Breast and Female reproductive system

Question 1

Breast pathology

Answer 1

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.

Question 2

Aberrations of normal development and involution (ANDI)

Answer 2

The following pathological entities are included within this umbrella term.

• Fibrosis

• Cyst formation

• Adenosis

• Sclerosing adenosis

• Epithelial hyperplasia

Question 3

Aberrations of normal development and involution (ANDI): Fibrosis

Answer 3

The following pathological entities are included within this umbrella term.

• Fibrosis – an increase in collagen rather than an overgrowth of fibrous tissue

Question 4

Aberrations of normal development and involution (ANDI): Cyst formation

Answer 4

• 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;

Question 5

Aberrations of normal development and involution (ANDI): Adenosis

Answer 5

• 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

Question 6

Aberrations of normal development and involution (ANDI): Sclerosing adenosis

Answer 6

• 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;

Question 7

Aberrations of normal development and involution (ANDI): epithelial hyperplasia

Answer 7

• 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.

Question 8

Atypical hyperplasia

Answer 8

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).

Question 9

lobular carcinoma-in-situ (LCIS)

Answer 9

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).

Question 10

Fibroadenoma

Answer 10

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).

Question 11

Duct ectasia

Answer 11

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.

Question 12

Fat necrosis

Answer 12

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.

Question 13

Infection and inflammation of the breast

Answer 13

Inflammation and infection of the breast occurs almost exclusively in adult females, most commonly during lactation.

Question 14

Periductal inflammation

Answer 14

Periductal inflammation occurs in perimenopausal women and is often sterile, at least initially. This can progress to periareolar sepsis with abscess formation.

Question 15

Puerperal breast abscesses

Answer 15

Puerperal breast abscesses occur during or soon after lactation and are usually pyogenic with the causative organism being Staphylococcus aureus.

Question 16

Infection and inflammation

Answer 16

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.

Question 17

Carcinoma-in-situ

Answer 17

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.

Question 18

Ductal carcinoma in situ

Answer 18

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.

Question 19

Non-high grade DCIS

Answer 19

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.

Question 20

Lobular carcinoma in situ

Answer 20

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.

Question 21

Invasive mammary cancer: Gross pathology

Answer 21

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.

Question 22

Spread of breast cancer: Halstedian model

Answer 22

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.

Question 23

Spread of breast cancer: Fisherian model

Answer 23

• 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
mammographic detection.

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.

Question 24

Spread of breast cancer: Local spread signs

Answer 24

Local spread
• peau d’orange (orange peel skin) – dermal oedema
causing apparent retraction of the ligaments of
Astley Cooper
• skin dimpling – fi brous stromal reaction;
• nipple retraction – stromal reaction shortening
ducts;
• shrinkage and distortion of the breast contour;
• ulceration of tumour through the skin;
• fungation of proliferative tumour above the
skin; and
• local recurrences in chest wall after therapy.

Question 25

Spread of breast cancer: Regional spread signs

Answer 25

Regional spread
• most commonly to axillary lymph nodes
• to internal mammary lymph nodes
• supraclavicular lymph nodes in advanced cases
• contralateral axillary or supraclavicular nodes (rare).

Question 26

Distant spread and clinical features

Answer 26

• bone – bone pain, pathological fractures,
hypercalcaemia;
• liver – hepatomegaly;
• peritoneal seedlings – malignant ascites, intestinal
obstruction;
• 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.

Question 27

Special type invasive carcinomas: Tubular carcinoma

Answer 27

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.

Question 28

Special type invasive carcinomas:

Answer 28

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.

Question 29

Special type invasive carcinomas: Mucinous carcinoma

Answer 29

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.

Question 30

Special type invasive carcinomas: Medullary carcinoma

Answer 30

Medullary carcinoma – these have a characteristic
gross appearance and are well demarcated with
a fi rm consistency like a fi broadenoma. They have a
pushing margin and the outer surface is lobulated.
In contrast to other special types of carcinoma, the
tumour cells have high grade nuclei and medullary
carcinomas are invariably grade III. However, they
have a better prognosis than other grade III tumours
of NST and occur in younger women. There is a
prominent lymphoplasmocytic infi ltrate involving the
periphery of the tumour.

Question 31

Special type invasive carcinomas: Invasive lobular carcinoma

Answer 31

Invasive lobular carcinoma – this is the second most
frequent invasive carcinoma after the ductal type
but lack of concordance with diagnostic criteria has
yielded a range in reported incidence (2–15%). These
tumours are bilateral in 30% of cases and frequently
multicentric.

The pure forms have a better prognosis
than invasive ductal carcinoma (NST) and there is
a tendency to metastasize not only to lymph nodes
and the usual distant sites, but also to serous cavities.
A higher proportion of invasive lobular carcinoma is
found in screening programmes (14%) but this histological type can be mammographically occult and
magnetic resonance imaging (MRI) more accurately
assesses the size and extent of these lesions. This is
particularly important prior to breast conservation
surgery in order to reduce the chance of completion
mastectomy for positive surgical margins and/or
extensive disease.

Question 32

Invasive (ductal) carcinoma (no special type)

Answer 32

These represent about three-quarters of invasive breast cancers and are a diagnosis by exclusion. Once the histopathologist is confi dent there are no ‘special type’ features present, then the tumour is designated invasive ductal carcinoma (NST). There is a wide range of histological patterns from solid through small tightly cohesive nests to single infi ltrative patterns. There are degrees of gland formation but no acinar pattern.
Localised areas of special type carcinomas may occur, consistent with intra-tumoural heterogeneity.

Question 33

Predicting the outcome of breast cancer: prognostic indicators

Answer 33

• tumour size;
• nodal status;
• presence or absence of distant metastases;
• histological grade;
• histological type; and
• hormone receptor status.

Question 34

Tumour stage

Answer 34

Tumour stage
TNM is an international system for staging tumours
and is a valuable prognostic indicator for breast cancer.
It incorporates three variables:
• Tumour size;
• Nodal status; and
• distant Metastases.

The clinical TNM staging is summarized in Table
15.2. However, maximal prognostic information is
derived from a histopathological refi nement of this
basic classifi cation system. This includes more accurate pathological measurement of tumour size (pT) and assessment of nodal metastatic load (pN). Similar variables can be used for adjuvantonline (www.adjuvantonline.com) which is a computerized model for quantitative assessment of prognosis and calculation of absolute benefi ts from adjuvant systemic therapies.

Question 35

Histological grading

Answer 35

The combined histological grading system of Scarff,
Bloom and Richardson (modifi ed by Elston and Ellis)
has excellent concordance rates between histopathologists and clinico-pathological correlation (relapse-free and overall survival). A score is provided for each of the following:

• Degree of tubule formation (1–3);
• Degree of nuclear pleomorphism (1–3); and
• Mitotic activity (1–3).
The higher the aggregate score (total 9), the higher the grade. The spread of grade is wide enough to be useful amongst 2000 cases, 10% were grade I, 34% were grade II and 47% were grade III. Lymphatic or blood vessel invasion (LVI) at the edge of the tumour is routinely reported and when present predicts for lymph node involvement.

Question 36

Ideal histopathological
report

Answer 36

An ideal histopathological report on a specimen of invasive carcinoma
would include the following:
• size;
• invasive tumour type;
• grade;
• status of margins (nearest radial margin);
• associated in situ tumour (DCIS);
• peritumoural lymphovascular invasion;
• hormone receptor status (oestrogen/progesterone
receptor);
• cerb-b2 receptor status;
• total number of axillary nodes;
• number of positive nodes (micrometastases/
macrometastases)
• HER2/neu (now being tested for routinely
following successful trials of the humanized
monoclonal antibody herceptin).

Question 37

Male Breast Cancer

Answer 37

Breast cancer is uncommon in males, accounting for
between 0.5% and 1% of all cases. The mean age at
diagnosis is between 60 and 70, which is about 10 years older than female breast cancer. Male breast cancer is rare under the age of 50. The tumour usually presents as a lump, but there can be nipple discharge or retraction.

Male breast cancer tends to involve axillary nodes
at an earlier stage, possibly due to the smaller volume of breast tissue. There is an increased risk in patients with Kleinfelter’s syndrome and in families with a mutation in the breast cancer gene BRCA-2.

The pathology of male breast cancer is similar to females, but LCIS is almost unknown amongst males. Overall survival is comparable stage for stage between the sexes.

Question 38

Disorders of the uterus: Fibroleiomyoma (fibroid)

Answer 38

Fibroids are common tumours of smooth muscle origin. They grow during the reproductive years but regress after the menopause, but do not completely disappear.

They are firm, white, whorled, well-circumscribed lesions which may be submucosal, subserosal, or intramural. The subserosal variety may be peduncu- lated. Their aetiology is unknown.

Clinically they may present as follows:

• abdominal mass
• abnormal uterine bleeding
• urinary problems due to pressure on the bladder
• pain due to complications e.g.
- Red degeneration, torsion of the pedicle of a pedunculated fibroid.

Complications include cystic degeneration, necro- sis with haemorrhagic infarction (red degeneration) and dystrophic calcification (calcified fibroids may be seen on abdominal x-ray). Sarcomatous change is extremely rare.

Question 39

Disorders of the uterus: Endometriosis

Answer 39

This is the presence of endometrial glands and stroma in sites other than the body of the uterus.

The sites include:

• ovaries (80%)
• round ligaments
• fallopian tubes
• pelvic peritoneum
• intestinal wall
• umbilicus
• laparotomy scars
• lymph nodes (rare)
• lung and pleura (rare)
• synovium (rare)

The aetiology is unknown. In the peritoneal cavity retrograde menstruation may be important but this certainly cannot explain the spread to distant sites. The endometrial tissue retains its sensitivities to hor- mones and bleeding occurs into the lesions at the time of menstruation. Fibrosis may occur at the site of the lesion. In the peritoneal cavity this may lead to adhesion formation.

Question 40

Disorders of the uterus: Endometrial carcinoma

Answer 40

Two types are recognised.

The first type occurs in young women with the polycystic ovary syndrome or in perimenopausal women. It may complicate post- menopausal oestrogen replacement therapy. This type usually is associated with a good prognosis.

The second type affects elderly postmenopausal women and does not appear to be oestrogen related. It is poorly differentiated with deep myometrial invasion and carries a poor prognosis.

Aetiological factors for endometrial carcinoma include obesity, hypertension, diabetes mellitus, nulliparity and long-term tamoxifen therapy.
Spread occurs by direct extension into the pelvis and adjacent viscera as well as to the iliac and para-aortic nodes and via the blood stream to the liver and lungs.

Question 41

Fallopian tubes: Salpingitis

Answer 41

This is usually due to ascending infection from the uterine cavity. It may be acute or chronic. Organisms involved include Chlamydia, Bacteroides, E. coli and N. gonorrhoea. Clinical presentation may resemble acute appendicitis. Suppuration may occur with development of a tubal abscess (pyosalpinx).

Longstanding chronic inflammation may lead to distension of the tube, loss of mucosa, and accumulation of a watery fluid (hydrosalpinx). Inflammation may also lead to loss of tubal patency with the development of secondary infertility.

Question 42

Fallopian tubes: Cysts

Answer 42

Small benign fimbrial cysts are common. They cause abdominal pain by undergoing torsion.

Question 43

Fallopian tubes: Ectopic pregnancy

Answer 43

The fallopian tube is the commonest site for ectopic pregnancy. The incidence is 10 per 1000 pregnancies in the UK. The presenting symptoms are due to distension of the tube. The common presenting symptoms are:

• lower abdominal pain which may mimic acute appendicitis

• rupture with haemoperitoneum / sepsis.

Question 44

Ovary: Cysts

Answer 44

Both the normal follicle and corpus luteum are cystic. Retention cysts form quite frequently and by definition must be greater than 2 cm. Luteal cysts are lined by an inner layer of large luteinised granulosa cells and outer thecal cells.

They may rupture with slight haemorrhage into the peritoneal cavity. Follicular cells have an inner layer of granulosa cells and contain clear fluid. They are often multiple. ‘Chocolate’ cysts of the ovary are a feature of endometriosis.

Question 45

Ovarian tumour types

Answer 45

Tumours

Ovarian tumours may be divided into five main categories

• epithelial
• germ cell
• sex-cord stromal
• metastatic
• miscellaneous

Question 46

Ovary: Epithelial tumours

Answer 46

The majority of ovarian tumours are derived from the surface epithelium. There are several varieties which depend upon their embryonic differentiation.

One group of these is the mucinous type, which may be benign or malignant. A benign mucinous cystadenoma may grow to a very large size, filling the peritoneal cavity, and may be mistaken for ascites. Benign tumours may rupture, releasing tumour cells which seed in the peritoneum and continue to produce mucus (pseudomyxoma peritonei).

This condition carries a poor prognosis and is often complicated by intestinal obstruction. Some tumours are borderline between cystadenoma and cystadenocarcinoma. The commonest malignant ovarian tumour is the serous carcinoma. They occur most frequently in women between 40 and 60 years. They may be largely cystic (25%) semisolid (65%), or entirely solid (10%).

Question 47

Ovary: Germ cell tumours

Answer 47

These may be either benign or malignant. The commonest is the benign or mature cystic teratoma (dermoid cyst). It may present at any age, although usually in younger patients, as a smooth-walled unilateral ovarian cyst. It characteristically contains hair, sebaceous material and teeth, the latter often being appar- ent on a plain abdominal x-ray. They may undergo torsion. Malignant transformation is rare.

Question 48

Ovary: Sex-cord stromal tumours

Answer 48

These form about 5% of all ovarian tumours, with fibromas comprising about half the cases. Ovarian fibromas are not associated with steroid hormone production as are other sex-cord stromal tumours, e.g. thecoma, granulosa cell tumour, Sertoli-Leydig tumours. Meig’s syndrome occurs in approximately 1% of patients with ovarian fibromas and includes ascites and pleural effusions which disappear following removal of the ovarian fibroma.

Question 49

Ovary: Metastatic tumours

Answer 49

Metastatic tumours
Large intestine, stomach and breast are the most com- mon sites giving rise to metastatic tumours of the ovary. Krukenberg tumours of the ovaries relate specifically to secondary deposits of signet-ring mucus- secreting adenocarcinoma, usually of gastric origin.

Clinical presentations of ovarian tumours include:
• pain
• rupture or torsion of a cyst
• abdominal mass
• ascites – peritoneal seedlings, pseudomyxoma
peritonei, Meig’s syndrome
• excess hormone production – abnormal uterine
bleeding with oestrogen production; virilisation
due to androgen production
• pleural effusion – Meig’s syndrome, lung
secondaries
• symptoms of other distant metastases.

Question 50

Gynaecomastia

Answer 50

1. Malnutiriton
2. Spironolactone
3. Ketoconazole
4. Cirrhosis
5. Endocrine Disease