Risk Factors For Breast Cancer

Describe the etiopathogenesis, clinical features, investigations and principles of treatment of benign and malignant tumours of breast.

Carcinoma Breast Incidence:

• Breast cancer is a major global public health concern for women in the 21st century.
• Worldwide it is the leading cause of cancer in women and the leading cause of cancer-related mortality.
• In India as of 2018 ICMR statistics obtained from Indian Cancer Registries, it is the number one cancer afflicting women, also the leading cause of cancer-related mortality.
• In the United States, breast cancer remains the most frequent cancer in women and the second most frequent cause of cancer death.
• A better understanding of tumour biology, genetics and the availability of advanced multimodality treatment options is gradually increasing survival.

Risk Factors For Breast Cancer

The aetiology of breast cancer is multifactorial. A combination of risk factors appears to have a role in its causation. The majority of these factors carry a small to moderate increase in risk for any individual woman. We cannot identify risk factors in least half of women who develop breast cancer. These factors can be divided into two broad categories:

1. Non-modifiable
2. Modifiable

1. Non-Modifiable Risk Factors:

Female sex: Women are 100 times more likely to have breast cancer as compared to men.

Age: Increasing age is a strong risk factor. Carcinoma breast is very rare below 20 years of age. More common in 35 to 75 years of age. Indian women tend to get carcinoma breast a decade earlier than Western women.

Race: Highest in whites, rare in Japanese and Taiwanese populations.

Breast Cancer and Hereditary Factors:

• A family history of breast cancer has long been recognized as a risk factor for the disease, but only 5 to 10% of women who develop breast cancer have a true hereditary predisposition. Overall, the risk of developing breast cancer is increased 1.5- to 3-fold, if a woman has a mother or sister with breast cancer.
• BRCA 1 and BRCA 2 genes have been found in long arm of chromosome 17 and 13 respectively in women with a family history of carcinoma of the breast. BRCA I and BRCA II are the genes associated with increased risk.
• BRCA I and II mutations are more common in Ashkenazi Jews. They are more prone to ovarian cancer also.
• Hence all patients with BRCA I and BRCA II mutations should consider a prophylactic bilateral oophorectomy after childbearing is completed, with bilateral mastectomy.
• Cowden’S Disease (multiple hamartoma syndrome):
• It is associated with reduced tumour suppressor gene PTEN. 30–50% of patients will develop breast cancer by 50 years of age. The lesions found in this syndrome are multiple facial trichilemmoma (pathognomonic), oral papilloma, bilateral breast cancer, haemangiomas, lipomas, thyroid tumours, etc.
• Ataxia Telangiectasia: It is associated with haemangioma and carcinoma breast.
• Li-Fraumeni syndrome is a rare disease with familial breast cancer and is associated with inherited mutation of tumour suppressor P53 gene.
• It is a rare autosomal dominant disorder. 90% of carriers will develop breast cancer by the age of 50. They also can have other tumours in childhood, such as soft tissue sarcoma, osteosarcoma, and leukaemia.

Patient which Requires Genetic Evaluation:

• Diagnosis of DCIS (ductal carcinoma in situ) or invasive breast cancer + one or more of the following:
• Diagnosed at 50 years and younger
• Triple-negative breast cancer diagnosed at 60 years and younger
• At any age:
• A known mutation in a cancer susceptibility gene within the family
• An additional breast cancer primary
• ≥1 close blood relative (first to third degree) with breast cancer 50 years and younger
• ≥1 close blood relative with ovarian cancer at any age
• ≥2 close blood relatives with breast cancer, pancreatic cancer, or prostate cancer (Gleason score ≥7 or metastatic) at any age
• An individual of Ashkenazi Jewish ancestry
• Male breast cancer Patients without a diagnosis of cancer should consider further genetic risk evaluation if they have:
• A close relative with a known mutation in a cancer susceptibility gene; 2 or more breast primaries in a single individual; 2 or more individuals with breast cancer on the same side of the family with at least one diagnosed at age of 50 years or younger; ovarian cancer Male breast cancer
• A first- or second-degree relative with cancer at age of 45 years or younger.
• A family history of 3 or more of the following:
• Breast cancer, pancreatic cancer, prostate cancer (Gleason 7 or higher or metastatic), melanoma, sarcoma, adrenal cortical carcinoma, brain tumours, leukaemia, diffuse gastric cancer, colon cancer, endometrial cancer, thyroid cancer, kidney cancer, dermatologic manifestations, and/or macrocephaly, or hamartomatous polyps of GI tract.

History of Breast Cancer:

• Risk of developing second breast cancer is about 0.5 to 0.7% in women with previous invasive breast cancers.
• Breast cancer is 3 to 4 times more likely to develop in women with a first degree relative who had breast cancer.
• This risk is further increased, if they had premenopausal and bilateral cancer.
• Women with ductal carcinoma in situ (DCIS) are at an increased risk of developing ipsilateral and contralateral breast cancers (4.1% after 5 years).

Hormonal Factors:

• The development of breast cancer in many women appears to be related to female reproductive hormones, particularly endogenous oestrogens.
• Early age at menarche, nulliparity or late age at first full-term pregnancy, and late age at menopause increase the risk of developing breast cancer.

Benign Breast Disease:

• Benign breast lesions are classified as proliferative or nonproliferative. Nonproliferative disease is not associated with an increased risk of breast cancer.
• Proliferative disease without atypia results in a small increase in risk, whereas proliferative disease with atypical hyperplasia is associated with a greater risk of breast cancer.

1. Modifiable Risk Factors:

• Breastfeeding, particularly for longer duration, lowers the risk of breast cancer.
• Postmenopausal hormone replacement therapy (HRT) particularly when a combination of oestrogen and progesterone is used.
• Diet: Increased risk has been found in postmenopausal obese women and is due to increased synthesis of oestrogen (oestradiol) in the body fat.
• As a result of the aromatisation of androgens in adipose tissue, circulatory oestrogen levels are increased.
• Increased intake of saturated fats and reduced intake of phytoestrogens increase risk.
• Decreased intake of nutrients such as vitamin C, folate, and β-carotene increases the risk.

Lifetime risk factors and relative risk factors:

• Obesity is associated with both an increased risk of breast cancer development in postmenopausal women and increased breast cancer mortality.
• Smoking is risk factor for carcinoma breast.
• Alcohol intake is associated with a 1.5-fold increased risk of breast cancer.

Environmental Factors

Exposure to ionizing radiation at a young age increases risk of breast cancer. There is marked increased risk ofbreast cancer development has been reported in women who received mantle irradiation for the treatment of Hodgkin lymphoma before age of 15 years.

Breast Cancer Pathology

Non-Invasive Breast Cancers (Precursor Lesions):

• These are lesions which may or may not turn into invasive breast cancer.
• They do not invade the basement membrane and survive by assimilation.
• They are diagnosed by screening mammogram or biopsy.

Ductal Carcinoma in Situ (DCIS):

• Proliferation of malignant-appearing mammary ductal epithelial cells without evidence of invasion beyond the basement membrane.
• A comedo-type ductal carcinoma in situ, also known as comedo-carcinoma in situ is the high-grade subtype of ductal carcinoma in situ (Figs 39.30 and 39.31 shown here to compare with infiltrative carcinoma).
• It completely fills and dilates the ducts and lobules in the terminal ductal-lobular unit with plugs of high-grade tumour cells with central necrosis “comedonecrosis”.
• Common presentation
  • Mammographically detected calcifications
  • Mass on a mammogram (no palpable mass)
  • Palpable lump
  • An incidental finding at biopsy
  • Paget disease of the nipple

There is no regional lymphadenopathy or distant metastasis

Treatment:

• Breast conserving surgery followed by whole breast radiotherapy is the treatment of choice.
• Alternatively simple mastectomy with sentinel lymph node biopsy should be done because mastectomy alters the lymphatic drainage pattern and makes future SLNB unfeasible.
• There is no role for chemotherapy.
• Premenopausal women receive tamoxifen.
• Postmenopausal women receive letrozole.

Van Nuys Prognostic index for DCIS:

The Van Nuys Prognostic Index (VNPI) classifies patients with DCIS to guide decisions on the best treatment option. The index uses patient age, tumour size, tumour growth patterns (histological grade) and the amount of healthy tissue surrounding the tumour after removal (resection margin width) to predict the risk of cancer returning.

Low-risk (total VNPI score of 4–6):

• Breast conserving surgery (BCS) without radiotherapy is recommended.
• Intermediate-risk (total VNPI score of 7–9)
• BCS with radiotherapy is recommended.
• High-risk (total VNPI score of 10–12)
• Mastectomy is recommended.

Lobular carcinomas vs ductal carcinoma in situ:

Lobular Carcinoma in Situ (LCIS):

• Proliferation of generally small and often loosely cohesive cells originating in the terminal duct-lobular unit, with or without pagetoid1 involvement of terminal ducts.
• It does not present clinically and is diagnosed on biopsy or surgery for other lesions.
• It cannot be detected usually by imaging like mammogram.
• There are two types: Classic and pleomorphic
• Enlargement and distension of acini making up the terminal duct lobular unit (TDLU).
• Proliferation of monomorphic, dyshesive, small, round, or polygonal cells with loss of polarity and inconspicuous cytoplasm.
• Essentially, groups of round, almost identical looking cells that fill and expand the lobule spaces, occasionally extending into the adjacent terminal ducts.
• Pleomorphic LCIS
• One or multiple distended lobules
• Enlarged and dyscohesive cells
• Irregularly shaped nuclei and abundant eosinophilic cytoplasm
• Regularly associated with comedo necrosis and calcification and hence is often mammographically detectable.
• Classic LCIS requires no surgical treatment and since there is a risk of carcinoma breast which may be bilateral and hence patients should be followed up closely.
• Patients should be informed of this risk.
• Pleomorphic LCIS requires an approach just like DCIS. Comparison of DCIS and LCIS is given.

Lobular carcinomas vs ductal carcinoma in situ:

Invasive Breast Cancer:

• The most widely used classification is that of the World Health Organization. It is based on the growth pattern and cytological features of the invasive tumour cells.
• Most invasive breast cancers arise in the terminal duct lobular unit regardless of histologic type.
• WHO classification (the list is not complete but a list of important histological subtypes).
• Invasive breast carcinoma (This term is used when cancer cells invade through basement membrane).
• Foot-Stewart Classification of Invasive Breast Cancer

1. Paget’s disease of the nipple

2. Invasive ductal carcinoma: 85%

• Adenocarcinomas [scirrhous, simple, NST (80%)]
• Medullary carcinoma 4%
• Mucinous (colloid) carcinoma 2%
• Papillary carcinoma 2%
• Tubular carcinoma 2%

3. Invasive lobular carcinoma 10%:

4. Rare types: Adenoid cystic, squamous cell, apocrine:

Invasive Carcinoma of No Special Type (NST): (Commonest)

• Invasive lobular carcinoma
• Tubular carcinoma
• Cribriform carcinoma
• Mucinous carcinoma (colloid carcinoma)
• Medullary carcinoma
• Papillary carcinoma
• Paget’s disease of the breast/nipple
• Inflammatory breast cancer

Invasive (Infiltrating) Ductal Carcinoma:

• The most common histologic type of breast cancer is invasive (infiltrating) ductal carcinoma, composing 70 to 80% of cases.
• Since it is diagnosed after excluding all other types of breast cancer, it is classified as infiltrating carcinoma of no special type (NST).
• The older terminology was infiltrating ductal carcinoma, not otherwise specified (NOS).
• Scirrhous carcinoma was a term previously used as it presents as a hard lump and produces grating sound when it is cut.
• Atrophic scirrhous is an infiltrating duct carcinoma seen in elderly patients when there is atrophy of the breast.
• Tumor cells induce desmoplastic reaction in stroma causing excessive fibrosis and less cellular reaction.
• Depending on the grade the tumour may form glands and tubules and shows stromal desmoplasia.
• Welldifferentiated tumours show gland/tubule formation in >75% of the invasive component.
• Malignant cells are round to polygonal with round to oval dark nuclei with a few mitoses. Perivascular and perineural space infiltration is common.

Invasive Lobular Carcinoma (ILC):

• Comprises approximately 10% of breast cancers.
• Incidence of this type of breast cancer is increasing, especially among postmenopausal women.
• Characterized by small, round cells that are bland in appearance and have scant cytoplasm, which infiltrate the stroma in single file and surround benign breast tissues in a targeted manner.

• Infiltration typically does not destroy anatomic structures or incite a substantial connective tissue response.
• They do not form distinct masses or have mammographic findings and hence are difficult to diagnose.
• They tend to be multifocal and multicentric and have a propensity for bilaterality.

Special Types:

Medullary Carcinoma:

• Accounts for less than 5% of all breast cancers.
• Medullary breast cancer is more common carriers of BRCA-I mutation.
• It is commonly a triple-negative breast cancers: ERve PR-ve HER2/neu negative.
• Occurs in younger women breasts in the reproductive age group.
• It feels more soft than hard.
• Medullary growth of large cells with a high histological grade (particularly high mitotic count), circumscribed edges, central fibrosis and necrosis, and is often accompanied by lymphocytic infiltration. This is thought to represent a good host response.
• Despite its aggressive histological features (such as the lack of hormonal receptors and grade of 3), medullary carcinoma has a better prognosis than nonmedullary carcinoma.

Inflammatory Carcinoma:

• The word inflammatory is a misnomer and given because of the physical findings of erythema and warmth.
• It constitutes less than 1% of all cases of carcinoma breast.
• It may be misdiagnosed as breast abscess.
• Predominantly seen during pregnancy and lactation

• Malignancy grows so rapidly that it invades more than half of the breast tissue.
• It is classified as a type of locally advanced breast cancer (LABC).
• Dermal lymphatic invasion is characteristic. Redness, pain and enlargement appear so suddenly that it is diagnosed as mastitis. Hence the name, mastitis carcinomatosa.
• It is differentiated from breast abscess by absence of fever and a classic ‘peau d’orange’ or ‘orange peel’ appearance of the affected breast.
• Presence of gross peau d’orange due to blockage of subdermal lymphatics.
• This variety has the worst prognosis as it has high angiogenic and angioinvasive capability. Most of them are ER negative.

Paget’s Disease of the Nipple:

• Paget’s disease of the breast has been recognized as a distinct clinical entity for over 120 years.
• It is rare (1–4.3% of all the breast carcinomas).
• It is a misnomer as it is not a disease of the nipple but is often associated with underlying ductal carcinoma in situ and/or invasive ductal cancer.
  
  

 

• It is usually a thickened, sometimes pigmented, eczematoid, erythematous weeping or crusted lesion with irregular borders.
• Usually, the lesion is limited to the nipple or extended to the areola, and in advanced cases, it also may involve the surrounding skin.
• The surface of the lesion is occasionally slightly infiltrated.
• Complaints of pain or itching are frequent. The nipple may be retracted or deformed.
• Early changes including scaling and redness may be mistaken for eczema or some other inflammatory conditions.
• Retraction of the nipple can be seen.
• Lump appears much later than changes in the nipple.
• It characterized by the invasion of epidermis by Paget’s cells, malignant glandular epithelial cells with enlarged pleomorphic and hyperchromatic nuclei, with discernible but not prominent nucleoli, with abundant pale, clear cytoplasm, which often contains mucin. The cytoplasm may also contain melanin pigment.

Mucinous Carcinoma (Colloid Carcinoma):

• It accounts for about 2% of breast cancers and tends to occur in older women above 75.
• If palpable, it tends to manifest as soft masses.
• At pathological examination, the dominant feature is the presence of mucin within and surrounding cancer cells.
• A core biopsy specimen usually gives a gelatinous appearance.
• Microscopically, it is formed by large mucin lakes surrounded by mucus-producing cancer cells.
• It has a good prognosis.

Comedocarcinoma of Breast:

Comedos means cast or plug. It is a peripheral carcinoma wherein the tumour cells block the ductules by forming a case or plug producing a small cystic lesion. It is an example for intracystic carcinoma.

Multicentric and Multifocal:

• Multifocality refers to occurrence of a second in situ breast cancer within same breast quadrant as the primary in situ cancer.
• Upper and outer quadrant is commonly involved (60–65%) because breast tissue is more there.

Clinical Features Of Carcinoma Breast

Carcinoma Breast Symptoms:

• Lump in the breast is the most common presentation. It is the breast tissue in the upper and outer quadrant which is most frequently involved (65%) as this area has the most amount of tissue.
• Bleeding per nipple is an uncommon symptom of carcinoma of the breast. It involves multiple ducts and is unilateral.
• Pain is a late sign in carcinoma breast.
• About 5% of patients present with bony metastasis give rise to bony pains, i.e. pathological fractures, paraplegia, quadriplegia.

Carcinoma Breast Signs:

• Important signs are described here first, later clinical methods are described.
• The nipple may be elevated and retracted. It is a centrally retracted nipple: Recent retraction indicates malignancy.
• It is due to fibrosis caused by extension of growth along the lactiferous duct.
• Fixation to the skin, ulceration, peau d’orange, fixation to pectorals and chest wall occurs late.

• Destruction of the nipple is a feature of Paget’s disease of the nipple.
• The lump is usually hard and irregular but it can also be firm and in some subtypes—soft.
• It gets fixed to breast tissue and cannot move independent of the breast.
• In the later stages, it can get fixed to the pectoralis major muscle (lumps which are located in the upper outer and inner quadrants and lower inner quadrants).
• The lower outer quadrants tend to get fixed to the seratous anterior muscle (part of chest wall). In advanced cases, the ribs and intercostal muscles are involved (chest wall).
• Puckering or dimpling of skin is due to thin fibrous bands which are embedded in the subcutaneous fat and are attached to the skin and pectoral fascia called ligaments of Cooper which are infiltrated by the malignancy.
• It is not considered as skin involvement and, therefore, is not a late sign.
• Oedema of the breast is involvement of the skin and is, therefore, a late sign.
• Peau d’orange: Literally means orange peel appearance. It is due to obstruction of the subdermal lymphatics by malignant cells, sparing the sweat glands and hair follicles, therefore, giving an orange peel-like appearance.
• Satellite nodules are multiple nodules in the skin. Their presence indicates advanced disease.
• Ipsilateral axillary lymph nodes: They are the first station of regional lymph node spread and they should be examined for enlargement, size, consistency and fixity.
• Ipsilateral supraclavicular nodes are the next station of involvement

Signs which do not Affect Staging:

• Nipple retraction
• Dimpling
• Involvement of pectoralis major muscle

Signs of Locally Advanced Breast Cancer (Important for Staging):

Skin Involvement:

• Peau d’orange
• Oedema of the breast
• Ulceration of the skin
• Satellite nodules in the skin

Fixity To The Chest Wall:

• Seratous anterior
• Ribs
• Intercostal muscle

Inflammatory Breast Cancer:

• 2/3rds of the breast have oedema.
• 1/3rd of the breast has Peau d’orange.

Regional Lymph Nodes:

• Fixed axillary group of lymph nodes
• Internal mammary group of lymph nodes are involved.
• Ipsilateral supraclavicular group of lymph nodes.

Distant Metastasis:

• The carcinoma can spread to the contralateral axilla and supraclavicular nodes. They should be always examined.
• Bony tenderness should be looked for in the spine, long bones, skull, etc. (axial skeleton).
• The respiratory system can be involved by secondaries and pleural effusion.
• The abdomen is examined for:
• Hepatomegaly with nodular liver
• Ascites due to peritoneal deposits
• Bilateral ovarian involvement Krukenberg’s tumour.
• Per vaginal and per rectal examination for deposits in the pouch of Douglas (rectouterine pouch).

Spread of Carcinoma Breast

Local Spread:

Infiltration into skin causing ulceration, fungation, bleeding, secondary infection and foul smelling discharge/subsequently it invades the pectoralis major and minor muscles, the serratus anterior and chest wall.

Lymphatic Spread:

• Axillary group of lymph nodes: Central group, pectoral, lateral, subscapular.
• The internal mammary lymph nodes: Drain the medial quadrant tumours may involve in the upper three or four intercostal spaces, close to the sternum.
  Ipsilateral supraclavicular lymph nodes.
• Earlier considered as distant metastasis, now is included under regional lymph nodes.
  Lymphatics from inner medial quadrant of the breast penetrate the rectus sheath and join the intraperitoneal lymphatics, thus producing ascites, Krukenberg’s tumour (in premenopausal patients, ovary is vascular and fertile), rectovesical deposits, secondaries in the liver.
• Blood spread
  • Liver
  • Lung parenchyma
  • Secondaries in flat bones are common (vertebral column, femur, ribs, scalp, etc.).
  • Secondaries in brain result in headache, vomiting and blurring of vision.
  • Malignant pleural effusion is the common cause of death in carcinoma of breast.

Breast Cancer Triple Assessment

The breast triple assessment is a hospital-based assessment that allows for the early and rapid detection of breast cancer. Triple assessment test is used as Gold standard in diagnosing all palpable breast lumps.

It includes:

• Clinical examination
• Radiological imaging (ultrasonography and mammography)
• Biopsy of the lump
• Combining the three modalities increases the overall accuracy of diagnosis to nearly 99%.

Clinical Examination Of A Case Of Carcinoma Breast

Inspection should be done only in two positions: Bending forward is no longer required as the same information can be obtained by palpation. Detailed examination is given in Manipal Manual of Clinical Methods, 1st edition.

1. Hands by the Side of the Patient

1. Examine the nipples:

• Compare the level of the nipples
• A tumour may push the nipple in the opposite direction.
• Inspect the nipple of the side with tumour for
• Destruction: This indicates Paget’s disease of nipple
• Retraction
• If it is present, ask the patient, if this was recent in origin: This indicates malignancy.
• The retraction of nipple in carcinoma breast is usually central
• Nipple discharge
• Bloody discharge indicates duct carcinoma.

2. Areola: Peau d’orange may occur in the areola because of subdermal lympatic obstruction leading to oedema, sparing the hair follicles.

3. Examine the skin of the breast for:

• Ulcerations
• Satellite nodules
• Dimpling
• Peau d’orange
• Oedema
• Erythema
• Scars
• Dilated veins

4. Inspect the breast to see whether a lump is visible:

If a lump is seen, it is described in detail. If it is not seen, ask the patient to press against her hip on the ipsilateral side, this contracts the pectoralis major and makes the lump more visible allowing its description.

2. Hands above the Head Prominent

• The effected breast may get lifted sometimes indicating fixity to pectoral fascia.
• Peau d’orange gets noticed better by this manoeuvre.
• Any lesions in the inframammary fold and inferior quadrant of the breast is better visualized.

Palpation

• Local rise of temperature and tenderness are usually not found in cases of carcinoma of the breast.
• However, rapidly growing carcinoma and inflammatory carcinomas do exhibit local rise of temperature, redness and tenderness.
• Describe the lump: The lump is the commonest presentation of carcinoma of the breast. The upper and outer quadrant is the commonest site of carcinoma of the breast because of more breast tissue in that quadrant.
• Typically, the lump is hard and irregular. However, very often carcinoma breast can present as a firm lump. In mastitis carcinomatosa, the lump can be soft due to tumour necrosis.
• Intrinsic mobility may be present but it moves with the breast tissue (fibroadenoma moves independent of breast tissue).
• Plane of the swelling Lift the skin. If it is not possible, it indicates that the tumour is fixed to skin.
• Pectoralis major contraction test: Ask the patient to keep the hands on the flanks and press against the hip.
• If the lump cannot be moved after contraction, it indicates fixity to pectoralis major.
• Fixity to the chest wall
• A tumour which is fixed to the chest wall will not be mobile when pectoralis major is relaxed.
• Serratus anterior contraction test by pressing the hand against the wall. The test has to be done when the tumour is situated in the outer and inferior quadrant.

Axillary Lymph Nodes Examination

• There are 5 groups of nodes in the axilla which are described under lymphatic drainage of the breast.
• However, very often, central group of nodes and pectoral nodes are enlarged. It is very difficult to feel the apical group of nodes.
• If the axillary nodes are hard, with or without fixity, they are significant.
• Soft to firm nodes need not be malignant but can be due to secondary infection because of fungating, ulcerating growth.

Examination of Supraclavicular Lymph Nodes:

Presence of these nodes indicates it is a N3C-stage 3

Examination for distal metastasis, opposite breast for any mass, opposite axilla, abdomen, skull and spine and respiratory system.

Workup for a carcinoma breast case

• Assessment of general
  • History health status
  • Menopausal status
  • Physical examination
  • Full blood count
  • LFT
  • RFT
  • Cardiac evaluation
• Assessment of primary
  • Physical examination tumour
  • Breast ultrasound
  • Mammogram
  • MRI (when indicated only)
  • Core biopsy: Histology, grade, ER, PR, HER2, Ki67
• Assessment of lymph
  • Physical examination nodes
  • Ultrasound
  • Ultrasound-guided FNAC
• Assessment of distant
  • CT scan chest and abdomen metastasis
  • Bone scan when symptoms of bone pain are present and in all stage III cases

Axillary Lymph Nodes Investigations

Axillary Lymph Nodes Laboratory:

• Full blood count: Hb% may be lowered. Planning for neoadjuvant chemotherapy requires the TLC and DLC.
• Liver function test: Elevated serum alkaline phosphatase indicates metastasis in the liver or bone.
• Renal function test is required when planning a chemotherapy regimen.

Axillary Lymph Nodes Local Imaging Studies

• These include ultrasound of breasts, bilateral mammogram and ultrasound of lymph nodes. All three are mandatory in assessment.
• Ultrasound of the breast is the first investigation
  • It accurately measures the lump size.
  • More accurate for lymph node assessment.
  • It can differentiate between cystic and solid lesions.
  • It is more accurate in assessment of breast lump in younger women.
• Mammogram
  • Detects any multifocal and multicentric lesions.
  • It is done before the biopsy as biopsy of any type will introduce artefacts and obscure its interpretation.
• Breast MRI: It is an optional investigation (not mandatory). Indications are:
  • BRCA-associated carcinoma breast
  • Bilateral tumours
  • Reconstructed breasts
  • Breast implants
  • Assessment of neoadjuvant chemotherapy

Mammography:

Details are given below.

• The process of using low-energy X-rays (usually around 30 kVp) to examine the human breast for diagnosis and screening.
  Diagnostic accuracy is about 90–95%.
• Mammography Procedure:
• A selenium coated X-ray plate is used directly in contact with the breast.
• The breast is compressed using a dedicated mammography unit.
• Parallel-plate compression evens out the thickness of breast tissue to increase image quality by reducing the thickness of tissue that X-rays must penetrate, decreasing the amount of scattered, reducing the required radiation dose, and holding the breast still (preventing motion blur).
• In screening mammography, craniocaudal view and mediolateral oblique images of the breast are taken.

• Diagnostic mammography may include these and other views, including geometrically magnified and spot-compressed views.
• A mammogram is reported using BI-RADS (breast imaging-reporting and data system)

Mammography:

• Screening: Asymptomatic women of more than 40 years.
• Diagnostic: Women with pain in the breast, mass, discharge, family history of breast cancer.
• Two views—mediolateral oblique view is for outer quadrant and axilla. Craniocaudal view is for medial quadrants.
• Radiation dose is 0.1 centigray (cGy)—4 times that of chest X-ray dose but no side effects.
• Benign lesions are round, punctate, popcorn-like, etc.
• Highly suspicious—pleomorphic, heterogeneous
• Solid mass with irregular edges, spiculation
• Long tentacles—tentaculation
• Fine scattered calcification—microcalcification
• Distortion of architectural pattern of the breast
• Asymmetrical thickening of breast tissues

Bi-Rads Scores Range From 0 To 6

1.  This score identifies a mammogram study that is still incomplete. The X-ray may have been cloudy, making it difficult to read the images. This can happen, e.g. if the patient moved at the precise moment the picture was taken.
2. This score means that mammogram is negative (i.e. no evident signs of cancer were found).
3.  This score also means that mammogram is normal, with no apparent cancer, but that other findings (such as cysts) are described in the report.
4.  A score of 3 means that mammogram is probably normal but that there is an approximately 2% chance of cancer. Hence, follow-up with a repeat mammogram in 6 months. And if there is a family or personal history of breast cancer, the radiologist may opt to do more tests at this stage rather than wait.
5.  This score means that the findings on the mammogram are suspicious and that there is an approximately 20 to 35% chance that a breast cancer is present. Core biopsy is a must in such cases for tissue sample.
6.  This score means that the mammogram results are highly suspicious, with a 95% chance of breast cancer.
7.  This means that patients have already been diagnosed with breast cancer and the pathologist has confirmed the diagnosis.

Screening Mammogram:

• Mammogram done for detection of breast cancer in breasts with no lumps
• Always bilateral
• Indications:
  • Women above 40. Below this age, women tend to have more fat in the breast so lesion can be missed.
  • Women who have a family history of breast cancer begin screening after the age of 30.

Diagnostic Mammogram:

• When it is performed in a palpable lump as a part of triple assessment.
• Always bilateral.
• It is always done before biopsy as biopsy of any type will introduce artefacts and obscure the BIRADS.
• Done to detect multicentricity and multifocality especially when breast conservation is planned.

Multicentricity:

• Multicentricity is defined by presence of carcinoma in a breast quadrant other than the one containing the dominant mass more than one quadrant.
• Multifocality
• Multifocality is defined as the extension of a single carcinomatous focus within ducts and lobules limited to one region or quadrant (limited to one quadrant).

Biopsy:

• The presence or absence of carcinoma can only be reliably determined by a tissue biopsy.
• Biopsy techniques include fine-needle aspiration cytology (FNAC), core needle biopsy, and excisional biopsy.

1. Fine Needle Aspiration Cytology (FNAC):

• No longer the investigation of choice.
• Is easily performed and results are obtained quickly.
• False positive rates are low (1%) but higher false negative rates (15%) can occur.
• Requires a trained cytopathologist for accurate specimen interpretation.
• Does not reliably distinguish invasive cancer from DCIS.
  Biological markers are difficult to obtain.
• Currently used in superficial tumours and for assessing lymph nodes.

2. Core Biopsy (Tru-cut Biopsy)

• It is the investigation of choice with clear advantages over FNAC.
• It can differentiate between invasive breast cancers and carcinoma in situ.
• Allows for placement of a clip to mark the area of interest in the event that subsequent surgical excision or definitive breast cancer treatment is indicated.
• Using vacuum-assisted biopsy (VAB) device increases amount of lesion sampled and reduces false negative rates to less than 1%.

Biological Markers which have become a critical component of multidisciplinary treatment planning are determined using the core biopsy samples therapy.

1. Estrogen Receptors: Estrogen receptors (ER) are overexpressed in around 70% of breast cancer cases, referred to as ‘ER-positive’, and can be demonstrated in such tissues using immunohistochemistry. Normal value of ER is 10fmol/mg proteins. It is considered positive >10 fmol/mg proteins. Upper levels as high as 1000 fmol/mg proteins may be there. The overexpression means hormonal therapy will be an option in treatment of carcinoma breast.

2. Progesterone receptors: Progesterone receptors (PR/PgR).

3. HER2/neu (human epidermal growth factor receptor 2):

It is a membrane tyrosine kinase receptor and a marker of cellular proliferation, expressed in up to 50% of cases. It is usually associated with ER negativity and high grade tumour, poor prognosis but there is a better response to adriamycin.

4. Ki-67: Proliferative index: Antigen Ki-67 is a nuclear protein that is associated with and may be necessary for cellular proliferation.

HER2:

• Measured by immunohistochemistry
• Test for gene amplification—fluorescent in situ hybridisation (FISH) is gold standard
• 25% of all breast cancers overexpress HER2
• It is a transmembrane tyrosine kinase receptor
• High grade tumours usually express this
• ER negative—poor prognosis
• Responds to ‘TRASTUZUMAB’
• Thus ‘FISH’ is done only when HER2/neu is 2+

Ki-67:

• Also known as MKI67
• It is a marker for cellular proliferation
• It depicts growth fraction of all proliferation
• Higher values suggest aggressive tumour
• A cut-off value of less than 14% is generally used to denote low and high values

Based on the biological markers Ca breast is classified into intrinsic subtypes which is given.

Association of clinicopathologic features of breast cancer with intrinsic subtype:

Adjuvant treatment approaches in breast cancer based on biological markers:

Treatment based on breast cancer intrinsic subtype:

Gene Expression Profiling:

• Expensive
• Individualized treatment
• Requires core biopsy sample or the excised tumour

MammaPrint:

• • 70-gene breast cancer assay which is a prognostic and predictive diagnostic test for early stage breast cancer patients that assess the risk that a tumour will metastasize.
  • Divides patients into low-risk and high-risk groups.
  • Determines whether or not a patient will benefit from chemotherapy.
  • High risk will get chemotherapy and low risk can avoid it without a risk of recurrence.

Oncotype DX:

• • 21 gene assay
  • It is done usually in oestrogen receptor positive tumours.
  • Results are reported as a recurrence score (RS),
  • where a higher RS is associated with a worse prognosis and will benefit from chemotherapy.

Image-guided Biopsy in Indeterminate Lesions:

• Done when lesions cannot be palpated or there is repeated inconclusive reports.
• Ultrasound guided.
• Wire localisation
• When lesions cannot be palpated.
• Under mammogram guidance, a hooked wire is placed in the vicinity of a suspicious lesion or microcalcifications.
• The patient is then shifted to the OT.
• In the theatre, the area around the hook is excised along with hook and the tissue is sent for histopathology.
• Mammogram-guided stereotactic biopsy
• It is the choice in case of microcalcifications or nonpalpable lesions seen only on mammogram.
• The coordinates of the lesion are calculated digitally and the patient is positioned accordingly.
  • Any of the methods of biopsy can then be done including FNAC, CORE biopsy or vacuum assisted core biopsy (VACB).\
  • MammotomeTM VACB is a hand held device which consists of a control unit which maintains aspiration at constant values (23–25 mmHg) and of a driver where a 11–14 G needle is placed.
• MR guided

Excision Biopsy:

• Seldom performed
• Incision is placed in planned manner
• Complete haemostasis
• No drains are placed
• Indications after core needle biopsy
• Imaging abnormalities that cannot be targeted for core biopsy
• Atypical ductal hyperplasia
• LCIS
• Lack of concordance between imaging findings and histologic diagnosis
• Radial scar
• Complex sclerosing lesions
• Papillary lesion

Incisional biopsy with frozen section:

• Frozen section is no longer proven very reliable in decision making in carcinoma breast
• However, some centres practice this method where an incisional biopsy is taken and on receiving a report of malignancy definitive surgery, i.e. mastectomy is performed.

Investigations for Metastasis

• Chest X-ray
  • Pleural effusion
  • Lung secondaries: They look like ‘cannonballs’ due to the lung compliance
  • Mediastinal widening
• Abdominal ultrasonography is done to rule out secondaries in the liver, ascites, rectouterine deposits. Incidence of liver metastasis in Ca breast is 6%.
• Contrast-enhanced CT scan of thorax and abdomen is gradually replacing ultrasound of abdomen and chest X-ray in investigating carcinoma breast as it is more accurate.
• Bone scan: Incidence of bone metastasis in stage IIb and stage III is high, hence recommended in these settings. CT scan of brain is not recommended unless there are symptoms.
• PET-CT scan is used only in locally advanced breast cancer and inflammatory breast cancer.

After the surgery, pathological assessment of carcinoma breast is done.

Pathological Assessment of the Tumour

• Size: The maximum diameter of tumour removed.
• Assessment of entire specimen of breast for any other tumours.
• The resected margins, especially the deep margins should be evaluated.
• The distance of the margins of tumour from resected margins should be evaluated.
• Vascular invasion should be noted.
• Tumour grade
  • Originally was used Scarff-Bloom-Richardson (SBR) grading system
  • Now the Elston-Ellis modification of the SBR grading system (Nottingham grading system) is preferred.
  • Depends upon three factors:
• Nuclear pleomorphism
• Tubule formation
• Mitotic rate
  • Tumours are given scores and graded.

Elston-Ellis modification of the SBR grading system:

• The scores for each of these three criteria are added together to give a final overall score and a corresponding grade as follows:
• 3–5 grade 1 tumour (well-differentiated). Best prognosis. 6–7 grade 2 tumour (moderately differentiated). Medium prognosis.
• 8–9 grade 3 tumour (poorly differentiated). Worst prognosis.

Lymph Node:

• Number of lymph nodes removed (a minimum of
• 10 is mandatory in axillary dissection).
• Number of positive nodes should be mentioned.

Biological Markers Should Be Assessed:

• Oestrogen receptor (ER)
• Progesterone receptor (PR/PgR)
• HER2
• Ki-67 index

American Joint Committee on Cancer Staging: Breast cancer:

Regional Lymph Nodes—Clinical (cN):

Regional Lymph Nodes—Pathologic (pN):

Distant Metastases (M):

Stage Group: