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CHAPTER 3 Surgical pathology
162
Carcinogenesis
Carcinogenesis is the process that results in malignant neoplasm formation. Usually more than one carcinogen is necessary to produce
a tumour, a process which may occur in several steps—multistep
hypothesis.
• Initiators produce a permanent change in the cells, but do not
themselves cause cancer, e.g. ionizing radiation: this change may be in
the form of gene mutation.
• Promoters stimulate clonal proliferation of initiated cells, e.g. dietary
factors and hormones: they are not mutagenic.
• Latency is the time between exposure to carcinogen and clinical
recognition of tumour due to:
Time taken for clonal proliferation to produce a signifi cant cell •
mass.
Time taken for exposure to multiple necessary carcinogens.•
• Persistence is when clonal proliferation no longer requires the presence
of initiators or promoters and the tumour cells exhibit autonomous
growth.
See Table 3.2 for a list of common risk factors for cancer.
Tumour growth
Tumour doubling time depends on cell cycle time, growth function, and cell
loss fraction. In tumours such as leukaemias, the doubling time remains
remarkably constant: the cell mass increases proportionally with time.
This is exponential growth. In solid tumours, doubling time slows as size
increases. This is referred to as Gompertzian growth.
Genetic abnormalities in tumours
Two genetic mechanisms of carcinogenesis are proposed:
• Oncogenes. Enhanced expression of stimulatory dominant genes.
• Tumour suppressor genes. Inactivation of recessive inhibitory genes.
Oncogenes
At least 60 oncogenes have been identifi ed. They can be classifi ed according to the function of the gene product (e.g. growth factors, cell signalling
agents). The proteins produced (oncoproteins) can be produced in abnormal quantities or be abnormally active forms and cause:
• Independence from extrinsic growth factors.
• Production of tumours in immunotolerant animals.
• Production of proteases to assist in invasion of normal tissues.
• Reduced cell cohesiveness assisting metastasis.
• Growth to higher cell densities and abnormal cellular orientation.
Examples include BRCA1, p53, k-ras, APC, DCC.
CARCINOGENESIS
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Table 3.2 Common risk factors for cancer
Known carcinogen Type of cancer
Chemicals
Polyaromatic hydrocarbons Lung cancer (smoking), skin cancers
Aromatic amines Bladder cancer (rubber and dye workers)
Alkylating agents Leukaemia
Viruses
HIV Kaposi’s sarcoma, lymphoma
Epstein–Barr virus Burkitt’s lymphoma, nasopharyngeal cancer
Human papillomavirus Squamous papilloma (wart), cervical cancer
Hepatitis B virus Liver cell carcinoma
Radiation
UV light (UVB>UVA) Malignant melanoma, basal cell carcinoma
Ionizing radiation Particularly breast, bone, thyroid, marrow
Biological agents
Hormones, e.g. oestrogens Breast and endometrial cancer
Mycotoxins, e.g. afl atoxins Liver cell carcinoma
Parasites, e.g. schistosoma Bladder cancer
Miscellaneous
Asbestos Mesothelioma and lung cancer
Nickel Nasal and lung cancer
Host factors Type of cancer
Race
Caucasians Malignant melanoma, stomach cancer
Diet
High dietary fat Breast, colorectal cancer
Alcohol Breast cancer
Gender, inherited risks
Female sex Breast cancer
Familial polyposis coli Colorectal cancer
Multiple endocrine neoplasia Phaeo, parathyroid, medullary cancer thyroid
BRCA1–17q21 Breast, ovarian and prostate cancer
Premalignant lesions and conditions
Adenomatous rectal polyp Colorectal adenocarcinoma
Mammary ductal hyperplasia Breast carcinoma
Ulcerative colitis Colorectal adenocarcinoma
Transplacental exposure
Diethylstiboesterol Vaginal adenocarcinoma
163
CHAPTER 3 Surgical pathology
164
Screening
Screening is testing any population for a disease.
The aim is reduction in morbidity and mortality from screened diseases.
Requirements for successful screening
• Screening test must be:
Sensitive (see • b p. 7).
Specifi c (see • b p. 7).
Safe.•
Inexpensive.•
Acceptable.•
• The population screened must be:
Easily identifi ed and contactable.•
Compliant.•
• The disease screened must be:
Detectable in a treatable, premalignant form or earlier stage.•
Preventable or more amenable to successful or curative •
treatment.
A suffi cient burden on the population to justify cost of screening.•
Chronic or of suitable evolution for sporadic testing to detect it.•
Disadvantages of screening
• Cost (time and resources).
• The benefi t may be small.
• False positive tests may be physically or psychologically detrimental.
Examples of screening programmes
Abdominal aortic aneurysm (4000 deaths/y)
The UK multicentre aneurysm screening study of 68 000 men showed
screening halves aneurysm-related deaths by reducing risk of rupture. The
conclusion was that aneurysm screening should be offered in the UK. The
MASS study showed a benefi t where other studies failed because:
• It was adequately powered (see b p. 8).
• Screening compliance was higher:
GP-based ultrasound had a better compliance than specialist •
clinics.
Participants unlikely to attend were excluded from the study.•
Breast cancer (14 000 deaths/y)
A meta-analysis of thirteen breast cancer screening trials concluded that
screening mammography signifi cantly reduced breast cancer mortality in
women aged 50–74. A BMJ analysis concluded that:
• For every 1000 women screened over 10y, around 200 (depending on
age) are recalled because of an abnormal result and of these:
Around 60 will have at least one biopsy.•
About 15 will have invasive cancer and 5 will have ductal carcinoma •
in situ (DCIS).
SCREENING
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• About 0.5, 2, 3, and 2 fewer deaths from breast cancer occur over 10y
per 1000 women aged 40, 50, 60, and 70y, respectively, who choose to
be screened.
• Ten per cent of invasive carcinoma is not radiologically detectable.
• Risk of a false positive screen is approximately 25% over 10y.
• Studies suggest up to a 30% reduction in mortality from screen-
detected early breast cancer.
• Features looked for on screening mammography include: spiculated
calcifi cation, microcalcifi cation.
What is offered?
• Since 1988, population-based screening offered.
• Starts age 50 and continues to age 70 (covers peak ages of incidence
of new diagnoses and excludes low risk younger women—prevents
‘psychological morbidity of screening the well’).
• Seventy per cent of women offered it accept screening (lowest take-up
in lower socio-economic groups and those diffi cult to contact, e.g.
rapidly changing addresses or no fi xed address).
• Two-view (lateral and oblique) mammography of both breasts.
• Suspicious or malignant-looking lesions invited for clinical assessment
by standard triple assessment.
Cervical cancer (1500 deaths/y)
Since the mid-1980s, incidence of and mortality from cervical cancer in
women under 70 in England and Wales has fallen. Screening is thought to
be the most likely explanation. A BMJ analysis concluded that:
• In the NHS cervical screening programme, 1000 women need to be
screened for 35 years to prevent one death:
150 have an abnormal result and 75 need repeat for inadequate test.•
80 undergo biopsy.•
55 have an abnormal biopsy result.•
2 have carcinoma, the rest have dysplasia.•
• At least one woman dies within the 35y despite being screened.
Prostate cancer (9000 deaths/y)
A third of men over 50y have evidence of prostate cancer at post-mortem,
but less than 1% of these have clinically active disease. Screening is controversial because:
• Prostate-specifi c antigen (PSA), rectal examination, and transrectal
ultrasound have low specifi city and sensitivity alone or in combination.
• Treatment of prostate cancer is controversial (see b p. 374).
• No randomized trial has shown a survival benefi t in screened
populations: screening may cause more harm than good.
• Screening can be carried out on request despite the evidence above.
Colorectal cancer (16 000 deaths/y)
The lifetime risk of colorectal cancer is about 1 in 20. A nationwide screening programme is likely, following current pilot centres:
• Several possible screening tests exist:
Faecal occult blood (low sensitivity, 90% specifi city)—requires •
colonoscopy for positive results (false positives common).
165
CHAPTER 3 Surgical pathology
166
Colonoscopy (sensitivity and specifi city near 100%).•
Flexible sigmoidoscopy (sensitivity 80%, specifi city near 100%).•
• Colorectal cancer is suited to screening:
It has a detectable premalignant phase.•
It is detectable at an earlier and potentially highly treatable stage.•
Screening has been shown to be cost-effective and acceptable.•
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CHAPTER 3 Surgical pathology
168
Grading and staging
• Staging is the process of assessing the extent of local and systemic
spread of a malignant tumour or the identifi cation of features which
are risk factors for spread.
• Grading is the process of assessing the degree of differentiation of a
malignant tumour.
Key facts
The objectives of staging and grading a tumour are:
• To plan appropriate (treatment) for the individual patient.
• To give an estimate of the prognosis.
• To compare similar cases when assessing outcomes or designing
clinical trials.
Staging and grading methods
Staging
The commonest system is the internationally agreed TNM classifi cation (see Table 3.3). It is not appropriate for leukaemia, lymphomas, or
myeloma. A four-stage classifi cation (I. II, III, IV) is also often used and is
compatible with TNM. Specifi c staging systems also exist for some tumour
sites (e.g. Duke’s stage in colorectal cancer, see b p. 400).
Staging may be:
• Radiological (often performed preoperatively): indicated by the prefi x
‘r’ before the letter (e.g. rT3, rM1). If different radiological modalities
are used, separate prefi xes can be used, e.g. ‘u’ for ultrasound (uT2).
Radiological staging is used to plan treatment (e.g. neoadjuvant
therapy, selection for surgery, planning of surgery).
• Pathological (performed on surgical specimens): indicated by the
prefi x ‘p’ before the letter (e.g. pT3, pN2, pM1). If there has
preoperative radiotherapy used, the prefi x ‘y’ is used to denoted that
the pathological stage may have been modifi ed by this (e.g. ypT2).
Pathological staging is used to plan adjuvant treatment (chemotherapy
or radiotherapy) and for informing prognosis.
An example of lung cancer staging is:
• Stage I (T1N0, T2N0), 85% 5y survival with surgery.
• Stage II (T1N1, T2N1, T3N0), 60% 5y survival with surgery.
• Stage IIIa (T3N1 or any N2), 20% 5y survival with surgery.
• Stage IIIb (any T4, any N3), <20% 5y survival, no benefi t with surgery.
• Stage IV (M1), <10% 5y survival, no benefi t with surgery.
Other pathological features may be included with the TNM system for
some tumours, for example:
• Presence of extratumoural vascular invasion V0 or V1.
• Presence of extratumoural lymphatic invasion Ly0 or Ly1.
• Presence of viable tumour cells at or within 1mm of the surgical
margin of excision R0, R1 (microscopic), R2 (macroscopic).
GRADING AND STAGING
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Table 3.3 Basic form of TNM classifi cation*
Classifi cation Interpretation
Primary tumour (T)
TX Primary tumour cannot be
T0 No evidence of primary tumour
Tis Tumour in situ
T1, T2, T3, T4 Size and extent of primary tumour
Regional lymph nodes (N)
NX Regional lymph nodes cannot be
N0 No regional lymph node
N1, N2, N3 Number and location of involved
Distant metastasis (M)
MX Distant metastasis cannot be
M0 No distant metastasis
M1 Distant metastasis
* Additional codes used with the TNM: pul, pulmonary; hep, hepatic; V, vascular; Ly, lymphatic
vessels; R, radial margin. Prefi xes used with the TNM: u, ultrasound; r, radiological; p,
pathological.
evaluated
evaluated
involvement
lymph nodes
evaluated
Histological grading
Gives a guide to the behaviour of a cancer by describing the degree of
differentiation of the tumour (e.g. breast cancer).
• Grade 1, represents the least malignant tumours.
• Grade 2, 25–50% of the cells are undifferentiated.
• Grade 3, 50–75% of the cells are undifferentiated.
• Grade 4, >75% of the cells are undifferentiated.
Other methods of describing tumours
• Depth of invasion (e.g. Breslow thickness in malignant melanoma).
• Tumour type (e.g. small cell versus non-small cell lung cancer).
169
CHAPTER 3 Surgical pathology
170
Tumour markers
Key facts
• Tumour markers (see Table 3.4) are complex molecules, often
proteins that can be detected by a variety of techniques, including
chemical, immunological, or bioactivity testing.
• Most are molecules normally produced by normal cells in small
amounts, but which may be produced in increased amounts by tumour
cells due to changes in cellular function (e.g. increased production,
increased gene expression, decreased degradation, increased release).
Testing
Testing is most commonly in vitro via serum measurements or testing tissue specimens. Common uses include:
• Screening (detection of subclinical disease).
• Diagnosis (including differentiation of tumour origin in metastatic
disease).
• Monitoring response to treatment.
• Monitoring for development of recurrence.
Non-tumour related elevations in tumour marker levels (reducing the specifi city of these tests for tumours) may occur due to:
• Increased production/release due to infl ammation, infection, trauma,
or surgery.
• Decreased removal/destruction due to renal or liver disease.
Abbreviations for some tumour markers
• AFP (alpha-fetoprotein).
• β-HCG (beta-human chorionic gonadotrophin).
• PAP (placental alkaline phosphatase).
• CEA (carcinoembryonic antigen).
• LDH (lactic dehydrogenase).
• PSA (prostate-specifi c antigen).
TUMOUR MARKERS
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Table 3.4 Commonly used tumour markers
Marker Useful in Notes/use
AFP Hepatoma; teratoma
(75% of cases); pancreatic
carcinoma some patients)
Elevated in liver disease,
e.g. hepatitis, cirrhosis, and
pregnancy
171
β-HCG Choriocarcinoma (almost
PAP Seminoma; ovarian
CEA Colonic adenocarcinoma;
CA 19–9 Pancreatic cancer (80%);
LDH Lymphoma
Thyroglobulin Thyroid cancer Used to monitor and
Calcitonin Medullary carcinoma of the
PSA Prostate cancer May be measured in
Alkaline
phosphatase
all cases); testicular
tumours/teratoma (75%);
other germ cell tumours
adenocarcinoma
ovarian adenocarcinoma;
advanced breast cancer;
pancreatic cancer
advanced colorectal cancer
(75%)
thyroid
Osteosarcoma Also raised in bony
Measured both in blood
and urine
Not useful for diagnosis or
screening. Used to monitor
response to treatment and
identify relapse in tumours
showing raised CEA at
diagnosis. May be elevated
in pancreatitis, ulcerative
colitis, gastritis, and heavy
smokers
A polysialated antigen
(Lewis blood group antigen).
Ratio of CA 19–9:CEA most
sensitive for pancreatic
cancer diagnosis
identify relapse after
treatment
Used to monitor and
identify relapse after
treatment
serum and tissue by
immunohistochemistry.
Serum level closely relates
to disease status
metastases, osteitis, Paget’s
disease
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