1. Methods of Spread of Malignant Tumours Professor of Pathology
Mechanism of Invasion
Neoplasia 4
Dr. Faten Ghazal
Professor of Pathology
Pathology Department

2. Intended Leaning Outcomes (ILOs)
By the end of this lecture YOU will be able to:
Describe methods of spread of malignant tumours
Explain what is meant by “organ tropism”
Explain mechanism of invasion & metastases

3. Methods of Spread of Malignant Tumours
Lymphatic spread
Haematogenous spread
Transcelomic spread (spread along body cavities to peritoneal surface)
Perineural spread
Intraepithelial spread

4. What is Sentinel Lymph Node?
1. Lymphatic Spread
Interconnections
Carcinomas spread mostly by Lymphatics
Sarcomas spread mostly haematogenously.
Follows mostly the anatomic consideration
Sentinel lymph node
is the first regional lymph node that receives lymph flow from the primary tumour.
Biopsy of the sentinel lymph node allows determination of the extent of spread of tumour and can be used to plan treatment
What is Sentinel Lymph Node?
Through either lymphatic permeation (growing along the wall of the lymphatics to reach the lymph node, or as tumour emboli. Tumour emboli enter through the convex surface of the LN under the capsule. Histopathologic verification of tumour within an enlarged lymph node is mandatory.

6. Metastatic carcinoma
A lymph nodal tissue shows infiltration by sheets & masses of malignant epithelial cells

7. Some Characteristics of Lymphatic Spread:
Regional lymph node enlargement can be reactive.
Obliteration of lymphatics by inflammation can lead to “skip metastases”.

8. Some Characteristics of Lymphatic Spread:
Virchow’s lymph node:
is nodal metastases to left supraclavicular lymph node from carcinoma of stomach, colon or gall bladder.
The sub diaphragmatic lymphatics draining into thoracic duct then to the left subclavian vein. Blockage of thoracic duct leads to retrograde spread to left supraclavicular LN.
Example of retrograde lymphatic spread

9. What is Krukenberg Tumour?
It is bilateral metastases of carcinoma in the ovaries from carcinoma of stomach, colon or breast. It is now considered most likely lymphatic spread and hematogenous spread rather than transcoelomic spread.

10. Methods of Spread of Malignant Tumours
2. Haematogenous Spread:
Is common in sarcomas but carcinoma of breast, thyroid, kidney, liver, prostate & ovary also do metastasize by blood.
Veins are invaded by tumour cells, resulting in thrombus formation, detachment of its parts give tumor emboli
Common sites are: liver (?), lungs (?), bones (?) and brain

11. Some Characteristics of Haematogenous Spread
Systemic veins drain into vena cava from limbs, head & neck & pelvis. Therefore cancers from these sites more often metastasize to lungs
Portal veins drain blood from the bowel, spleen, & pancreas into the liver.
Pulmonary veins provide another route of spread of not only from primary lung cancer but also from metastatic growths in lungs. Blood in pulmonary veins reach the heart to left side & then to systemic circulation.
Renal cell carcinoma often invades renal vein & inferior vena cava in a “snake like fashion”
Arterial spread is very rare (why?)
because of thick arterial wall and presence of elastic tissue
Give Reason

12. Give reason for the following:
Frequent involvement of vertebral column in carcinoma of thyroid & prostate
Since carcinomas of thyroid & prostate are near the vertebral column so, tumour emboli occurs through the paravertebral plexuses of veins (haematogenous spread) leading to metastatic deposits in vertebral column

13. Signet Ring Carcinoma of stomach
3. Spread Along Body Cavities
Transcoelomic Spread:
Cancer cells invade through the serosal wall of the coelomic cavity (peritoneal cavity) and will be carried in the coelomic fluid & are implanted elsewhere
Signet Ring Carcinoma of stomach

14. 3. Spread Along Body Cavities
Transcoelomic Spread:
Carcinoma of lung seeding in
pleura & pericardium
Mucoid adenocarcinoma of the appendix & ovary causing:
“Pseudomyxoma peritonei”

15. “Pseudomyxoma Peritonei”
Jelly like material in the abdominal cavity.
(b) Resected right iliac fossa mass involving terminal ileum, cecum and appendix due to a an mucoid adenocarcinoma of appendix

16. Methods of Spread of Malignant Tumours
3. Spread Along Body Cavities
b. Spread via Cerebrospinal Fluid:
Neoplasms of CNS (gliomas) may penetrate the cerebral ventricles to be carried by CSF to be implanted on meningeal surfaces in brain or spinal cord

17. Methods of Spread of Malignant Tumours
4. Peri-neural Spread:
Invasion of nerves, may be associated with pain and is considered a marker for poor prognosis.
e.g. adenoid cystic carcinoma of salivary glands and prostatic adenocarcinoma

18. Methods of Spread of Malignant Tumours 5. Intraepithelial Spread
From ducts to lobules
From lobules to ducts
From duct carcinoma to surface epithelium (Paget’s Disease of nipple)

19. Methods of Spread of Malignant Tumours 5. Intraepithelial Spread
Malignant cells may spread from:
Endometrium through the fallopian tube to the ovaries
Kidney into lower urinary tract through the ureters

20. Some tumours show distant sites
(Why??)
ORGAN TROPISM
It is related to expression of:
Adhesion molecules and Chemokines receptors by tumour cells whose ligands are expressed preferentially on the endothelium of the target organ.
Cancer breast, thyroid, kidney, prostate and lung give: bone metastasis
Lung Cancer give: adrenal, liver and brain metastasis.

21. Extended Modular Program
Complete the following sentences
The first regional lymph node that receives lymph flow from the primary site of the tumour is ………..
Spread of ovarian carcinoma to peritoneum and lung to pleura are example of ……
Spread of lung carcinoma to hilar and mediastinal lymph nodes are …..
Spread of breast carcinoma to the lung is …..
Quiz
Sentinel lymph node
Spread along body cavities (Transceolomic spread)
Lymphatic spread
Haematogenous spread
Extended Modular Program

22. Mechanism of Local Invasion & Metastases
This includes the passage of cancer cells by dissolution of extracellular matrix at several levels:
Basement membrane of tumour itself
Interstitial connective tissue
Basement membrane of blood vessels
Then again to go outside the blood vessels
Interstitial connective tissue to the secondary site

23. Mechanism of Local Invasion & Metastases
The first step that should be mentioned is:
Tumour is heterogenic.
It contains subpopulation of cells i.e. clone of cells that has the capability of to invade & metastasize.

24. Tumour cells are heterogeneous
Tumour cells are heterogeneous. Some clones have the ability to invade and metastasize more than others
Requiring fewer growth factors
Nonantigenic
Invasive
Metastatic
Tumour Cell Variants
Clonal Expansion of surviving cell variants
Carcinogen induced change
TRANSFORMATION
PROGRESSION
PROLIFERATION OF GENETICALLY UNSTABLE CELLS
TUMOUR CELL VARIANTS HETEROGENEITY
Normal Cell
Tumour cell
Human Solid Malignancy
Extended Modular Program

25. 1 2
1. Detachment of tumour cells from each other by Mutation Inactivation of E cadherin
2. Degradation: Tumour cells secrete proteolytic enzymes as collagenase
Cadherins 3 4
4. Migration: of tumour cells through release of cytokines by tumour cells as autocrine motility factors
3. Attachment to ECM components (cleavage of ECM) generates sites that bind to receptors on tumour cells)

26. Mechanism of Local Invasion & Metastases
Detachment ("loosening up") of the tumor cells from each other due to loss of cell to Cell Adhesion Molecules (CAMs) as E-(epithelial) –cadherin (normally acts as a glue between cells) and other CAMs. (mutational inactivation)
Degradation: Then tumour cells may either secrete proteolytic enzymes themselves or induce stromal cells & inflammatory cells to secrete proteases as matrix metalloproteinases (MMPs & Cathepsin D).
Invasion of the ECM is an active process that requires 4 steps

27. Mechanism of Local Invasion & Metastases
Attachment to ECM components:
cleavage of the ECM generates new sites that binds to receptors on tumour cells.
Migration & Locomotion:
The tumour cells move by secreting cytokines (autocrine motility factor), some growth factors & stromal paracrine effectors of motility.
Invasion of the ECM is an active process that requires 4 steps

28. Mechanism of Local Invasion & Metastases
Intravasation and Embolus Formation:
Tumour cells enter between endothelial cells
They circulate as single cells or adhered to blood cells as leucocytes & platelets to form an embolus where nourishment is provided to the cancer cells
Normally a large number of tumour cells are released in circulation but they get attacked by the host immune cells.

29. Mechanism of Local Invasion & Metastases
Extravasation of tumour cells:
Tumour cells in the blood vessels adhere themselves to its basement membrane then egress out of the vessels by a process similar to invasion.

30. Mechanism of Local Invasion & Metastases
Survival and growth of metastatic deposits:
the extravasated tumour cells grow in the new environment under influence of growth factors produced by:
host cells, tumour cells & cleavage of products of matrix components.
Growth Factors as VEGF, PDGF, FGF, & TGF (transforming growth factor β) trigger & regulate the process of angiogenesis in the new site.
This can further metastasize to the same organ or to distant site.

31. Transformation, Clonal Expansion of cells capable of invasion & metastases
Loosening of tumour cells
Degradation of BM & ECM
Attachment to cleavage components of ECM & BM by receptors
Migration by autocrine & paracrine factors
Intravasation: circulate singly or adhered to leukocytes & platelets
Adhesion & Extravasation
Metastatic growth

32. Extended Modular Program
Arrange the following events of invasion & metastases 1
Formation of a clone of cells capable more of invasion & metastases (tumour progression)
Migration of tumor cells by secreting motility cytokines & GFs
Tumour cells enter in the blood vessel to circulate singly or attached to platelets & leukocytes
Attachment to matrix components of BM by receptors on cancer cells to newly generated sites in the matrix
Tumour cells in vessels adhere themselves to basement membrane of the blood vessels then egress out a process similar to invasion.
Loosening of tumour cells from each other by loss of cell adhesion molecules (mutational inactivation)
Tumour cells grow in the new environment under influence of growth factors produced by: host cells, tumour cells & cleavage of products of matrix components.
Degradation of ECM by proteases & matrix degrading enzymes
Quiz 5 6 4 7 2 8 3
Extended Modular Program