Download SDL 37: Carcinoma of the Breast Objectives Discuss atypical ductal

SDL 37: Carcinoma of the Breast
 Objectives
1. Discuss atypical ductal and lobular hyperplasia: morphology, and clinical significance.
2. Discuss incidence and epidemiology of breast carcinoma
3. Discuss risk factors of breast carcinoma.
4. Describe etiology and pathogenesis of breast carcinoma: contrast hereditary and sporadic breast carcinoma.
5. Discuss principles of the classification of breast carcinoma.
6. Describe carcinoma in situ of the ductal and lobular type: morphology, clinical presentation and natural history.
7. Describe invasive carcinoma: morphologic types and their clinical behavior.
Carcinoma of the Breast
 Carcinoma of the breast is the MOST COMMON non-skin malignancy in women.
 A woman who lives to age 90 has a ONE IN EIGHT CHANCE of developing breast cancer.
 In 2007 an estimated 178,480 women were diagnosed with invasive breast cancer, 62,030 with carcinoma in
situ, and over 40,000 women died of the disease.
 As the "baby boomers" continue to grow older, the number of women with breast cancer is expected to
increase by about a third over the next 20 years.
 Only lung cancer causes more cancer deaths in women living in the United States.
 Breast cancer is a heterogeneous disease with a wide array of histologic appearances.
 Recent GENE PROFILING STUDIES have confirmed that there are many types of cancers but also show that
most carcinomas cluster into several major groups with important biologic and clinical differences.
 The majority of carcinomas are estrogen receptor (ER) positive and are characterized by a gene
signature dominated by the dozens of genes under the control of estrogen.
 Among the ER-negative tumors, many fall into a distinctive "BASAL-LIKE" group.
 Incidence and Epidemiology
 After remaining constant for many years, in the early 80’s the incidence of breast cancer began to increase in
older women.
 This was, in part, due to the introduction of MAMMOGRAPHIC SCREENING.
 The main benefit of screening is the detection of small, invasive carcinomas and in situ carcinomas.
 DCIS is almost exclusively detected by mammography, explaining the sharp increase in the diagnosis
of DCIS since 1980.
 Between 1983 and 1996, small node-negative carcinomas (stage I), which are best detected by mammography,
increased in frequency as the number of large, advanced-stage breast carcinomas (stages II to IV) diminished
modestly
 During the 1980s the number of women dying of breast cancer remained constant, while the incidence of breast
cancer was increasing.
 Since 1994 the breast cancer mortality rate for all women has slowly declined from 30% to 20%.
 This attributed to the detection of clinically significant cancers at a curable stage due to screening, as
well as better and more effective treatment modalities.
 However, the decline in the death rate has been less impressive for African American women, women in
other ethnic groups, and women with ER-negative cancers.
 Risk Factors
 The most important risk factor is gender; only 1% of breast cancer cases occur in men.
 Common risk factors for women identified by epidemiologic studies have been combined into the Breast Cancer
Risk Assessment Tool (BCRAT).
 The BCRAT incorporates the following risk factors:
 Age
 Race and ethnicity
 Age at menarche
 Estrogen exposure
 Age at first live birth
 Breast density
 First degree relatives with breast cancer
 Radiation exposure
 Atypical hyperplasia



Carcinoma of the contralateral breast or
 Exercise
endometrium
 Breastfeeding
Geographic influence
 Environmental toxins
Obesity
 Tobacco
 Age
 THE INCIDENCE RISES THROUGHOUT A WOMAN'S LIFETIME, PEAKING AT THE AGE OF 75-80 YEARS
and then declining slightly thereafter.
 The average age at diagnosis is 61 for white women, 56 for Hispanic women, and 46 for African
American women.
 Breast cancer is very rare in all groups before the age of 25.
 Although carcinoma is uncommon in young women, almost half of these are either ER
negative or human epidermal growth factor receptor 2 (HER2/neu) positive, whereas these
cancers make up less than a third of cancers in women over the age of 40.
 Age at Menarche
 Women who reach menarche when younger than 11 years of age have a 20% increased risk
compared with women who are more than 14 years of age at menarche.
 Late menopause also increases risk.
 Age at First Live Birth
 Women who experience a first full-term pregnancy at ages younger than 20 years have HALF THE
RISK of nulliparous women or women over the age of 35 at their first birth.
 It is hypothesized that pregnancy results in terminal differentiation of milk-producing luminal
cells, removing them from the potential pool of cancer precursors.
 First-Degree Relatives with Breast Cancer
 The risk of breast cancer increases with the number of affected first-degree relatives (mother, sister,
or daughter), especially if the cancer occurred at a young age.
 However, most women do not have a family history.
 Only 13% of women with breast cancer have one affected first-degree relative, and only 1%
have two or more.
 Atypical Hyperplasia
 A history of prior breast biopsies, especially if revealing atypical hyperplasia, increases the risk of
invasive carcinoma.
 There is a smaller increase in risk associated with proliferative breast changes without atypia
 Race/Ethnicity
 Non-Hispanic white women have the highest rates of breast cancer.
 The risk of developing an invasive carcinoma within the next 20 years at age 50 is 1 in 15 for this
group, 1 in 20 for African Americans, 1 in 26 for Asian/Pacific Islanders, and 1 in 27 for Hispanics.
 However, women of African or Hispanic ancestry present at a more advanced stage and have an
increased mortality rate.
 Social factors such as decreased access to health care and lower use of mammography may well
contribute to these disparities, but biologic differences also play a role.
 Estrogen Exposure
 Postmenopausal hormone replacement therapy INCREASES the risk of breast cancer 1.2- to 1.7-fold,
and adding progesterone increases the risk further.
 Drugs that block estrogenic effects (e.g., tamoxifen) or block the formation of estrogen (e.g.,
aromatase inhibitors) DECREASE the risk of ER-positive breast cancer.
 Geographic Influence
 Breast cancer incidence rates in the United States and Europe are four to seven times higher than
those in other countries.
 Diet
 Moderate or heavy alcohol consumption increases risk.
 Higher estrogen levels and lower folate levels may underlie this association.
 Obesity
 There is DECREASED risk in obese women younger than 40 years as a result of the association with
anovulatory cycles and lower progesterone levels late in the cycle.
 The risk is INCREASED for postmenopausal obese women, which is attributed to the synthesis of
estrogens in fat depots.
 Etiology and Pathogenesis
 The major risk factors for the development of breast cancer are hormonal and genetic.
 Breast carcinomas can therefore be divided into SPORADIC CASES, probably related to hormonal exposure,
and HEREDITARY CASES, associated with germline mutations.
1. Hereditary Breast Cancer
 The inheritance of a susceptibility gene or genes is the primary cause of approximately 12% of breast
cancers.
 The probability of a hereditary etiology increases with multiple affected first-degree relatives, when
individuals are affected before menopause and/or have multiple cancers, or there are family members
with other specific cancers.
 Mutations in BRCA1 and BRCA2 account for the majority of cancers attributable to single mutations and
about 3% OF ALL BREAST CANCERS.
 Penetrance (the percentage of carriers who develop breast cancer) varies from 30% to 90% depending
on the specific mutation present.
 Mutations in BRCA1 also markedly increase the risk of developing ovarian carcinoma, which occurs
in as many as 20% to 40% of carriers.
 BRCA2 CONFERS A SMALLER RISK FOR OVARIAN CARCINOMA (10% to 20%) but is associated more
frequently with male breast cancer.
 BRCA1 and BRCA2 carriers are also at higher risk for other epithelial cancers, such as prostatic and
pancreatic carcinomas.

BRCA1 and BRCA2 are both large genes over 80 kilobases in size.
 Hundreds of different mutations distributed throughout the coding regions have been reported for
each.
 THE FREQUENCY OF MUTATIONS THAT INCREASE BREAST CANCER RISK IS ONLY 0.1% TO 0.2% IN
THE GENERAL POPULATION.
 As a result, genetic testing is difficult and generally restricted to individuals with a strong
family history or those belonging to certain ethnic groups, eg, 2% to 3% of people of
Ashkenazi Jewish descent carry one of three specific mutations, two in BRCA1 and one in
BRCA2.
 Identification of carriers is important, since increased surveillance, prophylactic
mastectomy, and oophorectomy can reduce cancer-related morbidity and mortality.
 The major susceptibility genes for breast cancer are tumor suppressors that have normal roles in DNA
repair, cell cycle control, and the regulation of apoptosis in many tissues.
 The known high-risk breast cancer genes account for only about one quarter of FAMILIAL breast cancers.
 The search for an additional high-risk gene has been unsuccessful, and other highly penetrant
genes may not exist.
 Thus, it is likely that the remaining familial cancers are caused by multiple genes with weak
effects.
2. Sporadic Breast Cancer
 The majority of sporadic cancers occur in POSTMENOPAUSAL WOMEN and are ER POSITIVE.
 The major risk factors for sporadic breast cancer are related to hormone exposure (estrogen excess
/hormonal imbalance ): including gender, age at menarche and menopause, reproductive history,
breastfeeding, and exogenous estrogens.
 Hormonal exposure increases the number of potential target cells by stimulating breast growth during
puberty, menstrual cycles, and pregnancy.
 Exposure also drives cycles of proliferation that place cells at risk for DNA damage.
 Once premalignant or malignant cells are present, hormones can stimulate their growth, as well as the
growth of normal epithelial and stromal cells that may also be involved in tumor development.
 Carcinogenesis and Tumor Progression
 One model of carcinogenesis postulates that a normal cell must acquire several new capabilities to become
malignant.
 Each may be achieved by a change in the activity of one of many different genes that regulate common
cellular activities.
 POPULATIONS OF CELLS THAT HARBOR SOME, BUT NOT ALL, OF THE GENETIC AND EPIGENETIC
CHANGES THAT ARE REQUIRED FOR CARCINOGENESIS GIVE RISE TO MORPHOLOGICALLY RECOGNIZABLE
BREAST LESIONS THAT ARE ASSOCIATED WITH AN INCREASED RISK OF PROGRESSION TO CANCER.
 The earliest such alterations are proliferative changes, which may stem from the loss of growthinhibiting signals, aberrant increases in pro-growth signals, or decreased apoptosis.
 eg, most early lesions (such as ATYPICAL DUCTAL HYPERPLASIA AND ATYPICAL LOBULAR
HYPERPLASIA) show increased expression of hormone receptors and abnormal regulation of
proliferation.
 The "cancer stem cell hypothesis" proposes that malignant changes occur in a stem cell population that has
unique properties distinguishing them from more differentiated cells.
 The most likely cell type of origin for the majority of carcinomas is the ER-EXPRESSING LUMINAL CELL, since
the majority of cancers are ER-positive and precursor lesions, such as atypical hyperplasias, are most similar
to this type of cell.
 ER-negative carcinomas may arise from ER-NEGATIVE MYOEPITHELIAL CELLS.
 This would explain why many proteins found in myoepithelial cells are shared by the "triple-negative" or
basal-like cancers.

Proposed precursor-carcinoma sequences in breast cancer. Morphologic changes are displayed from left to
right according to the risk for subsequent invasive carcinoma.
 The final step of carcinogenesis, THE TRANSITION OF CARCINOMA IN SITU TO INVASIVE CARCINOMA (red
arrows), is the most important and least understood.
 Genetic markers specific for invasive carcinomas have been difficult to identify.
 Classification of Breast Carcinoma
 Greater than 95% of breast malignancies are adenocarcinomas, which are divided into IN SITU CARCINOMAS and
INVASIVE CARCINOMAS.
 Carcinoma in situ refers to a neoplastic proliferation that is limited to ducts and lobules by the basement
membrane.
 Invasive carcinoma (synonymous with "INFILTRATING" carcinoma) has penetrated through the basement
membrane into stroma.
 The cells have the potential to invade into the vasculature and thereby reach regional lymph nodes and
distant sites.
 DESPITE EVIDENCE THAT ALL BREAST CARCINOMAS ARISE FROM CELLS IN THE TERMINAL DUCT LOBULAR UNIT,
THE USE OF THE TERMS LOBULAR AND DUCTAL TO DESCRIBE BOTH IN SITU AND INVASIVE CARCINOMAS
PERSISTS.
 Carcinoma in situ was originally classified as ductal or lobular based on the resemblance of the involved
spaces to normal ducts or lobules.
 It is now recognized that varied patterns of growth in situ are not related to the site of origin, but reflect
differences in tumor cell biology, such as whether the tumor cells express the cell adhesion protein ECADHERIN or not.
 By current convention, "lobular" refers to carcinomas of a specific type, and "ductal" is used more
generally for adenocarcinomas that have no other designation.
Carcinoma in Situ
 Ductal Carcinoma in Situ (DCIS; Intraductal Carcinoma)
 With the advent of mammographic screening, the diagnosis of DCIS rapidly increased from fewer than 5% of all
carcinomas to 15% to 30% of carcinomas in well-screened populations.
 Among cancers detected mammographically, almost half are DCIS.
 Most are detected as a result of CALCIFICATIONS
 Less commonly, periductal fibrosis surrounding DCIS forms a MAMMOGRAPHIC DENSITY OR A VAGUELY
PALPABLE MASS.
 Rarely, DCIS (often of micropapillary type) produces a NIPPLE DISCHARGE or is detected as AN
INCIDENTAL FINDING upon biopsy for another lesion.
 DCIS CONSISTS OF A MALIGNANT CLONAL POPULATION OF CELLS LIMITED TO DUCTS AND LOBULES BY THE
BASEMENT MEMBRANE.
 The myoepithelial cells are preserved, although they may be diminished in number.
 DCIS can spread throughout ducts and lobules and produce extensive lesions involving an entire sector of a
breast.
 Morphology of Ductal Carcinoma in Situ (DCIS; Intraductal Carcinoma)
 Historically, DCIS has been divided into FIVE ARCHITECTURAL SUBTYPES:
1. comedocarcinoma
2. solid
3. cribriform
4. papillary
5. micropapillary
 Some cases of DCIS have a single growth pattern, but THE MAJORITY SHOW A MIXTURE OF PATTERNS.
 Comedocarcinoma
 CHARACTERIZED BY THE PRESENCE OF SOLID SHEETS OF PLEOMORPHIC CELLS WITH "HIGH-GRADE"
HYPERCHROMATIC NUCLEI AND AREAS OF CENTRAL NECROSIS.
 The necrotic cell membranes commonly calcify and are detected on mammography as clusters or linear
and branching MICROCALCIFICATIONS.
 Periductal concentric fibrosis and chronic inflammation are common, and extensive lesions are
sometimes palpable as an area of vague nodularity.
Ductal carcinoma in situ (DCIS) comedo
type. A, The specimen radiogram reveals
linear and branching calcifications within
the ductal system. B, Ducts filled with
punctate areas of necrosis ("comedone"
like) and surrounded by periductal fibrosis
are seen. C, DCIS with large central zones of
necrosis and calcifications fills several
adjacent ducts.

Noncomedo DCIS
 CONSISTS OF A MONOMORPHIC POPULATION OF CELLS WITH NUCLEAR GRADES RANGING FROM LOW
TO HIGH.
 Several morphologic variants can be seen.
 Cribriform DCIS, has intraepithelial spaces are evenly distributed and regular in shape (cookie cutterlike).
 Solid DCIS completely fills the involved spaces .
 Papillary DCIS grows into spaces along fibrovascular cores that typically lack the normal
myoepithelial cell layer.
 Micropapillary DCIS is recognized by bulbous protrusions withOUT a fibrovascular core, often
arranged in complex intraductal patterns .
Noncomedo DCIS. A, Cribriform DCIS composed of cells forming round, regular ("cookie cutter") spaces. The lumens
are filled with calcifying secretory material. B, This solid DCIS has almost completely filled and distorted this lobule
with only a few remaining normal luminal cells visible. This type of DCIS is not usually associated with calcifications
and may be clinically occult.
Noncomedo DCIS. A, Papillary DCIS. Delicate fibrovascular cores extend into a duct and are lined by a monomorphic
population of tall columnar cells. Myoepithelial cells are absent. B, Micropapillary DCIS. The papillae are connected
to the duct wall by a narrow base and often have bulbous or complex outgrowths. The papillae are solid and lack
fibrovascular cores.
 DCIS - Paget Disease of the Nipple
 A rare manifestation of breast cancer (1% to 4% of cases) that presents as a unilateral erythematous
eruption with a scale crust.
 Pruritus is common, and the lesion may be mistaken for eczema.
 Malignant cells (Paget cells) extend from DCIS within the ductal system, via the lactiferous sinuses, into
nipple skin without crossing the basement membrane.
 The tumor cells disrupt the normal epithelial barrier, allowing extracellular fluid to seep out onto the nipple
surface.
 The Paget cells are readily detected by nipple biopsy or cytologic preparations of the exudate.
 A palpable mass is present in 50% to 60% of women with Paget disease, and almost all of these women have
an underlying invasive carcinoma.
 In contrast, the majority of women without a palpable mass have only DCIS.
 The carcinomas are usually poorly differentiated, ER negative, and overexpress HER2/neu.
 Prognosis of Paget disease depends on the features of the underlying carcinoma.
 DCIS with Microinvasion
 This is diagnosed when there is an area of invasion through the basement membrane into stroma measuring
NO MORE THAN 0.1 CM.
 MICROINVASION IS MOST COMMONLY SEEN IN ASSOCIATION WITH COMEDOCARCINOMA.
 If only one or a few foci of microinvasion are present, the prognosis is very similar to DCIS.
 DCIS
 The natural history of DCIS has been difficult to determine because, until recently, all women were treated
with mastectomy, and the current practice of surgical excision, usually followed by radiation, is largely
curative.
 If untreated, women with small, low-grade DCIS develop invasive cancer at a rate of about 1% per year.
 It is assumed that women with high-grade or extensive DCIS progress to invasive carcinoma at higher
rates.
 Mastectomy for DCIS is curative for over 95% of patients.
 Breast conservation is appropriate for most women with DCIS but results in a slightly higher risk of
recurrence.
 THE MAJOR RISK FACTORS FOR RECURRENCE ARE (1) GRADE, (2) SIZE, AND (3) MARGINS.
 If wide margins (i.e., at least 1 cm) can be achieved, the rate of recurrence is quite low.
 Complete excision of DCIS presents a challenge, since its extent can only be reliably predicted by
pathologic evaluation.
 Postoperative radiation therapy and tamoxifen also reduce the risk of recurrence.
 WHATEVER THE TREATMENT, DEATHS FROM BREAST CANCER ARE VERY UNCOMMON, OCCURRING IN
FEWER THAN 2% OF WOMEN WITH DCIS.
 Lobular Carcinoma in Situ (LCIS)
 LCIS is always an incidental biopsy finding, since it is not associated with calcifications or stromal reactions that
produce mammographic densities.
 Thus, its incidence (1% to 6% of all carcinomas) has not been affected by the introduction of mammographic
screening.
 When both breasts are biopsied, LCIS is BILATERAL in 20% to 40% of cases, compared with 10% to 20% of cases
of DCIS.
 LCIS is more common in young women, with 80% to 90% of cases occurring before menopause.
 The cells of LCIS and invasive lobular carcinoma are identical in appearance and share genetic abnormalities,
such as those that lead to LOSS OF EXPRESSION OF E-CADHERIN, a transmembrane cell adhesion protein that
contributes to the cohesion of normal breast epithelial cells.
 Morphology
 Atypical lobular hyperplasia, LCIS, and invasive lobular carcinoma all consist of dyscohesive cells with oval or
round nuclei and small nucleoli.
 THE CELLS LACK THE CELL ADHESION PROTEIN E-CADHERIN, resulting in the cells appearing rounded
without attachment to adjacent cells.
 Mucin-positive signet-ring cells are commonly present.
 LCIS rarely distorts the underlying architecture, and the involved acini remain recognizable as lobules.
 LCIS almost always expresses ER and PR.
 Overexpression of HER2/neu is not observed.
Lobular carcinoma in situ. A, A monomorphic population of small, rounded, loosely cohesive cells fills and
expands the acini of a lobule. The underlying lobular architecture can still be recognized. The cells extend
into the adjacent lobule by pagetoid spread. B, An immunoperoxidase study shows E-cadherin-positive
normal luminal cells that have been undermined by E-cadherin-negative LCIS cells spreading along the
basement membrane.
 Women with LCIS develop invasive carcinomas at a frequency similar to that of women with DCIS.
 Although BOTH breasts are at increased risk, the risk is slightly higher in the ipsilateral breast.
 Invasive carcinomas developing in women after a diagnosis of LCIS are threefold more likely to be of the
lobular type, but the majority do not show specific lobular morphology.
 Treatment choices include bilateral prophylactic mastectomy, tamoxifen, or, more typically, close clinical followup and mammographic screening.
Invasive (Infiltrating) Carcinoma
 Invasive (Infiltrating) Carcinoma Presentation
 IN THE ABSENCE OF MAMMOGRAPHIC SCREENING, INVASIVE CARCINOMA ALMOST ALWAYS PRESENTS AS A
PALPABLE MASS.
 Palpable tumors are associated with axillary lymph node metastases in over 50% of patients.
 Larger carcinomas may be fixed to the chest wall or cause dimpling of the skin.
 When the tumor involves the central portion of the breast, retraction of the nipple may develop.
 Lymphatics may become so involved as to block the local area of skin drainage and cause lymphedema and
thickening of the skin.
 Here, tethering of the skin to the breast by Cooper ligaments mimics the appearance of an orange peel,
an appearance referred to as PEAU D'ORANGE.
 IN OLDER WOMEN UNDERGOING MAMMOGRAPHY, invasive carcinomas MOST COMMONly present as a
radiodense mass.
 Mammographically detected cancers are, on average, half the size of palpable cancers.
 Fewer than 20% will have nodal metastases.
 Invasive carcinomas presenting as mammographic calcifications without an associated density are very small in
size, and metastases are unusual.
 Invasive (Infiltrating) Carcinoma Types:
1. Invasive Carcinoma, No Special Type (NST; Invasive Ductal Carcinoma)
 Comprise the majority of infiltrating carcinomas (70-80%).
 On gross examination, most tumors are firm to hard and have an irregular border.
 The hard, gray to white areas correspond to DESMOPLASTIC STROMAL RESPONSE, where there is associated
fibrosis.
 These areas are sometimes described as “SCIRRHOUS”, derived from the Greek word for “hard”.
 Invasive (Infiltrating) Ductal Carcinoma - Morphology
 There is a wide range of histologic appearances.
 Well-differentiated carcinomas show prominent tubule formation, small round nuclei, and rare mitotic
figures.
 Moderately differentiated carcinomas may have tubules, but solid clusters or single infiltrating cells are also
present.
 These tumors have a greater degree of nuclear pleomorphism and contain mitotic figures.
 Poorly differentiated carcinomas often invade as ragged nests or solid sheets of cells with enlarged irregular
nuclei.
 A high proliferation rate and areas of tumor necrosis are common.
 Recently developed techniques that examine the DNA, RNA, and proteins of carcinomas globally have provided
a framework for NEW MOLECULAR CLASSIFICATIONS for infiltrating ductal carcinomas.
 Gene expression profiling, which can measure the relative quantities of mRNA for essentially every gene, has
identified five major patterns of gene expression in the “invasive carcinoma, NST” group:
A. Luminal A
B. Luminal B
C. Normal
D. Basal-like
E. HER2 positive
 These molecular classes correlate with prognosis and response to therapy, and thus have taken on clinical
importance.
A. "Luminal A" (40% to 55% of NST cancers):
 This is the largest group and consists of cancers that are ER positive and HER2/neu negative.
 THE GENE SIGNATURE IS DOMINATED BY THE DOZENS OF GENES UNDER THE CONTROL OF ER.
 These show increased transcription of genes thought to be characteristic of normal luminal cells.
 The majority are well- or moderately differentiated, and most occur in postmenopausal women.
 These cancers are generally slow growing and respond well to hormonal treatments.
 Conversely, only a small number will respond to standard chemotherapy.
B. "Luminal B" (15 - 20% of NST cancers):
 This group of cancers also expresses ER but is generally of higher grade, has a higher proliferative rate,
and often overexpresses HER2/neu.
 They compose a major group of ER-positive cancers that are more likely to have lymph node
metastases, and that may respond to chemotherapy.
C. “Normal breast-like" (6 -10% of NST cancers):
 This is a small group of usually well-differentiated ER-positive, HER2/neu-negative cancers characterized
by the similarity of their gene expression pattern to normal tissue.
 It is not yet clear whether or not this is a specific tumor expression pattern.
D. "Basal-like" (13% to 25% of NST cancers):
 THESE CANCERS ARE NOTABLE FOR THE ABSENCE OF ER, PR, AND HER2/NEU (TRIPLE-NEGATIVE) AND
THE EXPRESSION OF MARKERS TYPICAL OF MYOEPITHELIAL CELLS (e.g., basal keratins, P-cadherin, p63,
or laminin), progenitor cells, or putative stem cells (e.g., cytokeratins 5 and 6).
 Members of this group include MEDULLARY CARCINOMAS, METAPLASTIC CARCINOMAS (E.G., SPINDLE
CELL CARCINOMAS OR MATRIX-PRODUCING CARCINOMAS), AND CARCINOMAS WITH A CENTRAL
FIBROTIC FOCUS.
 Many carcinomas arising in women with BRCA1 mutations are of this type.
 There is also an increased incidence in certain ethnic populations and in young women.
 These cancers are generally high grade, associated with an aggressive course, and a poor prognosis.
E. HER2 positive (7% to 12% of NST cancers):
 THIS GROUP COMPRISES ER-NEGATIVE CARCINOMAS THAT OVEREXPRESS HER2/NEU PROTEIN.
 In over 90% of HER2/neu positive cancers, overexpression is due to amplification of the segment of
DNA on 17q21 that includes the HER2/NEU gene and varying numbers of adjacent genes.
 These cancers are usually poorly differentiated, have a high proliferation rate, and are associated with a
high frequency of brain metastasis.
2. Invasive Lobular Carcinomas:
 Usually present as a palpable mass or a mammographic density with irregular borders.
 In about one fourth of cases the tumor infiltrates the tissue diffusely and causes little desmoplasia.
 Such tumors are difficult to detect by palpation and may cause only very subtle mammographic
changes.
 Metastases can also be difficult to detect clinically and radiologically because of this type of
invasion.
 Historically, lobular carcinomas have been reported to have a greater incidence of bilaterality.
 The actual fraction of women who develop invasive carcinomas in the contralateral breast is only 5% to
10%, similar to the incidence for NST carcinomas.
 Morphology
 The histologic hallmark is the presence of dyscohesive infiltrating tumor cells, often arranged in SINGLE
(“INDIAN”) FILE or in loose clusters or sheets.
 Tubule formation is absent.
 The cytologic appearance is identical to the cells of atypical lobular hyperplasia and LCIS.
 Signet-ring cells containing an intracytoplasmic mucin droplet are common.
 Desmoplasia may be minimal or absent.
 LOBULAR CARCINOMAS HAVE A DIFFERENT PATTERN OF METASTASIS THAN OTHER BREAST CANCERS.
 Metastasis tends to occur to the peritoneum and retroperitoneum, the leptomeninges (carcinoma
meningitis), the gastrointestinal tract, and the ovaries and uterus.
 In some cases, metastatic lobular carcinoma may be mistaken for signet ring carcinoma of the GI
tract, which it closely resembles.
 The morphologic resemblance of these two tumors reflects a common underlying molecular
etiology, as both are characterized by the loss of E-cadherin.
3. Medullary Carcinoma
 MOST COMMON in women in the sixth decade and presents as a WELL-CIRCUMSCRIBED MASS.
 It may closely mimic a benign lesion clinically and radiologically, or present as a rapidly growing mass.
 Medullary carcinomas have a SLIGHTLY BETTER PROGNOSIS than do NST carcinomas, despite the almost
universal presence of poor prognostic factors.
 Lymph node metastases are infrequent and rarely involve multiple nodes.
 Medullary carcinomas have a BASAL-LIKE gene expression profile.
 Among cancers arising in BRCA1 carriers, 13% are of medullary type, and up to 60% have a subset of
medullary features.
 Morphology
 These tumors produce little desmoplasia and are distinctly softer on palpation than typical breast
carcinomas.
 The tumor is soft, fleshy (MEDULLA is Latin for "marrow"), and well circumscribed.
 Histologically characterized by:
 SOLID, SYNCYTIUM-LIKE SHEETS OF LARGE CELLS with vesicular, pleomorphic nuclei, and prominent
nucleoli, which compose more than 75% of the tumor mass.
 FREQUENT MITOTIC FIGURES.
 A MODERATE TO MARKED LYMPHOPLASMACYTIC INFILTRATE surrounding and within the tumor.
 A PUSHING (NONINFILTRATIVE) BORDER.
4. Mucinous (Colloid) Carcinoma
 These carcinomas occur in OLDER WOMEN (median age 71) and tend to grow slowly over the course of
many years.
 Lymph node metastases are uncommon.
 The overall prognosis is slightly better than that of NST carcinomas.
 Morphology
 The tumor is soft or rubbery and has the consistency and appearance of pale gray-blue gelatin.
 The borders are pushing or circumscribed.
 The tumor cells are arranged in clusters and small islands of cells within large lakes of mucin.
5. Tubular Carcinoma
 These are typically detected as small irregular mammographic densities in women in their late 40s.
 They are uncommon, but constitute up to 10% of tumors that are smaller than 1 cm in size.
 More than 95% of all tubular carcinomas are ER positive, and HER2/neu negative.
 Axillary metastases occur in fewer than 10% of cases unless multiple foci of invasion are present.
 This subtype is important to recognize because of its excellent prognosis.
 Morphology
 These tumors consist exclusively of well-formed tubules and are sometimes mistaken for benign
sclerosing lesions.
 However, the myoepithelial cell layer is absent, placing the tumor cells in direct contact with the
stroma.
6. Invasive Papillary Carcinoma
 Invasive papillary carcinomas are rare, representing 1% or fewer of all invasive cancers.
 Invasive papillary carcinomas are usually ER positive and have a favorable prognosis.
7. Metaplastic Carcinoma
 "Metaplastic carcinoma" includes a variety of rare types of breast cancer (<1% of all cases), such as matrixproducing carcinomas, squamous cell carcinomas, and carcinomas with a prominent spindle cell component.
 They are ER-PR-HER2/neu "triple negative," often express myoepithelial proteins, and appear to be related
to the basal-like carcinomas.
 The prognosis is generally poor.
 Prognostic and Predictive Factors
 The outcome for women with breast cancer varies widely.
 Except in women who present with distant metastasis (<10%) or with inflammatory carcinoma (<5%) (in whom
the prognosis is poor regardless of other findings), prognosis is determined by the pathologic examination of the
primary carcinoma and the axillary lymph nodes.
 The major prognostic factors are as follows:
1. Invasive carcinoma vs. in situ disease
2. Distant metastases
3. Lymph node metastases
4. Tumor size
5. Locally advanced disease
6. Inflammatory carcinoma
 Minor prognostic factors include :
1. Histologic subtype
2. Histologic grade
3. Estrogen and progesterone receptors –
 Current assays use immunohistochemistry to detect nuclear hormone receptors, a finding that is
correlated with a better outcome and is an important predictor of response to hormonal therapy(eg.
TAMOXIFEN, WHICH BLOCKS ER RECEPTORS).
 Eighty percent of carcinomas that are ER and PR positive respond to hormonal manipulation,
whereas only about 40% of those with either ER or PR alone respond.
4. Her2/neu
 HER2/neu overexpression is associated with poorer survival.
 ITS MAIN IMPORTANCE IS AS A PREDICTOR OF RESPONSE TO AGENTS THAT TARGET THIS
TRANSMEMBRANE PROTEIN (E.G., TRASTUZUMAB ).
5. Lympho-vascular invasion
6. Proliferative rate
 Proliferation can be measured eg, by mitotic counts.
 Breast Cancer Staging