METASTASIS
Metastases are tumor implants discontinuous with the primary tumor. Metastasis unequivocally marks a tumor as
malignant because benign neoplasms do not metastasize. The invasiveness of cancers permits them to penetrate
into blood vessels, lymphatics, and body cavities, providing the opportunity for spread. With few exceptions, all
malignant tumors can metastasize. The major exceptions are most malignant neoplasms of the glial cells in the
central nervous system, called gliomas, and basal cell carcinomas of the skin. Both are locally invasive forms of
cancer, but they rarely metastasize. It is evident then that the properties of invasion and metastasis are separable.
In general, the more aggressive, the more rapidly growing, and the larger the primary neoplasm, the greater the
likelihood that it will metastasize or already has metastasized. There are innumerable exceptions, however. Small,
well-differentiated, slowly growing lesions sometimes metastasize widely; conversely, some rapidly growing, large
lesions remain localized for years. Many factors relating to both invader and host are involved.
Approximately 30% of newly diagnosed individuals with solid tumors (excluding skin cancers other than melanomas)
present with metastases. Metastatic spread strongly reduces the possibility of cure; hence, short of prevention of
cancer, no achievement would be of greater benefit to patients than methods to block metastases.
Pathways of Spread
Dissemination of cancers may occur through one of three pathways: (1) direct seeding of body cavities or surfaces,
(2) lymphatic spread, and (3) hematogenous spread. Although direct transplantation of tumor cells, as for example
on surgical instruments, may theoretically occur, it is rare and we do not discuss this artificial mode of dissemination
further. Each of the three major pathways is described separately.
Seeding of Body Cavities and Surfaces.
Seeding of body cavities and surfaces may occur whenever a malignant neoplasm penetrates into a natural “open
field.” Most often involved is the peritoneal cavity, but any other cavity—pleural, pericardial, subarachnoid, and
joint space—may be affected. Such seeding is particularly characteristic of carcinomas arising in the ovaries, when,
not infrequently, all peritoneal surfaces become coated with a heavy layer of cancerous glaze. Remarkably, the
tumor cells may remain confined to the surface of the coated abdominal viscera without penetrating into the
substance. Sometimes mucus-secreting appendiceal carcinomas fill the peritoneal cavity with a gelatinous
neoplastic mass referred to as pseudomyxoma peritonei.
Lymphatic Spread.
Transport through lymphatics is the most common pathway for the initial dissemination of carcinomas , and
sarcomas may also use this route. Tumors do not contain functional lymphatics, but lymphatic vessels located at the
tumor margins are apparently sufficient for the lymphatic spread of tumor cells. The emphasis on lymphatic spread
for carcinomas and hematogenous spread for sarcomas is misleading, because ultimately there are numerous
interconnections between the vascular and the lymphatic systems. The pattern of lymph node involvement follows
the natural routes of lymphatic drainage. Because carcinomas of the breast usually arise in the upper outer
quadrants, they generally disseminate first to the axillary lymph nodes. Cancers of the inner quadrants drain to the
nodes along the internal mammary arteries. Thereafter the infraclavicular and supraclavicular nodes may become
involved. Carcinomas of the lung arising in the major respiratory passages metastasize first to the perihilar
tracheobronchial and mediastinal nodes. Local lymph nodes, however, may be bypassed—so-called “skip
metastasis”—because of venous-lymphatic anastomoses or because inflammation or radiation has obliterated
lymphatic channels.
In breast cancer, determining the involvement of axillary lymph nodes is very important for assessing the future
course of the disease and for selecting suitable therapeutic strategies. To avoid the considerable surgical morbidity
associated with a full axillary lymph node dissection, biopsy of sentinel nodes is often used to assess the presence or
absence of metastatic lesions in the lymph nodes. A sentinel lymph node is defined as “the first node in a regional
lymphatic basin that receives lymph flow from the primary tumor.” Sentinel node mapping can be done by injection
of radiolabeled tracers and blue dyes, and the use of frozen section upon the sentinel lymph node at the time of
surgery can guide the surgeon to the appropriate therapy. Sentinel node biopsy has also been used for detecting the
spread of melanomas, colon cancers, and other tumors.
Carlos S. - Metastasis
In many cases the regional nodes serve as effective barriers to further dissemination of the tumor, at least for a
while. Conceivably the cells, after arrest within the node, may be destroyed by a tumor-specific immune response.
Drainage of tumor cell debris or tumor antigens, or both, also induces reactive changes within nodes. Thus,
enlargement of nodes may be caused by (1) the spread and growth of cancer cells or (2) reactive hyperplasia.
Therefore, nodal enlargement in proximity to a cancer, while it must arouse suspicion, does not necessarily mean
dissemination of the primary lesion.
Hematogenous Spread.
Hematogenous spread is typical of sarcomas but is also seen with carcinomas. Arteries, with their thicker walls, are
less readily penetrated than are veins. Arterial spread may occur, however, when tumor cells pass through the
pulmonary capillary beds or pulmonary arteriovenous shunts or when pulmonary metastases themselves give rise to
additional tumor emboli. In such vascular spread, several factors influence the patterns of distribution of the
metastases. With venous invasion the blood-borne cells follow the venous flow draining the site of the neoplasm,
and the tumor cells often come to rest in the first capillary bed they encounter. Understandably the liver and lungs
are most frequently involved in such hematogenous dissemination, because all portal area drainage flows to the
liver and all caval blood flows to the lungs. Cancers arising in close proximity to the vertebral column often
embolize through the paravertebral plexus, and this pathway is involved in the frequent vertebral metastases of
carcinomas of the thyroid and prostate.
Certain cancers have a propensity for invasion of veins. Renal cell carcinoma often invades the branches of the renal
vein and then the renal vein itself to grow in a snakelike fashion up the inferior vena cava, sometimes reaching the
right side of the heart. Hepatocellular carcinomas often penetrate portal and hepatic radicles to grow within them
into the main venous channels. Remarkably, such intravenous growth may not be accompanied by widespread
dissemination. Histologic evidence of penetration of small vessels at the site of the primary neoplasm is obviously an
ominous feature. Such changes, however, must be viewed guardedly because, for reasons discussed later, they do
not indicate the inevitable development of metastases.
Many observations suggest that mere anatomic localization of the neoplasm and natural pathways of venous
drainage do not wholly explain the systemic distributions of metastases. For example, breast carcinoma
preferentially spreads to bone, bronchogenic carcinomas tend to involve the adrenals and the brain, and
neuroblastomas spread to the liver and bones. Conversely, skeletal muscles and the spleen, despite the large
percentage of blood flow they receive and the enormous vascular beds present, are rarely the site of secondary
deposits.
Comparisons between Benign and Malignant Tumors
Characteristics Benign Malignant
Differentiation/ana
plasia
Well differentiated; structure sometimes typical of
tissue of origin
Some lack of differentiation with anaplasia;
structure often atypical
Rate of growth Usually progressive and slow; may come to a
standstill or regress; mitotic figures rare and normal
Erratic and may be slow to rapid; mitotic figures
may be numerous and abnormal
Local invasion Usually cohesive expansile well-demarcated masses
that do not invade or infiltrate surrounding normal
tissues
Locally invasive, infiltrating surrounding tissue;
sometimes may be seemingly cohesive and
expansile
Metastasis Absent Frequently present; the larger and more
undifferentiated the primary, the more likely are
metastases
Carlos S. - Metastasis