Download Path Chapter 23 [4-20

Path Chapter 23: The Breast
The breasts (mammary glands) provide nourishment and immune defense for offspring
Mammary glands rest on the pectoralis muscle
The breasts are made of specialized epithelium and stroma
Keratinizing squamous epithelium of the overlying skin dips into the orifices at the nipple, and then
abruptly changes to a double-layered cuboidal epithelium lining the ducts
Branching of the large ducts eventually leads to the terminal duct lobular unit – page 1066
-
In adult women, the terminal duct branches into a grapelike cluster of small acini to form a
lobule
Each duct system usually occupies more than one quadrant of the breast, and the stems extensively
overlap one another
2 cell types line the ducts and lobules:
-
-
Contractile myoepithelial cells – have myofilaments and lie in a meshlike pattern on the
basement membrane
o They help in milk ejection during lactation, & provide structural support to the lobules
Luminal epithelial cells - overlie the myoepithelial cells
o Only the lobular luminal cells are able to produce milk
Two types of breast stroma:
-
Interlobular stroma – consists of dense fibrous connective tissue mixed with adipose
Intralobular stroma envelops the acini of the lobules, and has breast-specific hormonally
responsive fibroblast-like cells mixed with scattered lymphocytes
Changes in the breast happen most in the reproductive years
-
The breast grows and shrinks with each menstrual cycle
o In the first half of the menstrual cycle, the lobules are quiescent (inactive)
o After ovulation, increased estrogen and progesterone cause cell proliferation to
increase, and the # of acini to increase
o The intralobular stroma also becomes very edematous
o At menstruation, the fall in estrogen and progesterone causes regression of the lobules
and the disappearance of edema in the stroma
Only during pregnancy does the breast become completely mature and functional
-
-
-
Lobules increase in # and size, so by the end of pregnancy, the breast is made almost entirely of
lobules with very little stroma
Immediately after delivering the baby, the luminal cells of the lobules make colostrum (higher in
protein) which changes to milk (higher in fat and calories) over the next 10 days as progesterone
levels drop
Breast milk also provides protection against infection, allergies, and some autoimmune diseases
o Mom antibodies (mainly IgA), vitamins, and enzymes all help the babies own developing
immune defense
Mom can also pass bad stuff on to the baby too, like drugs, radioactive stuff from diagnostic
tools, and viruses
Once lactation stops, the breast epithelium and stroma change
-
Epithelial cells undergo apoptosis, lobules regress and atrophy, & the total breast size decreases
Full regression doesn’t happen though, so pregnancy causes permanent increase in the size and
# of lobules
After your 30’s, long before menopause, lobules and their specialized stoma start to involute
-
The lobular atrophy may be almost complete in elderly women
The radiodense fibrous stroma of a young female is progressively replaced by radiolucent
adipose
Disorders with breast development:
-
-
-
Milk-line remnants – extra nipples or breasts result from persistence of epidermal thickenings
along the milk line, which extends form the axilla to the perineum
o They respond to hormones and cause painful premenstrual enlargements
o They’re aren’t affected by normal breast problems
Accessory axillary breast tissue – when the normal duct system extends into the subcutaneous
tissue of the chest wall or axillary fossa
o This epithelium can undergo lactational changes, resulting in a palpable mass, or give
rise to carcinomas outside the breast
o So removing the breast greatly reduces, but doesn’t completely eliminate the risk of
breast cancer
Congenital nipple inversion – common problem where the nipple fails to evert
o This usually corrects spontaneously during pregnancy, or by simple traction
o Acquired nipple retraction is more concerning, since it can be caused by cancer or
inflammation
The most common symptoms of the breast reported by women are pain, a palpable mass, “lumpiness”
without a discrete mass, or nipple discharge
-
Asymptomatic women with abnormal mammograms also need further evaluation
-
-
-
Breast pain is called mastalgia or mastodynia – common symptom that may be cyclic with
menses, or not
o Diffuse cyclic pain has no pathologic cause, and you treat by adjusting hormone levels
o Noncyclic pain is usually localized to one area of the breast
 Causes include ruptured cysts, physical injury, and infections, but most often no
specific lesion is identified
 About 95% of painful breast masses are benign
 But only 10% of breast cancers are painful
Discrete palpable masses are also common
o The most common palpable lesions are invasive carcinomas, fibroadenomas, and cysts
o Palpable masses are most common in premenopausal women
o The likelihood of a palpable mass being malignant increases with age
 Only 10% of breast masses in women under 40 are malignant, compared with
60 % of masses in women over 50
o About half of carcinomas of the breast arise in the upper outer quadrant
Nipple discharge – less common finding that is more worrisome when it is spontaneous and
unilateral, since that could be a sign it’s from an underlying carcinoma
o A small discharge is often produced by manipulation of normal breasts
o Milky discharges (galactorrhea) happen when there are high prolactin levels,
hypothyroidism, or endocrine anovulatory syndromes, and in people taking oral
contraceptives, antidepressants, methyldopa, or phenothiazines
o Repeated nipple stimulation can also induce lactation
o Galactorrhea is not associated with malignancy
o Bloody or serous discharges are most often associated with benign conditions, but a
minority can be a sign of malignancy
 The most common causes are single large duct papillomas and cysts
 Bloody discharge risk for cancer increases with age – less than 7% of women
with this under 60 have carcinoma, but 1/3 over 60 do
Mammographic screening – used to detect small, nonpalpable, asymptomatic breast carcinomas
-
The average size of an invasive carcinoma detected by mammogram is less than half that of
carcinoma caught by palpation
The sensitivity and specificity of carcinomas increase with age, due to replacement of the
fibrous radiodense tissue of youth, with the fatty, radiolucent tissue of old people – page 1067
At age 40, the probability that a lesion seen on mammogram is cancer, is only 10%
o Over age 50, this jumps to over 25%
The main signs on mammogram of breast carcinoma are densities and calcifications
o Densities – produced most commonly by invasive carcinomas, fibroadenomas, or cysts
 Most tumors are radiologically denser than the normal breast tissue around it
o Calcifications – formed from secretions, necrotic debris, or hyalinized stroma



Benign calcifications are often from clusters of apocrine cysts, hyalinzied
fibroadenomas, and sclerosing adenosis
Calcifications associated with malignancy are usually small, irregular, numerous,
and clustered
 Ductal carcinoma in situ is most commonly detected as a mammogram
calcification, deposited in a linear, branching pattern as the carcinoma
fills the duct system
 About 10% of the time, carcinomas are missed by mammograms
o The main reason is the presence of surrounding radiodense
tissue, especially in young women, obscures the tumor, along
with the absence of calcifications, small size, diffuse infiltrative
pattern with little to no desmoplastic response, or a location
close to the chest wall or in the periphery of the breast
So radiodensity in young women of their normal breasts hides the radiodensity
of a tumor, making them hard to see, while the radiolucent fat in old women
makes them easy to see
Ultrasonography distinguishes between solid and cystic lesions, and can better define the borders of
solid lesions
-
Most palpable masses that aren’t imaged by mammograms are detectable by ultrasound
Magnetic resonance imaging (MRI) detects cancers by the rapid uptake of contrast agents due to
increased tumor vascularity and blood flow
-
It’s useful in screening for cancer in women with dense breasts or at high risk for cancer, how
far cancer has spread into the chest wall, or women with breast implants to look for implant
rupture
o It gives a lot of false positives in women not in one of these groups, so it’s not used for
them
Inflammatory diseases of the breast are uncommon
-
-
Women usually present with an erythematous swollen painful breast
“inflammatory breast cancer” mimics inflammation by obstructing dermal vasculature with
tumor emboli, causing an enlarged erythematous breast
o Should always be suspected in a nonlactating woman with mastitis
Mastitis – inflammation of the breast
Almost all cases of acute mastitis happen during the first month of breastfeeding
o During this time the breast is vulnerable to bacterial infection because of the
development of cracks and fissures in the nipples
 This gives a site of entry for bacteria, usually staph, which invade the breast
tissue
o The breast is erythematous and painful, and there’s usually a fever
o
o
-
-
-
At first, only one part of the breast is involved, but then the infection spreads
Staph infections usually produce a localized area of acute inflammation that can
progress to the forming of one or more abscesses
 As opposed to strep infections, which tend to cause a diffuse spreading
infection that eventually involves the entire breast
o You treat lactational mastitis with antibiotics, and they’re still allowed to lactate
Periductal mastitis (aka subareolar abscess, squamous metaplasia of lactiferous ducts, and
Zuchka disease) – women and sometimes men present with a painful erythematous subareolar
mass that looks infected
o Most (90%) of affected people are smokers
o In recurrent cases, a fistula tract often tunnels under the smooth muscle of the nipple
and opens onto the skin at the edge of the areola – page 1069
o Many women with periductal mastitis have an inverted nipple, secondary to the
underlying inflammation
o The main histo feature of periductal mastitis is keratinizing squamous metaplasia of the
nipple ducts
 Keratin shed from these cells plugs the duct system, causing dilation and
eventually rupture of the duct
 Once keratin spills from the rupture into the surrounding periductal tissue, you
get an intense chronic and granulomatous inflammatory response that causes
an erythematous painful mass – page 1069
o Treat by surgically removing the involved duct and fistula tract
 If you just do incision to drain the abscess, the keratinizing epithelium is still
there and often causes recurrence
Mammary duct ectasia – page 1070
o Happens in your 50’s-60’s, usually in women who have had several pregnancies
o They present with a poorly defined palpable perioareolar mass, that often has thick
white nipple secretions and sometimes skin retraction
o Usually there is no pain or erythema
o Unlike periductal mastitis, there is no association with smoking
o Mammary duct ectasia lesion is characterized by dilation of ducts, thickening of breast
secretions, and a marked periductal & interstitial chronic granulomatous inflammation
 The dilated ducts are filled with granular debris with lipid filled macrophage
 Fibrosis can eventually cause skin and nipple retraction
Fat necrosis – can present as a painless palpable mass, skin thickening or retraction, or a
density or calcification on mammogram
o Most women with breast fat necrosis have a history of breast trauma or surgery
o Acute lesions may be hemorrhagic and have central areas of liquefactive fat necrosis
 The lesions can look like firm gray/white nodules with small chalky white areas
or dark hemorrhagic areas
o Eventually the lesion turns into a scar, or is walled off by fibrous tissue
-
-
Lymphocytic mastopathy (sclerosing lymhocytic lobulitis) – presents as one or several hard
palpable masses, so hard that it’s hard to biopsy them with a needle
o On microscope they show collagenized stroma surrounding atrophic ducts and lobules
o There’s lots of lymphocyte infiltrate
o Lymphocytic mastopathy is most common in women with type 1 (insulin-dependent,
autoimmune) diabetes or autoimmune thyroid disease
Granulomatous mastitis – granulomatous inflammation of the breast
o Could be caused by systemic granulomatous diseases, like Wegener granulomatosis or
sarcoidosis, or granulomatous infection
o Granulomatous breast infection is most common in either immunocompromised
people, or people with nipple piercings
o Granulomatous lobular mastitis – uncommon inflammation of the breast lobules only,
caused by hypersensititivity rxn to lobule antigens during lactation
Benign breast epithelial lesions – seen in the ducts and lobules of the breast
-
Most are found in mammograms or incidental findings during surgery
Benign breast epithelial lesions are divided into 3 groups, based on risk of developing into breast
cancer: nonproliferative breast changes, proliferative breast disease, & atypical hyperplasia
Nonproliferative breast changes (fibrocystic changes) – page 1071
o Doctors also called it “lumpy bumpy breasts” on palpation
o Radiologists say there’s a dense breast with cysts
o There are 3 morphologic changes in nonproliferative breast lesions:
 Cysts, fibrosis, and adenosis
 Small cysts form by dilation and unfolding of lobules
 These cysts can combine into larger cysts
 The cysts have cloudy semitranslucent fluid that looks brown or blue
 The cysts are lined by either a flat atrophic epithelium, or by
metaplastic apocrine cells
o The apocrine cells look like those in sweat glands, with lots of
granular eosinophilic cytoplasm
 Calcifications are common
o Calcification that lines the bottom of a cyst is referred to as
“milk of calcium”
 Cysts are alarming when they are solitary and firm to palpate
 You get rid of the cyst by fine needle aspirating its contents
 Cysts often rupture, releasing secretory stuff into the adjacent stroma, causing
chronic inflammation and fibrosis, adding to the firm feeling of the breast
 Adenosis – increase in the # of acini per lobule
 A normal physiologic adenosis happens during pregnancy
 Adenosis in nonpregnant women is usually a localized change
 The acini are usually enlarged, but not distorted

-
-
The acini are lined by columnar cells, which can look benign, or show
atypical features, which may be the earliest recognizable precursor of
epithelial cancer
o Lactational adenomas present as palpable masses in pregnant or lactating women
 They’re formed by normal-looking breast tissue from physiologic adenosis and
lactational changes
 They’re not a true tumor, and are instead a exaggereated local response to
hormones
Proliferative breast disease without atypia
o Commonly found on mammogram as densities or calcifications
o Usually there is more than one lesion, often along with nonprolfierative breast changes
o Proliferative breast changes are characterized by proliferation of duct epithelium and/or
stroma, but they don’t look like cancer (no cytologic or morphologic features of cancer)
o Epithelial hyperplasia – the presence of more than 2 cell layers lining the breast ducts
and lobule – page 1072 – normal is left, and hyperplasia is right
 Normal breast ducts and lobules are lined by a double layer of myoepithelial
cells and luminal cells
 The extra cells are both luminal and myoepthelial cells, that fill and distend
ducts and lobules
o Sclerosing adenosis – the # of acini per terminal duct is increased to at least double
normal – page 1072 bottom right pic
 They still have the normal arrangement as a lobule
 The acini are compressed and distorted in central parts of the lesion, but
characteristically dilated at the periphery
o Papillomas – made of many branching fibrovascular cores, each with a connective tissue
axis lined by luminal and myoepthelial cells – page 1073 bottom right pic
 Growth happens in a dilated duct
 Often you see epithelial hyperplasia and apocrine metaplasia
 Large duct papillomas are usually solitatry and found int eh lactiferous sinuses
of the nipple
 Small duct papillomas are usually multiple and found deeper in the duct system
o Complex sclerosing lesion – shows features of sclerosing adenosis, papillomas, and
epithelial hyperplasia
 Radial sclerosing lesion (radial scar) – the only common benign lesion that forms
irregular masses and look similar to carcinoma on mammograms, grossly, and
on histo – page 1073 top pics
 There is a center of trapped glands in a hyaline stroma with long projections
Proliferative breast disease with atypia – includes atypical ductal hyperplasia and atypical
lobular hyperplasia
o Atypical ductal hyperplasia is found next to up to 1/5 of breast calcifications
 Atypical lobular hyperplasia is found in less than 5% of cases
o
-
Atypical hyperplasia – cell proliferation resembling carcinoma in situ, but lacks too many
features to be considered a carcinoma
 It has some of the same genetic changes seen in carcinoma in situ
o Atypical ductal hyperplasia – looks like ductal carcinoma in situ (DCIS)
 Shows proliferation of regularly spaced cells – page 1074 left pic
 The difference between atypical ductal hyperplasia and DCIS, is it doesn’t
proliferate as much, and there’s only partial filling of the ducts
o Atypical lobular hyperplasia – proliferation of cells identical to lobular carcinoma in situ
(LCIS), but the cells don’t fill or distend more than half of the acini within a lobule
 Page 1074 right pic
Nonproliferative changes in breast epithelial cells do not increase the risk of cancer
Proliferative changes have a mild increase in the risk for cancer
Proliferative with atypia has a moderate increase in risk for breast cancer
Both breasts are at risk, but the breast these changes started in will have a few more carcinomas
You can treat these changes with bilateral prophylactic mastectomy, or estrogen antagonists like
tamoxifen
More than 80% of women with atypical hyperplasia will not develop breast cancer
Carcinoma of the breast is the most common non-skin malignancy in women
-
-
A woman who reaches age 90 has a 1/8 chance of developing breast cancer
It’s expected the # of women with breast cancer will increase 1/3 over the next 20 years
Only lung cancer causes more cancer deaths than breast cancer in women
Most breast carcinomas are estrogen receptor (ER) positive, and characterized by genes
controlled by estrogen
The main benefit of mammogram screening is to find small, mainly ER-positive invasive breast
carcinomas or carcinomas in situ
o DCIS is almost entirely caught by mammogroms
The death rate from breast cancer has decreased over the past 20 years – due to catching them
at a curable stage and better treatment
The most important risk factor for breast cancer is being a girl
o Only 1% happen in men
Common risk factors for women – age, age at menarche, age at first child born, first degree
relatives with breast cancer, atypical hyperplasia, race, estrogen exposure, breast density,
radiation exposure, carcinoma of the other breast or the endometrium, geography, diet,
obesity, exercise, breastfeeding, environmental toxins, and tobacco
o Age – the risk for breast cancer increases the older you get
 Peaks at 75-80 years old
 The average age of diagnosis for breast cancer is age 61 in whites, & 46 in blacks
 Only 1/5 of white women with breast cancer are under age 50, while 1/3 of
breast cancer in black and hispanic women is in women under age 50
 BREAST CANCER IS VERY RARE IN ANYONE UNDER 25 YEARS OLD

o
o
o
o
o
o
o
o
In these rare cancers, more of them are ER negative or human
epidermal growth factor receptor 2 (HER2/neu) positive, than in older
women
Age at menarche – women who reached menarche younger than 11 years old have a
20% increased risk for breast cancer (you’re exposed to estrogen longer)
Late menopause also increases risk for breast cancer (exposed to estrogen longer)
Age of first child born – women who go through a full term pregnancy younger than age
20 have half the risk for breast cancer than women who have their first kid later or
don’t have any
 It’s thought pregnancy causes final differentiation of milk making luminal cells,
removing them from the potential pool of cancer precursors
 In older women, this protective effect might be too late, since there are already
precancerous lesions, and the pregnancy stimulates them
 Pregnancy also changes the stroma in a way that may allow carcinoma in situ to
progress to invasive, which may be why there’s a temporary increased risk for
breast cancer after pregnancy
First degree relatives with breast cancer – the risk you have increases with the # of first
degree relatives (mom, sister, daughter) you have who have had breast cancer,
especially if they had cancer at a young age
 Most women with breast cancer though don’t have a family history
 Also, most women with a family history of breast cancer won’t develop breast
cancer
 Most family risk is due to interaction of low risk susceptibility genes with
nongenetic factors
Atypical hyperplasia – increases the risk for breast cancer
Race – white women have the highest rates of breast cancer, but black or Hispanic
women present at more advanced stages and have the highest death rate from breast
cancer
 Black and Hispanic women tend to develop breast cancers at a younger age,
before menopause, that are more likely to be aggressive
Estrogen exposure – postmenopausal hormone replacement therapy increase the risk
of breast cancer, and adding progesterone increases the risk even more
 Most of these cancers are ER positive carcinomas, that tend to be small when
found
 Oral contraceptives aren’t proven to affect breast cancer risk, but do decrease
the risk of endometrial and ovarian cancers
 Removing the ovaries (oophorectomy) and drugs that block estrogen effects
(tamoxifen) or estrogen making (aromatase inhibitors) decrease the risk of ER
positive breast cancer
Breast density – high breast radiodensity is a strong risk factor for developing cancer
 High density is associated with young age and hormone exposure, and clusters
in families
o
-
-
Radiation exposure – radiation to the chest increases the risk for breast cancer
 The risk is greatest with exposure at young ages and high radiation doses
 So we watch our use of radiation therapy in young women
 Mammograms have low radiation doses, and isn’t likely to affect the risk for
breast cancer
o Cancer of the other breast or endometrium – the risk for this is highest in women with
high risk cancer genes like BRCA1 and BRCA2
 Endometrial cancer, like breast cancer, also has increased risk from prolonged
estrogen stimulation
o Geography – breast cancer rates are much higher in the US and Europe
o Diet – caffeine decreases risk of breast cancer, and alcohol increases the risk
o Obesity – obese women under 40 are more likely to have anovulatory cycles, so much
lower progesterone in the 2nd half of the cycle, so they have decreased risk for breast
cancer
 Obese postmenopausal women though have increased risk for breast cancer
o Exercise – decreases risk for breast cancer
o Breastfeeding – the longer women breastfeed, the more decreased the risk for breast
cancer is
 Lactation suppresses ovulation, & can trigger final differentiation of luminal cells
 Women in less developed countries breastfeed longer, so this is a major reason
why there’s less breast cancer there
o Toxins – pesticides may have an estrogen effect and increase risk for breast cancer
o Tobacco – causes periductal mastitis, but we’re not sure about breast cancer
The major risk factors for breast cancer are hormonal and genetic
o So breast carcinomas are divided into sporadic (from hormone exposure) and hereditary
(from germline mutations)
Hereditary breast cancer:
o Inheriting a susceptibility gene is the main cause of about 12% of breast cancers
 Risk goes up the more first degree relatives you have affected, when affected
family members are younger, or when they have multiple tumors
o Most single mutations to a gene to cause breast cancer are single mutations to BRCA1
and BRCA2 (90% of hereditary cancers)
 BRCA mutations have high penetrance, meaning a high % of carriers of BRCA
will develop breast cancer
 BRCA1 mutations also increase the risk for ovarian cancer
 BRCA2 mutations have a smaller risk for ovarian cancer, but cause more male
breast cancer
 BRCA1 and BRCA2 carriers also have a higher risk for other epithelial cancers,
like prostate and pancreas carcinomas
 BRCA1 and BRCA2 are large genes with many kinds of mutations anywhere
throughout them

-
-
It’s very uncommon for the general population to develop a mutation to BRCA1
or BRCA2 that causes breast cancer, and there’s often many mutations in the 2
that don’t lead to cancer
 So genetic testing is tough and usually only done when there’s a family
history or certain ethnic groups
o Up to 3% of Ashkenazi Jews have a mutation in a BRCA gene to
cause cancer
 BRCA1 breast cancers are usually poorly differentiated, have “medullary
features” (means syncytial growth pattern with pushing margins and a
lymphocytic response), and don’t express hormone receptors or overexpress
HER2/neu (nicknamed the “triple negative phenotype”)
 BRCA1 mutations also cause you to lose the inactive X chromosome and
reduplicate the active X chromosome, leading to there being no Barr
body
 BRCA2 mutations also tend to be poorly differentiated, but are more often ER
positive than BRCA1 cancers
o Other single mutations to a gene that cause breast cancer include Li-Fraumeni
syndrome (germline mutation to p53) and Li-Fraumeni variant syndrome (germline
mutation to CHEK2)
 These 2 are 8% of hereditary cancers
 PTEN (Cowden syndrome), LKBI/STK11 (Peutz-Jeghers syndrome), ataxia
telangiectasia, cause 1% of hereditary breast cancers
o High risk breast cancer genes only account for ¼ of familial breast cancers
 The other ¾ are caused by multiple genes being affected
o The major susceptibility genes for breast cancer are tumor suppressors that normally
work in DNA repair, cell cycle control, and regulate apoptosis
o Mutations in genes that cause hereditary breast cancer are uncommon in sporadic
breast cancers, except for p53, BRCA1, and CHEK2
The major risk factors for sporadic breast cancer are from hormone exposure and include
gender, age at menarche and menopause, # of births, breastfeeding, and exogenous estrogen
o Most sporadic breast cancers happen in postmenopausal women, and are ER positive
o Hormone exposure increases the # of potential target cells by stimulating breast
growth during puberty, menstrual cycles, and pregnancy
o Exposure also drives cycles of proliferation that place cells at risk for DNA damage
o Once premalignant or malignant cells are there, hormones can stimulate their growth,
and growth of tissues that may help them grow
o Estrogen metabolites can also cause mutations or form free radicals
In cancer, a cell mutates, proliferates, and one of its progeny gains another mutation, and so on
o The precancerous lesions for breast cancer have some of the mutations of breast
cancer, but not all of them, so they have increased risk to progress to breast cancer
o The earliest changes are proliferative changes, because apoptosis is inhibited and it
doesn’t listen to growth inhibiting signals anymore

-
-
Atypical ductal and lobular hyperplasias show increased expression of hormone
receptors and abnormal regulation of proliferation
o Loss of heterozygosity is rarely seen in proliferative change, but its seen more in atypical
hyperplasia, and always seen in cancer
o DNA instability leading to aneuploidy manifests as nucleus enlargement, irregularity,
and hyperchromasia
 This is seen only in high grade DCIS and some invasive carcinomas
o The most likely cell of origin for most breast carcinomas is the ER expressing luminal
cell, since most breast cancers are ER positive
o ER negative carcinomas may arise from ER negative myoepithelial cells
 This is why many proteins found in myoepithelial cells are shared by the “triple
negative or basal like cancers”
o The final step of carcinogenesis is the transition from carcinoma in situ to invasive
carcinoma
o Page 1080 – pics of progression from normal breast tissue to carcinoma
Most (over 95%) of breast cancers are adenocarcinomas, which can be in situ or invasive
o Carcinoma in situ- cancerous proliferation that is limited to ducts and lobules by the
basement membrane
o Invasive carcinoma – penetrates through the basement membrane into stroma, where
they can invade the vessels and lymph
o All breast carcinomas arise from cells in the terminal duct lobular unit
 We still say lobular and ductal though, not to refer to where the tumor cells
came from, but rather to refer to differences in tumor cell biology
 Lobular – specific carcinomas
 Ductal – general carcinomas
Ductal carcinoma in situ (DCIS, intraductal carcinoma)
o Half of cancers detected by mammograms are DCIS, usually by calcifications
 Less common ways to find it are nipple discharge or mammogram density from
periductal fibrosis surrounding DCIS
o DCIS – malignant cells limited to ducts and lobules by the basement membrane
 The myoepithelial cells are preserved, but there may be less of them
o DCIS can spread throughout ducts and lobules and cause extensive lesions involving
whole parts of the breast (in situ can spread, just not outside ducts into the stroma)
o When DCIS involves the lobules, the acini are usually distorted and unfolded, and look
like small ducts
o 5 types of DCIS – comedocarcinoma, solid, cribiform, papillary, and micropapillary
 Most grow in a mix of these types
o Comedocarcinoma – characterized by solid sheets of pleomorphic cells with high grade
hyperchromatic nuclei and areas of central necrosis – page 1081 top pic
 The necrotic cell membranes often calcify, and are seen on mammograms as
clusters, or linear and branching microcalcifications

-
Periductal concentric fibrosis and chronic inflammation are common, and
extensive lesions can sometimes be felt as nodules
o Noncomedo DCIS – monomorphic cells that can be any grade from low to high
 Cribiform DCIS – intraepithelial spaces are evenly distributed and regularly
shaped, looking like a “cookie cutter” – page 1081 bottom left pic
 Solid DCIS – completely fills the involved spaces – p. 1081 bottom right pic
 Papillary DCIS – grows into spaces along fibrovascular cores and usually lack the
myoepithelial cell layer – page 1082 top left pic
 Micropapillary DCIS – bulbous protrusions without a fibrovascular core – page
1082 top right pic
o Paget disease of the nipple is a rare manifestation of breast cancer, and presents as a
unilateral erythematous eruption with a scale crust
 Itching is common
 Malignant Paget cells extend from DCIS within the ductal system through
lactiferous sinuses, into nipple skin – page 1082 bottom pic
 The tumor cells disrupt the normal epithelial barrier, allowing ECF to leak out
onto the nipple surface
 Paget disease has a palpable mass over half the time, and almost all of these
women have underlying invasive carcinoma
 Most women with paget disease without a mass have only DCIS
o DCIS with microinvasion – when it barely gets through the basement membrane
 Microinvasion is associated with comedo DCIS
o DCIS is treated with surgical excision followed by radiation, which works well
o Untreated DCIS turns invasive
 Those with higher grade DCIS progress to invasive at a higher rate
o Mastectomy for DCIS cures most (95%) of patients
 Most cases of DCIS don’t need breast removal though, but they have a higher
risk of recurrence then
o The major risk factors for recurrence are grade, size, and margins
o If DCIS is treated right, the risk of recurrence int eh same breast is barely higher than the
risk in the opposite breast for carcinoma
o Deaths from breast cancer from DCIS are very uncommon
Lobular carcinoma in situ (LCIS) – it’s always an incidental biopsy finding, since it doesn’t cause
calcifications or stromal rxns to cause mammograms densities
o You look for LCIS with biopsies
o LCIS only causes up to 6% of breast carcinomas
o LCIS is more often bilateral than DCIS
o Most (90%) of LCIS happen in young women before menopause
o The cells of LCIS and invasive lobular carcinoma look identical & share genetic problems
 One shared genetic problem is loss of expression of E-cadherin, which is a cell
adhesion protein that helps keep breast epithelial cells cohesive
o
-
-
Atypical lobular hyperplasia, LCIS, and invasive lobular carcinoma all have not-cohesive
cells with round/oval nuclei and small nucleoli – page 1083
 They lack E-cadherin, causing cells that don’t attach to adjacent cells
 Often you see mucin-positive signet ring cells
o LCIS almost always expresses ER and PR, but there is no overexpression of HER2/neu
o Over 20 years, up to 1/3 of women with LCIS develop invasive carcinoma
Invasive (infiltration) breast carcinoma:
o If you don’t get a mammogram, then invasive carcinoma almost always presents as a
palpable mass
o Palpable tumors metastasize to the axillary lymph nodes over half the time
o Larger carcinomas may be fixed to the chest wall, or cause dimpling of the skin
o When the tumor involves the central part of the breast, you may get retraction of the
nipple
o Lymphatics can be so blocked they cause lymphedema and thickening of the skin from
poor drainage
 In these cases, tethering of the skin to the breast by Cooper ligaments mimics
the appearance of an orange peel, called peau d’orange
o On mammogram, invasive carcinomas usually present as a radiodense mass
 Mammograms catch them earlier than palpation, so they’re smaller and less of
them metastasize to lymph nodes (1/5)
o Inflammatory carcinoma – tumors that present with a swollen erythematous breast
 This is caused by extensive invasion and obstruction of dermal lymphatics by
the tumor
 The underlying carcinoma usually infiltrates diffusely and doesn’t form a
discrete palpable mass
 Has a poor prognosis
 Page 1084 – table 23-3 shows how common the types of breast cancer are
Invasive carcinomas of no special type (NST, invasive ductal carcinoma) – the majority (80%) of
breast carcinomas and the most common invasive breast carcinoma
o They’re firm, hard, and have irregular borders
o When you cut or scrape them, they make a characteristic grating sound due to streaks
of chalky-white elastic-like stroma
o Well differentiated carcinomas show lots of tubule formation, small round nuclei, and
rare mitotic figures – page 1085 left pic
o Moderately differentiated carcinomas may have tubules, but also have solid clusters or
single infiltrating cells, more pleomorphism, and mitotic figures – middle pic
o Poorly differentiated carcinomas often invade as ragged nests or solid sheets of cells
with enlarged irregular nuclei, with a high proliferation rate and areas of tumor
necrosis – right pic
o There’s 5 major patterns of gene expression in NST carcinomas – page 1086
 Luminal A, luminal B, normal, basal-like, and HER2 positive
 Luminal A – half of NST cancers



-
Luminal A NST cancers are ER positive and HER2/neu negative
It’s dominated by genes under the control of estrogen receptor (ER)
ER positive carcinomas also show increased transcription of genes
characteristic of normal luminal cells
 Luminal A are well or moderately differentiated
 Most luminal A happen in postmenopausal women
 Luminal A are slow growing and respond well to hormone treatment,
and few respond to chemo
 Luminal B (aka “triple positive cancers”) – 1/5 of NST cancers
 Luminal B also express ER, but are usually higher grade, have a higher
proliferative rate, and overexpress HER2/neu
 They’re ER positives that are more likely to have lymph node
metastases, and may respond to chemo
 “normal breast-like” – up to 1/10 of NST cancers
 They’re well differentiated ER positive, HER2/neu negative cancers
characterized by their gene expression being similar to normal tissue
 “basal-like” – up to ¼ of NST cancers
 Basal-like don’t have ER, PR, and HER2/neu, or expression of markers
typical of myoepithelial cells, progenitors, or stem cells
 They’re a subtype of ER-PR-HER2/neu “triple negative” carcinomas
 “basal-like” breast cancers include medullary carcinomas, metaplastic
carcinomas (spindle cell or matrix producing), and carcinomas with a
central fibrotic focus
 Many BRCA1 breast cancers are basal-like
 “basal like” are usually high grade and have a high proliferation rate
 They’re aggressive, often metastasize to viscera and the brain, and
have a poor prognosis
 Up to 1/5 respond to chemo
 HER2 positive – up to 12% of NST cancers
 HER2 positives are ER negative carcinomas that overexpess HER2/neu
protein
 Most (over 90%) of HER2/neu positive cancers overexpress it due to
amplififcation of the part of DNA that has the HER2/neu gene
 HER2/neu positives are usually poorly differentiated, have a high
proliferation rate, and often metastasize to the brain
o Trastuzumab (Herceptin) – antibodiy specific to HER2/neu
 Trastuzumab plus chemo is very effective at treating carcinomas that
overexpress HER2/neu
 It can’t cross the blood brain barrier though, so they can still have metastasis to
the brain
Invasive lobular carcinoma:
o
o
-
Usually presents as a palpable mass or mammogram density with irregular borders
In about ¼ of invasive lobular carcinomas, the tumor infiltrates the tissue diffusely and
causes little desmoplasia, which are hard to detect
o The hallmark of invasive lobular carcinoma is non-cohesive infiltrating tumor cells, often
arranged in a single file or in loose clusters of sheets
o It looks identical to atypical lobular hyperplasia and LCIS
o Signet-ring cells containing mucin are common
o Well differentiated and moderately differentiated lobular carcinoma is usually diploid,
ER positive, and associated with LCIS
 Usually there is no HER2/neu overexpression in, and they instead express genes
similar to luminal A cancers
o Poorly differentiated lobular carcinomas are usually aneuploidy, lack hormone
receptors, and can overexpress HER2/neu
o Lobular carcinomas have the same prognosis per grade as NST carcinomas
o Lobular carcinomas metastasize different than other breast cancers
 Metastasis tends to go to the peritoneum and retroperitoneum, meninges, GI,
and ovaries and uterus
o Lobular carcinoma has loss of E-cadherin, by losing both alleles of the E-cadherin gene
CDH1
 E-cadherin’s also lost in atypical lobular hyperplasia & LCIS, so it’s an early event
Medullary carcinoma – most common in women in their 60’s, and presents as a wellcircumscribed mass – page 1088 top pics bottom left
o Medullary carcinomas cause little desmoplasia, and are way more yielding on palpation
and cutting than typical breast carcinomas
o Medullary carcinomas are poorly differentiated, soft, fleshy, and well circumscribed
o Medullary carcinoma is characterized by:
 Solid syncytium-like sheets of large cells (medullary growth pattern) with
vesicular pleomorphic nuclei and big nucleoli that make up over ¾ of the tumor
 Mitotic figures
 Lymph infiltrate around the tumor
 A pushing (noninfiltrative) border
o Medullary carcinomas have a slightly better prognosis than NST carcinomas, despite
signs of poor prognostic factors, like high nuclear grade, aneuploidy, absence of
hormone receptors, and high proliferative rates
o It rarely spreads to lymph nodes
o The syncytial (cohesive) growth pattern and pushing borders may come from
overexpression of adhesion molecules and E-cadherin, which limits its ability to
metastasize
o Medullary carcinomas express genes in a “basal-like pattern (triple negative)”
 13% of BRCA1 cancers are medullary, and over half have medullary features

-
-
-
-
-
-
Most medullary carcinomas aren’t associated with germline BRCA1 mutations,
but hypermethylation of the promoter for BRCA1 is seen in 2/3 of medullary
carcinomas
Mucinous (colloid) carcinoma – soft rubbery tumor that looks & feels like pale gray-blue gelatin
o Happen in women in their 70’s and grow slowly over many years
o The tumor cells are arranged in clusters or islands of cells within large lakes of mucin –
top pics bottom right
Tubular carcinoma – rare small tumors made entirely of well formed tubules – page 1088
bottom pic
o Usually found as small irregular densities on mammaograms in their late 40’s
o Tubular carcinoma is rare, but is 10% of small breast tumors
o They lack a myoepithelial layer
o Tubular carcinomas are often associated with atypical lobular hyperplasia, LCIS, or low
grade DCIS
o Most (over 95%) of tubular carcinomas are well-differentiated, diploid, ER positive, and
HER2/neu negative
o Tubular carcinoma has a great prognosis
Invasive papillary and micropapillary carcinomas – rare papillary tumors associated with DCIS
o Papillary is ER positive with a good prognosis, and micropapillary is ER negative, HER2
positive, and has a poor prognosis
Metaplastic carcinoma – group of rare breast cancers, like matrix-making, squamous cell
carcinomas, and carcinomas with a prominent spindle part
o They’re ER-PR-HER2/neu “triple negative”
Prognosis of breast cancer is determined by pathologic examination of the primary tumor and
axially lymph nodes
o Except in those with distant metastasis or inflammatory carcinoma, which are always
bad regardless of the tumor characteristics
Page 1090 – staging breast cancer
The major prognostic factors:
o Invasive carcinoma or carcinoma in situ?
 Carcinoma in situ is confined to the duct system and can’t metastasize
 So most women with DCIS are cured if treated right
o Distant metastasis – once is spreads far, cure is unlikely
o Metastasis to lymph nodes:
 Axillary lymph node status is the most important prognostic factor for invasive
breast carcinoma, when there is no distant metastasis
 You need to biopsy the lymph nodes to look at them
 If lymph nodes aren’t involved, 10 year survival rate is about ¾
 This drops to 1/3 with 1-3 nodes, & at most 15% at more than 10 nodes
 Lymphatic vessels in most breast carcinomas drain first to one or two sentinel
nodes, which can be identified with dyes

-
If a biopsy of a sentinel node is negative for metastasis, it’s unlikely that other
more distant nodes will be involved
o Tumor size – 2nd most important prognostic factor
 The risk for axillary lymph node metastasis increases the bigger the tumor is
o Local advanced disease – carcinomas that invade into skin or skeletal muscle are usually
large and hard to remove with surgery
o Inflammatory carcinoma – show breast swelling and skin thickening due to dermal
lymphatics being blocked
 This has a bad prognosis – 3 year survival rate is at best 10%
 Inflammatory carcinoma happens more in black and young women
Minor prognostic and predictive factors:
o Histo subtype – women with special types of invasive breast carcinoma (tubular,
mucinous, medullary, lobular, & papillary) have a higher survival rate than those with
NST
 Most of these are well-moderately differentiated, ER positive, and HER2/neu
negative
o Histo grade – based on nuclear grade, tubule formation, and mitotic rate
 Grade 1 – well differentiated, 1/5 of breast carcinomas, and has a longer
survival rate
 Grade 2 – moderately differentiated, about 1/3 of breast carcinomas, and has a
low survival rate
 Grade 3 – poorly differentiated, almost half of breast carcinomas, and patients
die much younger
o Estrogen and progesterone receptors – if a breast carcinoma has receptors, it has a
better outcome and well better respond to hormone therapy
 4/5 of both ER and PR positive tumors respond to hormone manipulation,
compared to less than half of just ER or PR alone
 ER positive cancers are less likely to respond to chemo
 1/10 of cancers that are negative for receptors respond to hormone therapy,
but are more likely to respond to chemo
o HER2/neu – overexpression is associated with poor survival
 Drugs like trastuzumab or lapatinib target HER2/neu
o When it invades lymph or blood vessels – half of invasive breast carcinomas have tumor
cells in lymphatics or capillaries
 This strongly suggests lymph node metastases
 If there is no lymph node metastasis, this is a poor prognostic factor for survival,
and a risk factor for local recurrence
 Extensive plugging of the lymph of capillaries of the dermis with carcinoma cells,
called inflammatory carcinoma, has a very poor prognosis
o Proliferative rate – measured by mitotic counts, detection of cell cycle proteins, or
thymidine labeling

-
Carcinomas with a higher proliferation rate has a poorer prognosis, but may
respond better to chemo
o Amount of DNA per tumor cell – those with abnormal amounts of DNA have worse
prognosis
o Response to neoadjuvant therapy
 Most patients complete their surgery and then get systemic treatment, called
adjuvant therapy
 Neoadjuvant therapy is when they’re treated before surgery
 How much the tumor responds to the therapy is a prognostic factor
Current treatment of breast carcinoma for local and regional control is a combo of surgery
(mastectomy or some of the breast is left) and postoperative radiation
Treatment for systemic control is hormone treatment, chemo, or both
Breast stroma tumors – intralobular and interolobular stroma types can give rise to tumors
-
-
-
-
Intralobular stroma – gives rise to fibroadenoma and phyllodes tumor
o Intralobular stroma may make growth factor for epithelial cells, causing proliferation of
the non-cancerous epithelial part of the tumor
Interlobular stroma – causes systemic connective tissue tumors, like lipomas and
angiosarcomas, or more localized breast tumors, like pseudoangiomatous stromal hyperplasia,
myofibroblastomas, and fibrous tumors
Fibroadenoma – most common benign tumor in the breast, comes from intralobular stroma
o Most happen in women in their 20’s and 30’s, are usually multiple and bilateral
o Young women usually present with a palpable mass, while old women you catch it with
calcifications on mammogram
o The epithelium of the fibroadenoma responds to hormones
 So pregnancy can make it bigger, and menopause makes it hyalinize and calcify
o Large fibroadenoma calcifications have a characteristic lobulated or “popcorn” look on
mammogram
o Fibroadenomas are nodules that are sharply circumscribed & freely movable – p. 1091
o FIbroadenomas are rubbery grayish-white nodules that bulge above the surrounding
tissue and often have slit-like spaces
o The stroma looks like normal intralobluar stroma
o Some fibroadenomas are hyperplasias of lobular stroma due to some stimulus
 Almost half of women receiving cyclosporine A after kidney transplants, develop
fibroadenomas, and go away when you take away the cyclosporine
Phyllodes tumors – also come from intralobular stroma
o Most phyllodes tumors happen in your 60’s, and are detected as palpable masses
o Most phyllodes tumors are benign, but a minority are cystic
o Phyllodes is greek for “leaf-like”
 Large phyllodes tumors have bulbous protrusions due to nodules of proliferating
stroma covered by epithelium
o
-
-
Low grade phyllodes tumors resemble fibroadenomas, but are more cellular and have
mitotic figures
Benign breast stroma tumors:
o Tumors of the interlobular stroma of the breast are made of stromal cells without an
accompanying epithelial part
o Pseudoangiomatous stromal hyperplasia and fibrous tumors present as palpable masses
or mammogram densities, and are benign proliferations of interlobular fibroblasts and
myofibroblasts
o Myofibroblastoma is the only breast cancer that is more common in guys
o Fibromatosis – proliferation of fibroblasts and myofibroblasts
 Presents as an infiltrating mass that can involve both skin and muscle
 It’s locally aggressive, but doesn’t metastasize
 Most cases are sporadic, but some happen as part of familial adenomatous
polyposis (familial adenomatous polyposis (FAP), hereditary desmoid syndrome
 FAP is caused by mutation in the adenomatosis polyposis coli (APC)
gene, which would normally inhibit making of β-catenin
 So finding β-catenin in the nucleus can be diagnostic
Malignant breast stroma tumors – breast sarcomas
o Sarcomas usually present as bullky palpable masses, that often spread through blood to
the lung
o Angiosarcomas can be sporadic or be caused by radiation therapy, like for treating
breast cancer
o Angiosarcomas are usually high grade and have a poor prognosis
Guy breasts have a rudimentary duct system ending in terminal buds without lobule formation
Gynecomastia – enlargement of the male breast
-
-
Presents as a button-like subareolar enlargement
In advanced cases, the swelling can act like a female breast
There’s an increase in dense collagenous connective tissue, and lots of micropapillary epithelial
hyperplasia of the duct lining – page 1093
Like the female breast, the male breast listens to hormones
o Gynecomastia can happen from an imbalance between estrogens (stimulate breast
tissue) and androgens (counteract estrogen effects on breast)
Liver metabolizes estrogen, so liver cirrhosis can cause hyperestrogenism, leading to
gynecomastia
In old men, the loss of adrenal androgens can cause estrogens to win out and cause
gynecomastia
Drugs like alcohol, marijuana, heroin, antiretroviral therapy, anabolic steroids, can all cause
gynecomastia
Rarely, gynecomastia can be part of Klinefelter syndrome (XXY karyotype)
Male breast carcinoma is rare
-
-
Risk factors are the same for those in girls, and include decreased testicle function, exposure to
exogenous estrogens, increasing age, infertility, obesity, prior benign breast disease, exposure
to radiation
Up to 15% of cases in guys is from BRCA2 mutation
o There is a ¾ chance of BRCA2 mutation in a family if a guy gets breast cancer
The same types of cancer are present in guys as in girls
o Papillary carcinomas are most common
ER positivity is seen in 4/5 of guy breast cancers, and the incidence of ER positive tumors
doesn’t increase with age, unlike in girls
Since breast epithelium in men is limited to large ducts near the nipple, carcinomas usually
present as a palpable subarreolar mass
Nipple discharge is a common symptom
The carcinoma is close to the overlying skin
Metastasis to the lungs, brain, bone, dn liver are common
Men present at higher stages, with half already having lymph node metastasis
Prognosis is similar to women
Treat with mastectomy and axillary node dissection