neoplasia 1 - definition and classification

what does neoplasia mean?

• New growth

• A tissue state characterised by a permanently altered growth pattern

• Abnormal mass of tissue, the growth of which is uncoordinated with that of normal tissues and persists after the stimulus is removed

• the term ‘neoplasm’ doesn’t give any insight on how exactly the tumour behaves

what is the definition of a tumour?

Swelling, generally without inflammation, caused by an abnormal growth of

tissue whether benign or malignant

how can you classify tumour behaviour?

benign/ malignant

how can you classify tumours pathologically? 4

consider the cell type of origin…

1. Epithelium

2. Connective tissue

3. Lymphoid / haematopoietic tissue

4. Germ cells

tumour differentiation / grade

• The extent to which a tumour resembles its normal counterpart, both

• morphologically and functionally

• There are tumours for which no normal cell of origin can be determined: unable to comment therefore on differentiation

this relates more to malignant tumours - as benign tumours resemble their tissue of origin well

In general terms well differentiated lesions are

less proliferative and less aggressive with less potential for metastatic spread than their poorly differentiated counterparts

There are exceptions

grade 1 tumours

well differentiated

grade 2 tumours

moderately differentiated

grade 3 tumours

poorly differentiated

Hyperplasia

Increase in the number of cells in a tissue

Hypertrophy

Increased in the size of cells in a tissue

Atrophy

Reduction in the size of cells in a tissue

Involution

Decrease in the number of cells in a tissue

Metaplasia

A change from one to another normal differentiated cell type within a tissue - cellular instability - may increase risk of cancer developing

Dysplasia

A state in some tissues which denotes an increased risk of

malignant change (*)

*fibrous dysplasia: abnormal development

morphological abnormalities of cells seen in the microscope which are not yet cancerous

Neoplasia

A tissue state characterised by a permanently altered growth pattern

hyperplasia example

Bone marrow cells in people living at high altitudes

Hypertrophy example

Bodybuilders / athletes

Atrophy example

Muscle atrophy in a dis-used limb

Involution example

Breast tissue on cessation of breastfeeding

Metaplasia example

Barrett’s oesophagus

Dysplasia example

Cervical screening

what is barretts oesophagus?

• example of metaplasia

• oesophagus is usually lined with squamous cell epithelium

• stomach is lined by glandular epithelium- produces acids and enzymes - but is resistant to these products

• squamous epithelium is easily damaged - so its therefore important to keep the stomach contents within the stomach via the lower oesophageal sphincter - but in reflux there is escape into lower oesophagus - damages the epithelium - the body can change the type of epithelium here to combat this - makes itself glandular - notice how the mucosa looks more red instead of paler

• right image shows the interface between the pale and the red mucosa

benign vs malignant - differentiation

• benign- well differentiated, likely to resemble original tissue of origin

• malignant - spectrum of differentiation from well to poorly differentiated

benign vs malignant - growth rate

• benign - slow growth

• malignant - growth rate variable and unpredictable

benign vs malignant - mitotic figures

• benign - mitotic figures rare and normal

• malignant - mitotic figures may be numerous and atypical

demarcation - benign vs malignant

benign - well demarcated

malignant - poorly demarcated

benign vs malignant - expansible growth vs locally invasive

benign - expansible growth

malignant - locally invasive

benign vs malignant - metastasis - spread to other parts of the body

benign - does not metastasise

malignant - regional and distant metastasis

compare benign and malignant tumours 6

some benign tumours may be locally aggressive but can still be classified as benign - why?

• because they don’t metastasise- but they may require more surgery than atypical benign tumour

• consider benign and malignant to be a spectrum

• two purple examples are malignant but at the benign end as they can metastasise but they rarely do

tumours can be three types - birds, rabbits and tortoises

• cancer patients will survive if their tumours are contained - aim of cancer therapy is to fence them in

• birds cant be fenced in - they will fly away - disseminated tumours - widespread at the time of diagnosis

• rabbits can jump - can escape - can be contained - treat them aggressively

• tortoises - all benign tumours, and indolent malignant tumours

which is more common - epithelial tumours or mesenchymal tumours?

epithelial - with squamous tumours being more common than glandular tumours → arise from the mucosa

granular - salivary glands

wb the stomach?

epithelial squamous tumour B and M

B - squamous cell papilloma

M - squamous cell carcinoma

epithelial glandular tumour B and M

B - adenoma

M - adenocarcinoma

mesenchymal smooth muscle tumour

B - leiomyoma

M - leiomyosarcoma

mesencymal skeletal muscle tumour

B - rhabdomyoma

M - rhabdomyosarcoma

mesenchymal fat tumour

lipoma

liposarcoma

mesenchymal bone tumour

B - osteoma

M- osteosarcoma

mesenchymal cartilage tumour

B - chondroma

M - chondrosarcoma

mesenchymal endothelial tumour

haemangioma B vs angiosarcoma M

lymphoma

ALWAYS malignant - tumours of the lymphoid system

melanoma

always a malignant tumour of melanocytes

leukaemia

tumour of bone marrow cells - always malignant

teratoma

a tumour which includes elements of all 3 embryonic germ layers - rare

hamartoma

a developmental anomaly - not a tumour

some tumours are named after the person who first described them

what causes tumours?

• chemical carcinogens - lung and mouth cancers - smoking

• breast and ovarian cancers - genetic predisposition

can cancers be caused by viruses?

yes!

• Cervical, oropharyngeal and anal squamous cell carcinoma: high risk HPV

• “Oropharyngeal HPV associated squamous cell carcinoma”

• Nasopharyngeal carcinoma and Burkitts lymphoma: EBV

• Kaposi sarcoma: HHV-8 (human herpes virus 8)

can use in situ hybridisation techniques to detect viral DNA in tumour cells

Cancers associated with infection / inflammation?

• Hepatitis and liver cancer (hepatocellular carcinoma)

• H pylori and gastric cancer (adenocarcinoma)

• Pancreatitis and pancreatic cancer (adenocarcinoma)

cytokines may encourage proliferation in neighbouring cells

benign tumours tend to be

encapsulated, and grow slowly and expand rather than infiltrate

Spread of malignant tumours 5

• infiltrate local tissues

• may gain access to lymphatics

• may gain access to venous circulation

• may head straight to lungs liver bone etc

• may spread along nerves

normal structure and function of squamous cell epithelium

• forms lining of oral mucosa

• barrier formation

• multiple layers of cells

• loose layer of keratin on the surface

• epithelium sits on a layer of connective tissue called the lamina propria nd is well demarcated by the basement membrane

squamous cells

attached by intercellular bridges

spread of malignant squamous carcinoma local infiltration

undergo genetic changes - lose those tight attachments

• Lose tight attachments

• Disrupt / dissolve the basement membrane - no longer confined

• Enter connective tissues / acquire mobility and gain destructive powers to damage the stromal tissues that are in their way

• notice the infiltrating islands of cells that extend from the surface epithelium on the top right

• they’re entering and breaking up the muscle layers - which still remain quite bright pink

• lots of associated inflammation

• the tumour islands do bear some resemblance to the surface squamous epithelium - but more chaotic version of it

• normal epithelium, beneath it, there’s a very similar looking island (tumour) - keratin pink centre - looks chaotic, atypical cells

• invasive infiltrating squamous cell carcinoma

• if the cells resemble the epithelium but theyre away from the basal cells - them why do they resemble epithelial cells? surely theyre in the lamina propria now and should resemble fibroblasts or adipocytes

• cant diagnose as a squamous cell carcinoma because you’d need a piece of tissue

• mass with a different signal - measure size depth and extent - could be a carcinoma, sarcoma or lymphoma

• white area - same signal as normal bone - bone tumour - osteosarcoma

some salivary gland tumours have a propensity for neural spread - coronal MRI scans of a mass in the parotid

• extension of this mass into the facial nerve - cranial fossa

• symptoms may include sensory loss or loss of motor function

spread of malignant tumours - lymphatic spread

anterior tongue, floor of mouth and gingival mucoperiosteum

fibrofatty tissue of the upper central and left lateral neck 1,2,3,4 contain the tymph nodes - yellow-bown

distant metastasis

• liver - probably a post-mortem sample

• contains multiple white nodules - consistent with metastasis

• disseminated picture - likely from somewhere else compared to a lone, primary tumour - usually GI, breast and lung

how do you go from primary to a metastatic tumour?

metastatic cascade

• tumour cells have a tendency to secrete vascular growth factors - which encourages angiogenesis

• a well vascularised tumour has a good supply of nutrients and oxygen - can keep growing

• detach and dissociate spread away from each other by down regulating proteins that would normally mediate their connection

• invasion requires involving mobility and possibly enzymatic destruction of stromal/connective tissues

• host inflammatory cells are present in most tissues carrying out surveillance - ready to respond to tissue damage or infection

• tumour cells will likely encounter CD8 T cells that could recognise them as foreign - tumour cells can develop complex pathways to downregulate T cells that could recognise them as foreign

• once the migrating tumour cells reach the small calibre vessels - they can undergo a reverse of the process which allows inflammatory cells out of the vessels - gain access to the lumen

• once they’re in the vessels they need to continue to evade host defences - macrophages lymphocytes

• adhesion to vessel walls - but i thought immune cells also marginate?

• extravasation - leave the vessels - set up their own blood supply

metastatic cascade

what are some non malignant effects of tumours? 3

1. increased tendency to thrombosis

2. Cellular over activity e.g. overproduction of a hormone that would be expected to be produced by that particular tumour cell type, such as parathyroid adenoma or carcinoma - hypercalcaemic

3. Paraneoplastic phenomenon - Set of signs and symptoms that are a consequence of the presence of the tumour but not directly attributable to it e.g secretion of hormones and other substances that wouldn’t normally be secreted by the tumour cell type - eg raised parathyroid levels - but no parathyroid tumour - they have a lung cancer - lung cancer cells are producing parathyroid hormone

Factors affecting prognosis 8

1. Tumour type - some have an excellent prognosis such as a thyroid cancer called papillary carcinoma vs small cell carcinoma of lung - disseminates readily

2. Site and size; resectability - 1cm in brain is worse thana 5cm on finger

3. Differentiation - well differentiated tumours do better

4. Degree of cellular atypia

5. Depth and extent of invasion

6. Mitotic index and degree of mitotic atypia

7. Regional lymph node involvement

8. Distant metastasis - already metastasized - poor

• well differentiated - look almost identical to the cells you’d find in mucosal tissue - filling and invading the connective tissues - carcinoma - because they’re not where they’re meant to be

• constituent cells are bland and monotonous and evenly spaced - normal - keratin formation

• moderately differentiated tumour

• intercellular bridges - normal characteristic of squamous cell

• is some keratin

• much uglier - cellular atypia

• in the fibrous layer of the connective tissue of lamina propria - not in the surface - infiltrative - carcinoma

• poorly differentiated - no intercellular bridges - no keratin - why squamous?

• we’d diagnose by looking a at a bigger sample and try and look for one that looks like a squamous cell/has a intercellular bridge

• or immunohistochemical stains - antigens that correlate to squamous differentiation

factors affecting prognosis - subjective vs objective observation

• subjective - differentiation/atypia

• objective - depth and extent of invasion, mitotic count

prognostic indices - melanoma

• clack level - depth of invasion of melanoma

• distance from basement membrane to the lowest down tumour cell - Breslow thickness - approximate 5 year survival

Prognostic indices: Dukes for colorectal cancer

• Dukes A: Confined to bowel wall

• Dukes B: Invading into the muscularis propria layer or beyond, lymph node negative

• Dukes C: Lymph node metastases

• Dukes D: Distant metastases

Prognostic indices: mitotic count

count how many mitosis there are - and atypical forms which may indicate greater level of genetic derangement

diagnosis - techniques

You need a tissue sample for diagnosis of presence of a tumour and also to sub-type it

Radiology can help to define size, extent and structures involved and might give some clues as to the tumour type

Tissue

• Fine needle aspirate (FNA) - cells aspirated and placed on a slide - accurate subtyping not possible and prognostic indices also not possible - but may be required for assessing lymph nodes who has a positive tissue biopsy for squamous cell carcinoma

• Histology (biopsy) - gold standard

Immunohistochemistry and genetic testing of tumours

Refer to laboratory diagnosis of disease lecture

Screening

The systematic search for cancer in people who have no signs or symptoms of cancer - find cancers early - treatment more simple

what are the two issues of screening?

False positives, Over diagnosis

Well established screening programs

Cervical, Breast ,Colorectal

why is screening not a thing for lung, prostate or thyroid cancer?

Lung: CT screening 70-90% patients had 1 false positive result - also consider radiation dose of a CT

Prostate: PSA (protein in blood) screening 25-30% of patients had 1 false positive result

* typically each test has 5-10% false positive risk, but screening is repetitive and these can add up

campaigns for thyroid cancer

papillary thyroid cancer has a good prognosis - overdiagnosis - cancer may not have gievn them medical problems

are there any oral cancer screenings

no but examine mucosa in intraoral examination

staging vs grading

grading is assessing tumour differentiation- well/moderate. Poor

staging uses a TNM classification

• T- tumour 1-4 - size and structure of tumour

• N - lymph NODES 1-3 - number and type of lymph nodes invaded

• M - metastasis 0 no, X yes

cancers have unique staging systems