Metastasis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

## Overview

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## Pathophysiology

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## Modes and sites of metastatic dispersal

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Metastatic tumors are very common in the late stages of cancer. The spread of metastases may occur via the blood or the lymphatics or through both routes. The most common places for the metastases to occur are the adrenals, liver, brain, and the bones. There is also a propensity for certain tumors to seed in particular organs. This was first discussed as the "seed and soil" theory by Stephen Paget over a century ago in 1889. For example, prostate cancer usually metastasizes to the bones. In a similar manner, colon cancer has a tendency to metastasize to the liver. Stomach cancer often metastasizes to the ovary in women, then it is called a Krukenberg tumor. It is difficult for cancer cells to survive outside their region of origin, so in order to metastasize they must find a location with similar characteristics.

For example, breast tumor cells, which gather calcium ions from breast milk, metastasize to bone tissue, where they can gather calcium ions from bone. Malignant melanoma spreads to the brain, presumably because neural tissue and melanocytes arise from the same cell line in the embryo.[1]

Cancer cells may spread to lymph nodes (regional lymph nodes) near the primary tumor. This is called nodal involvement, positive nodes, or regional disease. Localized spread to regional lymph nodes near the primary tumor is not normally counted as metastasis, although this is a sign of worse prognosis.

In addition to the above routes, metastasis may occur by direct seeding, e.g., in the peritoneal cavity or pleural cavity.

## Factors involved

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Metastasis is a complex series of steps in which cancer cells leave the original tumor site and migrate to other parts of the body via the bloodstream or the lymphatic system. To do so, malignant cells break away from the primary tumor and attach to and degrade proteins that make up the surrounding extracellular matrix (ECM), which separates the tumor from adjoining tissue. By degrading these proteins, cancer cells are able to breach the ECM and escape. When oral cancers metastasize, they commonly travel through the lymph system to the lymph nodes in the neck. The body resists metastasis by a variety of mechanisms through the actions of a class of proteins known as metastasis suppressors, of which about a dozen are known.[2]

Cancer researchers studying the conditions necessary for cancer metastasis have discovered that one of the critical events required is the growth of a new network of blood vessels, called tumor angiogenesis.[3] It has been found that angiogenesis inhibitors would therefore prevent the growth of metastases.

## Metastasis and primary cancer

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It is theorized that metastasis always coincides with a primary cancer, and, as such, is a tumor that started from a cancer cell or cells in another part of the body. However, over 10% of patients presenting to oncology units will have metastases without a primary tumor found. In these cases, doctors refer to the primary tumor as "unknown" or "occult," and the patient is said to have cancer of unknown primary origin (CUP) or Unknown Primary Tumors (UPT). It is estimated that 3% of all cancers are of unknown primary origin.[4] Studies have shown that, if simple questioning does not reveal the cancer's source (coughing up blood -'probably lung', urinating blood - 'probably bladder'), complex imaging will not either.[4] In some of these cases a primary may appear later.

The use of immunohistochemistry has permitted pathologists to give an identity to many of these metastases. However, imaging of the indicated area only occasionally reveals a primary. In rare cases (e.g., of melanoma), no primary tumor is found, even on autopsy. It is therefore thought that some primary tumors can regress completely, but leave their metastases behind.

## Common sites of origin

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* Lung
* Breast
* Skin: Melanoma (other skin tumors rarely metastasize)
* Colon
* Kidney
* Prostate
* Pancreas

## Primary v/s Secondary Tumors

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The cells in a metastatic tumor resemble those in the primary tumor. Once the cancerous tissue is examined under a microscope to determine the cell type, a doctor can usually tell whether that type of cell is normally found in the part of the body from which the tissue sample was taken.

For instance, breast cancer cells look the same whether they are found in the breast or have spread to another part of the body. So, if a tissue sample taken from a tumor in the lung contains cells that look like breast cells, the doctor determines that the lung tumor is a secondary tumor. Still, the determination of the primary tumor can often be very difficult, and the pathologist may have to use several adjuvant techniques, such as immunohistochemistry, FISH (fluorescent in situ hybridization), and others. Despite the use of techniques, in some cases the primary tumor remains unidentified.

Metastatic cancers may be found at the same time as the primary tumor, or months or years later. When a second tumor is found in a patient that has been treated for cancer in the past, it is more often a metastasis than another primary tumor.

## Gross Pathology

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Cut surface of a liver showing multiple metastatic nodules originating from pancreatic cancer. |  | Cut surface of a humerus sawed lengthwise, showing a large cancerous metastasis (the whitish tumor between the head and the shaft of the bone).

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## References

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1. ↑ Robert Weinberg, The Biology of Cancer, cited in Basics: A mutinous group of cells on a greedy, destructive task, by Natalie Angier, New York Times, April 3, 2007
2. ↑ Yoshida, BA, Sokoloff, MM, Welch, DR, Rinker-Schaeffer CW. 2000. Metastasis-suppressor genes: a review and perspective on an emerging field. Journal of the National Cancer Institute 92: 1717-1730.
3. ↑ N Weidner, JP Semple, WR Welch, and J Folkman; Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma; The New England Journal of Medicine, Volume 324:1-8, January 3, 1991; Number 1.
4. ↑ 4.0 4.1 Evangelos Briasoulis, Nicholas Pavlidis; Cancer of Unknown Primary Origin; The Oncologist, Vol. 2, No. 3, 142–152, June 1997

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