Tumour spread, grading and staging

Overview

The ability to invade and metastasise is what makes cancer deadly. Metastasis is the spread of tumour to sites not connected to the primary, forming new tumours there. It is the most reliable sign of malignancy.

Invasion and metastasis: the steps

1. Loosening of tumour cells: loss of the adhesion molecule E-cadherin.
2. Degradation of the extracellular matrix: tumour cells secrete matrix metalloproteinases (collagenases, especially type IV collagenase, which digests the basement membrane).
3. Attachment to new matrix proteins (laminin, fibronectin) through receptors such as integrins.
4. Migration through the broken basement membrane and stroma.
5. Intravasation into lymphatics or vessels.
6. Survival in the circulation (tumour cells clump with platelets).
7. Extravasation and growth at the distant site, which needs angiogenesis.

Metastasis is inefficient: millions of cells may enter the blood daily, but very few form metastases.

Routes of spread

1. Direct (local) invasion

Spread into adjacent tissues along tissue planes, vessels and nerves (perineural invasion, for example in prostate, pancreas and adenoid cystic carcinoma).

2. Lymphatic spread

• Typical of carcinomas.
• Tumour cells reach the regional lymph nodes first; the pattern follows normal lymphatic drainage.
• Sentinel lymph node: the first node draining the tumour; biopsied in breast cancer and melanoma to decide whether more nodes need removal.
• Enlarged nodes are not always tumour; they may show reactive hyperplasia.

Examples: Virchow's (Troisier's) node, the left supraclavicular node, from gastric and other abdominal cancers; breast cancer to axillary nodes.

3. Haematogenous (blood-borne) spread

• Typical of sarcomas.
• Veins are invaded more easily than arteries (thin walls).
• Portal vein drainage → liver; caval drainage → lungs.
• Carcinomas that prefer blood spread: renal cell carcinoma (into the renal vein), hepatocellular carcinoma (into hepatic and portal veins), follicular thyroid carcinoma, choriocarcinoma.

4. Transcoelomic spread (seeding of body cavities)

• Tumour cells spread across the peritoneal, pleural or pericardial cavity.
• Ovarian cancer commonly coats the peritoneum.
• Krukenberg tumour: metastatic signet-ring cell carcinoma to both ovaries, usually from the stomach (also colon, breast).
• Pseudomyxoma peritonei: mucinous tumour filling the peritoneal cavity (appendix or ovary).
• Sister Mary Joseph nodule: metastasis at the umbilicus.

Implantation

Transfer on instruments or needles during surgery or biopsy (rare).

Common sites of metastasis

• Liver and lungs are the commonest organs for blood-borne metastasis.
• Lung metastases may look like round "cannonball" deposits (renal cell carcinoma, sarcomas, choriocarcinoma).
• Bone: breast, prostate, lung, kidney, thyroid. Vertebrae are a favourite (Batson's venous plexus for prostate).
  • Osteoblastic (sclerotic, dense on X-ray): prostate.
  • Osteolytic: kidney, thyroid, lung, multiple myeloma; breast is often mixed.
• Brain: lung, breast, melanoma, kidney, colon.
• Adrenal: lung cancer.

Grading

Grading is a microscopic assessment of how abnormal the tumour cells look:

• degree of differentiation (well, moderately or poorly differentiated, or undifferentiated);
• number of mitoses;
• architecture.

Usually expressed as grades I to III or IV: higher grade = less differentiated = more aggressive. Examples: the Gleason system for prostate cancer and the Nottingham system for breast cancer.

Staging

Staging measures how far the cancer has spread, using clinical examination, imaging and surgical findings.

TNM system:

The T, N and M values combine into an overall stage I–IV. Older systems include Dukes staging for colorectal cancer.

Quick revision

• Invasion: lose E-cadherin, digest basement membrane (type IV collagenase), migrate.
• Carcinoma by lymph; sarcoma by blood; exceptions: renal cell, HCC, follicular thyroid, choriocarcinoma.
• Liver and lungs: commonest blood-borne sites.
• Krukenberg: signet-ring cells in both ovaries (stomach).
• Prostate: osteoblastic; myeloma, kidney, thyroid: osteolytic.
• Grade = differentiation; stage = TNM spread; stage matters more.

Written by The House Job from standard pathology references (Robbins and Cotran Pathologic Basis of Disease is the book named in the UHS PGET syllabus).

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