Breast Cancer Pathology

Question 1

What is the largest category of breast cancer?

Answer 1

Carcinoma, by far (more than 95%)

Question 2

In situ carcinoma

Answer 2

Limited by basement membrane of ducts and lobules

Cannot metastasize (if unassociated with invasive carcinoma)

Ductal carcinoma in situ (DCIS)
Paget’s disease of the nipple
Lobular carcinoma in situ (LCIS)
Atypical hyperplasia

Question 3

Ductal carcinoma in situ (DCIS)

Answer 3

In situ carcinoma

Clonal proliferation of epithelial cells within the ducts leaving the myoepithelial layer and basement membrane intact

Typical clinical presentation is as calcifications seen on mammography. Generally asymptomatic and nonpalpable.

Graded into three categories based on nuclear size, pleomorphism, quantity of mitoses and presence of necrosis

Five classic histologic patterns include comedo, solid, cribriform (punched-out holes), papillary (large projections into the lumen) and micropapillary (small projections into the lumen)

Comedo pattern contains central necrosis and is always high grade, other types range from low to high grade

Low grades often express hormonal receptors (estrogen and progesterone), high grades often overexpress Her2/neu

DCIS is associated with a significant risk of developing invasive carcinoma

Surgical excision (+/- other therapies) is curative in the vast majority of cases of tumors consisting purely of DCIS

Risk factors for recurrence of DCIS include (1) histologic grade, (2) extent of breast involvement (size of DCIS), (3) if the DCIS is completely excised (if the margins are negative for DCIS)

Question 4

Atypical hyperplasia

Answer 4

In situ carcinoma

Technically not yet a carcinoma, but has some histologic features of in situ carcinoma

Can resemble DCIS, termed atypical ductal hyperplasia (ADH)

Can resemble LCIS, termed atypical lobular hyperplasia (ALH)

“cellular proliferation resembling carcinoma in situ but lacking sufficient qualitative or quantitative features for diagnosis as carcinoma.”

Carries approximately a 5-fold relative risk of developing invasive carcinoma, compared to hyperplasia without atypia (proliferative disease), which carries approximately a 2-fold risk of developing invasive carcinoma

Question 5

Invasive carcinoma

Answer 5

Commonly present as a palpable mass or as a mammographic abnormality

Uncommon presentations include an enlarged erythematous breast (termed “inflammatory carcinoma”) or as metastatic disease (typically an axillary lymph node)

Advanced lesions fix the mass to the underlying chest wall and cause dimpling of the overlying skin

Carcinoma most commonly occurs in the upper outer quadrant; these tumors spread first to axillary lymph nodes. When tumors occur in the inner quadrant they preferentially spread to the internal mammary lymph nodes.

Inflammatory carcinoma results from diffuse involvement of dermal lymphatics and is ultimately a clinical diagnosis; though, the histologic correlate of either empty dilated lymphatic channels or carcinoma involving lymphatic channels may be seen. Inflammation is not a feature. This diagnosis carries a poor prognosis.

Numerous histologic types of invasive breast carcinoma; most important:

Invasive ductal carcinoma (No special type)
Invasive lobular carcinoma (ILC)
Tubular carcinoma
Mucinous (colloid) carcinoma
Medullary carcinoma
Inflammatory carcinoma (Not a morphologic subtype)

Question 6

Invasive ductal carcinoma (No special type)

Answer 6

The majority of carcinomas fall in to this category and do not demonstrate specific features for one of the other types

These have a range of histologic appearances that depend on the degree of differentiation

Well-differentiated tumors contain well-formed ducts with relatively bland appearing cells infiltrating a dense fibrous stroma

Poorly-differentiated tumors have either poorly formed ducts or no duct formation in which case they are composed of irregular groupings of markedly atypical appearing cells

Invasive tumors are often associated with DCIS and the grade of the DCIS tends to correlate with the grade of invasive tumor

The expression of hormone receptors (Estrogen and Progesterone) also correlates with the degree of differentiation. Hormone receptors are typically expressed in well-differentiated lesions and less often in poorly-differentiated lesions.

Poorly differentiated tumors also tend to overexpress the epidermal growth factor receptor HER2/neu more frequently, whereas well-differentiated tumors infrequently do so.

Molecular studies (gene expression profiling) have further subdivided this “no special type” group into subgroups. (ER, PR and HER2/neu expression)

Question 7

Well-differentiated vs poorly-differentiated invasive ductal carcinoma

Answer 7

Well differentiated: often expresses hormone receptors

Poorly-differentiated: overexpress the epidermal growth factor receptor HER2/neu more frequently

Question 8

What are the 5 subgroups of invasive ductile carcinoma

Answer 8

Luminal A: Largest group. ER positive, HER2 negative, low proliferation. (40-55% of breast cancers). Majority of cancers in older women and men.

Luminal B: ER positive, HER2 positive, high proliferation. (approx. 10% of breast cancers). Most common type associated with BRCA2.

Normal breast-like: ER positive, HER2 negative just like “luminal A,” but their gene expression more closely resembles normal breast tissue

Basal like: ER and HER2 negative. (approx. 15% of cancers) Gene expression profile does not resemble epithelial cells, but more closely resembles myoepithelial cells and stem cells. More common in younger women and non-white women. Most common type associated with BRCA1

HER2 positive: HER2 positive ER negative or ER low positive expression. (Approximately 20% of cancers). More common in younger women and non-white women. Most common type associated with TP53 mutation (Li-Fraumeni).

Question 9

Invasive lobular carcinoma (ILC)

Answer 9

Second most common histologic type

Characteristically these tumors have lost the function or expression of key cell-cell adhesion molecules, most notably e-cadherin

The cells have a similar appearance as LCIS cells and are frequently associated with LCIS

Classic appearance is of individual tumor cells, sometimes in single file rows, infiltrating the stroma

Generally express hormone receptors and negative for HER2/neu overexpression

If matched by both histologic grade and stage (extent of tumor spread) ILC has the same prognosis as invasive ductal carcinoma

Question 10

Where does ILC tend to metastasize compared to invasive ductal carcinoma?

Answer 10

ILC tends to metastasize more frequently to CSF, G.I. tract, ovaries/uterus and peritoneum and less frequently to the lungs and pleura than ductal carcinomas

Question 11

Tubular carcinoma

Answer 11

Characteristically present in the 5th decade

Very well differentiated tumor composed of well-formed tubules and relatively bland appearing cells (compared to other carcinomas) with low nuclear grade

Almost all express hormone receptors and usually do not demonstrate HER2/neu overexpression

Has an excellent prognosis

“Cribriform carcinoma” is a similar subtype that forms cribriform spaces in additional to well-formed tubules; this is often considered together with tubular carcinoma

Question 12

Mucinous (colloid) carcinoma

Answer 12

Often presents as a well-circumscribed mass (mimicking a benign lesion) in relatively older age groups

Has a striking histologic appearance with small islands of tumor cells floating in pale-blue lakes of mucin

Tumors usually express hormone receptors

More frequent in patients with BRCA1 mutation

Question 13

Medullary carcinoma

Answer 13

Often presents as a well circumscribed mass (mimicking a benign lesion)

Histologically the tumor is composed of solid sheets of enlarged cells with high-grade nuclei and frequent mitoses; marked associated inflammation; and a pushing, rounded border

Typically negative for hormone receptors and does NOT overexpress Her2/Neu (referred to as a “triple negative” pattern)

More frequent in patients with BRCA1 mutation

Despite the ominous appearance of the cells, these tumors do NOT have a worse prognosis then typical invasive ductal carcinomas, in fact these patients do slightly better

Question 14

Inflammatory carcinoma

Answer 14

(Not a morphologic subtype)

Clinical subtype that presents with breast erythema and swelling of breast

Histologic correlation is extensive dermal lymphatic invasion

The underlying carcinoma is typically high grade and may belong to any of the molecular subtypes

Question 15

Sarcoma of breast

Answer 15

Rare primary tumors of the breast

Can have similar types of mesenchymally derived tumors as may arise in most organ systems (angiosarcoma, rhabdomyosarcoma, liposarcoma, etc.)

Tumors derived from blood vessels, angiosarcoma and lymphangiosarcoma, are among the most common primary breast sarcomas. These can arise (1) spontaneously, (2) following radiation therapy and (3) in the setting of chronic edema (Stewart-Treves syndrome)

Question 16

Lymphoma of breast

Answer 16

Uncommon

May occur as primary breast lesions or disseminated disease may secondarily involve the breast

Most commonly patients present with a palpable mass or masses

Of primary lesions, non-Hodgkin lymphomas (NHLs) are the most frequent, of these, Diffuse large B-cell lymphomas are the most common

Question 17

Mixed (Biphasic) tumors of breast

Answer 17

This category includes fibroadenoma (benign) and phyllodes tumors, both are composed of stromal and epithelial components and both arise from the stroma immediately surrounding the breast lobules (intralobular stroma)

Phyllodes tumors are composed of stromal growths covered by epithelium often forming a leaf-like appearance (“phyllo” Greek for “leaf”)

Phyllodes tumors are distinguished from fibroadenomas by mitotic rate, overgrowth of the stromal component and infiltrative boarders

Phyllodes tumors vary from low-grade lesions that may recur but do not typically metastasize to high-grade lesions that resemble sarcomas. Only the stromal component is prone to metastasize, not the epithelial component

Question 18

Staging of breast carcinoma

Answer 18

Stage 0: DCIS or LCIS

Stage I: Invasive carcinoma ≤2cm, minimal lymph node involvement (≤2mm)

Stage II: Invasive carcinoma ≤5cm with ≤3 involved lymph nodes or invasive carcinoma >5cm without lymph node involvement

Stage III: Invasive carcinoma ≤5cm with >3 involved lymph nodes or >5cm with lymph node involvement or any size invasive carcinoma with ≥10 lymph nodes involved or any size invasive carcinoma with involvement of ipsalateral internal mammary lymph nodes or any size invasive carcinoma with skin involvement, chest wall fixation or clinical inflammatory carcinoma

Stage IV: Any breast carcinoma with distant metastasis

Question 19

Major prognostic factors

Answer 19

Lymph node metastasis. In the absence of distant metastases, this is the most important factor. This is now typically assessed by performing a sentinel lymph node biopsy where the lymph nodes most likely to be involved are removed and examined.

Tumor size. Second most important factor. Size has prognostic significance independent from lymph node status

Presence of invasion. Nearly all women with treated in situ disease will be cured

Distant metastases. Makes cure unlikely

Locally advance disease. Tumor invading skin or skeletal muscle has poor prognosis.

Inflammatory carcinoma. A clinical diagnosis associated with poor prognosis

Question 20

Minor prognostic factors

Answer 20

1. Hormone receptor expression. Tumors that express estrogen and progesterone receptors have a better prognosis and are more likely to respond to therapy directed at these hormonal receptors. The pathologist can perform an immunohistochemical study on tissue sections of tumor to evaluate for hormone expression.
2. HER2/neu overexpression. This is a transmembrane molecule involved with cell growth. Overexpression is associated with a poor prognosis. Also, therapies (trastuzumab, Herceptin) directed against this molecule work better if it is being overexpressed. The degree of expression can be determined with immunohistochemical studies or Florescence In Situ Hybridization (FISH).
3. Histologic type. Tubular, mucinous and medullary carcinoma all have better prognosis than invasive ductal carcinoma (no special type).
4. Histologic grade. This is the degree of differentiation and it correlates with survival. Current grading systems use three histologic features:
   • Amount of tubule formation (1-3 points)
   • Mitotic rate (1-3 points)
   • Degree of nuclear atypia (1-3 points)
   • Add points to arrive at a combined score: 3-5 points = Grade I (well-differentiated), 6-7 points = Grade II (moderately-differentiated), 8-9 points = Grade III (poorly-differentiated)
5. Lymphovascular invasion. Associated with lymph node involvement.
6. Proliferative rate. Higher proliferation associated with a worse prognosis.
7. Gene expression profiling. Can predict survival and responsiveness to specific therapies.

Question 21

Epidemiology of breast cancer

Answer 21

If skin cancers are excluded, breast cancer is the most common malignancy in women and the second most common cause of cancer-related death.

The lifetime risk of developing breast cancer in the U.S. is 1 in 8 women

Approximately 1/5 women with breast cancer will die of the disease by 10 years (all stages combined)

Question 22

Risk factors for breast cancer

Answer 22

1. Age. The risk increases throughout life.
2. Age at menarche. A young age of menarche is associated with an increased risk.
3. Age at menopause. Late menopause is associated with an increased risk.
4. Age at first live birth. Having a child earlier in life is associated with a decreased risk.
5. Family history (1st degree relatives). Risk increases with the number of affected 1st degree relatives
6. Prior biopsies. Results from prior biopsies may suggest an increased risk
7. Race. Caucasian>African American>Asian/Pacific Islanders>Latina. Note that although Caucasians have a higher incidence than African Americans; however African Americans have the highest mortality.
8. Estrogen exposure. Postmenopausal hormone replacement increases the risk. Oophorectomy decreases risk.
9. Radiation exposure. Not likely significant at mammography levels, but at high levels used to treat for another malignancy or other exposure (bomb) increases the risk
10. Cancer of opposite breast/endometrium. Associated with an increased risk. Relationship may be associated with hormone exposure which is associated with both breast and endometrial carcinomas
11. Obesity. Risk is decreased in young (younger than 40) obese women (related to anovulatory cycles and altered hormone exposure). Risk is increased in obese postmenopausal women (related to hormone synthesis by adipose tissue)
12. Breast-feeding. The longer women breast feed, the lower the risk of cancer

Question 23

Hereditary breast cancer

Answer 23

Approximately 12% or breast cancers occur due to inheritance of an identifiable gene or genes

80%-90% of cases of “single gene” familial breast cancer are attributed to BRCA1 and BRCA2 ( but only 3% of all breast cancers)

1. Both are tumor suppressor genes, thus loss of function is responsible for progression to cancer
2. Progression to cancer occurs when both copies of one of these genes are inactivated (ie. one inherited mutation and one sporadically mutated)
3. Both genes function in facilitating DNA damage repair
4. Approximately 3/4 of female carriers will get breast cancer if no prophylactic measures are taken
5. Also increased susceptibility to other cancers (colon, prostate, pancreas)
6. BRCA1: increased risk for ovarian cancer, the breast carcinomas have a distinct histologic appearance and are typically ER, PR and Her2/neu negative
7. BRCA2: also at increased risk for ovarian cancer (but smaller than BRCA1), increased risk for male breast cancer

CHEK2 gene accounts for approximately 5% of familial breast cancer

1. Tumor suppressor genes, thus loss of function is responsible for progression to cancer
2. Also increased susceptibility to other cancers (prostate, thyroid, kidney, colon)

Hereditary breast cancer also occurs as part of some well known syndromes:

1. Li-Fraumeni syndrome: mutation in P53 gene; approximately 5% of familial breast cancer
2. Cowden syndrome: Mutation in PTEN gene (rare; less than 1% of familial breast cancer cases)
3. Peutz-Jeghers syndrome: Mutation in STK11/LKB1 gene (rare; less than 1% of familial breast cancer cases)

Question 24

What is the site of origin for breast carcinoma?

Answer 24

Terminal Duct Lobular Unit

Question 25

ER positive, HER2 negative cancers

Answer 25

Dominant pathway

Majority of cases (50-65%)

Associated with gains of chr1q, loss of chr 16q and activating mutations in PIK3CA

Same genetic lesion found in ADH, flat epithelial atypia and low grade DCIS thus this is the assumed precursor lesion

Question 26

Her2 positive cancer pathway

Answer 26

Strongly associated with amplification of Her2 gene on chr17q

Approximately 20% of all breast cancers

Most common subtype associated with Li-Fraumeni syndrome

These cancers have a distinct gene expression pattern associated with proliferation of Her2 gene

Same genetic lesion found in high grade DCIS thus this is the assumed precursor lesion

Question 27

ER negative, HER2 negative

Answer 27

Approximately15% of all breast cancers

Most common subtype associated with BRCA1 mutation

The precursor lesion is still unknown.

Question 28

Male Breast Carcinoma

Answer 28

Breast carcinoma is a rare disease in the male breast (less than 1% of all breast cancers)

Risk factors are similar to females and include hereditary and hormonal elements

BRCA2 mutations significantly increase the risk for males, approximately 1/10 male breast cancers are due to BRCA2 mutations

Male breast cancer is also associated with Klinefelter’s syndrome, approximately 1/20 male breast cancers are due to this disorder, likely related to altered testicular hormonal function

Breast cancer in males most often clinically present as a subareolar palpable mass

The identical histologic types found in females are found in males, although in different proportions

Breast cancer in males more often involve the chest wall and skin than female cancers due to the smaller amount of tissue

Expression of estrogen receptors is more common in male breast cancer

Men often present at higher stage, but their prognosis (by stage) is similar to women