Breast Disease Flashcards
ANATOMY AND HISTOLOGY of breast
- “modified sweat gland”
- 15-20 lobes, each acting as an independent glandular unit with a lactiferous duct opening to the nipple
o Functional unit is the “Terminal Duct Lobular Unit” (TDLU)
o TDLU→intralobular ducts →interlobular ducts→lactiferous duct
o Interlobular stroma is present between lobes & divides each lobe into numerous lobules
o Intralobular stroma surrounds each TDLU
Many TDLU in close proximity to each other will empty into a lactiferous duct
- lactiferous duct will travel to nipple. Right before they reach the nipple, the lactiferous duct transforms into lactiferous sinuses
- lining of major ducts ranges from double-layered cuboidal epithelium in the smaller ducts (those closest to TDLU)→to pseudostratified columnar→to stratified squamous epithelium in largest ducts (those nearest the nipple)
- luminal (lining epithelium) with surrounding myoepithelial layer and basement membrane
- TDLU has central lumen, which is surrounded by an inner layer of ep cells. The ep cells are the functional cells of the breast and secrete milk. The inner ep cells are surrounded by myoepithelial cells, which is surrounded by basement membrane
- in cancer, the inner layer of ep cells undergo cancerous change
- the cancer is in situ if the ep cells are surrounded by the myoepithelial cell and basement layer still. And invasive if not surrounded
Terminal ductal-lobular unit
Composed of lobule and terminal duct
- non-proliferative (fibrocystic) changes
- proliferative changes without atypia
- proliferative changes with atypia (atypical hyperplasia)
- in situ carcinoma
- invasive carcinoma
Large lactiferous ducts & sinuses & nipple
- intraductal papillary lesions
- duct ectasia
- squamous metaplasia of lactiferous ducts
- subareolar abscess
- mastitis
- nipple adenoma
- paget’s disease of the nipple
Intralobular stroma
- fibroadenoma
- phyllodes tumour
- PASH (in notes)
Interlobular stroma
- fat necrosis
- benign mesenchymal tumours
- malignant mesenchymal tumours/SARCOMAS
- PASH (in lecture)
List of BENIGN BREAST lesions/DISORDERS
Mastitis
Fibroadenoma
Non-proliferative lesions/Fibrocystic Change
Proliferative lesions without Atypia
Proliferative lesions with Atypia aka atypical hyperplasia
Mastitis
Most cases occur during lactation/breastfeeding/chestfeeding
Predisposing factors: cutaneous fissures in nipples & breast engorgement
Etiologic agents: Staphylococci & Steptococci
Signs & Symptoms: breast is tense, hot, red, painful; axillary lymphadenopathy; general signs
and symptoms of acute infection, tender axillary lymph nodes
Differential diagnosis: inflammatory carcinoma
Complications: abscess formation requiring surgical drainage; healing of area by fibrosis may
result in fixation of overlying skin mimicking carcinoma
Fibroadenoma
Most common cause of a benign breast mass
May occur at any age, but most common in female patients between ages of 20 and 35 years
Features:
o Discrete, mobile, usually non-tender breast mass
o Rounded/lobulated contours
o Firm to rubbery texture
o No dimpling/retraction of overlying skin
o Composed of both stromal and epithelial elements
o No atypia, rare stromal mitoses
Can be excised
More aggressive counterpart of a fibroadenoma: phyllodes tumour
Non-proliferative/Fibrocystic Change, Proliferative Change without Atypia, Proliferative Change with Atypia
Although the term “fibrocystic disease” is frequently used by both clinicians and pathologists, this does not represent a distinct entity, either clinically or pathologically.
- Clinically, this term has been applied to a condition in which there are palpable breast masses that fluctuate with the menstrual cycle and may be associated with pain and tenderness.
However, at least 50% of female patients have palpably irregular breasts and, in many patients, these palpable lumps represent physiologic changes rather than a pathologic process.
- Thus, the term “fibrocystic change” is a more appropriate term to use.
The removal of the word disease also removes the implication that all of the changes encompassed by this term are associated with an increased risk of carcinoma development.
- Indeed, the vast majority of patients designated as having fibrocystic change are not at any increased risk for developing breast cancer.
Several studies have shown that by separating the various histologic components of fibrocystic change, subgroups of patients with different risks for breast carcinoma development may be identified.
Non-proliferative lesions
aka Fibrocystic change
- no increased risk for subsequent breast
cancer
o cysts
o apocrine change
o duct ectasia
o fibrosis
o mild hyperplasia
Proliferative lesions without atypia
mildly increased risk for subsequent breast cancer: RR X 1.5-2
o florid/moderate epithelial hyperplasia
o intraductal papillomas
o sclerosing adenosis
o complex sclerosing lesion/radial scar
o complex fibroadenoma
Proliferative lesions with atypia
aka atypical hyperplasias
- moderately increased risk for subsequent breast cancer: RR X 4-5
o atypical ductal hyperplasia
o atypical lobular hyperplasia
BREAST CANCER EPIDEMIOLOGY AND RISK FACTORS
Lifetime risk of breast cancer is approximately 1 in 8 for females living in North America
Important epidemiologic considerations and risk factors include:
o Age & sex
- F > M
- 75% occur in the 50+ age group
o Family history
- 80% sporadic, 20% family history
o Geographic factors
- Americas/Europe > Asia/Africa
o Race/ethnicity
- Genetic, social determinants of health
- white women have most breast cancer
- black women has less breast cancer than white women, have tend to have it at younger ages and have more aggressive versions
o Reproductive history
- early menarche
- nulliparity (never been pregnant)
- no Breast feeding
- older age at first pregnancy
o Ionizing radiation
- especially if exposure occurs while breast is still developing
o Others: obesity, hormone replacement, mammographic density, EtOH
FAMILIAL BREAST CANCER
Approximately 20% of cases of breast cancer are associated with a penetrant dominant genetic predisposition.
- Clinical suspicion is warranted if:
o there are 3 or more affected members in a family
o breast cancer occurs in a patient <35 years of age
o patient has bilateral breast cancer
o family has members with breast and ovarian cancers as well as endometrial and colon cancers or sarcomas in both females and males
Penetrance: the proportion of individuals carrying a particular variation of a gene that also express an associated phenotype
High penetrance mutations (5-7%)
- familial breast and ovarian cancer (BRCA1/2)
- Li-fraumeni (p53)
- cowden syndrome (PTEN)
- Peutz-Jeghers (STK11)
Moderate penetrance mutations (< 3%)
- Li-fraumeni variant (CHEK2)
- Ataxia Telangiectasia (ATM)
Low penetrance mutations (>10%)
- much of the genetic component of breast cancer risk remains uncharacterized and probably arises from combinations of flow-penetrance variants that, individually, might be quite common in the population
Of all families with a strong family history, about 40-45% will have an abnormality in the BRCA1
gene (chromosome 17) and about 30-40% will have an abnormality in the BRCA2 gene
(chromosome 13)
Other mutated genes associated with familial breast cancer include TP53 (Li-Fraumeni
Syndrome) and PTEN (Cowden Syndrome)
Using molecular genetic techniques, it is possible to identify individuals who have these
abnormal genes, and who are therefore at high risk of developing breast cancer. The best way to manage such patients clinically is, however, still uncertain.
CLASSIFICATION OF BREAST CANCER
Non-invasive (in situ) carcinoma (i.e. carcinoma confined to ducts or lobules by an intact myoepithelial cell layer)
* ductal carcinoma in situ (DCIS)
* lobular carcinoma in situ (LCIS)
Invasive
* ductal carcinoma aka no special type
* special type:
o lobular carcinoma
o tubular carcinoma
o mucinous carcinoma
o cribriform carcinoma
o medullary carcinoma
o metaplastic carcinoma
o combined
Paget’s disease of the Nipple:
- Special clinical and histological manifestation of either DCIS or invasive carcinoma.
Inflammatory Carcinoma:
- Special clinical manifestation of invasive carcinoma, often with characteristic accompanying histological features.
DCIS
Ductal carcinoma in situ
o Pre-mammographic era, DCIS accounted for only 5% of all cancers
o Since introduction of mammography, DCIS now represents about 20% of new breast cancer cases. (The remaining 80% are invasive carcinomas).
o Often shows mammographic abnormality. Often linear/casting/pleomorphic calcifications on mammography; sometimes nipple discharge
o DCIS carries a local risk for recurrence or invasive carcinoma
o Goal of treatment is complete excision
o Radiotherapy reduces risk of recurrence if margins close
o Higher risk of recurrence or invasive carcinoma if extensive, high grade, incompletely
excised.
LCIS
Lobular carcinoma in situ
o Incidence varies - around 1% of breast biopsies
Usually found incidentally on biopsy for another reason
Risk factor for invasive carcinoma
- non-obligate precursor
o There are no good clinical or anatomic correlates that can be used to identify patients
with LCIS
o Subsequent invasive carcinoma after biopsy only occur at an incidence of:
- 15-20% in the same breast
- 10-15% in the contralateral breast
o Goal is usually not excision but close clinical followup
Invasive ductal carcinoma
aka infiltrating mammary carcinoma of no special type
o Incidence of no special types is about 80% of all invasive mammary carcinoma
o On clinical examination, a poorly defined mass of variable hardness and mobility
o Grossly, roughly circumscribed and non-encapsulated, with fibrous extension into the
adjacent breast stroma that create a “crab-like” or stellate appearance that feels gritty; cut surface is depressed below surface of adjacent breast tissue and is hard, grey and granular. Often, pinpoint foci or streaks of chalky-white necrotic tumour centrally
o Microscopically, the malignant cells are arranged as solid nests, ductules/tubules, cords, anastomosing masses, and mixtures of all these patterns. Cytological detail varies from relatively bland to very pleomorphic. There may be invasion into lymphovascular spaces.
- malignant cells invade stroma
o Meaningful histological grading (also applies to special type): Semiquantitative method based on i) degree of tubule formation, ii) degree of nuclear atypia, and iii) mitotic count or rate to assign an overall score (3-9) and grade (1-3).
Special histological types of invasive mammary carcinoma
o Incidence of special types is about 20% of all invasive mammary carcinoma
o Some (but not all) of these subsets of invasive carcinoma, when in pure form, indicate a
more favourable prognosis compared to those of “no special type”
- exceptions are metaplastic and lobular
Paget’s Disease of the Nipple
- Reddening of the nipple and areola, scaling, eczematous change, eventually erosion and ulceration of the nipple
- Painless mass is palpable in the underlying breast in 50% of cases
- “Paget” cells are present singly or in clusters within the surface epithelium of the nipple, areola,
or both - “Paget” cells are large cells with abundant pale cytoplasm and large nuclei with prominent
nucleoli - “Paget” cells = carcinoma cells
- Paget’s disease of the nipple are almost always associated with underlying breast carcinoma,
either in situ or invasive - in situ lesions predominate in patients without a palpable mass, while invasive carcinomas are
more common in the presence of a palpable mass
Inflammatory Carcinoma
- Clinical appearance resembling diffuse acute mastitis. Often, a clinical appearance of peau d’orange is also present. The microscopic correlate is usually diffuse dermal lymphatic obstruction by tumour
- Peau d’orange without clinical appearance of acute mastitis does not qualify as inflammatory carcinoma
- Dermal lymphatic invasion without clinical appearance of acute mastitis does not qualify as inflammatory carcinoma
- A worse prognosis is associated with the clinical picture of “inflammatory carcinoma.”
Is a T4 disease or high stage disease
BEHAVIOUR OF BREAST CANCER
Local Extension
Lymphatic Invasion
Vascular Invasion
Local Extension
- Invasive breast carcinoma can infiltrate and cause fixation to adjacent structures.
- If the tumour is deep, fixation may occur to the pectoralis (chest) muscles
- If the tumour is superficial, fixation may occur to the skin. Skin involvement can also result
in nipple retraction and inversion when the tumour arises near the central zone. Once skin fixation occurs, cutaneous ulceration may follow. Skin involvement may impart a “peau d’orange” appearance even in the absence of tumour emboli within lymphatics as the skin involvement interferes with dermal lymphatic drainage.
Lymphatic Invasion
- Lymphatic invasion results in spread to lymph nodes draining the quadrant of the breast in which the tumour is located.
- “Inflammatory carcinoma” and “peau d’orange”: often tumour emboli are detectable microscopically within dermal lymphatics
Vascular Invasion
- Occurs as the result of vascular permeation in the breast in the region of the tumour, in areas of lymph node metastases with the neoplastic tissue breaking into adjacent tissue and involving blood vessels, or tumour overwhelming the lymph node barrier and reaching the systemic circulation.
- Vascular metastases usually occur to lungs and pleura, liver and bone.
- Not infrequently, vascular metastases may also be seen in adrenal glands and brain.
PROGNOSTIC FACTORS IN BREAST CANCER
Major prognostic factors:
1. invasive vs in situ
- presence of distant metastases
- occurs by vascular permeation in region of primary tumour, at site of lymph node metastasis, or by tumour overwhelming the lymphatic system and eventually reaching systemic circuation
- usual sites: lung, pleura, liver, and bone
- other sites: adrenal, brain
tumour size - lymph node metastases
- if no distant metastases, then axillary lymph node status is the most important prognostic factor for invasive carcinoma - Tumour size
- Local extension
- deep location extension –> fixation to pectoralis muscle
- superificial local extension –> skin fixation, nipple retraction, ulceration, peau d’orange - clinical picture of “inflammatory carcinoma”
Minor prognostic factors:
1. histological subtype of IMC (invasive mammary carcinoma - special type or no special type)
- tumour type and grade
- lymphatic/vascular invasion
- detect by H and E
- histologic grade
- detect by H and E - lymphovascular space invasion
- lymph node status
- detect by H and E - hormone receptors: ER/PR, HER2/neu
- estrogen and progesterone receptors
- Her2/neu
- detect by special tests - proliferative activity or rate
- detect by special tests - Gene expression profiling
- detect by special tests
Clinical presentation of breast disorders
- palpable mass
- lumpiness (without discrete mass)
- pain
- nipple discharge
- mammographic abnormaility
Sampling of breast disorders
Nipple discharge
- nipple discharge collected and smeared under microscope
- not as common anymore
- diagnostic yield is low
Fine needle aspiration biopsy
- if patient has a mass or bump
Core biopsy
- if patient has a mass or bump
- most common way that breast tissue is sampled in NA
Punch biopsy
- if patient has skin changes
Breast duct excision
- invasive surgical procedures
Lumpectomy/ Partial mastectomy
- invasive surgical procedures
- commonly performed if patient had a prior diagnostic core biopsy
Mastectomy
- invasive surgical procedures
- commonly performed if patient had a prior diagnostic core biopsy
Fat necrosis
Firm, irregular mass with or without erythema of overlying skin, skin retraction and dimpling
May indicate cancer
May be history of trauma
Lesions are often superficial
- breast cancer is often deep though
Doing biopsy will show
- empty spaces representing adipose tissue
- adipose tissue surrounded by chronic inflammatory infiltrate such as histiocytes and lymphocytes
Intraductal papilloma
Happens to people in their 30s to 50s
Bloody nipple discharge or palpable areolar mass (more rarely)
Tan-pink friable lesion within a dilated duct
Treatment is local excision
Fibrocystic change
Common in younger women
- has lumpy, bumpy breasts
Clinical: palpable breast masses that fluctuate with the menstrual cycle and may be associated with pain or tenderness
Common finding, most often represent physiological changes rather than a pathological process
Cysts, fibrosis, apocrine, metaplasia, mile usual epithelial hyperplasia
Immunohistochemistry
First, detect cancer via histology like H and E, then do immunohistochemistry to determine ER, PR, and HER2 status
ER and PR positivity is a favourable prognostic feature
- ER and PR positivity predict response to hormonal therapy (i.e. tamoxifen or aromatase inhibitors)
Her2/neu overexpression is a poor prognostic feature
- Her2/neu overexpression predicts response to agents that target this protein (i.e. trastuzumab)
Sometimes tumour will be ER and PR positive, or only ER positive.
- Sometimes, it can be negative for ER, PR, and HER2, and is called triple negative breast cancer, which usually has a poor prognosis
