Case 11.5 – Breast Cancer (new diagnosis)

The most important part of the diagnostic process will be to gain a tissue diagnosis, using the most appropriate sampling technique.

Factors that will influence this are:

• Risk factor assessment for breast cancer
• General medical history
• Presence/absence of a palpable lump
• Examination for evidence of metastasis

Next Steps:

• Core needle biopsy for histological diagnosis
• Staging investigations if cancer confirmed
• Multidisciplinary team discussion for treatment planning

Carcinoma in Situ (CIS)

Carcinoma in situ refers to the period during which normal epithelial cells undergo apparent malignant transformation but do not invade through the basement membrane. There are two forms:

Lobular Carcinoma in Situ (LCIS):

• Not associated with any radiological markers
• May not be detected early
• Approximately 10-37% go on to develop invasive carcinoma
• Future cancers may be in either breast regardless of the site of in-situ changes
• Approximately 50-65% of future malignancies are of ductal origin
• LCIS is a marker of increased risk of diffuse bilateral disease rather than a true anatomic precursor of lobular cancer

Ductal Carcinoma in Situ (DCIS):

• Represents all types of CIS that are not identified as lobular
• Can be further subdivided into:
  • Comedo (particularly menacing type)
  • Solid
  • Cribriform
  • Micropapillary
• Necrosis and microcalcification are common
• May be seen on mammography - incidence increasing with earlier diagnosis
• Approximately 30-50% go on to develop invasive carcinoma
• Subsequent malignancies are ductal in origin, arise in the ipsilateral breast and usually confined to the same quadrant

Ratio: DCIS to LCIS is 3:1

Infiltrating Ductal Carcinoma

This is the commonest form of cancer of the breast - approximately 80%. The most common form is of non-descript but highly variable histological type. Sheets, cords, nests and trabeculae of tumour cells may be present all in varying amounts. If the main bulk of tumour is of this type then the presence of more-specific histological features in small amounts does not appear to alter the prognosis.

Medullary Carcinoma

This form constitutes about 6% of the total.

Histologically:

• Completely circumscribed borders
• Syncytial sheet-like growth pattern
• Diffuse infiltrate of lymphocytes
• Variable number of plasma cells
• Nearly 50% of these tumours are associated with intraductal carcinoma, usually at the periphery of the main tumour

Colloid (Mucinous) Carcinoma

Largely confined to the elderly population, this tumour accounts for approximately 2% of breast cancers.

Histologically:

• Large pools of mucin surrounded by variable groups of tumour cells
• The classical signet ring appearance of mucinous tumours in other sites is NOT seen in breast colloid carcinoma

Tubular Carcinoma

Clinical Features:

• Found in younger than average patients, with the late 50s being the peak age
• Diagnosis usually made at mammography
• Lesion is still small (less than 1 cm)
• Up to a fifth of breast tumours identified at mammography may be of this type

Histologically:

• Well differentiated
• Randomly arranged tubular elements in a loose stroma

Papillary Carcinoma

This accounts for less than 2% of cases of breast carcinoma and usually presents in the seventh decade.

Histologically:

• Well circumscribed
• Marked papillary differentiation

Inflammatory Breast Carcinoma

This tumour accounts for 1% or slightly more of breast carcinomas. It is rapidly progressive.

Characterised by:

• Erythema
• Peau d'orange
• Skin ridging
• With or without a palpable mass
• Unlike other breast cancers, the commonest presenting feature is pain

Pathophysiology:

• The characteristic appearance of a diffusely enlarged breast is consequent upon the dissemination of tumour cells through the lymphatics of the dermis
• If tumour cells remain within superficial lymphatics and blood vessels, then telangiectatic carcinoma may arise with numerous purple papules and haemorrhagic, vesicle-like lesions covering the breast
• Extensive involvement along tissue planes may produce a nodular pattern or, when associated with extensive fibrosis, a diffuse thickened lesion - a thoracic girdle (carcinoma en cuirasse)

Paget's Disease of the Nipple

This condition presents clinically as a chronic, eczematoid eruption of the nipple. Indeed the diagnosis may be confused with eczema although there are distinct differences.

• Constitutes approximately 2% of histological types
• Almost always associated with an underlying intraductal or invasive carcinoma

The international TNM classification allows grouping of the disease into clinical stages. Staging allows comparison between groups of patients and also defines those unsuitable for an attempt at surgical removal but who may be suitable for other forms of adjuvant therapy.

TNM Classification of Breast Cancer

T - Primary Tumour:

TNM Stage	Pathological Description
Tis	Carcinoma in situ (pre-invasive) Paget's disease (no palpable tumour)
T0	No clinical evidence of primary tumour
T1	Tumour less than 2 cm
T2	Tumour 2-5 cm
T3	Tumour greater than 5 cm
T4	Tumour of any size but with direct extension to chest wall or skin: (a) Fixation to chest wall (b) Oedema, lymphocytic infiltration, ulceration of skin or satellite nodes (c) Both (a) and (b)

N - Regional Lymph Nodes:

TNM Stage	Pathological Description
N0	No palpable ipsilateral axillary lymph nodes
N1	Palpable nodes not fixed: (a) Inflammatory only (b) Containing tumour
N2	Fixed ipsilateral axillary nodes
N3	Ipsilateral supraclavicular or infraclavicular nodes or oedema of arm

M - Distant Metastasis:

TNM Stage	Pathological Description
M0	No evidence of distant metastasis
M1	Evidence of distant metastasis

Stage and Prognosis According to TNM Classification

UICC Stage	TNM	Category	5-year Survival
I	T1, N0, M0	Early cancer	84%
II	T1, N1, M0 T2, N0-1, M0	Early cancer	71%
III	Any T, N2-3, M0 T3, any N, M0	LABC (Locally Advanced Breast Cancer)	48%
IV	Any T, any N, M1	Metastatic	18%

Breast Surgery

The principle of surgery in early breast cancer is to completely eradicate the primary tumour and any local extension.

2 Components: (1) Breast, (2) Staging of axilla, or if clinically positive, an axillary dissection

1. BREAST PROCEDURES:

Total Mastectomy:

• Involves complete excision of the breast and nipple with preservation of the underlying pectoral muscles
• Used to be standard therapy, but now reserved for:
  • Large cancers relative to breast size
  • Cancer that involves the nipple or overlying skin
  • Multifocal disease
  • Prior breast irradiation
  • Women who chose not to have breast conservation or breast radiotherapy

Radical Mastectomy:

• Involves excision of the breast together with pectoralis minor and major
• Used in locally advanced disease that involves these muscles

Breast Conservation Surgery:

• Involves complete local excision of the primary breast tumour with clear margins
• Whole breast adjuvant radiotherapy must be given post-op

2. AXILLA PROCEDURES:

Axillary Staging - Aims:

• Assess nodal status for prognosis
• Assess nodal status to determine adjuvant systemic therapy
• Axillary dissection for clinical positive axilla (palpable nodes or pre-op abnormal ultrasound/biopsy/metastases) OR finding of a positive sentinel LN biopsy

Radiotherapy

• Is indicated following breast conservation surgery, and reduces the risk of local recurrence
• The use of radiotherapy after mastectomy is more limited

Adjuvant Systemic Therapy

The aim is to eradicate micrometastases.

• Adjuvant systemic therapy with tamoxifen, with combination chemotherapy (most commonly CMF) or, in premenopausal women, ovarian ablation, reduces the risk of recurrence and death after treatment for node positive and node negative breast cancer

Ovarian Ablation (in some cases)

• Ovarian ablation in premenopausal women is associated with an improvement in recurrence-free and overall survival
• The benefits are greater in tumours which are oestrogen receptor positive
• Ovarian ablation is achieved by:
  • Surgical oophorectomy
  • Ovarian irradiation
  • Using luteinising hormone releasing hormone (LHRH) analogues e.g. goserelin

COMPLICATIONS OF SURGERY

Mastectomy/Breast Conservation Therapy:

• Breast haematoma
• Wound infection
• Seroma
• Psychological effects on body image

Axillary Dissection:

• Seroma of the axilla
• Limited shoulder movement
• Pain and numbness from division of the intercosto-brachial nerve
• Lymphoedema of the arm

COMPLICATIONS OF RADIOTHERAPY

• Redness and soreness of the field of radiation
• Lymphoedema after treatment of the axilla
• Breast-feeding from the affected breast is unlikely
• Cardiac damage following left breast irradiation
• Brachial plexus palsy
• Osteitis of the ribs
• Shoulder stiffness
• Pulmonary fibrosis

COMPLICATIONS OF ADJUVANT SYSTEMIC THERAPY

Chemotherapy:

• Nausea, vomiting, lethargy, alopecia, early menopause, anxiety
• Mucositis and diarrhoea
• Febrile neutropenia
• Cardiac toxicity

Tamoxifen:

• Hot flushes, vaginal discharge
• Increased incidence of endometrial cancer in post-menopausal women (protective effect greatly outweighs risk)
• Increased risk of coronary artery disease, stroke, TIA

Prognostic Variables Other Than TNM in Breast Cancer:

Biological Factors	Favourable	Unfavourable
Histological type	Tubular, colloid, papillary	Scirrhous
Size	Small	Large
Grade	Low (I)	High (III)
Necrosis	Absent	Present
Lymphocytic infiltration	Present	Absent
Oestrogen status	Positive	Negative
Involved lymph nodes	Absent	Present
Proliferative rate	Low S phase	Aneuploid
Chromosomal defect	-	Deletion/alteration 1, 3, 6, 7, 9 Shortening of allele on chromosome 11
Proto-oncogenes	-	c-erbB/c-H-ras
Growth factors (GF)	-	Epidermal GF Transforming GF Platelet-derived GF Fibroblast GF Insulin-like GF

Key Points:

• Most important prognostic factors: Tumour size, lymph node status, histological grade
• Oestrogen receptor status: Important for treatment decisions (hormone therapy)
• HER2 status: Predictive for targeted therapy (trastuzumab)