Mechanisms of Invasion and Metastases

Local Invasion:

• Almost all benign tumors grow as cohesive expansile masses
• Remain localized to their site of origin
• Do not have the capacity to infiltrate, invade, or metastasize to distant sites
• Usually have rim of fibrous capsule that separates them from host tissue
• Rim is composed of stroma of the native tissues as its parenchymal cells atrophy under the pressure of expanding tumor
• Tends to be contained as a discrete, readily palpable, and easily movable mass
• Some benign tumors can be encapsulated (example = hemangiomas)
• The growth of malignant tumors is accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue
• Poorly separated from surrounding normal tissue
• Slowly expanding malignant tumors may develop an apparently enclosing fibrous capsule; capsule has breaks along its margin
• Invasiveness is one of most reliable features (next to metastases) to differentiates malignant from benign tumors
• Carcinoma in situ – displays the cytologic features of malignancy w/out invasion of the basement membrane
• Example = carcinoma of the uterine cervix
• Can be considered one step removed from invasive cancer
• In time, most become invasive

Example of Disturbance of Growth:

• Progression in cervix from normal squamous epithelium to squamous cell carcinoma in situ
• Mild dysplasia is present when abnormal organization and cellular atypia is confined to the lower one third of the epithel layer
• Moderate dysplasia – 1/3 to 2/3 of epithelium is involved
• Severe dysplasia – indistinguishable from CIS since the full thickness of the epithelium is involved
• In each of these situations the basement membrane is intact
• Abnormal process is confined to the epith layer

Continuum:

• Progression of cellular dysplasia to carcinoma-in-situ- to locally invasive carcinoma followed by metastases

Metastases:

• Tumor implants discontinuous with the primary tumor
• Unequivocally marks a tumor as malignant b/c benign neoplasms do not metastasize
•  With few exceptions, all cancers can metastasize
•  Exceptions are gliomas and basal cell carcinomas of the skin – both are highly invasive but rarely metastasize
• More aggressive, more rapidly growing, and the larger the primary neoplasm, the greater the likelihood that it will metastasize
• Strongly reduces the possibility of cure
• About 30% of newly dx pts w/ solid tumors have metastases

Mechanisms of Invasion and Metastases:

1.      Clonal Expansion, growth, diversification, and angiogenesis

2.      Metastatic subclone adheres to and invades basement membrane

3.      Passes t/ ECM

4.      Intravasation

5.      Interaction w/ host lymphoid cells

6.      Tumor cell embolus

7.      Adhesion to basement membrane

8.      Extravasation

9.      Metastatic deposit

10.  Angiogenesis

11.  Growth

Factors in Invasion and Metastases:

Pathways of Spread:

1.      Direct seeding of body cavities or surfaces

2.      Lymphatic spread

3.      Hematogenous spread

Direct seeding of body cavities or surfaces:

• May occur whenever a malignant neoplasm penetrates into an open field
• Most often is the peritoneal cavity, but also can be any other cavity
• Esp common of carcinomas arising from ovaries à coats all peritoneal surfaces w/ cancerous glaze
• Pseudomyxoma peritonei – mucus secreting ovary and appendiceal carcinomas fill peritoneal cavity w/ gelatinous neoplastic mass

Lymphatic Spread:

• Most common p’way for initial dissemination of carcinomas
• Sarcomas also use this p’way
• Pattern of lymph node involvement follows the natural routes of drainage
• Local lymph nodes may be bypassed b/c of venous-lymphatic anastomoses, or b/c inflamm or radiation has obliterated channels
• Regional nodes serve as effective barriers to further dissemination, at least for a while
• Tumor-specific immune response may participate
• Enlargement of lymph nodes may be caused by:

1.      Spread and growth of cancer cells

2.      Reactive hyperplasia

• Nodal enlargement in proximity to a cancer does not necessarily mean dissemination of the primary lesion

Hematogenous Spread:

1. Typical of sarcomas, but also used by carcinoma
2.  Arteries have thicker walls, are less readily penetrated than are veins
3. Arterial spread may occur when tumor cells pass t/ pulmonary capillary beds or pulmonary arteriovenous shunts, or pulmonary metastases give rise to tumor emboli
4. Venous invasion: blood-borne cells follow the venous flow, draining the site of the neoplasm
5.  Liver and lungs are most frequently involved secondarily in venous dissemination

• All portal area drainage flows to liver
• All caval blood flows to lungs

Grading and staging of cancer Grading criteria Degree of differentiation (e.g., low, intermediate, or high grade) Nuclear features, invasiveness Staging criteria  Most important prognostic factor TNM system Universal system Progresses from the least to the most important prognostic factor T refers to tumor size  ≥2cm correlates with metastatic ability. N refers to whether lymph nodes are involved.  M refers to extranodal metastases (e.g., liver, lung). Other systems For individual cancers  Duke staging for intestinal cancer