The hallmark of malignancy is invasion
Early tumor growth procedes slowly due to lack of nutrients. However, when it reaches 1-2mm in diameter, its angiogenic switch turns on resulting in a net increased secretion of angiogenic promoters, forming new GF-secreting-leaky blood vessels, which allows the tumor to attain a much larger size and facilitates invasion and metastasis.
Basal cell carcinoma is not able to metastasize
Invasion and Metastasis is the major cause of cancer-related morbidity and mortality. Occurs through the interaction of cancer cells and the adjacent stroma, and is a rather inefficient process.
Invasion of extracellular matrix (ECM) involves
- 1. detachment of tumor cells - degrading intercellular adhesion molecules, eg E-cadherin
- 2. ECM degradation – secreting proteolytic enzymes, or causing stromal cells to do so.
- 3. attachment to new ECM components – integrins, laminins, and collagen, that signal the cells to keep them differentiated and help regulate their cell cycle. Normally, the loss of cellular adhesion leads to apoptosis, but this does not occur in neoplastic cells. Instead, once basement membrane proteins are cleaved, new binding sites are created that can adhere to the tumor cells and facilitate their migration into the stroma.
- 4. migration and invasion – reactions between signalling proteins and receptors ultimately influences the actin cytoskeleton. ECM components can attract tumor cell into the stroma.
the stroma and its cells (particularly fibroblasts and some cells of the immune system) are a dynamic system that interacts with the tumor in ways that can either facilitate or inhibit invasion.
tumor cells in circulation are vulnerable to apoptosis due to loss of adhesion, mechanical damage from shear forces, and host immune reactions.
Surviving tumor cells in circulation
- form aggregates with platelets and other blood cells - enhancing survival and implanting in distant sites
- activate coagulation factors forming tumor emboli - adhering to endothelium and migrating through the endothelial basement membrane
The area where circulating tumor cells/emboli leave the capillaries and establish metastatic deposits is related to:
- 1. the anatomic site of the primary tumor and its draining vasculature – the first capillary bed encountered
- 2. attraction to specific organ/tissues:
- a. tumor cells may have particular adhesion molecules displayed only on endothelium in certain organs
- b. some organs and/or tissues may have a molecular environment that is unfavorable to the growth of metastatic deposits, essentially blocking the establishment of metastases
Molecular Genetics of Metastasis Development - Theories
- 1. clonal evolution model - as genetically unstable tumor cells multiply, they develop new phenotypic subtypes that are able to metastasize.
- 2. genetic “metastasis signature” - predisposing them to develop the necessary proteins early in carcinogenesis and thus enhance their ability to spread.
- 3. metastatic signature is necessary, but additional mutations are needed.
- 4. properties of the cancer cell genome interact w/ particular molecular characteristics of the stroma, determine the ability to spread.
Both benign and malignant tumors can negatively affect the host:
- 1. anatomic site of the tumor and its effect on adjacent structures
- 2. cellular function - hormone secretion or development of paraneoplastic syndromes
- 3. bleeding and infection should the tumor ulcerate or invade hollow structures or surfaces
- 4. symptoms associated with infarction or organ dysfunction
- 5. cachexia/wasting
- a continuous loss of body mass, coupled with anorexia, anemia, and extreme weakness.
- loss of fat and muscle, increased basal metabolic rate, and systemic inflammation.
about 10 signs and symptoms that seem unrelated to the local effects of the tumor and/or any compounds released by the neoplasm.
Paraneoplastic syndromes include, in part:
- • endocrinopathies – non-endocrine tumors may ectopically produce hormones. Most common example is Cushing’s syndrome (obesity, “moon facies”, hirsutism), due to excessive production of corticotropin in the setting of small-cell carcinoma of the lung.
- • hypercalcemia – overall most common. production of calcemic humoral substances, such as parathyroid hormone-related protein. breast, ovarian, lung, and kidney carcinomas. Bone metastases of these lesions can increase serum calcium levels even further.
- • neuromyopathies – peripheral neuropathies, cortical cerebellar degeneration, and symptoms resembling myasthenia gravis.
- • acanthosis nigricans – the appearance of pigmented, velvety, hyperkeratinized plaques on the skin. genetic disease in the young; over age 40, half cases due to underlying cancer.
- • hypercoagulability – several coagulation disorders, including disseminated intravascular coagulation and nonbacterial thrombotic endocarditis.
Grading and Staging
- attempt to quantify the aggressiveness of a tumor and more effectively plan treatment.
- Neither system is exact.
- degree of cellular differentiation of a tumor
- criteria include nuclear size and shape, degree of mitotic activity, cell size, and cytoplasmic morphology.
- Well differentiated tumors typically are more amenable to treatment and behave less
- aggressively, but there are exceptions.
- microscopic examination
- extent of tumor spread
- used to determine treatment strategy and prognosis
- size of the primary lesion (T, scored from 1-4), the amount of regional lymph node metastasis (N, scored from 0-3), and the extent of distant metastasis (M, scored from 0-2)
- physical, radiographic, and microscopic examination.
Laboratory Diagnosis of Cancer
- 1. Routine histopathology
- 2. Frozen-section diagnosis
- 3. Fine-needle aspiration
- 4. Cytologic smears
- 5. Immunohistochemistry
- 6. Flow cytometry
- slide; microscope; diagnosis.
- Usually straightforward
- complicated by sparse clinical information and/or poor sampling. For example, normal processes, such a healing bone fracture, can resemble cancer histologically.
- performed when patient is under operation
- Indications - 1) a diagnosis of an unknown lesion, and 2) to ascertain that all lesional tissue has been removed.
- mounting medium and snap-frozen at about -40ºC, then sectioned and stained. A diagnosis can be made in as little as 10 minutes. However, severe processing artifacts are introduced that can make the sample non-diagnostic.
- a thin hollow-bore needle is used
- small amount of tissue is suctioned out, placed on a slide, and stained.
- diagnoses are possible with a minimum amount of patient discomfort, but sampling errors and nondiagnostic samples are not unusual.
- sample surface lesions, such as the uterine cervix, urinary bladder, and oral cavity.
- Superficial cells are scraped or rinsed off, and slide and fixed.
- Individual cells examined
- easy and convenient
- specific diagnoses are difficult to make, particularly in the setting of a poorly-differentiated tumor.
- incredibly important method
- Its specific applications are:
- a. categorization/diagnosis of tumors – for morphologically identical ones, particularly for poorly-differentiated. Identification of specific proteins can determine the neoplastic cell of origin.
- b. determination of the site of origin
- c. detection of molecules that have prognostic or therapeutic significance – breast cancers: estrogen/progesterone receptors determines cancer susceptibility to antiestrogen therapy
- fast measurement of various cellular characteristics
- particularly antigens in blood-based neoplasms (i.e. leukemias and lymphomas)
- Enables the simultaneous assessment of multiple antigens on a given cell, which cannot be done with IHC.