Pathology 7: intro to carcinogenesis + bone tumours

Question 1

Which two tumour types are associated with exposure to ionising radiation?

Answer 1

• Myeloid leukaemia (acute and chronic).
• Papillary carcinoma of the thyroid.

Question 2

List 3 skin tumours which are associated with non-ionising radiation (UVB from sunlight).

Answer 2

• Squamous cell carcinoma.
• Basal cell carcinoma.
• Malignant melanoma.

Question 3

What is an oncogene?

Answer 3

• Proto-oncogenes are essential for cell growth and differentiation
• Mutations of proto-oncogenes form oncogenes that lead to unregulated cell growth

Question 4

Which component of the mitogen-activated protein pathway activates BRAF?

Answer 4

RAS

Question 5

What is Knudsons two-hit hypothesis?

Answer 5

• Knudsons two hit hypothesis applies to tumour suppressor genes and states that both copies of the gene must be affected to cause disease.

Question 6

What is the function of the retinoblastoma gene in the cell cycle?

Answer 6

Retinoblastoma regulates the progression from the G1 to the S phase of the cell cycle. The E2F transcription factor is released when retinoblastoma is phosphorylated by the cyclin D/cyclin-dependent kinase 4 complex. Retinoblastoma mutation results in constitutively free E2F allowing progression through the cell cycle and uncontrolled growth of cells.

Question 7

What is the role of telomerase in carcinogenesis?

Answer 7

• Telomeres normally shorten with serial cell divisions eventually causing cell senescence
• Cancers often show upregulation of telomerase.

Question 8

How do cancers create a new blood supply to support their growth?

Answer 8

Cancers commonly produce fibroblast growth factor and vascular endothelial growth factor which are both angiogenic factors responsible for blood vessel creation.

Question 9

What is dysplasia?

Answer 9

Dysplasia is disordered cell growth, which most often refers to a proliferation of pre-cancerous cells. It is also called intraepithelial neoplasia. Dysplasia often arises from longstanding hyperplasia (endometrium) or metaplasia (oesophagus and bronchus). Dysplasia is theoretically reversible with alleviation of the inciting stress. If the stressor persists dysplasia can progress to carcinoma which is irreversible.

Question 10

What is a neoplasm?

Answer 10

Neoplasm means new growth. This growth is unregulated, clonal and irreversible. Neoplastic tumours can be benign or malignant.

Question 11

Describe the differences between benign and malignant tumours.

Answer 11

Benign tumours remain localised, have a slow growth rate and closely resemble the tissue from which they arise. They are often circumscribed or encapsulated.

Malignant tumours are by definition invasive and are capable of directly invading the surrounding tissue and many have the capacity to metastasise. They are often rapidly growing with an irregular margin. Well-differentiated malignant tumours may closely resemble the tissue from which they arise whereas poorly differentiated malignant tumours may not look anything like their tissue of origin.

Question 12

What is the difference between carcinoma in situ and invasive carcinoma?

Answer 12

The term carcinoma in-situ refers to an epithelial neoplasm showing all of the cellular features associated with malignancy but which has not yet invaded through the epithelial basement membrane, separating it from potential routes of metastasis (blood vessels and lymphatics).

Question 13

How do you distinguish a benign cell from a malignant cell?

Answer 13

Malignant cells have increased nuclear to cytoplasmic ratios, show nuclear pleomorphism and hyperchromasia, have an irregular chromatin distribution pattern within their nuclei, with irregular nuclear membranes +/- prominent nucleoli.

Benign cells have low nuclear to cytoplasmic ratios. All benign nuclei show a similar nuclear size and are not hyperchromatic. They have vesicular, evenly distributed chromatin with smooth nuclear membranes.

Question 14

What is the term used to describe a malignant tumour of epithelial origin?

Answer 14

Carcinoma

Question 15

What is the term used to describe a malignant tumour of glandular epithelium or a tumour showing glandular differentiation?

Answer 15

Adenocarcinoma

Question 16

What is the term used to describe a keratin-producing malignant tumour of squamous epithelium?

Answer 16

Squamous cell carcinoma

Question 17

What is the term used to describe a malignant tumour of soft tissue?

Answer 17

Sarcoma

Question 18

What is the term used to describe a malignant tumour of lymphocytes?

Answer 18

Lymphoma. If malignant lymphocytes or malignant myeloid cells involve the bone marrow and appear in the peripheral blood, this is leukaemia.

Question 19

What is the term used to describe a malignant melanocytic tumour?

Answer 19

Malignant melanoma

Question 20

What is the term used to describe a benign tumour of blood vessels?

Answer 20

Haemangioma

Question 21

What is the term used to describe a malignant tumour of blood vessels?

Answer 21

Angiosarcoma

Question 22

What is the term used to describe a benign tumour of fat?

Answer 22

Lipoma

Question 23

What is the term used to describe a malignant tumour of fat?

Answer 23

Liposarcoma

Question 24

What is a benign skeletal muscle tumour called?

Answer 24

Rhabdomyoma

Question 25

What is a malignant skeletal muscle tumour called?

Answer 25

Rhabdomyosarcoma

Question 26

What is a benign tumour of smooth muscle called?

Answer 26

Leiomyoma

Question 27

What is a malignant smooth muscle tumour called?

Answer 27

Leiomyosarcoma

Question 28

What is a benign peripheral nerve sheath tumour called?

Answer 28

Schwannoma

Question 29

What is a malignant peripheral nerve sheath tumour called?

Answer 29

A malignant peripheral nerve sheath tumour!

Question 30

What is a benign tumour of fibroblasts called?

Answer 30

Fibroma

Question 31

What is a malignant tumour of fibroblasts called?

Answer 31

Fibrosarcoma

Question 32

What is tumour grade?

Answer 32

The grade of a tumour is defined as the extent to which the tumour histologically resembles the cell or tissue of origin. Grade is synonymous with differentiation and is a measure of how aggressive the tumour is likely to be. Low grade tumours grow slowly while high grade tumours grow rapidly and metastasize quickly.

Question 33

Describe the 3 steps in the pathogenesis of invasion.

Answer 33

Step 1: Loosening of intercellular junctions. Inactivation of e-cadherin. Inappropriate expression of SNAIL and TWIST, which suppress e-cadherin expression. Activation of beta-catenin.

Step 2: Degradation of the extracellular matrix. Protease secretion by tumour or stroma dissolves proteins. Matrix metalloproteinases (MMPs) dissolve basement membranes and matrix and release growth factors from stroma.

Step 3: Migration and invasion. MMPs 2 and 9 cleave the basement membrane. Tumour cells produce autocrine motility factors and insulin-like growth factor 1 has chemotactic activity for malignant cells. Stromal cells produce hepatocyte growth factor/scatter factor which promotes malignant cell movement.

Question 34

Describe the steps which are involved in tumour metastasis.

Answer 34

Detachment of tumour cells.
Invasion of connective tissue to reach lymphatics and blood vessels.
Intravasation into the lumen of the vessels.
Evasion of host defence by natural killer cells and T-cells.
Adherence to endothelium at the remote location eg. liver, lung, bone.
Extravasation of cells from the vessel into the tissue at the new location.
Survival and growth at the new location.

Question 35

List the three possible routes of metastasis

Answer 35

Lymphatic - to draining lymph nodes. Usually the first site of metastasis for carcinomas.
Haematogenous - to liver, lung, bone and brain. Favoured by sarcomas, which do not tend to use the lymphatic route of metastasis.
Trancoelomic - seen with malignant ovarian tumours and tumours of the GIT in the peritoneal cavity and pleural/pericardial cavity spread is usually from lung or breast.

Question 36

List the 5 carcinoma primary sites which most commonly metastasise to bone.

Answer 36

Lung.
Breast.
Kidney.
Thyroid.
Prostate.

Question 37

Which virus causes patients who are immunosuppressed to develop multiple squamous cell carcinomas of the skin? Think here of any virus you know of which can infect squamous epithelium.

Answer 37

Human papilloma virus.

Question 38

List four mechanisms by which tumour cells can evade immune surveillance.

Answer 38

Selection of antigen-negative clones.
Loss of MHC molecules.
Expression of transforming growth factor beta.
Expression of PD1 ligand which can switch of T-cells.

Question 39

What is the tumour stage and what system is currently used for staging tumours?

Answer 39

The stage of a tumour refers to how large it is and how far it has spread. We currently use the TNM system for staging cancers. T refers to the tumour size or extent of local invasion. N refers to lymph node metastases and M refers to distant metastases.

Question 40

What is Horner’s syndrome?

Answer 40

A right upper lobe tumour of the lung can spread around the brachial plexus, compressing the nerves causing wasting, pain, weakness and paraesthesia in the arm. This tumour can also compress the sympathetic chain causing the eyelid to droop (ptosis), a constricted pupil (miosis), and absence of sweating of the face (anhidrosis). This is known as Horner’s syndrome.

Question 41

Why do tumours cause profound weight loss (cachexia)?

Answer 41

Disseminated malignant tumours are commonly associated with profound weight loss despite adequate nutrition. The catabolic state of a cancer patient with severe weight loss and debility is called cachexia and is thought to be mediated by tumour-derived humoral factors that interfere with protein metabolism causing muscle loss (sarcopenia). Weight loss can also be associated with nutrition interference eg. due to oesophageal obstruction severe pain or depressive illness.

Question 42

What is the Warburg effect?

Answer 42

Most cancers produce energy by a high rate of glycolysis with formation of lactic acid whereas normal cells have a low rate of glycolysis with oxidation of pyruvate in mitochondria. This effect is called the Warburg effect and is the reason why positron emission tomography (PET) scans work. The patient is given 2-18F-2-deoxyglucose (FDG), which is taken up by tumours and causes them to light up.

Question 43

How do tumours cause death?

Answer 43

Lung: If tumour obstructs a bronchus it may not be possible for secretions to get past and this predisposes to pneumonia. Acute bronchopneumonia is a common cause of death in patients with terminal cancer.

Bone: Metastatic carcinoma to the bones may cause hypercalcaemia which may be difficult to control leading to renal failure and cardiac arrhythmias. Cancer cells in the bone marrow impair haematopoiesis leading to anaemia, an increased risk of infection and increased risk of bleeding. Pathological fractures can also cause spinal cord compression.

Liver: Metastatic tumour in the liver can cause electrolyte abnormalities leading to death.

Blood vessels: Tumour invasion of blood vessels can cause haemorrhage and tumours can obstruct major veins such as the superior vena cava causing heart failure.

Brain: Metastatic tumours within the brain can be associated with raised intracranial pressure or they may develop intratumoral haemorrhage. The brain swelling can eventually cause the cerebellar tonsils to be pushed into the foramen magnum compressing the respiratory centre in the brainstem resulting in death.

GIT: Carcinomas which involve the gastrointestinal tract can cause obstruction. This can impair nutrition, cause ulceration or perforation. Impaired nutrition predisposes to developing infection.

Question 44

What is the term used to describe a benign tumour of osteoblasts?

Answer 44

Osteoma

Question 45

Which familial syndrome is characterised by osteomas and large bowel polyps and is associated with an increased risk of colorectal carcinoma development?

Answer 45

Gardner syndrome

Question 46

What is the term used to describe a benign tumour of cartilage and what does this look like on an x-ray?

Answer 46

Chondroma or enchondroma (if it arises within the medullary cavity). On x-ray, there is a circumscribed lucency with central irregular calcifications or a sclerotic rim and an intact cortex.

Question 47

A pathologist issues the following report on a pedunculated bone tumour taken from the lower femoral metaphysis of a 20-year-old male patient. The tumour was pointing away from the knee joint. “There is a cap of hyaline cartilage which is undergoing endochondral ossification and which merges with the underlying trabecular bone. There are no atypical features”. What tumour is being described here?

Answer 47

An osteochondroma (exostosis).

Question 48

A 25-year-old male presents with severe pain at night in his upper right thigh, which is relieved by aspirin. An x-ray shows a 1.1 cm lucency in the cortex of his right femur with a surrounding rim of reactive bone formation. Under the microscope, this shows a central nidus consisting of osteoid trabeculae separated by a vascular fibrous stroma. The nidus has a sharp margin which interfaces with a surrounding rim of mature bone. Which tumour is being described here?

Answer 48

This is an osteoid osteoma. Osteoblastoma is like an osteoid osteoma but is larger than 2 cm and involves the posterior components of the vertebrae and the pain does not respond to aspirin. In addition these tumours do not induce a marked bony reaction.

Question 49

Which bone tumour has a soap bubble appearance on x-ray and involves the epiphysis of long bones in young adults?

Answer 49

Giant cell tumour of bone. This is a locally aggressive tumour of osteoclast precursors which may recur after currettage treatment. There is also a small risk (4%) of lung metastasis but these may regress and are seldom fatal.

Question 50

What is the name given to a malignant tumour of osteoblasts?

Answer 50

Osteosarcoma.

Question 51

What is the name given to a malignant tumour of chondrocytes?

Answer 51

Chondrosarcoma.

Question 52

What is Ewing sarcoma?

Answer 52

A lucent tumour which involves the diaphysis of long bones in male children under the age of 15. It is a malignant proliferation of small round blue cells of neuroectodermal origin and often presents with metastatic disease but responds to chemotherapy. 5 yr survival is 65-80% for localized disease and 25-40% for metastatic disease.

Question 53

What is the typical x-ray appearance of Ewing sarcoma?

Answer 53

They usually present as moth-eaten, permeative, destructive lucent lesions in the diaphysis of long bones, with a large soft tissue component, without osteoid matrix and they show a typical onion skin periosteal reaction. In Ewing sarcoma, the periosteum cannot produce new bone as fast as the lesion is growing. If the lesion grows unevenly in fits and starts then the periosteum may have time to lay down a thin shell of calcified new bone before the lesion takes off again on its next growth spurt. This results in a pattern of one or more concentric shells of new bone over the lesion called a lamellated or “onion-skin” periosteal reaction.

Question 54

What are the risk factors for osteosarcoma?

Answer 54

Familial retinoblastoma: In familial retinoblastoma there is an inheritable mutation in the retinoblastoma tumour suppressor gene which predisposes the patient to develop eye tumours called retinoblastomas as well as other tumours, including osteosarcoma.
Paget’s disease is a disease causing an increased rate of bone turnover.
Damage to the bone caused by infarction and radiation also increase the risk of osteosarcoma. These are referred to as secondary osteosarcomas.

Question 55

What does an osteosarcoma look like on X-ray?

Answer 55

Osteosarcomas involve the metaphysis of long bones, in the region of the growth plate, often involving the knee region. Radiographs show a large destructive mixed lytic and sclerotic mass with infiltrative margins and a sunburst appearance. The tumour frequently breaks through the cortex and lifts the periosteum resulting in reactive sub-periosteal new bone formation. The triangular shadow between the cortex and raised ends of the periosteum (known radiologically as the Codman triangle) is indicative of an aggressive tumour but is not pathognomonic of osteosarcoma.

Question 56

What bone lesions can show a Codman triangle?

Answer 56

The Codman triangle may be seen with osteosarcoma, Ewing sarcoma, osteomyelitis, aneurysmal bone cyst, giant cell tumour, metastasis, chondrosarcoma and malignant fibrous histiocytoma.

Question 57

List 3 tumour suppressor genes that are involved in the pathogenesis of osteosarcoma.

Answer 57

Retinoblastoma (Rb). Somatic mutations are present in up to 70% of osteosarcomas.
p53.
CDKN2A. This gene encodes 2 tumour suppressors (p16 and p14). p16 is a negative regulator of cyclin-dependent kinases and p14 augments p53 function.

Question 58

List 2 oncogenes which are over-expressed in low-grade osteosarcomas.

Answer 58

MDM2, which inhibits p53.
2. CDK4, which inhibits Rb.

Question 59

What causes the sunburst pattern seen with osteosarcoma on imaging?

Answer 59

This occurs when the tumour grows quickly and the periosteum does not have enough time to lay down a new layer and instead the Sharpey’s fibres stretch out perpendicular to the bone.

Question 60

Which tumour shows a progressively enlarging, destructive mass involving the axial skeleton with a characteristic rings and arcs pattern of calcification?

Answer 60

Chondrosarcoma

Question 61

What does a pathologist see under the microscope to make a diagnosis of chondrosarcoma?

Answer 61

A mass formed of atypical/malignant chondrocytes with enlarged, dark, irregular nuclei, and binucleate forms.

Question 62

Which 5 tumours commonly metastasise to bone in adults?

Answer 62

Breast.
Prostate.
Kidney.
Lung.
Thyroid.