Flashcards in Breast and Female reproductive system Deck (50)
Terminal duct lobular units are the site of origin of most proliferative breast disease, including cancers and precursor lesions.
The epithelium of the terminal ducts rather than the acini is considered more prone to neoplastic transformation and more susceptible to environmental factors which initiate malignant change.
Lobules are embedded in a loose specialized connective tissue stroma which is itself altered in certain disease states.
Aberrations of normal development and involution (ANDI)
The following pathological entities are included within this umbrella term.
• Cyst formation
• Sclerosing adenosis
• Epithelial hyperplasia
Aberrations of normal development and involution (ANDI): Fibrosis
The following pathological entities are included within this umbrella term.
• Fibrosis – an increase in collagen rather than an overgrowth of fibrous tissue
Aberrations of normal development and involution (ANDI): Cyst formation
• Cyst formation – cysts are more common in women approaching the menopause and represent involutional changes. Lobular units unfold and coalesce with loss of specialized connective tissue. This creates a walled space filled with fluid which can vary in size from a few millimeters (microcyst) to several centimeters (macrocyst). Lining epithelial cells tend to be large with abundant granular eosinophilic cytoplasm and basal nuclei (apocrine metaplasia). Diagnosis is confirmed by aspiration and cytology is indicated only if the aspirate is blood-stained (intracystic papilloma
or carcinoma) or the cyst refills. Cysts constitute up to 15% of all discrete breast lumps and do not predispose to cancer;
Aberrations of normal development and involution (ANDI): Adenosis
• Adenosis – an increase in the number of acini or ductules within a lobule without thickening of the ductular epithelium. It is usually of the blunt duct type in which alveoli showed marked dilatation and an irregular outline
Aberrations of normal development and involution (ANDI): Sclerosing adenosis
• Sclerosing adenosis – this is an abnormality
of stromal involution leading to localized proliferation of both stroma and acini. There is prominent mitotic activity but no dysplasia and the lobules are distorted with infiltrative margins. These lesions often form a mass macroscopically containing microcalcification. They can be clinically, radiologically and pathologically indeterminate and mimic cancer;
Aberrations of normal development and involution (ANDI): epithelial hyperplasia
• Epithelial hyperplasia – this is a benign proliferation most commonly affecting the TDLU and the interlobular ducts. Hyperplasia is an increase in the number of cell layers above the basement membrane. Though there is no cytological atypia and the condition is benign, more severe forms (moderate or florid) are associated with increased risk of malignancy (relative risk (RR) 1.5–2.0 times). Ordinary hyperplasia or hyperplasia of the usual type is assumed to be of ductal origin and cannot readily be distinguished from hyperplasia arising in the lobules of the TDLU. In mild forms, spaces are lined by 3–4 cell layers, whilst in moderate to severe forms this exceeds 4 cells in thickness and there may be proliferating cell masses distending and distorting involved spaces.
Atypical hyperplasia refers to lesions with both an overgrowth of epithelium and cytological atypia. These are found in approximately 4% of benign breast biopsies from the pre-mammographic era and increase risk of breast cancer (4–5 times RR).
lobular carcinoma-in-situ (LCIS)
A specific pattern of atypical lobular hyperplasia is recognized which is often associated with lobular carcinoma-in-situ (LCIS).
Both atypical hyperplasia and LCIS distend the acini within a lobular unit to varying extent. Unlike ductal carcinoma-in-situ (DCIS), LCIS is considered
to be a marker of breast cancer risk and not a precursor lesion for invasive malignancy.
There are stringent histopathological criteria for describing atypical hyperplasia which lies on a pathological continuum with in situ carcinoma (CIS).
These include normal polarity of cells around the periphery of the space, but sharply defined secondary spaces and rigid cellular bars resemble CIS (Fig. 15.4).
1) Though often described as a benign tumour these circumscribed breast masses are hyperplastic lesions which are really a localized form of ANDI.
2) They arise from a single lobule rather than a single cell and respond to cyclical hormonal changes within the breast. Most undergo spontaneous regression; small fibroadenomas can be subclinical and discovered incidentally on imaging (commonest cause of a breast lump under 30 years of age).
This is an involutional change characterized by dilatation and shortening of the subareolar ducts.
Mild ectasia occurs in almost half of peri-menopausal women and more severe forms can be associated with periductal inflammation and fibrosis.
Trauma to the breast can result in localized ischaemia and fat necrosis. Subsequent inflammation and fibro-elastic reactions can produce a hard irregular lump tethered to skin which mimics a carcinoma.
Infection and inflammation of the breast
Inflammation and infection of the breast occurs almost exclusively in adult females, most commonly during lactation.
Periductal inflammation occurs in perimenopausal women and is often sterile, at least initially. This can progress to periareolar sepsis with abscess formation.
Puerperal breast abscesses
Puerperal breast abscesses occur during or soon after lactation and are usually pyogenic with the causative organism being Staphylococcus aureus.
Infection and inflammation
Infection probably is introduced via cracked or traumatized nipples during suckling. Infection commences within the main lactiferous ducts producing local inflammation which progresses to a generalized cellulitis affecting one radial section of the breast.
At this stage, when there is no focal collection of pus, the infection can be successfully treated with intravenous anti-staphylococcal agents.
However, once abscess formation occurs, pus must be surgically drained in order for resolution of the inflammatory process. If surgical intervention is deferred, then the combination of inflammation and scarring can destroy a large part of the breast parenchyma.
It may be possible to successfully drain these abscesses percutaneously under ultrasound control, provided they are not loculated and the contents are relatively pure pus with minimal debris.
More complex abscesses should be drained via an incision placed some distance from the areolar and the wound closed around a corrugated drain which is left in situ for a few days.
Carcinoma-in-situ was first described in 1932 as a neoplastic condition in which malignant epithelial cell proliferation was confined within the ducts and acini of the TDLU with no migration across the basement membrane.
There is an ‘unfolding’ of the lobules with incorporation into a single lumen. As the process involves mainly the ductules of the lobules, the term ductal carcinoma is used, but this refers to a histological pattern and not tissue of origin. LCIS has a readily recognized ‘pure’ form with characteristic histological appearances.
Ductal carcinoma in situ
This is a complex disease entity with several histo- logical variants, including comedo, cribriform, solid and micropapillary. These architectural forms do not predict behaviour and from a clinical and prognostic point of view, DCIS is categorized as high, intermediate and low nuclear grade.
Up to 85% of high grade lesions show comedo necrosis, so called because of the gross appearance of caseous material dotting the cut surface and resembling a ‘comedone’. This corresponds to necrotic debris within the ductule lumen. Dystrophic deposits of calcium produce coarse linear branching calcification on mammography. Neoplastic cells lining the ducts are usually arranged as solid sheets with central necrosis.
Non-high grade DCIS
Non-high grade DCIS (low and intermediate grade) can be associated with necrosis but more often are not, and consist of several architectural patterns including cribriform, micro- papillary as well as solid types.
There is a close association between nuclear grade and necrosis; high nuclear grade lesions with necrosis are more likely to exhibit obligate progression to invasive disease and to have foci of micro-invasion. They are more likely to recur after conservation surgery and for this reason all cases of high grade DCIS managed with wide local excision now receive radiotherapy to the breast.
Lobular carcinoma in situ
This has a rather monotonous histological appearance with uniform cells distending more than half the acini within a lobular unit (Fig. 15.5).
It is a silent process with the diagnosis made incidentally on biopsies performed for other conditions. LCIS is present in approximately 1% of screen-detected lesions, and tends to occur as multi-centric and bilateral lesions in pre-menopausal women.
The condition is not a direct precursor lesion but a marker of risk (10–11 times RR) for development of invasive cancer. Indeed, the con- dition may regress after the menopause. The absolute risk for invasive malignancy is 25–30% at 15–20 years.
Invasive mammary cancer: Gross pathology
1) The majority of cancers are less than 2–3 cm in size at the time of diagnosis and screen-detected lesions have no clinical correlate.
2) Many of the clinical findings and radiological appearances of an infiltrating carcinoma are determined by the stromal reaction around the tumour and not by the malignant epithelial component.
3) When the adjacent ligaments of Astley Cooper are involved in this stromal reaction, they become shortened and produce localized indrawing or dimpling of the skin (or nipple) due to insertion of these ligaments into the dermis.
4) The orange skin or ‘peau d’orange’ appearance is caused by swelling and oedema of the skin due to infiltration of dermal lymphatics, except at points where the dermis is anchored by these suspensory ligaments of the breast. This fibrous reaction is responsible for the spiculate features of a cancer which is thus named because the radiating strands have been likened to the limbs of a crab.
Spread of breast cancer: Halstedian model
The spread of breast cancer is complex and reflects its enigmatic natural history.
Two main patterns of spread are recognized, but these are not mutually exclusive.
• Halstedian model – breast cancers invade local
structures and spread in a centrifugal manner
along tissue planes to involve fi rst the regional
lymph nodes and the bloodstream.
Spread of breast cancer: Fisherian model
• Fisherian model – in contrast to the orderly
and sequential loco-regional spread, this
alternative model views breast cancer as a
systemic disease at the outset with cancer cells
entering the bloodstream at an early stage of
tumour development which may even precede
This haematogenous dissemination gives rise to micrometastases at distant sites in the bone, lung and liver. Most patients with breast cancer require some form of adjuvant systemic treatment in addition to
surgery (+/- radiotherapy).
This can eliminate micrometastases in some cases, but in others they can remain dormant for up to 20–30 years and then become ‘kick-started’ by unknown events.
Spread of breast cancer: Local spread signs
• peau d’orange (orange peel skin) – dermal oedema
causing apparent retraction of the ligaments of
• skin dimpling – fi brous stromal reaction;
• nipple retraction – stromal reaction shortening
• shrinkage and distortion of the breast contour;
• ulceration of tumour through the skin;
• fungation of proliferative tumour above the
• local recurrences in chest wall after therapy.
Spread of breast cancer: Regional spread signs
• most commonly to axillary lymph nodes
• to internal mammary lymph nodes
• supraclavicular lymph nodes in advanced cases
• contralateral axillary or supraclavicular nodes (rare).
Distant spread and clinical features
• bone – bone pain, pathological fractures,
• liver – hepatomegaly;
• peritoneal seedlings – malignant ascites, intestinal
• brain – headache, personality change, fi ts;
• lung – incidental fi nding of isolated metastases
or lymphangitis carcinomatosa on chest X-ray,
malignant pleural effusion; and
• skin – skin nodules.
Special type invasive carcinomas: Tubular carcinoma
Tubular carcinoma – these are well-differentiated
tumours which in pure form have minimal metastatic
potential. They represent 3–5% of all invasive cancers, but 9% of screen-detected lesions. Histologically, angulated tubular structures surrounded by a desmoplastic stroma and composed of cells with low grade nuclei make up at least 90% of the tumour. Axillary surgery, including sentinel node biopsy can be omitted for pure tubular cancers.
Special type invasive carcinomas:
Cribriform carcinoma – this is also a well differentiated
tumour with a similar prognosis to tubular carcinoma.
It exists in classical and mixed forms which
both resemble cribriform DCIS. The mixed variant
has a greater tendency to spread to axillary nodes, but this does not portend a poor prognosis.
Special type invasive carcinomas: Mucinous carcinoma
Mucinous carcinoma – these are sometimes called
colloid carcinomas and contain extracellular lakes of
mucin. They are of soft consistency and have a smooth outline suggesting benignity. They represent 5% of all invasive cancers and occur over a wide age range.