In this document, there is a detailed information about the breast cancer and its pathogenicity, how to diagnose, and its types. Also there is a full information about the ovaries and their main desorders. Hope you enjoy it.

1. BREAST CANCER AND OVARIAN CYSTS
BY: Serena Z. Hijazeen

2. Introductions
• Breast carcinoma is the most common malignancy of women globally and causes
the majority of cancer deaths in women.
• The worldwide incidence and mortality is increasing at an alarming rate; the major
factors underlying this trend in developing countries are thought to be social
changes that increase breast cancer risk such as
 Delayed childbearing, fewer pregnancies, and reduced breastfeeding.
 Lack of access to optimal health care.
• It is considered to be the second highest rate of deaths after lung cancer.
• Since mid-1980’s the deaths have dropped almost 10% from what they were
(30% to 20%), and this decrease is due to -improved screening which detects
some cancers before they metastasized, and -more effective systemic
treatments.
• We consider breast malignancies as adenocarcinomas –which mean cancer that
originates in the cells that line the walls or inner surface of an organ of the body.
• These classifications show notable differences in patient’s characteristics,
pathologic features, treatment responses,
metastatic patterns and time to relapse and
outcome.
All breast cancer tumors are tested for estrogen,
progesterone and HER2 receptors.
classifications of breast cancer based on the
expression of hormone receptors
estrogen receptor ER progesterone
receptor PR
expression of human epidermal
growth factor receptor 2
ER +ve
HER2 -ve
50-65% of cancer
HER2 positive
ER +ve or -ve
10-20% of cancer
Triple negative
ER. PR AND HER2
negative
10-20% of cancer

3. For each type of receptor, a “positive”
result means there are many receptors. A
“negative” result means there are few or
none.
• As we see from the provided figure
age has an important role in the increasing
the risk factor alongside with the type of receptor effected.
• Breast cancer is actually divided into four major types clinically which relies on
gene expression to
I. Luminal A ~ the majority lower grade ER+ cancers that are HER2-ve
II. Luminal B ~ the majority higher grade ER+ cancers that may be HER2-ve
III. HER2-enriched ~ the majority over express HER2 and do not express ER
IV. Basal-like ~ the majority by gene expression profiling resemble basally located
myoepithelial cells and are ER-ve and HER2-ve
• 75% of women with breast cancer are older than 50
years of age and only 5% are younger than 40%
• The risk is significant higher in America and Europe
than in Asia and Africa
• Hispanic and African-American women tend to
develop cancer at a younger age and are more likely
to develop aggressive tumors

4. Age and
gender
BC is rare in women
ypunger than 25 and
increases after 30.
in men the incidence
is only 1% of that in
women.
other risk
factors
postmenopausal
obesity,
postmenopasual
hormone
replacement,
mammographic
density and
alcohol
consumption
Family history
of BC
the greatest risk is
for individuals
with multiple
affected first-
degree realtives
with early-onset
BC, the lifetime
risk may be 90%
greater
Reproductive
history
early age of
menarche,
nulliparity,
absences of
breastfeeding and
older age of first
pregnancy
increase the risk
Geographic
factors
significant
differences in the
incidence and
mortality have
been reporsted in
various countries
Diet, Reprodictive
pattern and
breastfeeding
practices are
thought to be
involved
Race/Ethnicity
the higher rate of
BC is in women of
European
deacent, largely
because of higher
incidence of ER+
Ionizing
radiation
radiation of the
chest increases
the risk of BC if
exposure occurs
while the breast is
developing
Risks factors
In most families it is thought that
various combinations of low
penetrance (weak) cancer genes are
responsible for increased risk
Penetrance: the extent of which a particular
gene or set of genes is expressed in the
phenotype of individuals carrying; measured
by the proportion of carriers showing the
characteristic phenotype.
The risk associated with obesity probably is
due to exposure of the breast to estrogen
produced by adipose tissue
obesity is only associated with an increase
the risk of tumors that express ER.
Some facts that is worthy to know
• TNBC means that growth of the cancer is not fueled by the hormones estrogen and progesterone, or by
the HER2 protein. So, triple-negative breast cancer does not respond to hormonal therapy medicines or
medicines that target HER2 protein receptors. However, in a recent study carried out by PhD students
from Harvard University came to the conclusion that the presence of Ran protein in the breast
increases the chances of getting TNBC cancer which is invasive.
• Tumors that are ER/PR-positive are much more likely to respond to hormone therapy than tumors that
are ER/PR-negative.
• In about 20% of breast cancers, the cells make too much of a protein known as HER2. These cancers
tend to be aggressive and fast-growing.

5. Pathogenesis
In this section we
will be talking about
factors that directly
contribute to the
development of
breast cancer
As for the Genetic factor
➢ BRCA1 and BRCA2 are classic tumors suppressor gene, cancer arises only when
both alleles are inactivated or defective.
➢ Their function is to encode proteins that are required for repair of certain DNA
damage.
➢ The degree of penetrance, age of onset and susceptibility to other types of cancer
differ among the many BRCA1 and BRCA2 germline mutations; but most carriers
Genetics (will be discussed further below)
•the major germline mutations conferring susceptibility to breast cancer affect genes that regulate
genomic stability or that are involved in progrowth signaling pathways.
•as might be expected, the pathways in which familial breast cancer genes fuction also are often
disturbed in sporadic breast cancer
•a common clinically important driver mutation in breast cancer is expansion of HER2 gene
hormonal influences
•estrogen stimulate the production of GF, such as transforming growth factor-α, platelet-derived GF,
fibroblast GF and others; which may promote tumor development through autocrine or paracrine
mechanisms.
•hormonal influence likely drive proliferation during the development of cancers from precursor
lesions to fully malignant and even metastatic carcinomas.
•estrogen antagonists reduce the developemnt of ER+ve cancers
environmental factors
•as we mentioned earlier in the geographic factors that increase the risk of BC
•some risk factors could be modified because mirgrates from low to high-incidence areas
tend to acquire the rates of their new home countries

6. develop breast cancer by the age of 70 years as compared to about 12% of women
with an average risk of breast cancer.
➢ Sporadic breast cancer is the kind of cancer that
develops from genetic mutations that occur over a
lifetime by chance or exposure to something that
increases the risk of cancer; somatic mutations in
BRCA1 and BRCA2 are rare in sporadic cancers.
However BRCA1 is inactivated by methylation in up
to 50% of TNBC, somatic mutations in TP53 are common in breast cancer
particularly TN and HER+ve tumors. Whereas mutations that activate PI3K-AKT
signaling are frequently found in sporadic ER+ve and HER2+ve breast cancers.
➢ HER2 is a receptor tyrosine kinase that promotes cell proliferation and opposes
apoptosis by stimulating the RAS- and PI3K-AKT signaling pathways; so as
mentioned above HER2 Cancers are highly proliferative and pathogenically
distinct.
➢ The above figure show us the major pathways for breast cancer
development; the major pathway which is shown by the yellow arrow leads
to ER+ve cancer this type arises most commonly in individuals with germline
BRCA2 mutations, these cancers are classified as luminal. On the other hand
the blue arrow show gene amplification which will lead to HER2+ve, they
may be positive or negative ER and are usually associated with TP53
mutations. The least common but molecularly most distinctive type of BC is
negative for both ER and HER2, these cancers has lost their BRCA1 and TP35
function, they are classified by gene expression profiling as Basal-like.
BRCA1 mutations show a strong
association with triple-negative
cancers
BRCA2 mutations are primary
associated with ER-positive tumors.

7. Most common locations of tumors within the breast are in the upper outer quadrant;
followed by the central portion. Some women with breast cancer have bilateral primary
tumors or sequential lesions in the same breast.
Breast cancer can be classified morphologically according to whether they have
penetrated the basement membrane to
Noninvasive (in situ) carcinoma:
• They arise from cells in the terminal duck
that gives rise to lobular.
• LCIS expands involved lobules
DCIS distorts lobules into ductlike spaces
• They either do not reach the basement membrane or invade into stroma or lymphvascular
channels.
• ductul carcinoma in situ
• lobular carcinoma in situ
in situ carcinoma (remains
within boundries)
•invasive ductul carcinoma
•invasive lobular carcinoma
•carcinoma with medullary features
•mucinous carcinoma
•tubular carcinoma
•other types
invasive carcinoma (has
spread beyond)
LCIS
DCIS LCIS

8. DCIS LCIS
Histological
features
Solid, comedo, cribriform, papillary,
micropapillary, and clinging type.
comedo subtype is characterized by extensive
necrosis, which produce toothpastelike necrotic
tissue that exudates from transected ducts, on
applying gentle pressure
Monomorphic cells that has bland round
nuclei and are found in loosely cohesive
clusters within the lobules
Calcification Calcifications are associated with DCIS;
resulting from calcification of necrotic debris
or secondary material
Rarely associated with calcification
Mammographic
detection
Cannot be easily detected
Treatment
Surgery and irradiation to eradicate the
lesion
Treat with anti-estrogen agents decrease
the risk of recurrence of ER+ve; Such as
tamoxifon
Close clinical and radiologic follow up
Chemotherapy with tamoxifon
Less commonly, bilateral prophylactic masoectomy
Untreated
conditions
It progresses to invasive cancer in
roughly 1/3 of cases
In the same breast and quadrant as
the earlier DCIS
Marker of an increased risk of
carcinoma in both breasts and a direct
precursor of some cancers
Paget disease of the nipple is caused by extension of DCIS up the lactiferous ducts
into the contiguous skin of the nipple, producing a unilateral crusting exudate over
the nipple and areolar skin.
Invasive (Infiltrating) Carcinoma
• Invasive means that the cancer has “invaded” or spread to the surrounding breast
tissues.
• Ductal means that the cancer began in the milk ducts, which are the “pipes” that carry
milk from the milk-producing lobules to the nipple.

9. • Invasive ductal carcinoma (IDC), sometimes
called infiltrating ductal carcinoma, is the
most common type of breast cancer.
About 80% of all breast cancers are invasive
ductal carcinomas.
• All types of invasive breast carcinoma are
assigned a grade
 From 1 (low-grade) to 3 (high-grade)
based on nuclear pleomorphism, tubule formation, and proliferation.
 Low-grade nuclei are similar in appearance to the nuclei of normal cells.
 High-grade nuclei are enlarged and have irregular nuclear contours resulting
from abnormal DNA content and structure.
• Most low-grade carcinomas form well-defined tubules and may be difficult to
distinguish from benign lesions, whereas high-grade carcinomas lose this capacity
and invade as solid sheets or single cells.
• Proliferation is evaluated by counting mitotic figures.
• The majority of HER2-positive and triple-negative carcinomas are highly
proliferative, whereas ER-positive cancers show a wide range of proliferation.
Invasive ductal carcinoma Invasive lobular carcinoma Carcinoma with medullary features
Most grow as tubules and
stimulate a reactive
desmoplastic stromal
proliferation
Composed of noncohesive
tumer cells that invade as
linear cords of cells and
induce little stromal response
Consist of tightly adhesive
clusters of cells
there is abundant extracellular
mucin production

10. Other forms of growth:
❖ Mucinous (colloid) carcinoma
ER+ve/HER2-ve tumor that produces abundant amounts of extracellular
mucin
It is soft and gelatinous due to the presence of mucin pools
❖ Tubular carcinoma
ER+ve/ HER-ve tumor, it is detected on mammography as a small irregular
mass
Low grade nuclei, lymph nodes metastasis are rare and the prognosis is
excellent
❖ Inflammatory carcinoma
no specific morphology, patients present with a swollen erythematous
breast without a palpable mass
no actual inflammation but it has a inflamed appearance due to generally
poorly differentiated and diffusely infiltrates and obstruct dermal lymphatic
spaces.
Clinical outcome for a woman with breast cancer can be predicted based on the
molecular and morphologic features of the cancer and its stages at the time of
diagnosis
• Factors that influence outcome include the following
a. Biologic type.
The biologic type of cancer is
evaluated by a combination of
histologic appearance,
grade (including proliferative rate),
expression of hormone receptors,
and expression of HER2
b. RNA expression profiling
is a newer method of subclassifying
cancers. For breast cancers, many of the genes
that predict prognosis are involved in proliferation.
The greatest clinical value of these assays is their

11. ability to identify patients with slow-growing, antiestrogen-
responsive cancers who can be spared the
toxicity of chemotherapy.
c. Tumor stage.
Stage” is a measure of the extent of tumor
at the time of diagnosis and is important for all biologic
types of carcinoma. It is based on features of the primary
tumor (T), involvement of regional lymph nodes (N),
and the presence of distant metastases (M)
Some breast cancer cells have
hormone receptors allow them
to grow in the presence of
hormones
❖ Based on the type of
hormone receptors breast
cancers divided into major
types:
1) Estrogen receptor ER positive &HER2-negativecarcinoma (most common)
2) HER2-positive &ER-positive /negative carcinoma
3) ER-negative &HER2-negative carcinoma

12. • Ten-years breast cancer specific survival according to AJUU stage for ER+ve and
ER-ve cancers.
• Both stage and biologic type of cancer are important determinants of survival,
ER+ve invasive cancers have improved survival over ER-ve cancers at all stages,
but this advantage diminishes after 5 years because of late recurrences of ER+ve
tumers.
Ovaries
Follicle and luteal cysts:
• They are so commonplace that they may be considered variants of normal
physiology.
• There hurtles lesions originate from
unruptured Graafian follicle or from
follicle that rupture and immediately
seal
• Some cysts often are multiple and
develop subjacent to the serosa of the
ovary
• They are typically small and filled with clear serous fluid, when they become
sufficiently large they produce palpable masses and pelvic pain.
Polycystic ovarian syndrome (Stein-Leventhal syndrome)
• It is a complex endocrine disorder characterized by hyperandrogeism, menstrual
abnormalities, polycystic ovaries, chronic anovulation and decreased fertility.
• The ovaries are usually twice the normal size, grey-white with smooth outer
cortex and studded with subcortical cysts.

13. Tumors of the ovary
• They may arise from
any of the three cell
types in the normal
ovary
the multipotent
surface (coelomic)
epithelium: they
account for the
greatest majority of ovarian tumors in their malignant forms, account for almost
90% ovarian cancer
the totipotent germ cells and the sex cord-germ cells: they are much less
frequent, they consist of 20-30% of ovarian tumors, they are less responsible for
malignant tumors.
• Surface epithelial tumors
the majority of ovarian tumors arise from the fallopian tube or epithelial cysts in
the cortex of the ovary.
the epithelial lining the cortical cysts may be derived from displaced ovarian
surface epithelium or the lining of fallopian tube
these can become metastatic or undergo neoplastic transformation to give rise
to number of different epithelial tumors
✓ Benign lesions usually are cystic (cystadenoma)
✓ And may have an accompanying stromal component (cystadenofibroma)
✓ Malignant tumors may also be cystic (cystadenocarcinoma) or solid
(carcinoma)
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