Week 7 - C - Pathology 2 (malignant) - Lobular, D.C.I.S/Paget's, Invasive carcinoma - Incidence, Risk, Grading/Staging/Hormone, Prognostics

Question 1

What is a breast carcinoma defined as? Where do breast carcinomas arise? What type of carcinoma is the breast carcinoma?

Answer 1

A breast carcinoma is a malignant tumour of breast epithelial tissue arising in the glandular epithelium of the terminal duct lobular unit (TDLU) It is an adenocarcinoma as it arises in the glandular epithelium but is usually just referred to as a breast carcinoma

Question 2

As stated, breast carcinomas are malignant tumours of the breast epithelial tissue arising from the glandular epithelium of what? What are the two different precursor regions for

Answer 2

The malignant tumours of breast tissue arise from the glandular epithelium of the terminal duct lobular unit (TDLU)- therefore breast carcinomas are technically adenocarcinomas The two different regions they can arise from are the ducal or lobular region of the TDLU

Question 3

Name some precurosr lesions for breast carcinomas for both the ductal and lobular regions? Clue for ductal - the usual precursor lesions here are from intraductal papillomas

Answer 3

Ductal * Epithelial hyperplasia of usual type * Atypical ductal hyperplsia * Ductal carcinoma in situ * Also columnar cell change Lobular Lobular in situ neoplasia

Question 4

What is an in situ carcinoma of the breast?

Answer 4

It is a carcinoma of the breast confined within the basement membrane of the acini and ducts

Question 5

How would an in situ carcinoma be described cytologically?

Answer 5

An in situ carcinoma of the breast is confined to the basement membrane of the acini and ducts It is cytologically malignant but not invascive And carcinoma in situ is classified as either lobular or ductal

Question 6

Lobular in situ neoplasia can be classified as atypical lobular hyperplasia (ALH) or lobular carcinoma in situ (LCIS) What is the difference betwen these two?

Answer 6

Lobular in situ neoplasia:

• Atypical lobular hyperplasia - <50% of the lobule is involved with lobular neoplastic (LN) cells
• Lobular carcinoma in situ - >50% of the lobule is involved with LN cells

Question 7

Does lobular carcinoma in situ usually present with any symptoms?

Answer 7

Lobular carcinoma in situ (LCIS) is an incidental microscopic finding with characteristic cellular morphology and multifocal tissue patterns.

Question 8

How would a lobular carcinoma in situ be described under the microscope?

Answer 8

There is the intralobular poliferation of characteristic cells: The nucleus are small-intermediate sized and there is solid proliferation There is also intracytoplasmic lumens/vacuoles in the cells

Question 9

Lobular Carcinoma In Situ may mimic low grade Ductal Carcinoma In Situ histologically. In these scenarios, pathologists may employ immunohistochemical testing to differentiate between entities What is typically negative on immunohistocehmistry in LCIS? What receptors are typically positive in LCIS?

Answer 9

Typically LCIS is E-cadherin negative on immunohistochemistry Typically it is also oestrogen and progesterone receptor positive

Question 10

What is the function of E-Cadherin?

Answer 10

E-cadherin downregulation decreases the strength of cellular adhesion within a tissue, resulting in an increase in cellular motility. This in turn may allow cancer cells to cross the basement membrane and invade surrounding tissues.

Question 11

Are lobular in situ neoplasia typically single, unilateral, multifocal or bilateral? When does incidence of lobular in situ neoplasia decrease?

Answer 11

Lobular in situ-neoplasia is typically multifocal and bilateral in presentation The incidence of its occurrence typically decreases after menopause

Question 12

How does a lobular in situ neoplasia typically present? ie what does it feel like

Answer 12

It is typically not palpable and not visibile grossly and therefore usually only an incidental finding as it may calcify on mammography

Question 13

Do in situ lobular neoplasia’s raise the risk of developing invasive carcinoma?

Answer 13

They increase the risk of invasive carcinoma by 8 fold

Question 14

Having a family history of invasive carcinoma + lobular in situ neoplasia greatly increases the risk The management of lobular in situ neoplasia greatly depends on how it was discovered ie If it were discovered on core biopsy what would you then carry out? If it were discovered on vacuum or excision biopsy what would you then carry out?

Answer 14

If the lobular in situ-neoplasia was discovered on core biopsy, would go on to carry out a vacuum or excision biopsy to rule out higher grade lesion If it were discovered on vacuum or excision biopsy - would follow up to ensure no recurrence Lobular Carcinoma In-situ is both a risk factor and precursor of invasive carcinoma.

Question 15

What is meant by intraductal proliferation?

Answer 15

Neoplastic growth within the ductal cells

Question 16

What are some of the types of intraductal proliferation? Intraductal proliferation and lobular in situ neoplasia can both be a precursor to invasive carcinoma

Answer 16

Epithelial hyperplasia of the usual type Columnar cell change (lesion) Atypical duct hyperplasia Ductal carcinoma in situ

Question 17

What is the risk of progression to invasive carcinoma with the different intraductal proliferations: * Epithelial proliferation usual type * Atypical ductal hyperplasia * Ductal carcinoma in situ

Answer 17

Epithelial proliferation usual type - 2x increased risk Atypical ductal hyperplasia - 4x increased risk Ductal carcinoma in situ - 10x increased risk

Question 18

Ducal carcinoma in situ have the greatest risk out of the different types of epithelial proliferations of becoming an invasive malignancy What percentage of breast malignancies are they accountable for? Where do the malignancies arise?

Answer 18

They are accountable for 15-20 of breast malignancies and arise in the ductal part of the terminal duct lobular unit

Question 19

Characteristically, do ductal carcinomas in situ take up multiple duct systems or just a singular duct system?

Answer 19

Characteristically the ductal carcinoma in situ takes up a single duct system and therefore is known as characteristically unicentric

Question 20

The DCIS cytologically has malignant cells Histologically how would the DCIS be described? If it involves the lobules what is known as? If it involves the nipple sin what is it known as?

Answer 20

Histologically the DCIS is confined within the basement membrane of the duct and therefore has invaded the breast tissue If the DCIS spreads to the lobule then it known as a DCIS with canceristation of the lobules If the DCIS involes the nipple skin then it is known as pagets disease of the nipple

Question 21

How does DCIS usually present? How is it usually found?

Answer 21

Ductal carcinoma in situ is usally asymptomatic and is seen as microcalcification on the xray

Question 22

What is pagets disease of the nipple? Is this invasive cancer

Answer 22

This is a high grade ductal carcinoma in situ that has extended along the ducts to reach the epidermis of the nupple It is still classified as a carcinom in situ and therefore is non-invasive

Question 23

Paget’s disease of the nipple (breast) is an intrdermal spread of an intraduct cancer How does pagets disease of the breast present and what must be done?

Answer 23

Pagets disease of the breast presents with a nipple that may look like ther eis eczrma on the surface as it appears as a red and scaly lesion - a biopsy must be carried out in this It can sometimes present with an almost weeping discharge

Question 24

What type of biopsy is taken in pagets disease of the nipple?

Answer 24

The diagnosis is made by histologic tissue biopsy (incisional or punch biopsy).

Question 25

Ductal carcinoma in situ can be classified based on its cytological grade usually but also by its histological grade How is a DCIS managed?

Answer 25

This is managed by carrying out surgery and adjuvant radiotherapy Ensure sentinel node biopsy is also carried out if high grade

Question 26

What does a high grade ductal carcinoma in situ show the presence of?

Answer 26

A high grade ductal carcinoma in situ is one where there is the presence of necrosis on the histology

The necrosis usually occurs in the centre of the duct, this is known as a comedocarcinoma

Question 27

What is a microinvasive carcinoma defined as? How is treated?

Answer 27

A microinvasive carcinoma is defined as a DCIS which is high grade with less than 1mm invasion into the breast A mmicroinvasive carcinoma is treated as a high grade DCIS

Question 28

What is an invasive breast carcinoma?

Answer 28

This is where the malignant epithelial cells have breached the basement membrane of the acini or ducts and has infiltrated the normal tissue

Question 29

With invasive breast carcinoma comes the risk of metastases and death The risks are usually linked to age, reproductive history, hormones, history, life-style and genetics Is breast cancer a higher risk at older or younger age? What does reproductive history do for the risk of breast cancer?

Answer 29

Breast cancer risk increases with older age Uninterrupted exposure to oestrogen increases the risk of breast cancer also

Question 30

What are the different reproductive history risk factors for breast cancer? Remember uninterrupted exposure to breast cancer What are the hormone risk factors for breast cancer?

Answer 30

Reproductive history Age at menarche - early menarche Nullparity Age at first birth >30years old Late menopause Not breastfeeding Hormone risk factors - endogenous Exogenous - Combined oral contraceptive and HRT

Question 31

What type of cancers does the combined pill affect? what percentages does it reduce the risk of certain cancers?

Answer 31

Decreases the risk of Colorectal Endometrial - 20-50 reduction in this type Ovarian cancer - 20% reduction every 5 years use with a max of 50% reduction after 15 years use Increases the risk of breast and cervical cancer

Question 32

What were the uninterruped oestrogen exposure again for breast cancer risk factors? Previous breast disease is an obvious risk factor for breast cancer What are lifestyle risk factors for breast cancer?

Answer 32

* Early menarche * Nullparity * Age at first pregnancy >30 years old * Never breastfeeding * Late menopasue

Lifestyle risk factors * Bodyweight - obesity * Physical inactivity - increases risk of breast, endometrial and colorectal mainly * Alcohol consumption and smoking * Diet

Question 33

Genetics plays a large role in being a risk factor for breast cancer What are the two main mutations which greatly increase the risk of developing breast cancer? What percentage lifetime risk do carries of these mutations have for breast cancer?

Answer 33

These are BRCA1 and BRCA2 mutations BRCA1 mutations - confer a 65% lifetime risk of breast cancer BRCA2 mutations - confer a 40% lifetime risk of breast cancer

Question 34

What does an affected 1st degree relative do to the risk?

Answer 34

This double the risk fof having breast cancer

Question 35

We have now gone over different risk factors for breast cancer, the introduction of what in 1988 greatly reduced the mortality of breast cancer sin the UK?

Answer 35

The introduction of breast screening in 1988 greatly reduced the mortality of breast cancer

Question 36

For invasive breast cancer, how common is this amongst cancers in females? The mortality rates of breast cancer as stated is decreasing, what is happening to the incidence rates?

Answer 36

Breast cancers is the commnest female cancer and the 2nd commonest cause of cancer death in women The incidence of breast cancer is increasing

Question 37

Once the breast cancer invades the stroma of the breast and skin, it can invade the muscles of the chest wall as well What are the regional draining lymph nodes for breast cancer? Which is the sentinel node?

Answer 37

The regional draining lymph nodes are the axillary nodes The sentinel node would be the anterior axillary lymph nodes

Question 38

What are the different ways in which an invasive breast carcinoma can be classified?

Answer 38

Can be classified based on the * Type * Grade * Stage * Gene expression * Hormone receptor expression

Question 39

What are the two most common types of breast cancer histopathologically? What is the tumour grade a measure of?

Answer 39

The most common type is ductal invasive carcinoma of the breast Lobular invasive carcinoma is the next most common type of breast cancer Tumour grade is a measure of the tumour differentiation ie how similar the tumour is to the parent tissue

Question 40

In cancer, well-differentiated cancer cells look more like normal cells under a microscope and tend to grow and spread more slowly than poorly differentiated or undifferentiated cancer cells. WHat is the difference between low grade and high grade tumours?

Answer 40

Low grade * Very similiar * Well differentiated * This is a good prognosis High grade * Very different * Poorly differentiated * Poor prognosis

Question 41

There are different “scoring systems” available for determining the grade of a breast cancer. One of these systems is the Nottingham Histologic Score system. There are three factors that the pathologists take into consideration: * Tubular differentiation (the more the tubules change, the less clearly differentiated they are) * the nuclear pleomoprhism(how “ugly” the tumor cells look) * the mitotic activity What is the maximum score from this grading system?

Answer 41

This would be grade 9

Question 42

The grading from the 3 components – Tubular differentiation (1-3) – Nuclear pleomorphism (1-3) – Mitotic activity (1-3) The grading is added up and split into grad 1-3

WHat score would each grade be?

Answer 42

Grade 1 - Score of 3,4,5

Grade 2 - Score of 6or7

Grade 3 - Score of 8or9

The higher the grade of tumour the worse the survival prognosis

Question 43

After knowing the type of breast cancer and its grade, important to the know the staging of the breast cancer How is breast cancer staged? Can be stage 1-4 or TNM Just talk about stages 1to4 on this card

Answer 43

Stage 1 -confined to breast and breast is mobile Stage 2 - confined to breast, breast is mobile although lymph nodes in ipsilateral axilla are affected Stage 3 - the tumour is fixed to muscled but not the chest wall, skin involvement, there is ipsilateral nodal involvement and the nodes may be fixed Stage 4 - Complete fixation of tumor to chest wall, distant metastases

Question 44

Describe the TNM staging of breast cancer? (the T refers to the size of the tumour) N - nodes M - metastases

Answer 44

• T1 - tumour <2cm
• T2 - tumour 2-5cm
• T3 - tumour >5cm
• T4 - Fixed to skin or chest wall
• N0 - no nodal metastases
• N1 - Mobile ipsilateral nodes
• N2 - Ipsilateral nodes affected and fixed
• M0 - no distant metastases
• M1 - distant metastases

Question 45

Often the breast can be desribed as peau d’orange, what does htis mean? Which score for T in the TNM does the peau d’orange appearance of the breast score?

Answer 45

When the cancers blocks the dermal lymphatics draining causing oedema of the breast and dimpling over the cooper’s ligamenets giving an orange peel like appearance Gives a T score of 4, which also is when it may be fixed to the chest

Question 46

The breast cancer as said can be graded on its type, grade, stage and gene and hormone receptor expression Lets talk about hormone receptor expression What are the three different examples?

Answer 46

• 80% ER positive • 67% PgR positive • 14% HER2 positive Majority are oestrogen receptor positive then progesterone recepetor positive and finally her2 receptor positive

Question 47

What does ostreogen receptor positive breast cancers respond to?

Answer 47

Oestrogen receptor positive predicts the cancer response to anti-oestrogen therapy Ie oopherectomy Tamoxifen Aromatase inhibitors GnRH antagonsitis

Question 48

What type of drug is tamoxifen? What may it increase the risk of? Name an aromatase inhibitor? WHat does it do? When are these drugs used?

Answer 48

Tamoxifen is a selective oestrogen receptor modulator (SERM) May increase the risk of uterine cancer so warn to report vaginal bleeding Aromatase inhibitor ie letrozole or anastrazole - these inhibit peripheral oestrogen syntheseis Aromatase inhibitors only usually given if post menopasual

Question 49

If pre-menopasual and ER+ve, what drug can be used?

Answer 49

Tamozifen or GnRH receptor antagonist ie goserelin

Question 50

What does HER 2 stand for? When is the overexpression of the receptor seen? (ie how common in breast cancer) What does HER2 cause?

Answer 50

It stands for human epidermial growth factor receptor 2 (HER2) Overexpression and amplification seen in ~15% of breast cancers If you have too much HER2 expression, it makes the cells in the breast divide in an uncontrollable way.

Question 51

– HER 2 overexpression or amplification predict response to which drug? Can be given for HER2+ve tumours

Answer 51

This would be trastuzamab (Herceptin) • New class of anti-cancer agents • Humanised mouse monoclonal antibody • Active in HER2 positive disease

Question 52

What are the breast cancer tumour prognostic factors?

Answer 52

Tumour size, the grade, lymph node status, ER/PgR/HER2 status, presence of vascular invasion

Question 53

The nottingham prognostic index takes into account the histopathology of the tumour only ie the size, grade and stage How is this score calculated?

Answer 53

Nottingham prognostic index (NPI) - 0.2 x tumour size (in centimetres) x histological grade (1-3) x the nodal status (1-3 nodes involved)

Question 54

Pathology and Breast Cancer

• * • Breast cancer pathology predicts outcome
• * • Breast cancer pathology predicts response to specific therapies
• * • Pathology aids the rational management of breast cancer

State how the grades are caluculated and the stages

Answer 54

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Question 55

When assessing tumour invasion, it is important to known its extent of spread into the axilla How is this carried out?

Answer 55

Pretreatment ultrasound evaluation of the axilla should be performed for all patients being investigated for early invasive breast cancer and, if morphologically abnormal lymph nodes are identified, ultrasound-guided needle sampling should be offered. Sentinel lymph node biopsy (SLNB) is the preferred technique.

Question 56

What is the treatment of breast cancer? Stage 1and2 or Stage 3 and 4

Answer 56

Stage 1 and 2

• * Surgery - removal of tumour by wide local excision or mastectomy +/- breast reconstruction + axillary node sampling
• * Radiotherapy is also recommended for all patients after wide local excision and as is chemotherapy
• * Hormone agents given sometimes also

If stage 3 and 4

• Systemic so would probably use chemotherapy, hormonal therapy and targeted therapy

Question 57

When would radiotherapy be given after mastectomy?

Answer 57

Usuauly considered if there is 4 or more nodes involved or the tumour is greater than 5cm in size or there are positive surgical margins for cancer after mastectomy Or if it is T4 disease - fixed to skin or chest wall, or when peau d’orange

Question 58

What would be different about the treatment of breast cancer in women who are pregnant?

Answer 58

During pregnancy, hormonal therapy with trastuzamab or tamoxifen is contraindicated as is radiotherapy unless potentially life saving

Question 59

What is the treatment for lobular in situ neoplasia? What is the treatment for DCIS?

Answer 59

Lobular in situ neoplasia Always want an excision biopsy (or wide local excision) or vacuum assisted biopsy to take the large sample DCIS Surgery with adjuvant radiotherapy