The Breasts

- Accessory Axillary Breast Tissue

o Prophylactic mastectomies reduce, but do not eliminate, the risk of breast cancer because breast tissue may not be removed in these areas
- Nipple Inversion
o Congenitally inverted nipples are not significant
o Acquired nipple retraction may indicate invasive cancer or inflammatory nipple disease
- Pain (mastalgia or mastodynia)
o Diffuse cyclic pain - premenstrual edema
o Painful masses are usually benign 10% of breast cancers present with pain
- Palpable masses
o Cysts, Fibroadenomas, and Invasive carcinomas
o 10% in women < 40 are malignant, 60% in women > 50years
o 50% of carcinomas are located in the upper outer quadrant
Nipple discharge
- Galactorrhea (milk discharge)
o Elevated prolactin levels (Prolactinoma)
o Hypothyroidism (↓Thyroxine ↑ TRH which stimulates Prolactin)
o Endocrine anovulatory syndromes
o Patients taking oral contraceptives, tricyclic antidepressants, methyldopa, or phenothiazines
o Not associated with malignancy
o Ex. A 21-year-old woman delivered a normal term infant a week ago and is now nursing the infant. She now notes a lump in her right axilla that has
increased in size over the past week. On physical examination there is a rubbery, mobile, 1.5-cm mass beneath the skin at the right anterior axillary line.
The mass is excised and the microscopic appearance is shown in the figure. Which of the following hormones most likely produced the greatest effect upon
this tissue? Prolactin
 This is accessory breast tissue with lactational change. Prolactin secretion from the adenohypophysis increases in postpartum women to
support milk production in breast lobules. Oxytocin released from the posterior pituitary stimulates myoepithelial cells to contract during
nursing.
- Bloody or serous discharge
o Most commonly due to large duct papillomas and cysts
o During pregnancy, from the rapid growth and remodeling of the breast
o Associated with malignancy - 7% of women < 60 years, 30% > 60 years
- Purulent discharge
o Acute mastitis (area of erythema and firmness in the breasts, commonly during lacttation) due to S. aureus
o Ex. A 24-year-old woman is breastfeeding 3 weeks after giving birth to a normal term infant. She notices fissures in the skin around her left nipple. Over the
next 3 days, a 5-cm region near the nipple becomes erythematous and tender. Purulent exudate from a small abscess drains through a fissure. Which of the
following organisms is most likely to be cultured from the exudate? Staphylococcus aureus
 Staphylococcal acute mastitis typically produces localized abscesses, whereas streptococcal infections tend to spread throughout the breast,
because streptococci often produce streptolysins. Acute mastitis can be associated with the first few months of breastfeeding.
- Breast Pain
o Most common cause is fibrocystic change (FCC)
o Mondor disease
 Superficial thrombophlebitis of veins overlying the breast
 Presents as a palpable, painful cord
 Breast surgery appears to be a common antecedent risk factor
- Mammographic screening
o Currently the most common means to detect breast cancer
o Likelihood of cancer presenting as mammographic lesion  10% at 40 years, > 25% in women older than 50 years
o 10% of invasive carcinomas are not detected by mammography Younger women, small size, diffuse infiltrative pattern without desmoplasia
o Densities
 Rounded densities mostly fibroadenomas or cysts
 Irregular masses: invasive cancers
o Calcifications
 Benign lesions (apocrine cysts, fibroadenomas, and sclerosing adenosis)
 Malignancy - small, irregular, numerous, and clustered
 DCIS (Ductal carcinoma in situ): most commonly detected as calcifications

Inflammatory disorders
- Squamous Metaplasia of Lactiferous Ducts
o ‘Zuska disease’ or ‘Recurrent Subareolar Abscess’ or ‘Periductal Mastitis’
o Many women have an inverted nipple
o More than 90% are smokers
o Simple incision drains the abscess cavity, but can recur if the keratinizing epithelium remains
o En bloc surgical removal of the involved duct and contiguous fistula tract
- Mammary Duct Ectasia
o Plasma cell mastitis
o 5th to 6th decade of life, multiparous women Not associated with cigarette smoking
o Palpable periareolar mass associated with thick, white nipple secretions and occasionally with skin retraction
o Can mimic invasive carcinoma clinically and radiologically No increased risk for breast cancer
o Ectatic ducts filled with inspissated secretions and numerous lipid-laden macrophages
o Rupture - marked periductal and interstitial inflammation (lymphocytes, macrophages + plasma cells)
o Granulomas around cholesterol deposits and secretions
o Fibrosis - irregular mass with skin and nipple retraction
- Fat Necrosis
o Often related to breast trauma or prior surgery
o Can closely mimic cancer—as a painless palpable mass, skin thickening or retraction, or mammographic densities or calcifications
o Granulomatous Mastitis Manifestation of systemic granulomatous diseases (granulomatosis with polyangiitis, sarcoidosis, tuberculosis)
o Ex. A 30-year-old woman sustained a traumatic blow to her right breast. Initially, there was a 3-cm contusion beneath the skin that resolved within 3 weeks,
but she then felt a firm, painless lump that persisted below the site of the bruise 1 month later. What is the most likely diagnosis for this lump? Fat necrosis
  Fat necrosis is typically caused by trauma to the breast. The damaged, necrotic fat is phagocytosed by macrophages, which become lipid laden.
The lesion resolves as a collagenous scar within weeks to months. The firm scar can mammographically and grossly resemble a carcinoma
- Granulomatous lobular mastitis
o Uncommon disease that only occurs in parous women
o Hypersensitivity reaction to antigens expressed during lactation
o Cystic neutrophilic granulomatous mastitis caused by Corynebacteria
- Silicone breast implant
o Polymer of silica, oxygen, and hydrogen
o Silicone gel can leak, or the implant can rupture Silicone produces foreign body giant cells and chronic inflammation.
o Association with autoimmune disease

Benign Epithelial Lesions

- Benign epithelial lesions usually do not cause symptoms, but are frequently detected as mammographic calcifications or densities
- These lesions are classified according to the subsequent risk of cancer in either breast The majority are not precursors of cancer
- Mostly detected by mammography or incidental findings in surgical specimens
- Classification based on the risk of developing breast cancer
o Non-proliferative breast changes (FIBROCYSTIC CHANGE), Proliferative breast disease, Atypical hyperplasia
Non-proliferative breast changes (Fibrocystic change)
- Most common painful breast mass in women <50 years old
- Occurs in >50% of women in the reproductive period of life
- Distortion of normal cyclic breast changes
- Cysts
o Contain semi-translucent fluid of a brown or blue color (blue dome cysts)
o Lined by flattened atrophic epithelium or by metaplastic apocrine cells
o Calcifications are common and may be detected by mammography
o Disappear after fine-needle aspiration
o Ex. A study of mammographic findings on women of reproductive years is performed. The study identifies mammograms showing 1- to 5-cm cysts with
focal microcalcifications and surrounding densities. Subsequent fine-needle aspiration yielded turbid fluid with few cells. Which of the following
microscopic changes is most likely to be present in these lesions? Apocrine metaplasia
 Nonproliferative cysts are quite common in the breast. When they are fluid-filled, they are unlikely to contain proliferative elements. The cells
lining these cysts may be flattened cuboidal to atrophic, but often have abundant pink cytoplasm resembling apocrine change. Aprocrine
metaplasia are seen in cyst walls.
- Fibrosis
o Rupture of cysts results in chronic inflammation and fibrosis
- Adenosis
o Increase in the number of acini per lobule
- Ex. A 27-year-old woman feels a lump in her right breast. She has normal menstrual cycles, she is G3, P3, and her last child was born 5 years ago. On examination a 2-
cm, irregular, firm area is palpated beneath the lateral edge of the areola. This lumpy area is not painful and is movable. There are no lesions of the overlying skin and
no axillary lymphadenopathy. A biopsy specimen shows microscopic evidence of an increased number of dilated ducts surrounded by fibrous connective tissue. Fluid-
filled ducts with apocrine metaplasia also are present. What is the most likely diagnosis? Fibrocystic changes
o Nonproliferative (fibrocystic) changes account for the largest category of breast lumps. These lesions are probably related to cyclic breast changes that
occur during the menstrual cycle. In about 30% of cases of breast lumps, no specific pathologic diagnosis can be made. Fibrocystic changes include ductal
proliferation, ductal dilation (sometimes with apocrine metaplasia), and fibrosis.
Proliferative Breast Disease without Atypia
- Epithelial hyperplasia
o Increases luminal and myoepithelial cells fill and distend ducts and lobules
o Ex. A 47-year-old woman has a routine health examination. There are no remarkable findings except for a barely palpable mass in the right breast. A
mammogram shows an irregular, 1.5-cm area of density with scattered microcalcifications in the upper outer quadrant. A biopsy specimen from this area is
obtained and microscopically shows ductal hyperplasia. Which of the following is the most appropriate option for follow-up of this patient? Continued
screening for breast cancer
 Fibrocystic changes without epithelial hyperplasia do not suggest a significantly increased risk of breast cancer. Moderate to florid hyperplasia
increases the risk twofold, and atypical ductal or lobular hyperplasias increase the risk fivefold. The risk in this patient is not great enough to
suggestradical or simple mastectomy at this time, but follow-up
 is needed.
- Sclerosing adenosis
o Compressed and distorted acini in the central portion of the lesion
o Stromal fibrosis may completely compress the lumens
o Often contain microcalcifications and may be confused with cancer
- Complex Sclerosing Lesion - Radial Sclerosing Lesion (“Radial scar”)
o Mimics invasive carcinoma mammographically, grossly, and histologically
o A central nidus of entrapped glands in a hyalinized stroma is surrounded by long radiating projections into stroma
o Not associated with prior trauma or surgery
- Papilloma
o Most common cause of a bloody nipple discharge in women <50 years old
o > 80% of large duct papillomas produce a nipple discharge
o Large duct papillomas: solitary, in the lactiferous sinuses of the nipple
o Small duct papillomas: multiple, located deeper in the ductal system
o Within a dilated duct, composed of multiple branching fibrovascular cores
o No increased risk for cancer Surgically remove the duct or sinus
o Ex. A 34-year-old woman has noticed a bloody discharge from the nipple of her left breast for the past 3 days. On physical examination, the skin of the
breasts appears normal, and no masses are palpable. There is no axillary lymphadenopathy. She has regular menstrual cycles and is using oral
contraceptives. Excisional biopsy is most likely to show which of the following lesions in her left breast? Intraductal papilloma
Proliferative Breast Disease with Atypia
o Clonal proliferation with some, but not all histologic features required for the diagnosis of carcinoma in situ
o Moderately increased risk of carcinoma
- Atypical ductal hyperplasia
o 5 to 17% of specimens from biopsies performed for calcifications
o Histologically resembles ductal carcinoma in situ (DCIS) Unlike DCIS, it only partially fills the involved ducts
o Monomorphic proliferation of regularly spaced cells, with cribriform spaces
 - Atypical lobular hyperplasia
 Incidental finding, <5% of biopsies
 Cells identical to those of lobular carcinoma in situ The cells do not fill or distend more than 50% of the acini within a lobule
 Atypical lobular cells may lie between the ductal basement membrane and overlying normal luminal cells
 Ex. A 58-year-old woman sees her naturopathic health care provider for a routine health examination. There are no remarkable findings on
physical examination. A screening mammogram shows a 0.5-cm irregular area of increased density with scattered microcalcifications in the
upper outer quadrant of the left breast. Excisional biopsy shows atypical lobular hyperplasia. She has been on postmenopausal estrogen-
progesterone therapy for the past 10 years. She has smoked 1 pack of cigarettes per day for the past 35 years. Which of the following is the
most significant risk factor for the development of lobular carcinoma in patients with such lesions? Atypical cytologic changes
 Atypical lobular hyperplasia and atypical ductal hyperplasia increase the risk of breast cancer fivefold; the risk affects both breasts
and is higher in premenopausal women or women who have a family history of breast cancer.
- Gynecomastia
o Enlargement of the male breast
 Proliferative breast disease without atypia
 Unilateral or bilateral subareolar enlargement
 ↑dense collagenous connective tissue with epithelial hyperplasia of the duct lining with characteristic tapering micropapillae
 No lobule formation
o Imbalance between estrogens and androgens leading to hyperestrinism
 Cirrhosis of the liver
 Older males - relative increase in estrogens as testicular androgen production
 Alcohol, marijuana, heroin, antiretroviral therapy, and anabolic steroids
 Klinefelter syndrome
 Leydig cell or sertoli cell tumors
 Choriocarcinoma of testis produces hCG (LH analogue)
o May be associated with a small increased risk of breast cancer
o Ex. A 57-year-old man has developed bilateral breast enlargement over the past 2 years. On physical examination, the enlargement is symmetric and is not
painful to palpation. There are no masses. He is not obese and is not taking any medications. Which of the following underlying conditions best accounts for
his findings? Micronodular cirrhosis
 Micronodular cirrhosis is most often a consequence of chronic alcoholism and impairs hepatic estrogen metabolism,
which can lead to bilateral gynecomastia.

Stromal Tumors
- Both fibroadenoma and phyllodes tumor arise from intralobular stroma
- Fibroadenomas are the most common benign tumor of the breast
- Tumors of interlobular stroma consist only of stromal cells and include both benign and malignant lesions
- Angiosarcoma is the most common stromal malignancy and can either be sporadic or associated with radiation exposure or lymphedema
- Fibroadenoma
o Most common benign tumor - polyclonal hyperplasia of lobular stroma
o Duct epithelium is not neoplastic
o 20s and 30s, frequently multiple and bilateral
o Young women - palpable mass
o Older women - mammographic density/clustered calcifications
o Develop in 50% of women who receive cyclosporine after renal transplantation
o Increases in size during pregnancy (estrogen sensitive), may spontaneously disappear or involute during menopause
o Well circumscribed, rubbery, grayish white nodules
o Histology
 Delicate myxoid stroma resembling normal intralobular stroma
 Pericanalicular and Intracanalicular patterns
 Epithelial component is hormonally responsive
o Ex. A 26-year-old woman has noticed a lump in her right breast for the past year. A 2-cm, firm, circumscribed, movable mass is palpated in the lower outer
quadrant. The figure shows the excised mass (A) and the mammogram (B). What is the most likely diagnosis? Fibroadenoma
o Ex. A 27-year-old woman in the third trimester of her third pregnancy discovers a lump in her left breast. On physical examination, a 2-cm, discrete, freely
movable mass beneath the nipple is palpable. After the birth of a term infant, the mass appears to decrease in size. The infant is breastfed without
difficulty. What is the most likely diagnosis? Fibroadenoma
- Phyllodes Tumor
o Arise from intralobular stroma, less common than fibroadenomas
o 6th decade, mostly benign but can be malignant
o Clonal acquired chromosomal changes (gains in chromosome 1q)
o Histology
 “Leaf-like”protrusions due to the presence of nodules of proliferating stroma covered by epithelium
 Distinguished from fibroadenomas on the basis of higher cellularity, higher mitotis, nuclear
pleomorphism, stromal overgrowth, infiltrative borders
o A 48-year-old woman has felt a poorly defined lump in her right breast for the past year. On examination, she has
a nontender, firm, 6-cm mass in the upper inner quadrant of her right breast. There are no lesions of the overlying
skin and no axillary lymphadenopathy. A biopsy is performed, and microscopic examination of the specimen
shows the findings in the figure. The mass is excised with a wide margin, but recurs 1 year later. After further
excision, the lesion does not recur. What is the most likely diagnosis? Phyllodes tumor
 Phyllodes tumors, although grossly and microscopically similar to fibroadenomas, occur at an older age, are larger, and are more cellular than
fibroadenomas; they can recur locally following excision, but rarely metastasize. The figure shows cellular stroma protruding into spaces lined
by a single layer of cuboidal epithelium.

Carcinoma of the breast

- Most common non-skin malignancy in women (1:8 lifetime risk)
- Most common breast mass in women >50 years old, risk ↑ with age
- Second only to lung cancer as a cause of cancer deaths
- Adenocarcinomas
- 3 major biologic subgroups:
o Estrogen receptor (ER)-positive, HER2-negative (50 to 65%)
o HER2-positive (10 to 20% , may be ER-positive or ER-negative)
o ER-negative, HER2-negative (10 to 20% of tumors)
- Age Rare in women < 25 years
o ER-positive cancers continue to increase with age
o ER-negative cancers and HER2- positive cancers remain constant
- White women have the highest incidence of breast cancer but African-American women have the highest
mortality rate
o Unequal access to care
o More biologically aggressive cancers
- Germline BRCA1 and BRCA2 mutations are particularly prevalent in Ashkenazi Jewish populations
o Ex. A 25-year-old Jewish woman sees her physician after finding a lump in her right breast. On physical examination, a 2-cm, firm, nonmovable mass is
palpated in the upper outer quadrant. No overlying skin lesions and no axillary lymphadenopathy are present. The figure shows an excisional biopsy
specimen. The family history indicates that the patient’s mother, maternal aunt, and maternal grandmother have had similar lesions. Her 18-year-old sister
has asked a physician to determine whether she is genetically at risk of developing a similar disease. A mutated gene encoding for which of the following is
most likely to be found in her sister? BRCA1
 The biopsy specimen shows an invasive breast cancer. Given the young age of the patient and the strong family history of breast cancer, it is
reasonable to assume that she has inherited an altered gene that predisposes to breast cancer. There are two known breast cancer
susceptibility genes: BRCA1 and BRCA2. Both are cancer suppressor genes. Specific mutations of BRCA1 are common in some ethnic groups,
such as Ashkenazi Jews.
- Increased Risk
o Germline mutations - lifetime risk >90%
o First-degree relatives with breast cancer (15 to 20% cases)
o Race/ethnicity: Non-Hispanic white women
o Age – highest risk at 70 to 80 years
 Early age at menarche (<11 yrs) and late menopause
 Age at first live birth (More risk >35 yrs)
o Benign breast disease
o Estrogen exposure – menopausal hormone therapy ↑risk
o Breast density – higher density, higher risk
o Radiation exposure
 Carcinoma of the contralateral breast or endometrium
 Moderate or heavy alcohol consumption
 Postmenopausal obese women
 Environmental contaminants (organochlorine pesticides may have estrogenic effects )
- No increased risk/preventive factors
o If the only affected relative is a postmenopausal mother with cancer
o Full-term pregnancy before 20 halves the risk compared to nulliparous women or women older than 35 at the time of first birth
o Oral contraceptives do not appear to increase the risk of breast cancer
o Reducing endogenous estrogens by oophorectomy ↓ risk by up to 75%
o Drugs that block estrogenic effects (Tamoxifen) or block the formation of estrogen (aromatase inhibitors) ↓risk of ER-positive breast cancer
o Obese women < 40 years have a decreased risk as a result of anovulatory cycles and lower progesterone levels
o Exercise may have protective effect
o The longer women breastfeed, the greater the reduction in risk
o Ex. A 66-year-old nulliparous woman received hormone replacement therapy for 7 years following menopause at age 53 years. Her BMI is 33. She now
undergoes screening mammography, and an irregular mass is identified in the right breast. An excisional biopsy yields a 1.5-cm mass that microscopically
has invasive cells that are positive for estrogen receptor but negative for HER2, with low proliferation markers and mutated PIK3CA gene. Following surgical
removal of the mass, which of the following clinical courses will most likely occur over the next year? Very low likelihood of recurrence
o Ex. A study of women with breast carcinoma is done to determine the presence and amount of estrogen receptor (ER) and progesterone receptor (PR) in
the carcinoma cells. Large amounts of ER and PR are found in the carcinoma cells of some patients. These receptors are not present in the cells of other
patients. The patients with positivity for ER and PR are likely to exhibit which of the following traits? Higher response to therapy
- Etiology and Pathogenesis
o Familial Breast Cancer (12% of breast cancers)
 Mutations in BRCA1 & BRCA2 (80-90%), TP53, CHEK2
 BRCA1 mutation higher ↑ risk of ovarian carcinoma
 BRCA1 breast cancers similar to ER-negative/HER2-negative cancers
 ↑surveillance, prophylactic mastectomy, and salpingo-oophorectomy can reduce cancer-related morbidity and mortality
 Ex. A clinical study is performed on postmenopausal women living in Paris, France, who are between the ages of 45 and 70 years. All have been
diagnosed with infiltrating ductal carcinoma positive for estrogen receptor (ER) and progesterone receptor (PR), but negative for HER2
expression, which has been confirmed by biopsy and microscopic examination of tissue. None has the BRCA1 or BRCA2 mutation. Which of the
following is most likely to indicate the highest relative risk of developing the carcinomas seen in this group of women? First-degree relative
with breast cancer
 Ex. A 29-year-old woman and her 32-year-old sister were diagnosed with infiltrating ductal carcinoma of the breast, and both had bilateral
mastectomies. Which of the following risk factors is most significant for this type of cancer? Inheritance of a mutant p53 allele
o Sporadic Breast Cancer
 Hormone exposure: gender, age at menarche and menopause, reproductive history, breastfeeding, and exogenous estrogens
 Environmental factors: radiation exposure, chemicals
- Clinical findings
o Painless mass in the breast
o Usually in the upper outer quadrant
o Skin or nipple retraction
o Painless axillary lymphadenopathy
o Hepatomegaly, bone pain if metastasis has occurred
o Ex. A 79-year-old, previously healthy woman feels a lump in her right breast. The physician palpates a 2-cm firm mass in the upper outer quadrant.
Nontender right axillary lymphadenopathy is present. A lumpectomy with axillary lymph node dissection is performed. Microscopic examination shows that
the mass is an infiltrating ductal carcinoma. Two of 10 axillary nodes contain metastases. Flow cytometry on the carcinoma cells shows a small aneuploid
peak and high S-phase. Immunohistochemical tests show that the tumor cells are positive for estrogen and progesterone receptor (ER/PR), negative for
HER2/neu expression, and positive for cathepsin D expression. What is the most important prognostic factor for this patient? Presence of lymph node
metastases
- Mammography
o Primarily a screening test, detects 80%–90% of non-palpable masses
o Does not distinguish benign from malignant lesions
o Screening usually starts annually at age 40 years, but earlier if patient is high risk
o Identifies microcalcifications and spiculated masses with or without microcalcifications (30%–50% of cases)
o Microcalcifications: most often occur in DCIS and sclerosing adenosis
o Microcalcification pattern suggesting malignancy
o Five or more tightly clustered punctate , microlinear, branching microcalcifications
- Molecular Mechanisms of Carcinogenesis
o ER-positive, HER2-negative cancers (50 to 65% of cases)
 Germline mutations in BRCA2
 Gains of chromosome 1q, losses of chromosome 16q, activating mutations in PIK3CA
 “Luminal” - resemble normal breast luminal cells
o HER2-positive cancers
 Amplifications of the HER2 gene on chromosome 17q
 Germline mutations in TP53 (Li-Fraumeni syndrome)
o ER-negative, HER2-negative cancers
 Germline mutations in BRCA1
 African American women
 “Basal-like” pattern of mRNA expression
- Carcinoma in Situ
o Precedes >95% of breast malignancies (adenocarcinomas)
o Confined to the duct/lobular system by basement membrane
o Ductal carcinoma in situ (DCIS) or Lobular carcinoma in situ (LCIS)
o Based on the resemblance to normal ducts or lobules
o Different tumor cell genetics and biology
o Ex. A 54-year-old woman noticed a lump in her right breast. On examination, she has an ill-defined, 1-cm mass in the upper outer quadrant. The mass is
cystic on ultrasound. An excision is done, and microscopically the mass shows predominantly fibrocystic changes, but the lesion shown in the figure also is
present. Fine-needle aspirates of both breasts reveal additional foci of similar cells. Which of the following breast lesions is most likely to produce these
findings? Lobular carcinoma in situ
 Among primary malignancies of the breast, lobular carcinoma in situ (LCIS) is most likely to be bilateral. LCIS may precede invasive lesions by
several years. Lobular carcinoma may be mixed with ductal carcinoma, and it may be difficult to distinguish them histologically.
- Ductal Carcinoma in Situ (DCIS)
o Malignant clonal proliferation of epithelial cells limited to ducts and lobules by the basement membrane
o Detected by mammography
o Comedo DCIS
 Mammography: clustered or linear and branching areas of calcification
 Tumor cells with pleomorphic, high grade nuclei and areas of central necrosis
 Ex. A 63-year-old woman feels a small lump in her right breast. The physician palpates a firm
area that has a cordlike feel. No lesions of the overlying skin are present, and there is no axillary
lymphadenopathy. A mammogram shows a density that contains microcalcifications. An
excisional biopsy specimen contains soft, white material that is extruded from small ducts when
pressure is applied. Microscopic examination shows ducts that contain large, atypical cells in a
cribriform pattern. What is the most likely diagnosis? Comedocarcinoma
o Non-comedo DCIS
 lacks either high-grade nuclei or central necrosis
 Cribriform DCIS - have rounded (cookie cutter–like) spaces within the ducts
 Solid DCIS
 Micropapillary DCIS - protrusions without a fibrovascular core
o Ex. A 63-year-old woman has a screening mammogram that shows an irregular density with microcalcifications. On physical examination, there are no
lesions of the overlying skin, and there is no axillary lymphadenopathy. An excisional biopsy specimen shows no mass on sectioning. Microscopic
examination shows the findings in the figure. What is the most likely diagnosis? Ductal carcinoma in situ
 An intraductal carcinoma, or ductal carcinoma in situ (DCIS), may not produce a palpable mass. The figure shows ducts that contain large,
atypical cells in a cribriform pattern. If grossly soft, white material is extruded from small ducts when pressure is applied, then there is necrosis
of the neoplastic cells in the ducts (that leads to dystrophic calcification), and the term comedocarcinoma is applicable.
- Paget disease of the nipple
o 1 to 4% of breast cancer, unilateral erythematous eruption with a scale crust
o Pruritus is common (may be mistaken for eczema)
o Malignant cells (Paget cells) extend from DCIS within the ductal system via lactiferous sinuses into nipple skin without crossing basement membrane
o Tumor cells disrupt the normally tight squamous epithelial cell barrier, allowing extracellular fluid to seep out and form an oozing scaly crust
o Nipple biopsy or cytologic preparations of the exudate
o 50 to 60% of women have a palpable mass
o Almost all have an underlying invasive carcinoma
o Poorly differentiated, ER-negative, and overexpression of HER2
o Women without a palpable mass have only DCIS
o Prognosis depends on the features of the underlying carcinoma
o Clinical course
 Mastectomy curative in > 95% of women
 Breast conservation surgery
 Risk of recurrence (higher nuclear grade, necrosis, extensive disease and positive surgical
margins)
 Post-op radiation and tamoxifen reduce the risk
 Progression to invasive cancer, if untreated
 Low-grade small DCIS 1% per year
 High-grade extensive DCIS higher risk
 Death from metastatic cancer in 1 to 3% women
o Ex. A 48-year-old woman has noticed a red, scaly area of skin on her left breast that has grown slightly larger
over the past 4 months. On physical examination, there is a 1-cm area of eczematous skin adjacent to the
areola. The figure shows the microscopic appearance of the skin biopsy specimen. What is the most likely
diagnosis? Paget disease of the breast
- Lobular Carcinoma in Situ
o Clonal proliferation of discohesive cells within ducts and lobules
 Acquired loss of E-cadherin
o Cells expand but do not distort involved spaces and, thus, the underlying lobular architecture is preserved
o Mostly incidental biopsy finding
o Not associated with calcifications or stromal reactions that produce mammographic densities
o Bilateral in 20 to 40% of cases (10 to 20% of DCIS)
o Morphology
 Uniform looking cells involving ducts and lobules
 Rounded shape without attachment to adjacent cells (lack of E-cadherin)
 Mucin-positive signet-ring cells are commonly present
 No cribriform spaces or papillae
 No necrosis or secretory activity (no calcification)
 Expresses ER and PR, no HER2
o Clinical course
 Invasive carcinoma
 In 25 to 35% of women over 20 to 30 years
 Rate of about 1% per year, similar to untreated DCIS
 Risk equally high in the contralateral and ipsilateral breast
 3-fold more likely to be lobular carcinoma, mostly other morphologies
 Treatment
 Bilateral prophylactic mastectomy
 Tamoxifen
 Close clinical follow-up and mammographic screening
o Ex. A 57-year-old woman has felt a lump in her left breast for 4 months. She has had new onset headaches associated with nausea for the past month. Her
physician palpates a firm but irregular 2-cm mass in her left breast. CT imaging of her brain shows leptomeningeal enhancement. A lumpectomy with
axillary node sampling is performed. Immunohistochemical staining of these cells shows absence of E-cadherin and HER2, but presence of estrogen
receptor (ER) and progesterone receptor (PR). An H and E stained section is shown in the figure. No nodal metastases are present. Which of the following is
the most likely diagnosis? Lobular carcinoma
 In this lobular carcinoma, note the pleomorphic cells infiltrating single file through the stroma. The metastatic profile of this cancer includes the
carcinomatous meningitis suggested by her leptomeningeal enhancement, as well as intra-abdominal metastases. E-cadherin is an adhesion
molecule that serves as a tumor suppressor, and its loss characterizes another infiltrating carcinoma—signet ring carcinoma of the stomach.
- Invasive (Infiltrating) Carcinoma
o Molecular classification
 ER-positive, HER- negative “luminal” (50 -65 % of cancers)
 ER-positive, HER2-negative low proliferation (40 -55%)
 ER-positive, HER2-negative high proliferation (10%)
 HER2-positive (20% of cancers)
 ER-negative, HER2-negative tumors “basal-like” triple negative carcinoma (15% of cancers)
o Morphologic classification
 No Special Type (NST) - most common
 Special histologic types
o Ex. A 49-year-old woman felt a lump in her left breast 1 week ago. On examination, a firm, irregular mass is palpable in the upper outer quadrant of her left
breast. There are no overlying skin lesions. The gross appearance of the excisional biopsy specimen is shown in the figure. Which of the following additional
findings is she most likely to have on physical examination? Axillary lymphadenopathy
 This irregular, infiltrative mass is an infiltrating (invasive) ductal carcinoma, the most common form of breast cancer. Breast carcinomas are
most likely to metastasize to regional lymph nodes. By the time a breast cancer becomes palpable, lymph node metastases are present in more
than 50% of patients.
o Ex. A 51-year-old woman has noticed an area of swelling with tenderness in her right breast that has worsened over the past 2 months. On physical
examination, the 7-cm area of erythematous skin is tender with a rough, firm surface resembling an orange peel. There is swelling of the right breast, nipple
retraction, and right axillary nontender lymphadenopathy. Excisional biopsy of skin and breast is most likely to show which of the following lesions?
Infiltrating ductal carcinoma
 The gross appearance of the skin is consistent with invasion of dermal lymphatics by carcinoma—the so-called inflammatory carcinoma, which
is not a histologic type of breast cancer, but a descriptive phrase based upon the gross appearance (peau d’orange) resembling an inflammatory
process. Nipple retraction and nontender axillary lymphadenopathy also suggest invasive ductal carcinoma.
- ER-positive, HER2-negative, low proliferation
o Majority of cancers in older women and in men
 Most common type detected by mammographic screening and in women treated with menopausal hormone therapy
o Genes directly regulated by estrogen receptor
o Lowest incidence of local recurrence and often cured by surgery
o Metastasize after a long time (>6yrs), typically to bone
 Respond well to hormonal treatment
 Incomplete responses to chemotherapy
- ER-positive, HER2-negative, high proliferation
o ER-positive but ER/PR levels may be low
o Most common carcinoma associated with BRCA2 germline mutations
o mRNA expression pattern similar to other ER-positive cancers
o Higher expression of genes related to proliferation
o More chromosomal aberrations than low-grade ER-positive tumors
o 10% show a complete response to chemotherapy
 Much better prognosis than patients that do not respond
- HER2-positive
o 50% of these cancers are ER-positive (ER – low, PR – absent)
o Young women and in non-white women
o 53% of familial breast cancers in patients with germline TP53 mutations (Li-Fraumeni syndrome) - positive for both ER and HER2
o mRNA profile - ↑expression of HER2 + genes related to proliferation
o Complex interchromosomal translocations, high-level amplifications of HER2, and a high mutational load
o HER2-targeted therapy
- ER-negative, HER2-negative tumors
o Young premenopausal women, African American (20 to 25% of carcinomas in this group), Hispanic women (17% of carcinomas in this group)
o BRCA1 mutations, share genetic similarities with serous ovarian carcinomas
o Presents as a palpable mass in the interval between mammographic screenings (high proliferation and rapid growth)
o 10% express ER and 15% express HER2
o Can metastasize when small to viscera and brain
o 30% completely respond to chemotherapy
o Recurrences generally diagnosed within 5 years of treatment, prolonged survival after distant metastasis is rare
- Morphology – No Special Type
o Presenting on mammography
o Calcifications without an associated density, <1 cm in size
o In the absence of mammographic screening
o Mass of at least 2 to 3 cm in size
o Scirrhous carcinomas
 Hard, irregular radiodense mass with a desmoplastic stromal reaction
 Grating sound (similar to cutting a water chestnut) when cut
o Well-circumscribed masses
 Sheets of tumor cells with scant stromal reaction
o Imperceptible masses
 Scattered neoplastic glands or single tumor cells infiltrating fibrofatty tissue
o Larger carcinomas
 Invade pectoralis muscle - fixity to the chest wall
 Invade into the dermis - dimpling of the skin
 Involve central portion of breast - retraction of the nipple
o Occult Primary Tumor
 Present as involved axillary node or distant metastasis before cancer is detected in the breast
 Small, or obscured by dense breast tissue, or lack of desmoplastic response
 Detected by ultrasound or MRI
- Nottingham Histologic Score
o Grade I carcinomas
 Tubular pattern with small round nuclei , low proliferative rate
o Grade II carcinomas
 Some tubule formation + solid clusters or single infiltrating cells
 Greater nuclear pleomorphism
 Mitotic figures
o Grade III carcinomas
 Ragged nests or solid sheets of cells with enlarged irregular nuclei
 High proliferative rate
 Areas of tumor necrosis
- Morphology of molecular types
o ER-positive, HER2-negative carcinoma
 Mostly well differentiated carcinomas Some may be classified as “special histologic type” – mucinous, papillary, lobular
o HER2-positive carcinoma
 Poorly differentiated 50% of apocrine carcinomas and 40% of micropapillary carcinomas
 Associated DCIS is more extensive than with other types
o ER-negative, HER2-negative carcinomas
 Poorly differentiated Medullary type, Spindle cell, Squamous, and Matrix producing patterns
 DCIS - limited to absent
- Special Histologic Types of Invasive Carcinoma Lobular carcinoma
o Loss of expression of CDH1, the gene that encodes E-cadherin
o Discohesive, may fail to incite a desmoplastic response
 Difficult to palpate or detect by imaging
 Most common type of breast carcinoma to present as an occult primary
o Histology
 Discohesive infiltrating tumor cells
 Signet-ring cells containing intracytoplasmic mucin droplets
 Tubule formation is absent
o Unusual metastasis
 Involve the peritoneum and retroperitoneum, leptomeninges (carcinomatous meningitis), gastrointestinal tract, ovaries and uterus
- Special Histologic Types of Invasive Carcinoma
o Medullary carcinoma
 In BRCA1 carriers, 13% are medullary, 60% have a subset of medullary features
 Well-circumscribed mass, softer than other carcinomas (minimal desmoplasia)
 Histology
 Solid, syncytium-like sheets of large cells with pleomorphic nuclei and prominent nucleoli ( > 75% of the tumor mass)
 Frequent mitotic figures
 Moderate to marked lymphoplasmacytic infiltrate surrounding and within the tumor
 Pushing (non-infiltrative) border
 DCIS is minimal or absent
 Better prognosis: presence of lymphocytic infiltrates within the tumors is associated with higher survival rates and a greater response to
chemotherapy
o Ex. A 39-year-old woman has noticed an enlarging mass in her left breast for the past 2 years. The physician palpates a 4-cm firm mass. Following biopsy, a
simple mastectomy is performed with axillary lymph node sampling. On gross sectioning, the mass has a soft, tan, fleshy surface. Histologically, the mass is
composed of large cells with vesicular nuclei and prominent nucleoli. There is a marked lymphocytic infiltrate within the tumor, and the tumor has a
discrete, noninfiltrative border. No axillary node metastases are present. The tumor cells are triple negative, for HER2, estrogen receptor (ER), and
progesterone receptor (PR). What is the most likely diagnosis? Medullary carcinoma
 Medullary carcinomas account for about 1% to 5% of all breast carcinomas. They tend to occur in women at younger ages than do most other
breast cancers. Despite poor prognostic indicators (such as absence of HER2, ER, and PR), medullary carcinomas have a better prognosis than
most other breast cancers. Perhaps the infiltrating lymphocytes are a helpful immune response.
 o Ex. A 26-year-old woman has felt a breast lump for the past month and is worried because she has a family history of early onset and bilateral breast
cancers. On physical examination, there is a firm, 2-cm mass in the upper outer quadrant of her left breast. A biopsy is done, and the specimen
microscopically shows carcinoma. Genetic analysis shows that she is a carrier of the BRCA1 gene mutation, as are her mother and sister. Which of the
following histologic types of breast carcinoma has the highest incidence in families such as hers? Medullary carcinoma
o Mucinous (colloid) carcinoma
 Soft with the consistency and appearance of pale gray-blue gelatin
 Borders are pushing or circumscribed
 Tumor cells in clusters and small islands of cells within large lakes of mucin
o Tubular carcinoma
 Well-formed tubules, cribriform pattern may be present
 Apocrine snouts, calcifications
 Associated with flat epithelial atypia, atypical lobular hyperplasia, LCIS, or low-grade DCIS
o Apocrine carcinoma
 Cells with enlarged round nuclei, prominent nucleoli and abundant eosinophilic cytoplasm
o Secretory carcinoma
 Mimics lactating breast, forms dilated spaces filled with eosinophilic material
o Micropapillary carcinoma
 No true papillae, hollow balls of cells that float within intercellular fluid
 Anchorage-independent growth: cells are adherent to each other and express E-cadherin but lack adhesion to the stroma
o Papillary carcinoma
 True papillae (fronds of fibrovascular tissue lined by tumor cells)
- Surgical procedures
o Modified radical mastectomy
 Nipple/areolar complex + All breast tissue + Pectoralis minor + Axillary node dissection
 Complications:
 ‘Winged scapula ‘ from damage to the long thoracic nerve
 Lymphedema
o Breast conservation therapy
 Similar survival rate as modified radical mastectomy
 Lumpectomy with microscopically free margins
 Sentinel node biopsy
 Breast irradiation
- Prognostic and Predictive Factors
o Invasive carcinoma v/s Carcinoma in situ
o Distant metastases
o Lymph node metastases
 most important prognostic factor for invasive carcinoma in the absence of distant metastases
o Tumor size, Locally advanced disease
o Inflammatory carcinoma – poor prognosis
o Lymphovascular invasion
o Molecular subtype, Special histologic types
o Histologic grade, Proliferative rate
o Estrogen and Progesterone receptors, HER2
o Ex. A Tumor Registry tracks patients diagnosed with breast cancer. Statistical analyses are performed regarding survival of these patients. Which of the
following parameters recorded for these breast cancers is most likely to show the strongest correlation with longer patient survival? Tumor size
- Male Breast Cancer
o Lifetime risk of 0.11
o Risk factors
 Increasing age (typically 60 to 70 years)
 First-degree relatives with breast cancer
 Exposure to exogenous estrogens or ionizing radiation
 Infertility, obesity, prior benign breast disease
 Klinefelter syndrome
 Germline BRCA2 mutations
o ER positivity is more common (81% of tumors)
o Clinical course and outcomes similar to breast cancer in women
o Ex. An epidemiologic study is conducted with male subjects who have been diagnosed with breast carcinoma. Their demographic data, medical histories,
family histories, and laboratory data are examined to identify factors that increase the risk of cancer. Which of the following factors is most likely to be
associated with the greatest number of male breast carcinomas? Age older than 70 years
- Carcinoma Breast
o DCIS is treated locally, as subsequent invasive carcinomas usually occur at the same site, whereas LCIS confers bilateral risk
o Invasive carcinomas can be classified into molecular types based on expression of hormone receptors and HER2 along with proliferative rate
o Molecular types have important clinical, biologic, and therapeutic associations
o Special histologic types of carcinomas have distinctive pathways of tumorigenesis
o Prognosis is dependent on both the biologic type of cancer (molecular or histologic type) and the extent of cancer at the time of diagnosis (stage)
o Effective treatment requires both local and systemic control of disease