Benign & Malignant Tumours of Breast - 03-11-03

ANATOMY (Robbins Fig 25-1 pp 1094)
Histology: 2 epitheliums: inner epithelium, outer epithelium with myoepithelial cells. TDLU is most important in carcinomas + fibrocystic disease. 
Hormonal response: rise in oestrogen + progesterone = cell proliferation, vacuolisation, stromal oedema. fall in oestrogen + progesterone = reverse of above. 
Breast changes in life: mentrual cycle changes (above), lactational breast (lobules + little stroma), post menopausal breast (lobules regress + adipose tissue predominate). 

INFLAMMATORY LESIONS (Robbins pp 

1.	Acute Mastitits: This occurs during nursing as cracks begin to appear in the nipples. This allows Staph + Strep to invade --> acute inflammation --> breast abscess. 

2.	Fat Necrosis: Occurs 2nd to trauma
	Macroscopy: irregular hard mass of orange/brown colour (haemoglobin derived pigments). Microscopy: central necrotic fat surrounded by lipid laden macrophages and neutrophilic infiltration. Later on: fibrovascular changes wall it off. Later on: fibrosis associated with foamy macrophages laden with haemosiderin. 

3.	Breast abscess: Results from acute mastitis or rupture of a duct. 
	Microscopy: central cavity filled with neutrophilic debris surrounded by inflamed tissue --> eventually fibrosis occurs. 

BENIGN PROLIFERATIVE BREAST DISEASE

1.	Fibroadenoma: This is a benign breast tumour composed of new fibrous + glandular tissue. It affects young people (20-35)
	Macroscopy: firm mass, cut surface: sharply demarcated, gray-white. 
	Microscopy: glands present lined by cuboidal/low columnar cells & are surrounded by stroma (fibrous tissue). Glands appear distorted as stroma compresses them. Fig 25-13
	Risk of breast Ca: 0.1% cases progress to malignancy. 

2.	Intraductal papilloma (48yrs): Papillomas are tumours that extend into the lumen of ducts. Two types: 1) small duct, 2) large duct (bloody nipple discharge). 
	Macroscopy: palpable mass in some cases only
	Microscopy: central core of fibrovascular tissue surrounded by 2 cell epithelial layer. 
	Risk of breast Ca: depends on the microscopic appearance. If: presence of 2 cell layer, lack of cribiform/trabecular pattern, low mitotic activity etc --> benign. 

3.	Fibrocystic disease (25-45yrs): This is a disease where the stroma becomes increasingly fibrotic and there are cysts within the breast. The pathogenesis is related to hormonal imbalances. 
	Macroscopy: numerous microcysts + large cysts
	Microscopy: Components are: 1) Cysts: cystic dilatation of lobules and ducts produces numerous cysts, 2) apocrine metaplasia: cysts are lined by cells that look like those in apocrine sweat glands: polygonal cells, abundant granular cytoplasm, central nucleus, 3) Fibrosis: cysts rupture and release their contents --> result in chronic inflammation --> scarring/fibrosis of stroma, 4) epithelial hyperplasia: papillary projections of epithelium are common, 5) sclerosing adenosis: number of acini per lobule is increased 2 fold and the stroma compresses the glands distorting them --> mimicks Ca --> but staining for myoepithelial cells is reassuring. 


4.	Ductal hyperplasia: Usually the epithelium of ducts are 2 layers (columnar + myoepithelial cells). In this disease there is hyperplasia of epithelium --> more than 2 layers present. > 4 layers = increased risk of Ca but most often not. 
	Microscopy: The lumen is filled with populations of epithelial cells, leaving uneven fenestrations. If fenestrations are more regular/even --> more chance that is atypical. In addition: look for signs of atypicalness: hyperchromatic nuclei, loss of polarity, regular spaces, absence of myoepithelial cells etc. 
	
MALIGNANCY EPITHELIAL BREAST LESIONS

Breast cancer - General notes. 
Risk factors: family Hx (genes BRAC1 & BRAC2 are major factors), age, proliferative breast disease, personal Hx, radiation, oestrogen exposure (early menarche/late menopause), nulliparity, obesity, HRT (exogenous oestrogen therapy). 

Incidence in breast quadrants: Left breast affected more (110:100), upper outer quadrant accounts for 50% of tumours. 

Classification: In situ or Invasive. In situ (15-30%): ductal, lobular. Invasive (70-85%): ductal (no special type), lobular, tubular, colloid, medullary, papillary. 

All breast Ca arise from the terminal duct lobular unit (TDLU). 

1.	IN SITU CARCINOMA

	a) Duct carcinoma in situ: In this cancer, the epithelial cells lining the ducts show malignant characteristics: loss of polarity, pleomorphism, hyperchromasia, high nuclear/cytoplasmic ratio, increased mitotic activity, prominent nucleoli. The cancer is in situ, meaning there is NO invasion through basement membrane. The epithelium is more than 2 cell layers thick. 
	Morphology: Microscopy: Architecture: a) solid (lumen filled with malignant cells), b) cribiform/tubular (round regular spaces within glands --> indicates malignancy), c) papillary (epithelial projections into lumen without fibrovascular stroma). Cytological grade: a) low, b) intermediate, c) high. Low grade --> High grade just means cell atypia worsens (refer to above). Comedo (central) necrosis: present / absent. If present --> then its more likely to be high cytological grade --> worse. 
	Can it go to invasive Ca: 8-10 times more likely. 

	Lobular carcinoma in situ is not discussed in the notes. You can read about it on Pg 1109, Robbins, Fig 25-19. 

2.	INVASIVE CARCINOMA
	a) Invasive duct carcinoma of no special type (70-80%): In this cancer, the epithelial cells are malignant and invade into the stroma. Clinically, you will feel a mass of stony hard consistency. 
	Morphology: Microscopy: 1) tumours cells grow in sheets, cords, nests, individually, invade into stroma + fat 2) tumour cells vary from small - large, but are generally larger + prominent nuclei/nucleoli than their lobular counterparts, 3) absence of myoepithelial cells (special staining). 

	b) Tubular carcinoma: This cancer has lots of tubules lined with ductal epithelium. 
	Morphology: Microscopy: 1) tumour cells are arranged tubular fashion, absence of myoepithelial cells (special staining), 2) apocrine  snouts. 
	Prognosis: excellent

	c) Mucinous (colloid) carcinoma: This cancer usually occurs in post-menopausal women. Neuroendocrine differentiation occur in 25-50% of cases. 
	Morphology: Microscopy: 1) Small clusters of cells (solid/acinar formation) floating in a sea of mucin
	Prognosis: excellent (no nodal mets)

	d) Medullary carcinoma: This cancer is always 'pushing' the border type --> i.e: non infiltrative border. 
	Microscopy: 1) solid syncytium like sheets of large cells with pleomorphic nuclei, prominent nucleoli, high mitoses, 2) marked lymphoplasmacytic infiltrate at peripheral of tumour
	Prognosis: mets to lower axillary lymph nodes + prognosis is better than invasive duct carcinoma

	e) Invasive lobular carcinoma: This cancer has high proportion of bilaterality. 
	Morphology: 1) tumour cells growing in single file + invade into stroma, 2) tumour cells are not arranged in gland form, 3) signet ring configuration: if mucin abundant. Sometimes tumour cells do not grow in single file --> called variants (alveolar, trabecular, solid). 
	Prognosis: Although chances of bilaterality is high --> prognosis is same as invasive duct carcinoma. Particular mets to: abdominal cavity (GI tract, ovaries, serosal surfaces). 

	f) Paget's disease: This disease is characterised by eczema of the nipple. Paget's disease is like ductal carcinoma in situ where the cancer extends via the ducts into the nipple. Usually is accompanied by underlying duct carcinoma in situ
	Morphology: Microscopy: 1) skin of the nipple ulcerated, ozzing, 2) large clear cells with atypical nuclei

SPREAD AND METASTASES

Routes of invasion: direct, lymphatics (axillary nodes, supraclavicular, internal mammary), haemotogenous 
Distal metastases: skeletal system, lung, liver, ovary, adrenal, CNS. 

PROGNOSIS
Stage: The higher stage --> worse prognosis
Size: Bigger --> badder, more chance of spreading --> even badder
Cytoarchitecture: Metaplastic = bad, Duct vs Lobular = same prognosis, Medullary / tubular / colloid: good prognosis. 
Microscopic grade: The higher grade --> worse prognosis. Bloom-Richardson system is used for grading --> no need to know. 
Skin/Nipple invasion: worse prognosis
Axillary lymph node mets: most important prognostic factors --> involvement = worse prognosis (factors: how many, extent of invidual node involvement etc)
Local recurrence: bad prognosis. 

NON-EPITHELIAL BREAST MALIGNANCIES

Phylloides tumourL Basically this tumour is a cancer arising from intralobular stroma
Read Robbins pp 1103