 drinks) have a 40% higher risk
than nondrinkers to be diagnosed with ER+ and PR+
tumors, a 330% increased risk of lobular cancer and a 50% increased risk
of ductal cancer. However, the studies relied on women's self-reports of
how much they drank and research shows that most people don't accurately
report their alcohol consumption.
increases a woman's chance of being left-handed (Scheirs J. G. M.&
Vingerhoets A. J. J. M. J. Clin. Exp Neuropsychol., 17. 25 - 30 (1995)).
But the full mechanism behind handedness remains elusive. Some scientists
think that clues to breast cancer also lie in the prenatal period of human
development. Studies in mice have found that fetal exposure to oestrogen-like
compounds can increase the risk of breast or prostate cancer in later life.
These 2 links to oestrogen-like chemicals could be creating an association
between handedness and cancer. After examining the records of over healthy
middle-aged women born between 1932 and 1941, left-handed pre-menopausal
women face double the risk of developing breast cancer as right-handed
women do. This trend did not apply, however, to women who had not given
birth or to those who were overweight or obeseref.
It is not the first study to focus on this association. Other, retrospective
studies have found a similar link between handedness and breast tumours.
But the Dutch team thinks their thorough approach lends more support to
the idea that the effect is real, and that chemicals in the womb could
be to blame. In some countries, bans are in place to prevent oestrogen-like
chemicals from being used in plastics. Others are campaigning to reduce
the amount of such chemicals flooding into our environment from contraceptives
and other sources.
gene. This is the first population-based study to report a clearly significant
increase in TP53 mutations that is independent of race differences in other
tumor characteristics, socioeconomic status and other biomedical and lifestyle
factors : past explanations for the racial/ethnic differences included
socioeconomic factors, nutrition and healthcare behavior, but while many
factors contribute to the relatively poor outcome for some African-American
breast cancer patients, understanding the underlying mechanisms is critical
in premenopausal women (probably by inhibiting ovulation by abnormal estrous
cyclicity, even though estradiol
concentrations don't differ between the lean and fat animals)
associated with highly aggressive tumours that have a poor prognosis. Not
only did oleic acid suppress over-expression of the gene, other tests on
the cell lines showed that it also boosted the effectiveness of anti-ERBB2
/ HER2 / neu mAbsref
T29C SNP confers a reduced risk of breast cancer among premenopausal, but
not postmenopausal, Japanese women.-
tumors)
is mutated in 8% of all breast cancers : susceptibility to breast cancer
occurs only in females who inherit a mutation in BRCA1 as mutated BRCA1
inhibits the non-coding XIST RNA localization to the Xi chromosome,
reactivating genes that are normally silent on the Xi
(deleted in 2% of cancers)
(amplified in 18% of breast cancer cell lines and 20% of samples from newly
diagnosed patients : the degree of amplification correlates with the expression
level. Also amplified in 17% of high-grade ovarian carcinomas) inhibits
normally functioning BRCA2
by binding to a a region (exon 3 in aminoterminus) that is deleted in cancer,
associated with chromatin regulators HP1b and
BS69, and it localized to sites of repair following DNA damage. Prognosis
: average survival of 6.4 years, compared with 14 yearsref.
The sequence of the first few amino acids of the protein coded for by EMSY
- serine-isoleucine-serine-threonine-glutamic acid-arginine — spells out
a word when the standard abbreviations for these amino acids are used.
The word is S-I-S-T-E-R, so the gene was named after the sister of one
the researchers, Luke Hughes-Davies. This was particularly appropriate
as Emma Hughes-Davies (called Emsy when she was young) is a breast cancer
nurse. The 80-amino-acid EMSY N-terminal domain (ENT) was found
in 9 Arabidopsis proteins that also contain a Royal-family domain,
designated Agenet, that can recognize lysine-methylated histones, which
explains the link with chromatine remodelling. As EMSY does not possess
such a domain, it interacts with HP1b and BS69.
The median disease-specific survival for node-negative breast cancer was
6.4 years with EMSY amplification, but 14 years withoutref.
(20-30%) : mammary-specific expression of an activated ErbB2 allele leads
to the formation of mammary adenocarcinomas in mice. Despite levels of
ErbB2 expression in the mammary epithelium comparable to those of animals
with tissue-specific activation, mice carrying germline ErbB2 do
not develop tumours : feedback mechanisms during development compensate
for germline oncogene expressionref.
After preoperative chemotherapy, HER2 status may change from that detected
in the core biopsy specimen to that in a sample of the resected breast
cancer in 4-35% of cases as assessed by IHC and in 13% of cases as assessed
by fluorescence in situ hybridization (FISH)ref1,
ref2,
ref3,
ref4,
ref5.
HER2-negative status may convert to a positive status in 2 to 9%ref1,
ref2,
ref3
of patients, as assessed by IHC or FISH, and from a positive status to
a negative status in 15-26% of patients, as assessed by IHCref1,
ref2,
ref3
or in 4%, as assessed by FISHref
(15%)
(20-25%, well below its average of 50% in all types of cancer)
(< 10%, below its average of 25% in all types of cancer)
in healthy mammary glands and its loss in some breast cancers points to
a tumour suppressor role, which could have value in a diagnostic setting
(up-regulated thanks to positive selection exercted by hypoxia on tumour
cell clones lacking inhibition of the VHL tumour suppressor over HIF-1a)
and CCR7
and are characterized by a distinct metastatic pattern involving the regional
lymph nodes, bone marrow, lung and liver, ie tissues that express peak
levels of the ligand chemokines CXCL12
and CCL21
: signalling through CXCR4 or CCR7 mediates actin polymerization and pseudopodia
formation, and subsequently induces chemotactic and invasive responses.
of the lactiferous ducts
(a mutations seen also in congenital
mesoblastic nephroma
and congenital fibrosarcoma) results in constitutive activation
of wild-type NTRK3, which activates the Ras-MAPK and the PI(3)K pathways
for mitogenesis and cancer survival.
(2% of all invasive carcinomas)
(2% of all invasive carcinomas)
(1% of all invasive carcinomas)
can pick tumours that mammography would miss, such as DCIS, even if the
tissue is dense (as in younger females) or if the tumour is not calcified
: sensitivity = 76%, specificity = 88%detects
increased choline levels in malignant tissues.
in old females (fatty breast) : sensitivity = 36-90%, specificy = 95%.
Women with familial breast cancer are more susceptible to the mutagenic
effect of the low-dose irradiation used for a mammogram, so exposure to
X-rays should be kept to a minimum. No statistically significant differences
in detection rates were observed between the x-ray and full-field digital
mammography : anyway radiation for patients may be incrementally lower
with digital screening depending on the type of detector used. The overall
diagnostic accuracy of digital and film mammography as a means of screening
for breast cancer is similar, but digital mammography is more accurate
in women under the age of 50 years, women with radiographically dense breasts,
and premenopausal or perimenopausal womenref.
in young females (dense breast) differentiates between cystic and solid
nodules,
TK
and TPA
> CEA
(also CA125
for eventual association with ovarian tumors in patients with BRCA1 or
BRCA2
mutations)
for ovarian tumors in patients with BRCA1 or BRCA2
mutations
is a candidate markerthat may be useful for identification of breast lesions
that can develop into cancerref
confirmed by X-rays for osteolytic
bone metastases
for pulmonary
metastases
for liver metastases|
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(68%) only in clones overexpressing of IL-11
(which induces osteoclast formation), MMP1,
CXCR4,
osteopontin
(which stimulates osteoclast adhesion to the bone matrix), and CTGF,
usually occurring in association with widespread metastatic diseaseref1,
ref2.
The reported interval from the initial diagnosis to the development of
bladder metastases ranges from 7 months to 30 years, with a mean interval
of 7.5 yearsref.
Lobular carcinomas appear to have a stronger association with bladder metastases
than the more common ductal subtype of breast carcinomaref.
Lobular carcinomas have a propensity to metastasize to serosal surfaces,
the gynecologic tract, and the gastrointestinal tractref,
and perhaps spreading from these adjacent sites accounts for the greater
frequency of bladder involvement. Metastatic lobular carcinoma also often
occurs as a diffuse thickening of an affected organ, as seen in this case,
rather than as discrete tumor nodulesref.
The development of bladder metastases has generally been a poor prognostic
feature, and most patients die of the disease within 2 yearsref.
or BRCA2,
are, at present, offered prophylactic mastectomy
with eventual axillary lymphadenectomy
after positive sentinel lymph node (SLN)
detection : women whose tumours are removed in a particular phase of their
menstrual cycle are more likely to get metastases, but other studies have
found no such link
before surgery in patients with HER2
/ ERBB2+
breast
carcinomas : the release of TGF-a
and heparin-binding EGF
triggered by surgery (which directly relates with the amount of tissue
damage) causes the high level of recurrence, expecially in HER2
/ ERBB2+
carcinomas
+ axillary lymphadenectomy
+ eventually followed by adjuvant radiotherapy
(QUART)
(radical Meyer or
Halsted mastectomywhen
greater pectoral muscle is infiltrated)
(in T1 or T2 only when >= 4 axillary or >= 1 internal mammary lymph nodes
are involved; or when OncotypeDX® test is positive in tamoxifene-treated,
node-negative (based on 16 cancer genes and 5 noncancer genes, which can
identify 50% of patients who have an excellent prognosis and most likely
don't need chemotherapy)ref).
and opposed field (medial and lateral, both tangential to chest) irradiation
(CT planning with isodose curves allows maximal sparing of heart, lungs,
skin and subcutis). Radiotherapeutical burst (+ 10 Gy) over surgery scar.
Also electron bundles and high-dose rate (HDR) interstitial
brachytherapy
(worse aesthetic results) are used, while intraoperatory radiotherapy is
under study.
for control of osteolytic
bone metastases
: delay radiotherapy as CMF induces cells to enter G0, the least
radiosensitive cell cycle stage
: radiotherapy may be started simultaneously
and gemcitabine
for BRCA1 and BRCA2 mutations
is effective in the control of hot flashes at a dose of 900 mg/dayref
for 2 years