PATHOLOGY OF BREAST
 MANIFESTATIONS OF BREAST DISEASE
-Breast mass- a palpable mass in the breast is the earliest
manifestation of the breast cancer-the most important symptom of
breast disease
-possibility of the mass to be a cancer is higher
-if the patient is over 30 years of age
-if the mass has appeared rapidly
-if the mass increased rapidly in size
-if the mass is solid and solitary
-Nipple discharge -is a common symptom of variety of breast
diseases
-bloody discharge -typically in intraductal carcinoma or papilloma
-Skin changes -may be present in the skin overlying the advanced
breast cancer - infiltration of the skin may cause dimpling of the skin and
ulcerations
-lymphedema due to infiltration of lymphatics- thickening of the skin and
pitted appearance called "orange peel skin"
- Pain -painful lesion usually denotes a inflammatory disease, rarely
an advanced cancer
 INFLAMMATORY BREAST LESIONS
-acute mastitis and breast abscess formation- occurs commonly
in the postpartum period- cracks in the nipple -potential route of bacteria
(stasis of the milk)
staphylococcus aureus-the most common infecting agent
grossly: redness of the skin, swelling, pain, tenderness
-chronic
uncommon
mastitis-
chronic inflammation of the breast is
-it occurs in perimenopausal women as a result of obstruction of the
lactiferous ducts by inspissated luminal secretions
-mammary duct ectasia- involved ducts are dilated
-periductal inflammation- plasma cell mastitis
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-in other instances- rupture of small ducts- release of the secretions into
the stroma- cellular reaction with accumulation of foamy macrophagesgranulomatous mastitis
grossly: iregular fibrosis with induration of the involved area- may cause
nipple retraction- mimics symptoms of breast cancer
-fat necrosis
-is uncommon, but important lesion, because this may produce large and
sclerosing masses- thus the lesion may mimick macroscopically breast
cancer
-cause is unknown, or trauma or ischemia (in large pendulous breasts)
-in early stage- fat necrosis is characterized-by accumulation of
neutrophils and histiocytes
-later- replaced by granulation tissue - numerous foamy histiocytesgrayish-white firm lesion- clinically resemble cancer
 NONINFLAMMATORY BENIGN BREAST LESIONS:
-fibrocystic disease (FCD) -is characterized by combination of
cyst formation, epithelial hyperplasia and/or fibrous overgrowth in the
stroma
-grossly: FCD often produces palpable breast mass
-pathogenesis FCD results from response of the breast to cyclic changes
in levels of estrogens and progesterone- it is unusual before 20 years of
age, most commonly seen between ages of 25 to 40 years
-histologically -there are two dominant morphologic patterns:
1-nonproliferative change
cyst formation and fibrosis without epithelial hyperplasia- simple
fibrocystic disease- most common, is not associated with higher risk of
cancer
-the changes consist of increased synthesis of collagen, increased amount
of fibrous connective tissue, that compresses the acini and ducts
-grossly: there are large cysts, the content of the cysts may undergo
calcification- visible on mammograph
-histologically: ducts are lined by flattened epithelium, occasionally, mild
epithelial proliferation-papillae, apocrine metaplasia
2-proliferative change
FCD with epithelial cell hyperplasia- proliferative fibrocystic disease
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-there is combination of cyst formation and papillary proliferation and
hyperplasia of ductal or lobular epithelium
-sometimes there may be dysplasia in the epithelium- atypical
hyperplasia- these types of FCD are associated with 4-5fold increased
risk of cancer
 -changes not associated with an increased risk of breast carcinoma:
-fibrosis and increase in stromal fibrous tissue- ill defined massesrubbery in consistency
-cyst formation- cysts occur very commonly in FCD- lined by flattened or
apocrine epithelium
-inflammation-chronic reaction of lymphocytes and plasma cells or
granulomatous foci may be found
-usual ductal and lobular hyperplasia without atypia (1.5-2x)
 -changes associated with increased risk of carcinoma (5x):
-atypical ductal and lobular hyperplasia
-marked proliferation of ductal and and lobular epithelium with cytologic
atypia
clinically : patients with fibrocystic disease present with pain, nipple
discharge and palpable mass in the breast-necessary to rule out
carcinoma- biopsy, occasionally- these lesion produce microcalcification on
mammography

family history of carcinoma- increases risk of cancer in all
categories of proliferative lesions (more than 10x)
-sclerosing adenosisgrossly: hard in consistency, resembles carcinoma
is characterized by increased fibroblast activity and collagen production
in the involved lobules.- mammary ducts are compressed, distorted,
microscopically close resemblance to ductal invasive carcinoma- basement
membrane of ducts is intact, and ducts remain bilayered (outer
myoepithelial cell layer)
-the lesion is benign, only minimally increased risk of cancer
-apocrine adenosis (atypical)-variant of ductal usual
characterized by apocrine metaplasia of the epithelium
hyperplasia,
-microglandular adenosis- very rare, composed of small tubules, may show
infiltrative growth pattern, no myoepithelial layer, mimics carcinoma
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-columnar cell hyperplasia with and without atypia- these lesions are
often associated with microcalcifications, seen in mammography, now
more often diagnosed then erlier
-columnar cell hyperplasia without atypia- incidental finding, no
increase in risk of cancer
columnar cell hyperplasia with atypia- flat epithelial atypiarepresents a lesion with 4 times increased risk of cancer
 BENIGN TUMORS
1. fibroadenoma
-is the most common benign tumor of the female breast
-it occurs at any age within the reproductive period-highest incidence in
young women before 30 years of age
-grossly- freely movable, well circumscribed, firm nodule
-on section the tumor is uniformly grey-white, firm nodular
-usually between 1-5 cm in diameter
-infrequently, FA may grow to very massive proportions -called giant
fibroadenoma
histologically- fibroadenoma is characterized by proliferation of both
glandular and stromal elements-the tumor exists in two variantspericanalicular and intracanalicular fibroadenoma -often overlapping
patterns
-pericanalicular-fibroblastic
hypercellular
stroma
glandular and cystic epithelial spaces in concentric manner
encloses
-intracanalicular-connective tissue stroma reveals more active
proliferation with compression of the epithelial structures, glandular
lumina are compressed into narrow strands or slit-like irregular clefts
2. phyllodes tumor
-less common than FA
-large bulky tumor lobulated and cystic- they have been designated
cystosarcoma phyllodes - the lesion can be both benign and malignantgrossly: lobulated, cystic tumors, the tumor may cause a distortion of the
breast- produce a bulky mass, even pressure necrosis of the overlying
skin- this clinical behaviour does not imply malignancy
histologically: more cellular myxoid stroma than in fibroadenomas
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-increased stromal cellularity, high mitotic activity and anaplasia- imply
more aggressive clinical behaviour and transformation to malignancy rapid increase in size and invasive growth to adjacent breast tissue
3. lactating adenoma
-patients are young- pregnant or nursing
-associated with rapid increase in size- benign -may be even multiple
histologically composed of well differentiated glandular structureslobular arrangement, well-circumscribed by fibrous capsule
4. intraductal papilloma
-benign tumor originating in a major lactiferous duct- presents with
bloody nipple discharge -most are less than 1 cm in diameter
grossly-papillary mass projecting into the lumen of a large duct
-papilloma are generally solitary, less than 1 cm in diameter
-located in the subareolar region
-most commonly during the fifth and sixth decade of life
histologically- numerous delicate papillae composed of fibrovascular
stroma and covered by a layer of epithelial and myoepithelial cells epithelial cells line the luminal aspect of the papillae and a myoepithelial
cell layer is invariably present between the epithelial cells and the
basement membranes
5. papillomatosis
-is defined as a proliferation of papillary fronds supported by
fibrovascular stalks within multiple terminal duct-lobular units
-patients are younger than those with solitary papillomas- nipple
discharge in about one third of patients
-clinically- in some cases accompanied by atypical ductal hyperplasia and
increased incidence of cancer
mesenchymal tumors of the breast:
6. granular cell tumor
-is a rare benign tumour of the breast- is a well-recognized lesion which occurs in a wide variety of visceral and
cutaneous sites
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-untill recently- the histogenesis of the tumour has been controversial
resulting in a descriptive name (granular cell tumour) composed of
uniform cells with granular eosinophilic cytoplasm- neural origin is likely
-may occur in all ages
-grossly: resembles breast carcinoma - hard mass with skin retraction,
fibrous consistency and fixation to pectoral fascia
histologically: GCT is composed of infiltrating cords and clusters of
uniformly rounded or polygonal cell with coarsely granular cytoplasmimmunoreactivity for S-100 protein
7. myofibroblastoma- benign spindle cell tumor of the mammary stroma
composed of myofibroblasts- more common in male breast
8. desmoid type fibromatosis- rare locally aggressive lesion without
metastatic potential composed of mammary fibroblasts and
myofibroblasts- similar to desmoid tumor of abdominal skeletal muscle
 MALIGNANT TUMORS
1. Carcinoma of the breast
-common- breast cancer causes about 20% of cancer deaths in women,
the term breast cancer implies carcinoma arising in the ductal or lobular
epithelium of the breast
-in Czech Republic- about 4000 new cases per year, in the US 185 000
new cases in 1996
 incidence: rarely develops before the age of 25 years, age peak during
perimenopausal years.
 risk factors: positive family history, long reproductive life- means
early menarché and late menopause, more frequent in nulliparous than
in multiparous women, exogenous estrogens -still controversial, but
some data show moderately increased risk with high-dose therapy of
menopausal symptoms (HRT-hormone replacement therapy), oral
contraceptive -no clear-cut increased risk, obesity- increased risk
attributed to synthesis of estrogens in fat deposits, geographic
influences- five times more common in the States than in Japan
 genetics and family history: about 5-10% ca is believed to be related to
inherited gene mutations
 BRCA-1-relatively recently discovered gene on chromosome 17q21
 BRCA-2-gene located on chromosome 13q12-13, both genes are
suppressor, they are responsible of familial breast cancer- screening
for mutation of these genes in women with positive history
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 classification- two major categories- invasive (infiltrating) and
noninvasive
most tumors are invasive, careful examination and screening
mammography- increases a number of in situ diagnosed tumours
classification of breast cancer:
1- noninvasive carcinoma
-intraductal carcinoma- ductal ca in situ
-intraductal papillary carcinoma
-lobular carcinoma in situ
2- invasive carcinoma:
-invasive ductal carcinoma
-invasive lobular carcinoma
-medullary carcinoma
-colloid carcinoma (mucinous, gelatinous)
-Paget carcinoma of the nipple
-tubular carcinoma
-invasive papillary carcinoma
-adenoid cystic carcinoma
 Features common to invasive carcinomas
-local invasion into adjacent structures- tumor fixation, retraction of the
nipple, dimpling of the skin
-lymphatic invasion-causes lymph node metastases- about two-thirds of
breast carcinomas present with lymph node metastasesaxillary,
supraclavicular and mammary nodes often involved
blood vessel invasion- metastases to the skin, lung, liver, bone marrow,
etc.
 clinical features:
factors influencing the prognosis-tumor size- minimal cancer is less than 1 cm -associated with
favorable prognosis, most tumors are detected in larger size
-lymph node spread and number of positive nodes- two thirds of
breast cancers are detected as lymph node positive- 5year survival for
lymph node negative patients-80%, for positive patients only 50%
-histological grading- degree of differentiation, nuclear
polymorphism, mitotic count
-estrogen (ER)/progesterone (PR) status- 70% breast cancers
contain ER/PR, positive correlation with clinical outcomes and with low
grade
-proliferative activity- often measured as MIB1 index
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-presence of activated gene-c-erbB-2/HER-2/neu overexpression
of transmembrane oncoprotein-in about 15% of breast cancers- more
aggressive behavior
Grading and staging of breast cancer.
cancers may be first divided as follows:
-nonmetastasizing tumors- intraductal or comedocarcinoma without
stroma invasion, in situ lobular carcinoma
-uncommonly metastasizing tumors-pure colloid, medullary cancer,
tubular adenocarcinoma, adenoid cystic ca
-metastasizing- all other types
STAGING: TNM system- size of primary tumour- nodal involvement,
distant metastases
1. ductal carcinoma - the most common type of breast carcinomaover 90% of breast ca arise within the ducts
- may exist as ductal carcinoma in situ or invasive
-noninvasive type = carcinoma in situ -tumor restricted to
intraductal proliferation without penetrating the basement membranes of
ducts- ducts may be dilated and filled with carcinoma cells- sometimes central necroses with comedo-like appearance -called
comedocarcinoma
-invasive ductal carcinoma
-grossly- the tumor is poorly defined, firm, palpable mass -hard
consistency
-some tumors exhibit marked fibroplasia- increased production of dense
fibrous tumor stroma- desmoplastic carcinoma- skirrhus
- attachment to adjacent structures, fixation to the pectoral fascia,
dimpling of the skin, retraction of the nipple
-on section-the tumor is retracted below the cut surface
histologically: tumor consists of anaplastic duct epithelial cells disposed in
cords, solid foci, tubules, glandular and cribriform anastomosing
structures
-frequent finding- perineural and intravascular invasion - breast cancer
has usually high propensity for dissemination
New developments in breast cancerogenesis:
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Gene expression profiling analysis has been used recently for new
classification of breast carcinoma:
-breast cancer is very diverse disease in the terms of survival,
most tumors arecategorized as IDC (invasive ductal carcinoma)-based on
histological criteria alone
-recent molecular genetic studies have identified distinct subtypes
of breast cancer (based on genome)- prognostic significance
-most IDC represent so called “luminal subtype”, characterized by
expression of similar genes/ proteins as those found in normal luminal
cells of mammary ducts and lobules: ER+/PR+, presence of epithelial
membrane antigen and glandular types of cytokeratin filaments- good
clinical outcome
-in contrast- “basal-like/myoepithelial subtype”- has poor
prognosis, expression profiles are similar to cell of outer basal cell layer,
the tumors tend to be high grade, ER-/PR- and HER-2/neu- (negative)
2. Lobular carcinoma
may exist as lobular carcinoma in situ or invasive
-in situ -histologically distinctive proliferative lesion characterized by
proliferation in one or more terminal duct-acinar units
-in most cases- asymptomatic, incidental finding, not palpable, no picture
on mammo
-composed of the cells loosely cohesive, that are uniform in size, small,
round to oval in shape, with low mitotic rate
-it is not a precancerous lesion, it is associated with slightly increased
risk of ductal or lobular invasive ca
-invasive- these tumors are of particular interest because they may be
bilateral and/or multicentric within the same breast
grossly: poorly circumscribed, rubbery
histologically: consists of single layered cords of cancer cells infiltrating
the breast- often with skirrhous pattern -indian file pattern
- the cells are small, uniform with little cytologic polymorphism
3. Colloid (mucinous) carcinoma
-this variant tends to occur in older women, the tumour grows slowly
grossly-large gelatinous mass, the tumor is extremely soft
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histologically: composed of large lakes of mucinous extracellular matrixfloating within the mucin there are small islands of cancer cells
-better prognosis
5. Paget disease of the nipple
-is a special form of ductal breast cancer that arises in major ducts and
extends to the skin of the nipple
grossly: erosions and exematoid changes of the nipple-with discharge
histologically: the squamous epithelium of the skin is infiltrated by
carcinoma cells- Paget cells
-these cells are large, with pale cytoplasm and many mitoses
-careful studies often reveal the presence of ductal invasive or
noninvasive breast cancer
6. Metaplastic carcinoma
-is relatively rare neoplasm, characterized by squamous, adenosquamous,
spindle cell/sarcomatoid metaplasia, and focally sometimes with
heterologous elements, such as myxochondroid areas (called “ matrixproducing carcinoma)
-these are highly aggressive carcinomas with a high rate of extranodal
distant metastases (lung and visceral organs), in comparison with
conventional IDC, metaplastic carcinoma- less common axillar lymph node
meta
-ER/PR negative-prognosis often poor
PATHOLOGY OF THE MALE BREAST.
1- gynecomastia
-the male breast is subject of hormonal influences-enlargement of male
breast may occur due to stimulation by estrogens- hyperestronism
excess of estrogens may occur in a variety of circumstances, such as -in
puberty or in very old age- owing to relative increase in adrenal estrogens
as the androgenic function of the testis fails
-in testicular tumors with production of estrogens (Leydig cell tumors,
Sertoli cell tumors)
-in cirrhosis- the liver is responsible for metabolism of estrogens
grossly:unilateral or bilateral enlargement of the male breast
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histologically: proliferation of dense fibrous stroma and hyperplasia of
the epithelium of the ducts- ductal lining may appear multilayered with
papillae
2- carcinoma
-very rare in male breast- in advanced age
grossly: ulceration of the skin more common than in women
clinical behaviour-the same as that of the breast cancer in women,
including dissemination
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