L4 - Breast Pathology (Dr Muhammed Sohail) Flashcards
- Classify common diseases of breast - Describe risk factors for breast cancers - Explain different common types of breast cancers and their prognostic and therapeutic significance including the difference between in-situ and invasive tumours. - Understand the different diagnostic tools and treatment modalities for breast cancers - Explain the breast cancer screening program and role of histopathologists in diagnosis and management of breast cancer
What is a breast
a modified sweat glad covered by skin and subcutaneous tissue
How does histology and physiology play into pathology
Histology (tissue structure) and physiology (tissue function) are fundamental to pathology, as pathologists study the structural changes (histopathology) and functional alterations (pathophysiology) in tissues and organs caused by disease “ if you don’t know abnormal than you don’t know what abnormal is” - you have to understand both histology and physiology
what does the breast rest on
Pectoralis muscle from which it is separated by a fascia
What holds the breast upwards
the Cooper’s ligament ( dense connective tissue which extends from the underlying pectoralis fascia to the skin of the breast)
What is the breast divided into (histology of the breast)
two elements ( like any gland) :
1. parenchema, which is the functional part of the gland
2. stroma/ connective tissue, which supports the parenchema
what is the parenchyma divided into
again into two more elements:
1. terminal duct lobular units (TDLU)
2. branching duct system
What is a terminal duct lobular unit (TDLU)
a structural and functional unit of the breast made up of multiple acini grouped together and the terminal duct. it is the primary site for many breast pathologies e.g. fibroadenoma, lobular cancer or invasive ductal carcinoma
Acini vs acinus
- Acinus is the single functional unit of globular tissue, often sac shaped and responsible for secretion e.g. milk during lactation periods and enzymes
- acini is the plural of acinus and refers to clusters of the sac like cells that form the lobule.
Where do secretions made by the acini need to be drained to
the nipple through the terminal duct (ductal system)
What are interlobular ducts
Interlobular ducts are located between the acini lobules. They collect and transport secretions (e.g., milk or enzymes) from smaller ducts within the lobules (intralobular ducts) to a larger lactiferous duct which drains into the nipple
What are interlobular ducts lined by in the breast
by epithelial cells and surrounded by connective tissue
how many terminal duct lobular units are there on each side of the breast
around 15-20
Where is milk stored
in the lactiferous sinus (and then upon suckling it is released onto the nipple)
What are the two cell types that line the entire ductal lobular system
- the inner epithelial cells
- the outer myoepithelial cells
what characteristic gives myoepithelial cells its name
the fact that it has dual characteristics of both muscle and epithelial cells
what is the normal function of myoepithelial cells
to squeeze the secretion forward by contracting (mycin and actin filaments)
how can the outer myoepthlial cells be used to differentiate between in situ and invasive malignancy in pathology
Malignant invasive carcinomas invade the stroma and produce their own basement membrane, which can stain positive for collagen and laminin, potentially mimicking non-invasive tumours. To differentiate, the absence of myoepithelial cells is key, as invasive carcinomas destroy these cells when invading the basement membrane but cannot regenerate myoepithelial cells
what do you do to make sure that the tumour is benign
when you see the two cell types that line the entire ductal lobular system are intact through staining and using various markers … because the inner epithelium and outer myoepithelial layers have distinctive ultrastructural and immunohistochemical characteristics
what are some example markers used to identify myoepithelial cells
SMM, p63 and ck5/6
Why do we classify diseases
helps group diseases with common features, enabling effective communication across disciplines, understanding of their characteristics, and guiding appropriate treatment strategies.
What does it significy if a disease ends with itis
that it is typically an inflammatory disease
what are the classification for inflammatory conditions
- Acute mastitis
- chronic mastitis
- mammary duct ectasia
- fat necrosis
When does acute mastitis occur
During lactation, bacteria accumulate when it isn’t looked after properly.
when does chronic mastitis occur
when acute mastitis isnt dealt with and the inflammation lasts more than two weeks.
what is a type of chronic mastitis
chronic lymphocytic lobulitis
What is chronic lymphocytic lobulitis?
a condition characterised by a hard breast mass that can easily be mistaken for cancer by clinicians and radiologists. This occurs in females typically over the age of 40, and in particular in diabetic patients
how can chornic lymphocytic lobulitis be distinguished between cancer
through a biopsy and histological analysis, which will show an increased number of large lymphocytes within the lobules and dense fibrotic stroma. This helps reassure the patient that the condition is benign and not cancer.
What are the different stages in mammary duct ectasia
periductal inflammation rich in plasma cells which becomes very fibrotic
how does mammary duct ectasia often present itself
as bloody nipple discharge which appears cancerous (even though it isn’t - when you carry out a biopsy to reassure the patient)
What are possible reasons for fat necrosis
trauma and a cyst rupturing
What is the significance of fat necrosis in the breast
fat necrosis will result in saponification and later dystrophic calcification. On a mammogram (during a breast screening program), the lesion may have an irregular border, density, and calcification, which can mimic the appearance of breast cancer, potentially leading to diagnostic confusion.
what are some examples of proliferative conditions
- Fibrocystic change (most common lesion in the breast)
- Radial scar
What is the most common lesion in the breast
Fibrocystic change
What is radial scarring
a stellate lesion in which there is fibrosis in the stroma
What is the appearance of a radial scar
has similar morphology to cancer with radiating spikes that invades into the surrounding tissue. However they are lined by two cell layers which shows that they are not malignant
what happens in 0.125% of radial scar cases
a radial scar is associated with a carcinoma. therefore it is scored as a B3 lesion for adequate sampling / further investigation.
What are the two main classifications for neoplastic conditions of the breast
- Benign
- Malignant
What are the sub classifications of a benign neoplasm
- Adenoma (benign epithelial tumour of glandular differentiation)
- Fibroadenoma (most common tumour in the breast)
- Papilloma (benign epithelial tumour showing formation of finger like / papillary structures)
What are the sub classification of a malignant neoplasm
- Carcinoma (malignant tumour of epithelial differentiation)
- Sarcoma (malignant tumour of mesenchymal differentiation)
- Paget’s disease ( breast cancer that starts in the nipple and extends to the areola (the dark circle of skin surrounding the nipple)
- Phylloides tumour (malignant tumour of mixed differentiation)
Why is it important to understand how common diseases are
Because it makes diagnosis easier if we know what diseases are common for each age group, sex and how they present
What is the most common presentation of breast disease
a lump (which can be both benign or malignant)
What happens 70% of the time to the lump that forms in the breast
no disease forms or the lump was just part of normal fibrotic changes
what were the result of a survey done on 1000 patients attending a clinic with a breast lump
10% = CANCER
7 = Fibroadenoma
13% = benign tumour
30% = no disease
40% = fibrocystic change (age related change - not really a disease)
(~70% are normal with no disease)
Depending on which age group you are looking at (when they come into the clinic with a lump) what conditions are most common
Later age group –> cancer will be more common
early age group –> Fibroadenoma will be more common
Where and what are some signs and symptoms for diseases of the breast
- nipples
- breast pain
- skin features
- microcalcification
What are some signs and symptoms of diseases of the breast related to the nipple
- Discharge which can be milky if pregnant or bloody due to a duct papilloma or carcinoma
- Retraction which can be due to an invasive carcinoma
- Erythema and scaling which can be due to Paget’s disease or eczema
what are signs and symtoms of disease of the breast more related to the actual breast
- Breast pain which can be due to cyclical (benign breast diseases) or from palpatations (inflammation)
- skin features such as oedema peu d’orange ( carcinoma)
- Microcalcification from DCIS or fat necrosis
What is a skin feature of a carcinoma of the breast
oedema peu d’orange - a phenomenon in which hair follicles become buried in edema, giving the skin an orange peel appearance
What happens to cells in the breast in response to oestrogen
the epithelial cells of the breast (acini) have receptors and when they associate with oestrogen, they multiply (this is to prepare the breasts for pregnancy and lactation) and at the end of the menstrual cycle they will go back to their normal size
What happens if not all the acini go back to their original size in the menstrual cycle.
They will continue to grow, forming microcysts that may develop into larger cysts. Over time, the cyst can become so large that it ruptures, causing injury and inflammation in the surrounding tissue. The release of inflammatory mediators can lead to fibrosis in the affected area.
What is a cyst
A cavity lined by epithelium and containing a fluid secreted by the epithelium
What causes fibrocystic change?
hormonal fluctuations (particularly in oestrogen) during the menstrual cycle which lead to increased stimulation of breast tissue, cyst formation, fibrosis and changes in the size and structure of the acini over a person lifetime
in what age group is fibrocystic change common
in people aged 25-45 years old.
What fibrocystic changes can be seen when carrying out microscopic pictures
- TDLU (Terminal Duct Lobular Unit)
- Calcification
- Cysts
- Fibrosis
- Apocrine metoplasia (Change in the lining of breast cysts (columnar epithelium) to resemble apocrine sweat gland epithelial cells)
- Epithelial hyperplasia (An increase in the number of cells lining the ducts or lobules of the breast.)
When can you get cell hyperplasia during fibrocystic change?
when there is also an increase in the number of cell layers.
What is fibroadenoma
the second most common benign condition in the breast. It is a mixed tumour composed of both proliferating ducts (adenoma) and connective tissue stroma (fibroadenoma)
in what age group do fibroadenomas occur
between the ages of 20-35
when do fibroadenomas increase and decrease in size
- increase in size during pregnancy because of the increase in oestrogen (have oestrogen receptors)
- decrease in size with age
why are fibroadenomas typically not removed
because they are benign tumour that typically don’t cause harm to the patient, however, they may be removed if they grow very large (e.g., over 4 cm) for cosmetic reasons, mental health reasons, or if there is a family history of cancer.
how can you distinguish if a fibroadenomas is benign?
they are completely capsulated (with fibrous capsile surrounding it / well defined margins with no atypia) and don’t invade into the surrounding tissue.
What are carcinomas?
Malignant tumours of epithelial differentiation
what percentage of all cancers in women are carcinomas
20%
what is the ratio of women that develop breast cancer in the UK
1 : 8 (during their lifetime which is high and why we have breast screening programmes)
in what age group are carcinomas the most common cause of death in women
women aged 35-55 years old
What are risk factors for carinoma (in the breast)
- female sex and age
- reproductive history
- obseity
(all 3 linked with oestrogen) - family history in 1st degree relative
- geography (particularly in the west and industrialised countries)
- atypical hyerplasia
(oestrogen hormone and age are common similarities)
what type of reproductive history increases the risk of carcinomas
- early menarche (1st period under 12yo)
- late menopause
- nulliparous women
- 1st pregnancy after 30 years of age
factor increase if 1 vs 2 family relatives have history of carcinomas
- 1.5-2x if 1 relative
- 4-6 x if 2 relatives
what are genes involved / genetic factors that increase someones chances of developing a carcinoma
- BRACA 1 (ch17 - ovary and breast)
- BRACA 2 (ch13)
how common are genetic factors that increase cancer
5-10% of people
where (Geography) is breast cancer particularly common?
The west and industrialised nations
what are the 3 main aetiological mechanims in that case that increase the likelihood of breast cancer?
- Hormonal factors
- Genetic factors
- Environmental factors / influences
Carcinoma of the breast are broaddly classified on the basis of which two criteria
- invasion of the basement membrane ( in situ vs invasive)
- morphology (ductal vs lobular)
What is the significance of diagnosis of carcinomas in - situ
In situ carcinomas cannot metastasise therefore :
- you can potentially cure the patient by complete local excision
- lymph node excision is not required
- better prognosis.
each type of carcinoma classification and how often they occur
- In situ carcinoma (5%)
Ductal carcinoma in situ (DCIS)
lobular carcinoma in situ (LCIS) - Invasive carcinoma
Invasive ductal carcinoma NST (75-85%)
invasive lobular carcinoma (10%)
others (5%)
What is the significance of knowing the difference between ductal and lobular carcinomas e.g. DCIS and LCIS
because the prognosis and treatment are slightly different.
DCIS vs LCIS cancer and treatment
DCIS: If left untreated, is likely to progress into an invasive tumor, so treatment involves surgery to prevent development - prophylactic bilateral mastectomy
LCIS: isn’t considered cancer itself but increases the risk of developing invasive breast cancer in either breast ( tumour may occur in a different breast quadrant). treatment involves close monitor and may include medication to reduce the risk ( don’t need to get a bilateral mastectomy - see this more as a marker of risk factors)
why do many patients with lobular carcinoma diagnosis go through an MRI
because it is a more sensitive method for detecting carcinomas than mammograms to make sure there is no other cancer
what is the issue with lobular carcinoma in the future
lobular carcinomas can come back after many years (after the patient has forgotten which is important when diagnosing an issue that could be related) and can travel to various odd sites of the body
ductal carcinomas in situ (DCIS) features
appears as dilated ducts filled with neoplastic epithelial cells, with an intact myoepithelial cell layer indicating no basement membrane invasion. It may show central necrosis and calcification, aiding diagnosis on mammograms, and is classified into high, intermediate, or low nuclear grades based on cellular morphology.
Why do you sometime see central necrosis in ductal carcinomas in -situ
Rapid tumour growth outpaces the blood supply, creating a hypoxic environment (low oxygen levels) and insufficient nutrition in the centre. This leads to cell death and necrosis, often visible on mammograms as calcifications (necrosis results in dystrophic calcification)
lobular carcinomas in situ (LCIS) characteristics
features lobules with distended acini filled with round, regular neoplastic epithelial cells. The myoepithelial cell layer remains intact, and E-cadherin immunostaining is negative (90% of the time), which helps differentiate LCIS from low-grade DCIS.
What are the characteristics of invasive lobular carcinoma with LCIS?
cells arranged in a single-file pattern, infiltrating the stroma. The invasive component lacks a myoepithelial cell layer. These tumours can be deceptive clinically, radiologically, and histologically, and may be multifocal or multicentric.
What are the charcteristics of invasive ductal carcinoma with DCIS
the invasive tumour consists of small tubular structures lacking a myoepithelial cell layer meaning cells have invaded into the basement membrane
what are some treatment strategies for breast carcinomas
- Surgery
- Chemotherapy
- Radiotherapy
- Hormonal treatment
(sometimes a therapy/treatment is given prior to the surgery)
how is treatment for an individual patient decided
there are interdespilinary team meetings (around 4-5h long) discussing each breast cancer case individually
around how many breast cancer cases are here in Bristol
~1,500 (one of the largest centres in the country)
What is it called if surgery is given after treatment e.g. chemotherapy, radiotherapy or hormonal treatment
Adjuvent treatment (used to remove any tumour remaining after the primary treatment e.g. tumour has shrunk which makes surgery more effective)
What is it called if surgery is performed before other treatments like chemotherapy, radiotherapy, or hormonal therapy
neoadjuvent
What kind of breast surgeries are there?
- Breast Conserving e.g.
Wire guided wide local excision
segmentectomy
central wedge excision - Mastectomy e.g.
Simple mastectomy
Skin paring mastectomy
Sub-cutanous mastctomy
When is a mastectomy offered instead of breast conserving
If the tumour is too large relative to the size of the breast (mutaliating the breast) , if there are multiple tumours in different areas of the breast, the patient has had previous radiotherapy treatment, if there are no clear margins for the tumour ….
Why can’t radiotherapy be given to the same patient multiple times
because this is a carcinogen
What type of mastectomies are there
- Simple mastectomy
- Skin spring mastectomy
- Sub cutaneous mastectomy
( different types are offered depending upon the individual situation as well)
On top of removal of the carcinoma in the breast, what else is removed if the tumour is invasive
the lymph nodes
what kind of axillary lymph node surgeries are available?
- Sentine lymph node (least invasive - the first lymph nodes to which cancer cells are likely to spread from a tumor)
- Axillary node sampling (This involves removing a limited number of lymph nodes from the lower (level I) portion of the axilla (armpit)).
- Axillary lymph node clearance level 1,2,3 (It involves removing a larger number of lymph nodes from all three levels of the axilla.)
When is a sentinel lymph node biopsy (SLNB) performed in breast cancer cases, and what does it involve?
Performed in early-stage, clinically node-negative breast cancer. A dye or radioactive substance is used to identify the first lymph nodes likely to be affected by cancer (sentinel nodes). Only these nodes are removed for testing.
When are axillary nodes sampled
When there is suspician of lymph node involvement. only a sample of the lymph node is removed.
What is axillary lymph node clearance (ALNC) and what are the differences between Level 1, Level 2, and Level 3 lymph node dissection in breast cancer surgery?
Performed when cancer has spread to multiple lymph nodes, requiring removal of a larger number of nodes from the axilla.
Level 1: Removal of the first group of nodes closest to the tumour (near the armpit).
Level 2 : Removal of deeper nodes in the axillary chain.
Level 3 : Removal of nodes near the collarbone and under the pectoral muscle, if cancer has spread extensively.
What type of breast cancer gets chemotherapy
the aggresive kind (not all) e.g.
- large grade 3 tumours with nodal metastasis
- Triple negative or Her2 positive tumours
- Borderline cases have further genetic tests e.g. Oncotype DX to divide chemotherapy
- Adjuvent vs neo-adjuvent chemotherapy
What does it mean if a patient is triple negative
refers to a type of breast cancer that does not express three key receptors that commonly found on cancer cells which makes it more difficult to treat with hormone or HER2 targeted therapies. They also tend to be more aggressive and high risk of recurrence.
Receptors :
Estrogen receptor (ER)
Progesterone receptor (PR)
Human epidermal growth factor receptor 2 (HER2)
what is Her2
an EGFR receptor
What is a targeted therapy used to treat HER2 positive breast cancer
Herceptin
(During its trial in the mid-2010s, a significant response was noted in those who received Herceptin, particularly when combined with chemotherapy. Studies found that after one year of taking Herceptin, there were improved survival rates and reduced recurrence rates. )
what is oncotype DX
a genetic test usesd to assess the risk of breast cancer and help guide cases where c hemotherapy would be beneficial. It is available on NHS and costs ~ £5k
When is radiotherapy to the breast given
after conservative surgery in all caess except certain circumstances
When is raditiotherapy to the breast not given
in patients older than 65, when the tumour is less than 2cm in size or if it is a grade 1 tumour that is ER+ve and HER2 negative
When can radiotheray be given to the chest wall (mastectomy)
when the tumour is larger than 5cm, it is a grade 3 tumour with positive margins or 4 or more lymoh nodes involved
When can radiotherapy be given to the axilla
if the central lymph node is positive but the remaining lymph node isn’t going to be taken out
what percentage of breast cancers are positive for oestrogen receptors (ER)
~80%
What is the significance of the fact that ~80% of breast cancers are oestrogen receptor (ER) positive
this means that they can be given hormone therapy
how long is hormone therapy given for
5 years
what type of hormone therapy is given to premenopausal women
Tamoxifen
What type of hormone therapy is given to post-menopausal women
Aromatase inhibitors (AI)
What is the risk factor if Tamoxifen is given to post-menopausal women
It can cause endometrial cancer
What are the parameters used to make an educated prognosis (“Dr how much time do I have left”) / identify how the tumour is going to behave
- Size of the tumour
- Grade of the tumour
- Histological type of tumour
- Vascular invasion
- Stage of the tumour (nodal status)
- Receptor status of the tumour.
What is an example of a scenario when it is almost certain that a tumour will behave “nicely”
If the tumour was of smaller size, of low grade and tubular like carcinoma with no vascular invasion, T1 tumour with no nodule metastasis
What is the criteria for breast cancer screening programme
- Age group : All women aged between 48-69 years
- Eligibility: Names listed on the Family Practitioner Committee register.
- Screening frequency: Every 3 years.
- Technique: Mammography with two views (craniocaudal [CC] and oblique).
Why are cancer screenings not typically done before the age of 48
Younger women often have denser breast tissue which reduces mammogram accuracy and it isn’t cost effective with it being less common in women under 48
Why do we need a breast cancer screening programme
Breast cancer is highly prevalent in the Western world, with women in high-risk areas having a 1 in 8 lifetime risk. Early detection through screening significantly improves outcomes, as the 5-year survival rate is ~84% for stage I (<2 cm lesion) compared to ~18% for stage IV (>5 cm lesion)
Where do we see microcalcification gistologically
usually asssociated with DCIS mostly high grade with central necrosis (microcalcification isn’t always malignant and can also be associated with benign fibrocystic change)
