3. Robbins Breast Pathology Flashcards
(178 cards)
1
Q
A
2
Q
What is the functional unit of the breast and where many breast cancers arise?
A
Terminal duct lobular unit = lobule + duct
3
Q
Describe the TDLU.
A
- In each lobe, lactiferous duct branches repeatedly, forming many terminal ducts, each connecting to a LOBULE, which contains many acini that makes milk (TERMINAL DUCT + LOBULE = TDLU)
- Terminal duct can be broken down into:
- Intralobular terminal duct: within the duct, intralobular ducts carry milk from acini (functional unit of the breasts) => extralobular terminal duct for each lobule
- Extralobular terminal duct: attaches to the lobule
4
Q
Describe breast epithelium.
A
Lines surface of ducts and lobules.
Contains 2 layers of epithelium, over BM.
- Luminal columnar epithelial cells: innermost layer that secretes milk
- Myoepthielial cells: outermost layer that are contractile and respond to oxytocin.
5
Q
Breast stroma
A
2 different kinds
1. Intralobular stroma: surrounds acini and hormonally responsive fibroblast-like cells
2. Interlobular stroma: dense fibrous CT and fat
6
Q
What 6 lesions can arise in the lobules and terminal ducts of the breast?
A
- Cysts
- Sclerosing adenosis
- Small duct papilloma
- Hyperplasia
- Atypical Hyperplasia
- Carcinoma
7
Q
What are developmental disorders of the breasts?
A
- 1. Milk line remnants
- 2. Acessory axillary breast tissue
- 3. Congenital nipple inversion
8
Q
What are milk line remnants and how do they most commonly come to attention clinically?
A
- Breast tissue develops from embryonic structures called milk lines, two epidermal thickenings that form the breast and nipples.
- Milk lines run from axilla => groin and form usually dissppear in development, except in breasts. Persistance of epidermal thickenings (milk line remnants) along the milk lines that form a 3rd nipple or breast (supernumerary nipples/breasts called polythelia/polymastia), usually below NL breasts.
- Present as painful PRE-menstrual enlargements
9
Q
What is accessory axillary breast tissue?
A
NL ductual tissue extends to the subQ tissue of the chest wall or axilla.
10
Q
What are clinical presentation of breast disease?
A
- Pain (mastalgia/masodynia): cyclic with period or noncylic: almost all painful masses are benign but 10% of breast cancers are painful
- Palpable mass
- Nipple discarge
11
Q
Causes of:
- Cyclic breast pain
- Noncyclic breast pain
A
- Cyclic; often diffuse and due to premenstrual edema
- Noncyclic; often localized and due to ruptured cyst, injury, infection.
12
Q
What is the clinical significance of accessory axillary breast tissue; managed how clinically?
A
- Malignancy and other lesions can occur
- Prophylactic mastectomies ↓ risk, but do NOT completely eliminate
13
Q
Why is acquired nipple inversion of greater concern than congenital?
A
Can indicate invasive cancer or an inflammatory nipple disease
14
Q
Palpable masses of the breast are most commonly due to what 3 etiologies?
A
- Cysts
- Fibroadenomas
- Invasive carcinoma
15
Q
Are most palpable masses benign or malignant?
A
- Benign in premenopausal women, but ↑ chance of malignancy with ↑ age: 60% > 50YO.
16
Q
Why does screening for palpable masses have LITTLE effect on mortality?
A
Once a palpable mass is felt, the cancer is often metasized.
17
Q
In what setting is nipple discharge most worrisome that it is cancer?
A
Spontaneous, unilateral and >60YO
18
Q
In what situations do we most often see the following types of discharge:
1. Milky (galactorrhea)
2. Bloody or serous
A
- ↑ prolactin, hypothyroidism, endocrine anovulatory syndromes and meds (OC, TCA, methyldopa, phenothiazines)
-
Cysts or large duct (intraductal) papillomas;
- blood = pregnancy
19
Q
Where are benign breast masses and malignant breast cancers most common on the breast?
A
- Benign: anywhere
- Malignant breast cancer: Upper outer quadrant (50%) bc has most breast tissue > Subareolar/central region (20%)
20
Q
- ______\_ lesions are more common in premenopausal women
- _______ lesions are more common in post-menopausal women (corollary ^^)
- Only ____ of cancer are detected as a palpable mass. How are the others detected?
A
- Benign => premenopausal
- Malignant => post-menopausal
- 1/3; mammogram
21
Q
- What are the the principal signs of breast cancer on mammograms, the most common way to detect breast cancer?
A
- Densities
- Calcifications
22
Q
What characteristics of a density detected on mammogram is associated with benign vs. malignant lesions?
A
- Benign fibroadenoma or cyst = rounded densities
- Malignant = irregular masses
23
Q
On mammogram:
Benign calcifications are usually due to:
Malignant calfications (ductal carcinoma in-situ) are described as:
A
- Benign: clusters of apocrine cysts, hyalinized fibroadenomas and sclerosing adenosis
- Malignant: small, irregular, numerous and clustered
24
Q
- Screening with mammograms has increased the diagnosis of _____________.
- After mammogram, perform ____.
A
- DCIS (ductal carcinoma in-situ), because it is most often detected by calcifications
- Biopsy
25
**Breast inflammation (mastitis)** is RARE except during ________ and occurs due to what?
* Lactation
* Infections, AI disease and FB reactions to leaked keratin or secretions.
26
What can **mimic inflammation** of the breast?
**Inflammatory breast cancer** bc it can obstruct dermal vasculature with tumor emboli
27
What are the types of **inflammatory breast disorders?**
1. Acute mastitis
2. Squamous metaplasia of lactiferous ducts
3. Ductal ectasia
4. Fat necrosis
5. Lymphocytic mastopathy (diabetic mastopathy)
6. Granulomatous mastitis
28
**_KEY WORDS:_**
1. Mastitis
2. Mammary Duct Ectasia
3. Fat Necrosis
1. Mastitis: **erythema and tender**
2. Mammary Duct Ectasia: **white discharge**
3. Fat Necrosis: **due to trauma**
29
What is **acute bacterial mastitis?**
Symptoms?
Tx?
* During the 1st month of breastfeeding, sucking can cause trauma (cracks and fissures) of the nipple, making it vulnerable to bacteria, particulary **S. aureus.**
* Breast is **red, painful +/- fever**
* **Tx:** ABX, continue breastfeeding; rarely perform surgical drainage
30
What is **Squamous Metaplasia of Lactiferous Ducts** (also called what)?
Periductal mastitis; Recurrent subareolar abscess, and Zuska disease.
* Inflammation of the subaerolar ducts seen in smokers, that forms a **painful, red subaerolar mass** with **nipple retraction**
31
What symptoms is commonly seen in **Squamous Metaplasia of Lactiferous Ducts?**
Inverted nipples
32
Risk factors for **squamous metaplsia of lactiferous ducts** (aka recurrent subareolar abscess, periductal mastitis, and Zuska):
1. **Tobacco smoke**
2. **Relative vitamin A deficiency**
33
**Key morphological features** of squamous metaplasia of lactiferous ducts (aka recurrent subareolar abscess, periductal mastitis, and Zuska)?
* **Squamous metaplasia** of lactiferous duct: Cuboidal epithelium =\> keratinzed squamous epithelium
* =\> Keratin is shed and plugs ducts
* =\> Ducts rupture and dilate
* **=\> Intense chronic granuloma inflammation**
* =\> fibrosis =\> myofibroblasts contracts =\> invert nipple
34
Treatment for **Squamous Metaplasia of Lactiferous Ducts**
1. Simple incision **drains abcesses;** but can recur is keratinized epithelium stays
2. En **block surgical removal of duct** and fistula cures
35
What is **duct ectasia?**
What is it caused by?
* Benign chronic Inflammation and fibrosis of the subareolar duct =\> dilation due to build up of inflammatory debris=\> irregular, palpable periareolar breast mass (painLESS and NOT red) **below** the nipple + **white discharge**
36
Clinical case of **duct ectasia?**
**MC in who?**
Older W **(50-60 YO)** with **many children (multiparous)** presents to the clinic with breast mass right below nipple with thick, white disharge.
37
In **duct ectasia,** the ectatic ducts are filled with what?
1. **Inspissated secretions**
2. **Lipid-laden MO**
38
What is the **PRINCIPAL SIGNIFICANCE** of ductal ectasia worrisome?
**Mimics invasive carcinoma** clinically and on imaging because it is more common in **POST**-menopausal women
39
What is **fat necrosis** of the breast?
**Necrosis of breast fat, usually due to trauma or hx of prior surgery** that causes benign inflammatory process that forms a [**painless, palpable mass with thick skin/retraction]** and form **calcifications/densities.**
40
What inflammatory cells do we see in **fat necrosis** of the breast in acute vs chronic?
* **Acute** = MO and neutrophils;
* **Chronic**= *_fibroblasts_* and inflamm cells form *_giant cells,_ calficiation and deposition of _hemosiderin_*, forming **scar tissue**.
41
What are **lymphocytic mastopathy** (aka: \_\_\_\_\_\_\_\_\_\_\_\_)?
Sclerosing lymphocytic lobulitis/ diabetic mastopathy
* **Single or multiple rock hard masses** that on histology, show:
1. Atrophic ducts surrounded by collagenized stroma
2. Thick BM, surrounded by lympocytes
42
**Lymphocytic mastopathy** most commonly occurs in patients who have what?
1. **T1DM**
2. **Autoimmune thyroid diseases**
suggesting it is AI
43
How are **benign epithlial breast lesions** categorized?
Risk of development into breast cancer
* 1. **Non-proliferative breast changes/fibrocytic:** all benign; no increase risk in BC
* 2. **Proliferative breast changes, without atypia:** SMALL increase risk in BC
* 3. **Atypical hyperplasia:** moderate increase risk of cancer bc has SOME, but not all features to dx as CIS
44
**3 types** of nonproliferative breast changes (fibrocystic change),
1. **Cysts,** often with apocrine metaplasia
2. **Fibrosis**
3. **Adenosis**
45
* **Non-proliferative breast changes (fibrocystic change)** are a group of morphological fibrocystic changes of the breasts that are all benign =\> no risk of breast cancer (non-proliferative) that lead to ___________ most commonly in \_\_\_\_\_\_\_\_
**lumpy-bumpy breasts** in **pre-menopausal** women
46
Describe the **non-proliferative breast changes**
1. Simple Cysts: Fluid filled, round cysts that contain **dark fluid**: turbid, semi-translucent brown-blue fluid **(blue domed cyst)** formed by the dilation of lobules and lined with [flat, atrophic epithelium] or [metaplastic apocrine cells]
2. Fibrosis: Occurs when a **cysts ruptures** and releases secretory material into the =\> fibrosis, creating lumpy bumpy breasts
3. Adenosis: **↑ # of acini/lobule** that occurs normally during pregnancy
47
Diagnosis of **Simple Cysts**
**Fine needle aspiration** of cysts causes it to disappear
48
Adenosis,↑ in the number of acini per lobule, may show what **histological change** that is thought to be the earliest recognizable **precursor of low-grade cancer,** even though there is **NO** increase risk of breast cancer.
**"Flat epithelial atypia"** of columnar cells due to a **Chr16q deletion.**
49
**Proliferative breast disease without atypia** is characterized by what; what is the association with carcinoma?
* **Proliferations of epithelial cells without atypia,** causing only a **SMALL** **↑ risk** of breast cancer, but NOT true precursors to cancer
50
4 types of **Proliferative Breast Disease *_without Atypia_***
1. **Epithelial hyperplasia**
2. **Sclerosing adenosis**
3. **Complex Sclerosing Lesion**
4. **Intraductal papilloma**
51
What is **Epithelial Hyperplasia?**
* **↑ # of luminal and myoepithelial cell**, which fill & distend ducts and lobules usually found incidentally.
52
What is **Sclerosing Adenosis?**
* **↑ # of acini/glands** and **dense fibrosis** in **central** part of the lesion **=\> dense stroma compresses the glands**
* **Often** could undergo calcification.
53
What are **complex sclerosing lesions?**
Lesions that have compenents of
1. **sclerosing adenosis**
2. **papilloma**
3. **epithelial hyperplasia**.
54
Which lesions of proliferative breast disease without atypia has an **_irregular shape_** and can **_mimic invasive carcinoma_** mammographically, grossly, and histologically?
**Complex sclerosis lesion** =\> radial sclerosis lesion (aka radial scar)
55
When do cysts cause **concern**?
When **solitary** and **firm**
56
Describe a **radial sclerosing lesion.**
* **Central area of entrapped glands** in **hyalinized stroma** surrounded by long, radiating projections into stroma
57
Describe **intraductal** **papillomas**.
Fibrovascular projections lined with epithelial cells (both kinds) that extend inside of ducts (intraductal) that cause **blood/serous discharge MC** in **premenopausal women**
58
**80%** of **papillomas** present with **bloody/serous discharge.**
What is frequently seen with papillomas
**epithelial hyperplasia** & **apocrine metaplasia** (NOT a pre-cursor to cancer)
59
What is the **ONLY benign lesion** seen in the **male** breast?
**Gynecomastia** caused by **androgen/estrogen imbalance.**
60
What do we see physically in **gynocomastia**?
Associated with a increase risk of cancer?
* Unilateral or bilateral buttonlike subareolar enlargement that is associated with a **SMALL** increase risk of breast cancer.
61
What is the seen **histologically** in gynecomastia?
1. **↑ in dense collagen CT**
2. **+ epithelial hyperplasia** of ducts
3. **+ tapering micropapillae** (NO lobule formation)
4. No lobules form
62
What are some of the underlying risk factors for **gynecomastia**?
1. - **Cirrhosis**--\> liver is not metabolizing estrogen
2. - **Drugs** --\> alcohol, marijuana, heroin, antiretroviral's, and anabolic steroids
3. **Puberty**
4. **Klinefelters** (M 47 XXY; male hypogonadism =\> decrease testosterone)
63
Is gynecomastia associated with an increased risk for cancer?
Yes, **small ↑ risk** due to being proliferative breast disease without atypia
64
2 types of **Proliferative Breast Diseases with Atypia**
1. **Atypical *ductal* hyperplasia**
2. **Atypical *lobular* hyperplasia**
65
What is **proliferative breast diseases with atypia?**
Atypical hyperplasia that has with **some**, but **not all,** histological features of ductal carcinoma in situ (DCIS)
66
What is the difference between **atypical ductal hyperplasia** and **atypical lobular hyperplasia?**
* **Atypical ductal hyperplasia (ADH):** histologically looks like DCIS (ductal carcinoma in-situ), but duct is PARTIALLY FILLED\* with different cells:
* Periphery = oriented columnar cells
* Center = round cells.
* Some spaces are round and peripheral spaces have slits.
* **Atypical lobular hyperplasia (ALH):** histologically identical to LCIS**:** lobules are filled with discohesive cell growth (loose intercellular connections) dt lose of E-cadherin =\> cells become round/clump together, but do NOT take up more than 50% of lobule acini
67
What genetic abnormalities do we see in BOTH **ADH** and **ALH**?
1. **Loss of Chr 16q**
2. **Gain of Chr 17p**
* \*\*\* Both also seen in CIS
68
Which genetic feature of atypical lobular hyperplasia (**ALH**) is shared with **lobular CIS**?
* **Loss of E-cadherin**
69
What is seen on biopsy of **fat necrosis** in the breast in both acute and chronic settings?
- **Acute** = liquefactive fat necrosis w/ neutrophils and MO
- **Chronic** = giant cells + calcifications and hemosiderin =\> scar tissue
70
What is the most common **non-skin malignancy** in females?
**_Breast cancer_**
* 2nd leading cause of cancer deaths in women, after lung cancer
71
\_\_\_\_\_ of women in the US will get breast cancer by **90 YO**
**12.4%** or **1/8**
72
Almost all breast cancers are ______ and can be divided based on \_\_\_\_\_\_\_\_
* **Adenocarcinomas**
* if they express **estrogen receptor (ER)** and **HER2**
73
3 categories of breast cancers based on predictive markers, in order of MC to LC (each have different treatments and outcomes)
* 1. ER (+) / HER2 (-) = 50-65%
* 2. ER (+/-) / HER2 (+) = 10-20%
* 3. ER (-) / HER2 (-) = 10-20%
74
**Incidence** and **epidemiology** of breast cancer
* Most common in **white** women **\>60YO**
* **Rare in females \<25**
* **After 30**
* ****incidence of ER (+) ↑
* incidence of ER (-) and HER2 (+) are relatively constant
75
**Risk factors** that increase risk of breast cancer
Dense breasts on mammogram = higher risk of \_\_\_\_.
1. **Western lifestyle**: later pregnancy, less pregnancies, and decreased breastfeeding
2. _W women (Non-hispanic women \> Ashkenazi Jews) \>_ hispanics \> AA
3. Estrogen exposure
1. MHT
2. Earlier menarche or later menopause
3. Obesity
4. Breast feeding = protective
4. Age of pregnancy: later or no PG (younger bb= more protective)
5. Benign breast disease
6. Dense breasts on mammogram = 4-6 fold risk risk of ER +/-.
7. Radiation
8. Carcinoma of contralateral breast or endometrium
76
Why is breast cancer in **African American women** associated with a **higher overall mortality rate?**
1. **More** likely to have **aggressive cancers:** ER (-) and a high nuclear grade
2. Unequal access to care
77
What is the average age of diagnosis for breast cancer in **white** women, **hispanics** and **blacks**?
1. **White** = 61 y/o
2. **Hispanics** = 56 y/o
3. **Blacks** = 46 y/o
78
**BRCA1** and **BRCA2** mutations are particularly prevalent in which ethnicity?
**Ashkenazi Jews**
79
Breast cancer diagnosed in ppl **under 50** is most common in who?
**1. AA (35%)**
**2. Hispanics (31%)**
80
**QUESTIONS:**
1. Do **oral contraceptives** increase risk of BC?
2. Does **Oophorectomy** or **Antiestrogenic drugs** reduce risk of estrogen receptor (+) BC?
1. no
2. yes
81
Who is more likely to have an increase risk of BC:
* **1. Obese post-menopausal F**
* **2. Obese F under 40**
* **Obese postmenopausal females** due to estrogen synthesis in fat depots
* Obese females \< 40 ↓ risk due to **_anovulatory cycles_** & ↓ progesterone levels
82
Why do we see lower rates of breast cancer in **developing countries** where they breastfeed their kids longer?
* **Lactation suppresses ovulation** =\> trigger terminal differentiation of luminal cells
83
Breast cancer can be familial or sporadic.
## Footnote
**FAMILIAL BREAST CANCER**
84
**_FAMILIAL BREAST CANCER_**
* Inheritance:
* Makes up\_\_\_\_% of breast cancer**.**
* Susceptibility genes include: \_\_\_\_\_\_\_\_\_\_\_
* 80-90% of **single-gene** familial breast cancers are due to _____ mutations
* AD
* 12%
* Tumor suppressor genes BRCA1, BRCA2, TP53, CHEK2
* BRCA1 and BRCA2
85
What is the function of **BRCA** genes?
Tumor suppresors that **repair dsDNA breaks** via **homologous recombination**
86
Cancers **BRCA1/BRCA2** mutations increase risk for
* **BRCA1** = **higher** risk of developing **ovarian cancer** (20-40%); fallopian
* **BRCA2** = **lower** risk for developing **ovarian** **cancer** (10-20%); stomach, melanoma, GB, BD, pharynx
* **Both** increase risk of developing epithelial cancer (prostatic and pancreatic), male breast cancer (more often due to BRCA 2)
87
How are **BRCA mutations** commonly diagnosed?
Genetic testing is hard due to variants, but restritcted to those with a s**trong family history (Ashkanazi Jews) .**
88
**_BRCA1_**
* Located:
* % of single-gene heriditary breast cancers:
* Features (2)
* Markers
* Biologically similar to what type of breast cancers and thus, called what?
* **Chr17q21**
* **52%**
* **Features:**
1. **Poorly differentiated with medullary features (**syncytial growth-pattern w/ pushing margins and lymyphocytes);
2. have **TP53 mutations**
* **Basal-like (triple negative):** ER (-), HER2 (-), Progesterone (-)
* **ER (-)/HER2 (-) breast cancers**, thus they are called basal-like
89
**_BRCA2_**
* Located:
* % of single-gene heriditary breast cancers:
* Feature (1)
* Marker:
* **Biallelic germine mutation will cause what?**
* 13q12-13
* 32%
* Features
1. Poorely differentiated
* More often ER (+)
* rare Fanconi anemia
90
**Li-Fraumeni syndrome** is due to genetic mutation in what and is associated with what cancers?
- **TP53**
- Breast + sarcoma + leukemia + brain tumors + adrenocortical carcinoma
91
**_TP53 (Familial BC)_**
* Most common what?
* Markers
1. Most common mutated gene in **sporadic** breast cancer
2. 50% are **ER (-)/ HER2 (+)**
92
**_CHEK2_**
* Associated cancers:
* Increases risk for:
* Markers:
* **Prostate**, **thyroid**, **kidney** and **colon**
* ↑ risk for breast cancer after exposed to radiation
* 70-80% are **ER (+)**
93
**_SPORADIC BREAST CANCER_**
* What is the MAJOR risk factor to sporadic BC?
* How?
Hormone exposure: **estrogen =\>**
1. Stimulates breast growth in puberty, menstrual cycles and PG =\>
2. Proliferation of epithelium =\> damaged DNA accumlates =\>
3. Damage is fixed =\> Risk of cancer increases
4. Hormones stimulate growth of premalignant/malignany cells and stromal cells
94
**Flat epithelial atypia** and **atypical ductal hyperplasia** often show which genetic mutations associated with developing **ER(+) breast cancer**?
**Germline BRCA2** and **activating PIK3CA**
95
* Almost all of breast cancers are _____ that arise from what?
* When detected, what is their status?
* **Adenocarcinomas**, that arise from a **precursor lesions (DCIS/LCIS)**
* When detected, majority breached BM and invaded stroma.
96
Describe how **ER (+)/ HER2 (-) breast cancer** develops
* Which precursor lesions develop
* What type of breast cancer?
1. **Germline BRCA2** =\> [Flat epithelial atypia]
2. **PIK3CA mutation** =\> [Aytpical ductal hyperlasia]
3. **[DCIS]** =\> ER (+) / HER2(-) "luminal" invasive breast cancer
97
Describe how **HER2 (+) breast cancer** develops
1. Which precursor lesions develop
2. What type of breast cancer?
1. **_TP53 mutation_ + HER2 amplification** --\> [Atypical apocrine adenosis]
2. [DCIS] --\> HER2 (+) invasive breast cancer (can be ER+/-)
98
What is the most common marker of breast cancer in pt's with **Li-Fraumeni Syndrome?**
**HER2 (+)**
99
What is the precursor lesion of HER2 (+) breast cancers?
Atypical apocrine adenosis ---\> **DCIS**
100
**_ER (-)/HER2 (-) basal-like triple-negative cancer_**
* How do they arise?
* Most often is seen in breast cancer associated with what mutations?
* MC in who?
* Pathways not associated with ER/HER2
* **Mutations:**
1. Familial/heriditary = BRCA1\*\*\*\*
2. Sporadic = LOF TP53
* **African - Americans**
101
Development of **neoplastic cells** depend on what?
1. Interactions with stromal cells in the local environment
102
What are the **2 CIS** (carcinoma in-situs), which **arise** from the terminal duct lobular unit (**TDLU**)?
1. Ductal carcinoma in-situ (**DCIS**)
2. Lobular carcinoma in-situ (**LCIS**)
103
**DCIS (ductal carcinoma in-situ)**
* Definition :
* Bilateral/unilateral?
* Pattern:
* Detected:
* Complications:
* **Definition:** Tumor cells grow from the wall of the ducts, into and fill the lumen, but limited by an intact BM
* Bilateral in **only 10-20%** of cases
* **Pattern (2):**
* 1. Comedo DCIS
* 2. Non-comedo (cribiform pattern)
* **Detected**:
* Always by mammogram bc forms microcalfications, but nipple discharge is rare
* **Complications:**
* Paget syndrome: unilateral red eruption and crusty nipple indicative of invasive carcinoma caused when cancer cells migrate along the lacteriferous duct, without crossing BM =\> nipple skin =\> inflammation, ECF leaks onto nipple =\> blody nipple discharge that dries and forms crusts
104
Describe the comedo and non-comedo morphology of **DCIS**.
1. **Comedo:**
1. On mammogram: clustered or linear and branching calcifications
2. Histo:
1. Central necrosis
2. Pleomorphic nuclei
2. **Non-comedo (many patterns)**
1. Cribiform pattern: round cells in ducts (cookie cutter)
2. Micropapillary pattern: Bulbous protrusions w/t fibrovascular core in complex intraductal patterns
3. True papillae pattern: Fibrovascular core without myoepithelial cell layer
105
**Non-comedo DCIS** does not have what features?
**central necrosis** or **pleomorphic nuclei**
106
**_DCIS:_**
Best predictors of **local recurrence** and **invasion**
1. **Nuclear grade** and **necrosis**
2. **Extent of disease**
3. **Positive surgical margins**
107
What is this
**Comedo DCIS**
* A= linear and branching calficications on mamogram
* B= central areas and necrosis and pleiomorphic nuclei
108
What are the morphological features of **noncomedo DCIS,** including cribiform and micropapillary DCIS?
- **Cribiform** may have **rounded(cookie cutter-like) spaces** within ducts
- **Micropapillary** has **bulbous** protrusions **without** a fibrovascular core, often arranged in complex intraductal patterns
\*Pic on left = cribiform DCIS and on right = micropapillary DCIS
109
Treatment of DCIS
* Surgical excision and radiation/tamoxifen = Mostly curative
* **Mastectomy** = Cure in 95%; keeping breast increases risk of reccurance
110
When malignant cells in DCIS extend via the lactiferous sinuses into nipple skin, without crossing the basement membrane, what is it called?
**Paget Disease of the Nipple**
111
**Pagets Disease of the Nipple**
* Tumor markers
* Cell morphology
* Stain
* If palpable mass is felt =
* If palpable mass is not felt =
* ER (-)/ HER2 (+)
* Morphology
* Single or small clusters of large cells (larger than surrounding keratinocytes) in epidermis
* Pale cytoplasm w/ mucopolysaccharide
* Seen on PAS
* Invasive carcinoma
* only DCIS
112
**LCIS (Lobular carcinoma in-situ)**
* Definition :
* Bilateral/unilateral?
* Pattern:
* Detected:
* Complications:
* Proliferation of tumor cells WITHIN lobule that is limited by an intact BM, causing the alveoli to enlarge. Unlike DCIS, LCIS typically crosses BM to form invasive lobular carcinoma.
* Bilateral (20-40%) of cases
* Pattern: Discohesive cells due to LOF of adhesion protein E-cadherin =\> cells become round and clump together
* Incidental biopsy finding, bc does not form calcifications or stromal reactions on mammogram
113
**_LCIS_**
* Did we see a decrease incidence of LCIS after mammograms were introduced?
* Is a mass formed?
* Markers
* No
* No mass is formed
* ER(+), PR(+), HER2(-)
114
What is the typical **morphology** and **characteristic** cell types found with LCIS?
1. **Uniform** population of **discohesive round cells** with oval/round nuclei in ducts and lobules
2. **Mucin (+) signet-ring** cells are common
3. Pagetoid spread is common, but LCIS does **NOT** involve nipple skin
115
Which genetic mutation is associated with LCIS?
**CDH1** leading to loss of E-cadherin
116
\_\_\_\_ is a risk factor **invasive lobular carcinoma** in **either** breast!
**LCIS (not itself invasive tho)**
117
Treatment for LCIS
**Close clinical follow up** with mammographic screening since the risk of progression is similar to DCIS
118
What is the most common form of invasive breast cancer?
ER (+)/ HER2 (-) luminal invasive breast cancer
119
_**ER (+)/** HER2 (-) **low proliferation "luminal**" **breast cancer**_
## Footnote
- Present in ____ of breast cancers.
- Most commonly seen in?
- State when detected?
- Metastasis
- Treatment
40-50%
1. **Older women** and **men**
2. Most common type detected by **mammographic screening**
3. **F on HRT**
- Found at an early stage and cured by surgery; ↓ recurrence
- Metasasize after a long time to **bone**
- Antiestrogenic drugs
120
What is the recurrence and metastatic behavior of **ER-(+), HER2-(-), low-proliferation breast cancers** like?
- **Lowest recurrence rate**, occurs late, \>10 years
- Metastasis after a long time =\> **bone** and can survive **long time** w/ metastasis
121
How does ER-positive, HER2-negative, **low-proliferation** respond to chemotherapy vs. **high-proliferation** types?
**- Low-proliferation** = poor response to chemo, but respond well to hormonal tx
**- High-proliferation** = has a higher % of complete response to chemo
122
_ER(+), HER2(-), High Proliferation "Luminal Breast Cancer"_
## Footnote
- Present in ____ of breast cancers.
- Most commonly seen in?
- Increased nuclear staining for:
- Treatment
* 10%
* BRCA 2 mutations
* Ki67
* Chemotherapy
123
**ER-(+),** HER2-negative, **high**-**proliferation** will have increased nuclear staining for what?
Ki67
124
_**HER2 (+)** invasive carcinoma_
* ___ most common type of invasive breast cancer
* Most commonly seen in?
* Metasis
* Treatment
* 2nd (10-20%)
* MC in:
1. Young, non-white women
2. TP53 mutations = Li-Fraumeni (HER2+/ER+)
* Metastasize when **small** and **early** =\> **viscera, brain and bone**
* Targeted chemo to block HER2 (Herceptin)
125
Why have **HER2-+** cancers become associated with a better outcome?
1. \>1/3 **respond completely** to Herceptin (trastuzumab), a monoclobal AB, that inhibits HER2
1. Some resistance is developing (tumors are shortening HER2 binding site)
2. Cancers that respond have excellent prognosis
126
**_ER(-), HER2(-) == "Basal-like" triple negative carcinoma_**
* How do they present?
* MC in:
* Unique feature
* Metasis
* Recurrance
* Because highly proliferative and grow SO fast, presents as a **palpable mass in between mammograms**
* Most common in
1. *Young, premenopausal females (especially African American or Hispanic)*
2. *BRCA1 mutations*
* Share many genetic similarities with **serous ovarian carcinomas**
* **Metastastize** when **small** and **early** --\> viscera, brain and bone;
* Recurrences = common (within 5 years)
127
ER-negative, HER2-negative ("basal-like) breast cancer shows a number of genetic similarities with what other carcinoma?
**Serous ovarian carcinoma**; associated w/ **BRCA1**
128
What is the **response rate to chemo f**or ER-negative, HER2-negative ("basal-like) breast cancers?
- Survival after distant metastasis is \_\_\_
**30%** completely respond to chemo
= rare
129
Which invasive cancer is most common in **young, premenopausal F** (especially **African American** and **Hispanic**)
**Basal like; triple negative carcinoma**
130
**_Morphology of Invasive Carcinoma_**
* Gross and mammographic appearance of invasive carcinoma depends on \_\_\_\_\_\_\_\_\_.
* MC: invasive carcinomas are described how?
* How do invasive carcinomas present?
*
* Reaction with the stroma.
* Hard, irregular radiodense masses due to desmoplasic reaction
* On mammogram or mass
* Mammogram: \< 1cm
* Mass: 2-3cm
* Thus, dx earlier on mammogram
*
131
**Larger invasive carcinomas** can invade what structures?
* 1. **Pectoralis muscle** =\> fixed to the chest wall
* 2. **Dermis** =\> skin dimpling or nipple retraction
132
**Grading** of breast cancers is done using the **Nottingham Histologic Score.**
What factors does this take into consideration?
1. **Tubule formation**
2. **Nuclear pleomorphism**
3. **Mitotic rate**
133
**Grade 1**
1. Tubular pattern
2. Small and round nucli
3. Low proliferation
134
**Grade 2**
1. Some tubule pattern; solid clusters of infiltrating cells
2. More nuclear pleomorphism
3. Mitotic figures are present
135
**_Grade 3_**
1. Ragged nests/solid sheets of cells invade
2. Enlarged, irregular nuclei
3. Increase proliferation; tumor necrosis
136
**_Describe the morphology of the following:_**
1. **ER (+)**/HER (-)
2. **HER2 (+)**
3. ER (-)/ HER2 (-)
1. Essentally all well-differentiated carcinomas (but can range from well-poor)
1. Mucinous, lobula, papillary and cribiform
2. Most are poorly differentiated and no specific morphological pattern
1. 50% = apocrine
2. 40% = micropapillary
3. Almost all are poorly differentiated; circumscribed pushing borders + central fibrosis necrosis; prominent lymphocytic infiltrate (medullary features; medullary carcinoma)
137
\_\_\_\_\_ proto-oncogene encodes **HER2**, a RTK located where?
**HER2 cancers** are caused by \_\_\_\_\_\_
* **ERBB2**
* On the **cell surface**
* **ERBB2 amplification** =\> **overexpression of HER2** =\> growth and survial of tumor cells.
138
**_Lobular carcinoma_**
* Genetic abnormality
* Morphology
* Detection
* Often, what markers?
* **GA**: Biallelic loss of CDH1
* **Morphology**
1. Discohesive cells diffusely infiltrate in a single-file pattern "linear array" (d/t loss of E-cadherin), thus, no desmoplastic response
2. Signet-ring cells with mucin in cytoplasm
3. No ducts/tubules form bc no E-cadherin
* **Detection**: Hard to detect or dx on mammogram
* Often, **ER +**
139
What is this?
**Lobular carcinoma**
140
**_Inflammatory Carcinoma_**
* Most common in?
* Presentation:
* Morphology:
* Prognosis:
* Most common in **African-Americans**
* **Presentation:**
1. Tumor cells in dermal lymphatics =\> decreases drainage from breast =\> swollen, red breast without a mass (mimic acute mastitis)
2. Peau d'orange
* **Morphology**:
* Extensive invasion and proliferation in lymphatic channels
* **Prognosis**: VERY poor and most have distant metastases: 3 year survival is 3-10%
141
**Peau d' orange** = think of?
**inflammatory carcinoma**
142
**_Medullary Carcinoma_**
* Genetic abnormality
* Presents as
* Morphology
* Detection
* Markers
* Prognosis
* Many features of BRCA1- associated carcinomas
* 60% of cancers in BRCA1 carriers have medullary features
* 13% of cancers in BRCA1 carriers are medullary cancer
* **Presents:**
* Soft, well circumscribed mass with pushing (non-infiltrative border) because little desmoplasia
* **Morphology**
1. Syncytial sheets of large cells with pleomorphic nuclei, prominent nucleloi
2. Mitotic figures
3. Lymphocytes and plasma cells surround & in the tumor
* Markers: **ER-** / **HER2-**
* Lymphoplasmocytic infiltrates in tumor increase survival and better response to chemo
143
**_Mucinous (colloid) Carcinoma Morphology_**
* Genetic abnormality
* Presents as
* Morphology
* Detection
* Markers
* Prognosis
* **Presents as:** Soft and rubbery/ pale blue-grey gelatin circumscribed mass with pushing borders.
* **Morphology**
* Cells are arranged in groups within large lakes of mucin
*
144
**Medullary carcinoma**
145
**Mucinous carcinoma**
146
The **outcome** for women with breast cancer is dependent on what?
1. **Biological feature** of the cancer (molecular and histologic type)
2. **Extent the cancer spread** (**stage**) when it is diagnosed.
147
What is feature of **BREAST cancer** has prognostic significance?
**SIZE\***
**Chest wall involvement/Pec mustcle**
148
What is the most favorable cancer based on biology?
Least favorable?
* **Most**: Well-differentiate ER+ low proliferative
* **Least**: Poorly differentiated ER- and/or HER2+
149
What is a major challenge to the success in therapy of breast cancer?
**Genetic heterogeneity of breast cancer**
=\> increases liklihood of aggressive, therapy-resistant cancer
150
**ER-negative, HER-negative tumors** can have many histologic appearances, but which is most common?
**Medullary carcinoma**
151
Tubular carcinoma is somtimes mistaken for what lesion; what immunohistochemical feature can help differentiate between the 2?
- Sometimes mistaken for **benign sclerosing lesion,** like a radial sclerosing lesion
- Immunostain for ER can help since almost all special subtypes of breast cancer are ER (+)
152
What is the **most important** prognostic factor for invasive breast carcinoma in the absence of distant metastases?
**Axillary lymph node status**
153
**_Male Breast Cancer_**
* RF
* MC age diagnosed
* MC mutation
* Marker
* Presentation
* **RF**: same a F
* **Age**: 60-70 YO
* **Mutation**: BRCA2 mutation
* **Marker**: ER+
* **Presentation**: 2-3cm palpable, **_subareolar_** mass with discharge
154
**_Male Breast Cancer_**
* Metasteses
* Distant metasteses
* Typically presents at ____ stages than women, but have similar prognosis stage-for-stage
* Axillary LN (50% of cases)
* Lungs, liver, bone and brain
* Higher
155
What 2 features of breast cancer have **POOR** prognosis?
1. Distant metastases
2. Inflammatory carcinoma
156
What does it mean if **sentinel LN** are **negative**?
Unlikely that the cancer has spread any further & patients can be **spared complete axillary dissection**
157
Risk of __________ ↑ with **size** of primary tumor (independent factors)
**Axillary metastases**
158
Node (-), **\<1cm** = **90%** 10 year survival
Node (-), **\> 2cm** = **77%** 10 year survival
Size is less important for \_\_\_\_\_\_\_\_\_\_, carcinomas, which can metastasize when small
**HER2(+)** and **ER (-) carcinomas**
159
What causes peau d' orange in inflammatory carcinoma?
**Coopers ligament**s tethered to edematous skin
160
Predictive markers in **inflammatory carcinoma**
* **60%** =\> **ER -**
* **40-50%** =\> **HER2 +**
161
What is strongly indicative of **lymph node metastases?**
Tumor cells are present within **vascular spaces (lymphatic or small capillaries)** in about 1/2 of all invasive carcinomas
162
**Proliferative rates** are more important for what cancers?
**ER (+)** HER2 (-) carcinomas
163
What are the **stromal tumors** of the breast?
Two types
1. **Intralobular biphasic tumors: fibroadenoma, phyllodes tumors**
2. Interlobular tumors: lipoma and angiosarcoma
164
What is the most common **benign tumor** of the female breast?
**Fibroadenoma**
165
**Fibroadenoma**
* Who is most often affected by Fibroadenomas and how do they present based on age?
* **Premenopausal women (20-30 YO)**
* **Younger women** = multiple and bilateral palpable mass that fluctuates in size during pregnany and menstrual cycle because responsive to estrogen.
* **Older women** = radiographic density/clustered calcifications
166
**_Fibroadenoma_**
* Morphology:
* Presenation
* Can males get fibroadenomas?
* Epithelium of ducts is surrounded by stroma (peri-canicular) and can be compressed
* Well-circumscribed, rubbery, greyish-white bulges with slit-like spaces
* NO: males do not have intralobular stroma
167
Which benign tumor of the breast may fluctuate in size during pregnancy and menstrual periods; and occurs with **women who get cyclosporin A after kidney transplants?**
Fibroadenoma
168
**Fibroadenomas** are catergorized as what type of proliferative lesions of the breast and how is this related to risk of cancer?
- Proliferative changes **WITHOUT atypia**
- Mild ↑ risk for cancer
169
How does the age of presentation for **phyllodes tumor** differ from that of fibroadenomas?
**60's (post-menopausal women),** which is 10-20 years later than fibroadenoma
170
**Phylloides Tumors**
* Presentation
* Histology
* How do we differentiate from fibroadenoma?
* Most often present as a palpable mass.
* Histology
1. **Leaf-like** bulbous protrusions due to increased stoma cells and overgrowth
* Different from fibroadenoma because
1. Higher cellularity + mitotic rate + nuclear pleomorphism
2. Overgrowth of stroma + Infiltrative borders
171
**_Fibroadenoma or phyllodes tumor:_** which is associated with acquired changes in chromosome, most often a **gain of 1q?**
Phylloides tumor
172
Overexpression _________ is associated with **higher grade** and **more aggressive** phyllodes tumor?
**HOXB13**
173
Most **phyloides tumor**s are \_\_\_\_-grade.
**Low grade,** which **recur** but **DO NOT metastasize.** Can also be intermediate and high grade.
174
Where does phylloides tumor spread?
Regardless of grade, **lymphatic spread is rare, lymph node dissection** is **contraindicated**
175
Which benign tumor of the **interlobular** breast is unusual in that it is equally as common in both women and men?
Myofibroblastoma
176
Who do most sporadic **angiosarcomas** of the breast arise in, what is their grade and prognosis?
**- Young women** (mean age = 35 y/o)
- High grade and poor prognosis
177
What are risk factors **acquired angiosarcomas** of the breast and when do they arise?
**1. Radiation therapy**
**2. Edema**
- Most often arising 5-10 years after tx
178
**Fibromatosis:** clonal proliferation of fibroblasts and myofibroblasts that form a **irregular infiltrating mass** that can involve both **skin** and **muscle**.
Descibe their behavior
**locally aggressive**; does **not** metastasize
