MECHANISM OF SPREAD Invasion and metastasis are the

MECHANISM OF SPREAD Invasion and metastasis are the most important features of malignant tumors. Definition: Metastasis means that tumor cells break loose from the primary tumor, enter blood vessels and lymphatics, and produce a secondary growth at a distant site. To do that, they must go into a series of steps: (1)-Invasion of extracellular Matrix (ECM) (2)-Vascular Dissemination and Homing of Tumor Cells

(1)-INVASION OF EXTRACELLULAR MATRIX (ECM): Tissues are organized into a series of compartments separated from each other by two types of ECM; basement membranes (BM) and interstitial connective tissue (CT). A tumour must first penetrate the underlying BM, traverse the interstitial CT and gain access to the circulation by penetrating the vascular BM.

Invasion of the extracellular matrix is an active process that can be resolved at several steps. 1. Detachment “loosening up” of the tumor cells from each other (loss of cellular cohesion). 2. Attachment to matrix components. 3. Degradation 4. Migration of ECM. of tumor cells.

1. Detachment “loosening up” of the tumor cells from each other. Normal cells are glued to each other and to their surroundings by a variety of adhesion molecules e. g. : cadherins. Tumour cells lose the normal cadherin expression. This reduces the ability of them to adhere to each other and facilitates their detachment from the primary tumor and their advance into the surrounding tissues.

2. Attachment to matrix components: To penetrate the ECM, tumor cells must adhere first (through receptors) to the matrix components, mainly laminin of basement membrane and fibronectin of the interstitial tissue. Attachment of tumour cells to the components of the BM or interstitial ECM, promotes the next step

3. Degradation of ECM. Degradation of the ECM by proteolytic enzymes secreted by tumour cells or by stimulated host cells (stromal fibroblasts and macrophages). Several enzymes are released as type IV collagenase (causing lysis of basement membranes of epithelia and of vessels) and cathepsin D (causing degradation of interstitium). Degradation of the ECM is a very important step for the tumor cells to create passageways for migration.

4. Migration (mobility) of tumor cells: Occurs by pseudopodia. The tumor cell mobility is facilitated by decrease cell adhesiveness. The direction of migration is mainly guided by the chemotactic effect of the degradation products of the matrix.

(2)-VASCULAR DISSEMINATION AND HOMING OF TUMOR CELLS: Tumour mobility allow tumor cells to come in contact and invade lymphatics, veins, capillaries and rarely arteries. Lymphatics are commonly invaded as they lack a basement membrane. Arteries are rarely invaded as the wall is rich in elastic tissue. Tumour cells are carried in the circulation in single forms and 20% only as clumps.

Most of the tumour emboli are destroyed in the circulation by the mechanical trauma and immune defenses especially natural killer cells. The surviving tumour cells adhere to platelets; this affords them some protection from antitumour host immune cells. Finally tumour cells impacted in small vessels, adhere to the endothelium, cross the basement membrane (by a mechanism similar to that describe above) and settle in the new site (homing). In the new sites, tumour cells proliferate forming metastatic deposits (metastasis, secondary tumours).

ROUTES OF SPREAD I. Direct spread: * Direct infiltration of the surrounding tissues is common to all malignant tumors. * So, any excision which aims at removing all the neoplastic cells must include a wide extent of the surrounding tissue, the so called wide safety margin.

Malignant cells infiltrate the surrounding tissues in all direction along the lines of least resistance. Periosteum, bone, cartilage, elastic and fibrous tissues delay direct spread. Spread to the skin or mucous membranes results in a malignant ulcer. Perineural invasion and spread is responsible for the pain that is associated with carcinomas of salivary glands, prostate and pancreas.

II DISTANT SPREAD: (1) Lymphatic Spread: More common in carcinomas and occurs by two ways: a- Lymphatic embolism: The malignant cells invade the wall of a lymph vessel, detach as small groups and are carried by the current of lymph as tumour emboli. The emboli reach the draining lymph node and get arrested in the peripheral subcapsular lymph sinuses.

-The malignant cells proliferate, destroy the substance of the node and spread to the perinodal tissue. -The node becomes enlarged, firm, fixed and its cut surface is greyish white. -Distant groups are affected later and finally the thoracic duct is involved and the malignant cells enter the general circulation.

b- Lymphatic permeation: -The tumour cells grow within the lumen of the lymphatic vessels as solid cords which extend to a variable distance from the primary tumour. -Lymphatic permeation causes localized obstructive oedema in the area. Lymphatic permeation occurs specially in breast, prostate and bronchial carcinomas as these organs are rich in lymphatics.

2. Blood spread: More common in sarcomas Mechanisms of spread: Malignant cells invade small vessels or veins become detached and then carried by the blood stream as tumour emboli to some distant site , proliferate, acquire a blood supply and develop into secondary tumors.