Neoplasia 2: Histological Features of Malignancy, Tumour Growth and Evolution

List some further cytological criterias of malignancy.

11) Nuclear Moulding

12) Coarse Chromatin

13) Macronucleoli

14) Angular Nucleoli

15) Anisonucleosis

Noone can mail anything alright.

What is nuclear molding?

• Nuclei are deformed by adjacent nuclei

• In the same or adjacent cell(s)

• Reflections of rapid growth/overcrowding

• Cells physically squashed together

What does coarse chromatin tell us?

thickly corded chromatin

• Indicates cell is very active, usually dividing

What does macronucleoli tell us?

Nucleoli > 5um (erythrocytes = 5-6um diameter)

What does angular nuclei tell us?

prominant angular nucleoli - more malignant

What does anisonucleosis tell us?

variably sized nucleoli

What are the histological features of malignancy?

1) Enlarged nucleus with prominent nucleolus

• Small amounts of cytoplasm

2) Increased mitotic figures

• bizarre/abnormal mitoses

3) Multiple nucleoli

4) Bizarre / large nucleoli

• karyomegaly

What are some of the biggest markers of differentiation in malignant cells?

• Cell morphology

• neoplastic cells often lose any recognisable gross & histological appearance - see Lecture 1

• Cell function

• usually lost in malignant tumours

• regulatory mechanisms lost

• Cell behaviour

• Increasingly aggressive with loss of differentiation and function

What is the parenchyma of the tumour?

What is the stroma of the tumour?

Parenchyma

• Neoplastic or transformed cells

  • Determine biologic behavior

Stroma

• Non-neoplastic, host-derived support tissues

  • Connective Tissue

  • Blood vessels

  • Host-derived inflammatory cells

  • Essential for tumour growth, providing physical support and nutrients

Describe the complex stromal interactions taking place within tumours.

• Complex interaction (2-way)

• Signalling molecules - wide variety

  • » growth factors, cytokines, hormones, inflammatory mediators

• Modulate growth rate, differentiation state, behaviour of both cell groups

• e.g. tumour-derived TGF-a (transforming growth factor - a)

  • » fibroblasts differentiate to myofibroblasts

  • » pericytes at edge of vessels

• e.g. tumour cells release PDGF (platelet derived growth factor)

  • Scirrhous/desmoplastic responses

  • Allows new blood vessels to grow in

What percentage of canine cancers are believed to be hereditary?

5 - 10%

What cancer affecting GSDs is hereditary?

- renal carcinoma and nodular dermatofibrosis (RCND)

» autosomal dominant inheritance

» inactivation of tumour suppressor gene

• folliculin (FLCN)

What causes heritable alterations in cancer?

Progressive accumulation of genetic and epigenetic abnormalities in cells

• Initial change is due to:

• EITHER inherited germline mutation

• OR somatic mutation, DNA damage by…

  • EITHER intrinsic factors

    OR extrinsic factors

    » by-products of metabolism e.g. Reactive Oxygen Species (ROl)

    » a chemical carcinogen, radiation or an oncogenic virus

What is epigenetics?

Epigenetic: reversible, heritable changes in gene expression that occur without mutation

• e.g. hypermethylation of promoter sequence -> stop tumour suppressor

Describe the stepwise tumour development process.

**Best understood in carcinomas

• Stepwise tumour development

1) Initiation

• irreversible GENETIC change introduced

2) Promotion

• specific stimuli cause outgrowth of initiated cells

• the end result is a benign neoplasia

(Transformation)

• neoplastic cells become progressively more malignant

3) Progression

• increased dysregulation

eventually become a malignant tumour

• Can be irreversible or reversible

Describe key features of the initiation stage of tumour development.

• Irreversible genetic change induced in basal cells by an initiator

• Initiator = chemical or physical carcinogen

→ DNA lesion introduced

→ DNA lesion mispairing during subsequent replication

→ mutation fixation (Not caught by cytotoxic T cells or NK cells)

• Initiated cells

- morphologically normal

- possibly quiescent for years until triggered to next stage

Describe key features of the promotion stage of tumour development.

- outgrowth of initiated cells in response to selected stimuli

• promoters alter gene expression

• initiated cells have growth advantage over uninitiated cells

• not a mutation, so REVERSIBLE

• If stimulus removed, can return to quiescent cells

Describe key features of the transformation and progression stage of tumour development.

• Go from benign to malignant to metastatic (If stimulus causes)

  • Involves genetic and epigenetic changes

  • Increasingly malignant sub-clones selected

Summarize the stepwise tumour development.

Outline the stepwise development of squamous cell carcinoma (SCC).

• Step 1: epidermal hyperplasia - benign papilloma (A-B)

• Step 2: carcinoma beginning to invade (C)

• Step 3: invasive carcinoma (D)