Pathology of metastasis _mad_.docx - Wikispaces

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					    1.   Define the term metastasis

Metastases are tumour spreads that are discontinuous with the primary tumour i.e. where the
tumour first arose. Potentially all cancers have the possibility to metastasise to distant locations
most commonly being the brain, vertebral column, ribs, lungs and other major organs. Metastasis
marks a tumour malignant because benign neoplasms do not metastasise. Metastasis strongly
reduces the rate of cure. This is often considered the highest stage of tumour grading with the worst
prognosis and lowest survival rate.

    2. Describe routes of metastatic spread

#1. Transcoelomic spread Spreading through body cavities and surfaces

The invasion of the serosal lining of an organ by malignant cells This tends to occur where a
neoplasm penetrates a natural “open field” most commonly being the peritoneal cavity. It also
includes the pleural, pericardial, subarachnoid and joint space. Often the peritoneal surface
becomes coated with a heavy layer of cancerous glaze where even the tumour cells may remain
confined to the surface of the coated abdominal viscera without penetrating into the substance. The
malignant cells trigger an inflammatory response, which results in a serous exudate. This is
commonly associated with ovarian and colonic malignancies.

#2 Lymphatic spread

The most common pathway for carcinomas. Tumours do not contain functional lympathics but
lymphatic vessels located at the tumour margins are enough for the lymphatic spread of tumour
cells Malignant cells can gain access to the lymphatic system and travel along vessels to ‘Regional
draining’ lymph nodes. The malignant cells can then establish residency in these regional nodes,
where they replicate and eventually replace the lymph node with a malignant tumour.. There is
close and numerous interactions between the vascular and the lymphatic system often being the
primary cause of the spread to bone. Breast cancer most commonly involves the axillary lymph
nodes. Once the malignant cells have resided in the axillary lymph nodes they have the further
potential to spread to the deep lymph nodes, to the intercostal vessels  azygous system IVC
vertebral column, to the opposite breast, inguinal lymph nodes and deep through the abdomen.
Note that some lymph nodes may be bypassed i.e. “skip metastasis” because of the venous-
lymphatic anastomoses. The best procedure is via biopsy of sentinel nodes. A sentinel lymph node is
the “first node in a regional lymphatic basin that receives lymph flow from the primary tumour”.
Sentinel mapping can be done by injection of radiolabeled tracers or blue dyes. Lymphomas and
squamous cell carcinoma of the head and neck are two examples of where cancer commonly
spreads via the lymphatic system.

#3. Hematogenous spread

Typically seen with sarcomas but also seen with carcinomas. Arteries, due to the thick muscular wall
are less readily penetrated by cancerous cells compared to veins. With venous invasion, the blood-
borne cells follow the venous flow draining the site of the neoplasm. Therefore the liver and the
lungs are the most commonly involved organs in secondary dissemination. 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 embolise through the paravertebral plexus which causes vertebral
metastases. Malignancies which are linked to blood-borne spread include melanoma and small cell
carcinoma of the lung.
    3. Describe preferred metastatic sites for carcinoma, sarcoma and lymphoma (selected

Carcinoma – Cancer arising from epithelial cells. This form of cancer prefers to travel via the
lymphatic system. Bone is a favoured site of metastasis from carcinomas of lung, breast, thyroid,
kidney & prostate carinomas.
Sarcoma – Cancer arising from connective tissues and bones. This form prefers Bloodborne
travel.Commonly pulmonary metastases
Lymphoma – Originates in Lymphocytes/tissues
Spread via lymphatics to lymphoid tissues

    4. Outline the molecular basis of metastatic spread
Tumour cells must first interact with the extracellular matrix (ECM) at several stages in the
metastatic cascade. A carcinoma must first breach the underlying basement membrane, then
traverse the interstitial connective tissue and ultimately gain access to the circulation by penetrating
the vascular basement membrane.
    1. The tumour cell undergoes clonal expansion, growth and angiogenesis.
    2. It then adheres and invades the basement membrane of the target cell.
    3. Passes through the ECM
    4. Intravasation of the tumour cell into the blood vessel
    5. Interaction with host lymphocytes
    6. Tumour cell embolus forms
    7. Adhesion to basement membrane of blood vessel
    8. Extravasation outside into the ECM
    9. Metastatic deposit
    10. Angiogenesis by the tumour cell and further growth (repeat)
     5. Discuss the relationship between tumour grade with the spread of cancer and prognosis
Grading of a cancer is based on the degree of differentiation of the tumour cells and the number of
mitoses within the tumour as presumed correlates of the neoplasm’s aggressiveness. They are used
to classify neoplasms in terms of how abnormal the cells from the normal cells of the same tissue
type appear microscopically and what may be the outcome in terms of rate of growth, invasiveness,
and dissemination.
Grade is rated numerically (Grade 1-4) or descriptively (e.g. high grade or low grade).

 Grade                          Characteristic
 G1 (Low grade)               Well differentiated
 G2                           Moderately differentiated
 G3 (High grade)              Poorly differentiated
 G4 (High grade)              Undifferentiated

The more undifferentiated the tumour is, the more it is unlike the normal tissue appearance
therefore the worse the appearance.

    6. Describe the principles of cancer staging
Staging differs to differentiation by describing the depth and extent of spread of the tumour
invasion. This is needed for prognosis and discussions of a future management plan. E.g. if a patient
presented with a breast lump, which proved to be malignant, it would be inappropriate to offer the
patient a mastectomy if the cancer had already spread to the liver. Removal of the breast would not
affect the patient’sprognosis, because the cancer had already metastasized at the time of diagnosis.
This is why it is so important to ‘stage’ a patient’s cancer before detailed discussions can take place
regarding the most appropriate treatment option(s).

TNM SYSTEM  Tumour(0-4), Node (0-4), Metastases (0-1)

Stage #1: When the tumour is only confined to the mucosa layer and has not penetrated through
the muscularis mucosa (outer portion of the mucosa layer). T1, N0, M0. This represents a good
prognosis with 95% 5 year survival rate and 10% prevalence rate at diagnosis.

Stage #2: When the tumour has completely penetrated through the muscularis mucosa extending
throughout the muscular wall. T2, N0, M0. This has a 75% 5 year survival rate and a 35% prevalence
rate at diagnosis.

Stage #3: When the tumour has spread to the lymph nodes. T3, N1, M0. There is 50% 5 survival rate
and 30% prevalence rate at diagnosis.

Stage #4: When the tumour has metastasised to distant organs e.g. the liver, lungs and bone. T4, N1,
M1. The prognosis is very poor with a 5% survival rate and prevalence rate at diagnosis 25%. At this
stage, the cancer is incurable.

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