Breast Cancer Pathology Flashcards
Metastatic cancer to the breast (from another tissue)
Uncommon
Prognosis generally poor as this is typically associated with widely disseminated disease
Most common are hematologic malignancies
In persons younger than 20 yrs old metastatic lesions are more common than primary malignant lesions, but this is a very small subset of patients
What is the largest category of breast cancer?
Carcinoma, by far (more than 95%)
In situ carcinoma
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
Ductal carcinoma in situ (DCIS)
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)
Paget’s disease of the nipple
In situ carcinoma
Neoplastic DCIS cells grow from the ducts onto the adjacent skin without invading through the basement membrane of the ducts or skin
Clinically presents as a scaly rash on the nipple. Pruritus is common
Many have associated invasive carcinoma including 1/3 who present without an associated mass and >9/10 of those with a mass.
Prognosis depends on the presence of underlying carcinoma
Lobular carcinoma in situ (LCIS)
In situ carcinoma
“Classic” LCIS always an incidental finding, does not form masses or calcifications
Often multicentric and bilateral
Patients are at a significantly increased risk for development of invasive carcinoma in both breasts (compared with DCIS where the higher risk is predominantly in the ipsalateral breast)
Histologically composed of small, uniform cells with round nuclei filling the lobules and poorly adhering to adjacent cells
Some recognize a “pleomorphic” variant of LCIS that behaves more aggressively and some advocate treating these similar to DCIS
Atypical hyperplasia
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
Invasive carcinoma
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)
Invasive ductal carcinoma (No special type)
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)
Well-differentiated vs poorly-differentiated invasive ductal carcinoma
Well differentiated: often expresses hormone receptors
Poorly-differentiated: overexpress the epidermal growth factor receptor HER2/neu more frequently
What are the 5 subgroups of invasive ductile carcinoma
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).
Invasive lobular carcinoma (ILC)
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
Where does ILC tend to metastasize compared to invasive ductal carcinoma?
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
Tubular carcinoma
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
Mucinous (colloid) carcinoma
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
Medullary carcinoma
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
Inflammatory carcinoma
(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
Sarcoma of breast
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)
Lymphoma of breast
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
Mixed (Biphasic) tumors of breast
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
Staging of breast carcinoma
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
Major prognostic factors
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
Minor prognostic factors
- 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.
- 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).
- Histologic type. Tubular, mucinous and medullary carcinoma all have better prognosis than invasive ductal carcinoma (no special type).
- 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) - Lymphovascular invasion. Associated with lymph node involvement.
- Proliferative rate. Higher proliferation associated with a worse prognosis.
- Gene expression profiling. Can predict survival and responsiveness to specific therapies.
Epidemiology of breast cancer
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)
Risk factors for breast cancer
- Age. The risk increases throughout life.
- Age at menarche. A young age of menarche is associated with an increased risk.
- Age at menopause. Late menopause is associated with an increased risk.
- Age at first live birth. Having a child earlier in life is associated with a decreased risk.
- Family history (1st degree relatives). Risk increases with the number of affected 1st degree relatives
- Prior biopsies. Results from prior biopsies may suggest an increased risk
- 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.
- Estrogen exposure. Postmenopausal hormone replacement increases the risk. Oophorectomy decreases risk.
- 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
- 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
- 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)
- Breast-feeding. The longer women breast feed, the lower the risk of cancer
Hereditary breast cancer
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)
- Both are tumor suppressor genes, thus loss of function is responsible for progression to cancer
- Progression to cancer occurs when both copies of one of these genes are inactivated (ie. one inherited mutation and one sporadically mutated)
- Both genes function in facilitating DNA damage repair
- Approximately 3/4 of female carriers will get breast cancer if no prophylactic measures are taken
- Also increased susceptibility to other cancers (colon, prostate, pancreas)
- BRCA1: increased risk for ovarian cancer, the breast carcinomas have a distinct histologic appearance and are typically ER, PR and Her2/neu negative
- 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
- Tumor suppressor genes, thus loss of function is responsible for progression to cancer
- Also increased susceptibility to other cancers (prostate, thyroid, kidney, colon)
Hereditary breast cancer also occurs as part of some well known syndromes:
- Li-Fraumeni syndrome: mutation in P53 gene; approximately 5% of familial breast cancer
- Cowden syndrome: Mutation in PTEN gene (rare; less than 1% of familial breast cancer cases)
- Peutz-Jeghers syndrome: Mutation in STK11/LKB1 gene (rare; less than 1% of familial breast cancer cases)
What is the site of origin for breast carcinoma?
Terminal Duct Lobular Unit
ER positive, HER2 negative cancers
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
Her2 positive cancer pathway
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
ER negative, HER2 negative
Approximately15% of all breast cancers
Most common subtype associated with BRCA1 mutation
The precursor lesion is still unknown.
Male Breast Carcinoma
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
