specificity
Clinical Features of Tumours
(i) How does the tumour affect the host?
(1) Disfigurement
Many tumours will destroy or distort normal tissue resulting in physical disfigurement. All too commonly the patient will ignore or rationalise the disfigurement of their body in the hope that it will simply go away. A woman with a breast cancer may say that a malignant lump is only there because she bumped herself (probably she first noticed it as a consequence of bumping herself).
(2) Mechanical interference with normal function
Many examples occur. Often the mechanical interference is the symptom that the patient presents with. Neoplasms of the prostate - urinary difficulty; cancer of the lung - obstruction of a bronchus leading to infection; cancer of the colon - altered bowel habit and subsequently obstruction of the bowel and possibly intussusception; tumour of the midbrain - obstruction of the aqueduct leading to hydrocephalus; tumour of the larynx (vocal cords) - a hoarse voice; metastases to the mediastinal lymph nodes - obstruction of the superior vena cava; tumour of the head of the pancreas or bile duct - obstruction of bile duct, cholestasis and jaundice; tumour of the oesophagus - dysphagia.
(3) Interference with function of organ or tissue
The tumour may replace the normal tissue of an organ preventing it from functioning e.g. metastatic cancer cells replacing the liver parenchyma. Most organs have enormous reserves.
(4) Discontinuity of surface (ulcer)
As a consequence of invasion and necrosis of an epithelial surface, ulceration may occur, which may result in haemorrhage and infection at the site of the ulceration.
Bleeding from an ulcer may be the presenting symptom e.g. bleeding from the anus, bronchi (haemoptysis), stomach (haematemesis and malaena), cervix, urinary tract (haematuria).
The blood that is seen may not be red (fresh) e.g. malaena from the upper gastrointestinal tract is tarry black and offensive, due to alteration by acid and bacteria during its passage through the GIT.
Alternatively, the bleeding may not be macroscopic (visible) e.g. occult blood in faeces which is detected by special antibody tests for human haemoglobin and may be used as a screening test for cancer of the colon.
The bleeding may be slow but chronic, and present as anaemia (patient feels tired and pale).
(5) Nutritional competition
Cancer patients with widespread metastases usually become cachexic (progressive loss of body fat and lean body mass accompanied by profound weakness, anorexia and anaemia).
There are many possible causes that include widespread infections and haemorrhage, immunosuppression associated with chemotherapy and to a lesser extent radiotherapy, poor appetite, in part due to the depression associated with the patient's prognosis.
There is now good evidence that soluble factors such as cytokines (TNF-a and IL-1) produced by the tumour and by inflammatory macrophages are involved.
(6) Function of neoplastic cells, per se
Paraneoplastic effects are symptoms in cancer patients that can not be explained by the local or distant spread of the tumour, or by the elaboration of hormones indigenous to the tissue from which the tumour arose. Occur in about 10% of patients. These include:
(1) Endocrinopathies (ectopic hormone production): e.g ACTH or ACTH-like hormones from a lung cancer; ADH production, PTH production (cancers of the lung, breast, kidney, ovary and leukaemia, leading to potentially fatal hypercalcaemia), insulin, serotonin and erythropoietin.
(2) Nerve and muscle syndromes: e.g. myasthenia and peripheral neuropathies.
(3) Dermatological disorders.
(4) Osseous, articular and soft tissue changes: e.g. clubbing of the fingers.
(5) Other: vascular and nephrotic changes.
(7) Immunological effects
Patients may become immunosuppressed as a result of e.g bone marrow replacement by tumour or generalised wasting. Patients who are immunosuppressed are more susceptible to infections. Note that in many patients with cancer who are immunosuppressed, the treatment has caused their immunosuppression (i.e. chemotherapy or radiotherapy). Note that immunosuppression may also occassionally cause certain types of tumours e.g. Kaposi's sarcoma in AIDS, leukaemia in arthritic patients and transplantation patients being immunosuppressed, old age.
(8) Psychological disturbances
Metastases to the brain may affect behaviour (e.g. to frontal lobe).
Most psychological changes are probably due to depression associated with the diagnosis.
A positive "fighting" attitude may prolong survival, possibly via poorly understood effects on the immune system.
(ii) Effects of the host on the tumour
Sometimes (but all too rarely) cancers just disappear. The mechanisms involved are unclear, but certainly the host is able to mount an immune response to the tumour.
Facilitating the immune response is being investigated as a possible mode of treatment e.g. the use of interferon-g to stimulate cell-mediated immunity and treat melanoma.
(iii) Grading and staging of cancer
The grade and stage of a cancer has a significant impact on the management and prognosis of the patient. The stage is usually the more important parameter.
(1) Grading of a tumour involves estimating its degree of differentiation and the number of mitoses - Grade I well differentiated to Grade IV undifferentiated. Undifferentiated malignancies usually are more aggressive and carry a poorer prognosis. Criteria have been established for different tumour types to assist in grading e.g. mucin secretion by an adenocarcinoma of the colon suggests differentiation.
(2) Staging of a tumour is based on the size of the primary and extent of spread of the tumour, both to the regional nodes and to more widespread sites (blood borne). The TNM system is the more commonly used staging system:
T = size of the primary tumour; T0 in situ, then T1-T4 depending on size;
N = nodal involvement; N0 no nodes involved, then N1-N3 depending on the extent of nodal involvement;
M = distant metastases other than by lymphatics; M0 no distant metastases, M1-M2 depending on extent of metastasis.
(iv) Diagnosis of neoplasia
The patient usually presents to the physician with a particular symptom that the physician must investigate to exclude malignancy e.g. change in bowel habit or bleeding from the rectum. The earlier a tumour is detected the better the chance of a cure (usually prior to metastasis).
To this end a range of screening programmes have been introduced (examples):
* breast self examination and mammography
* Pap smears for cervical cancer
* occult blood testing in faeces for cancer of the colon
* regular prostate examination
* self examination for "nasty" moles that change size, colour, or that bleed (a melanoma).
* screening for specific blood borne proteins e.g. PSA (prostatic specific antigen).
To be effective a screening programme must be proven to be economically sound (i.e. the cost of the programme is less than the cost of the patient dying); the screening programme is often targeted (e.g. increase in frequency of Pap smears with age) and the screening programme must be safe (e.g. mammography involves irradiating the breast - a theoretical risk).
Diagnosis may then involve a wide range of modalities. Once a "lump" has been found, the mainstay of diagnosis is an histological diagnosis.
(1) Tumour tissue may be obtained in a number of ways:
* by direct surgical biopsy or resection;
* by fine-needle biopsy;
* by cytology: scrapings from the surface of the tumour, e.g. Pap smear, or by aspiration of fluid associated with a tumour e.g. ascites or a pleural effusion.
(2) Tumour tissue or cells that are obtained may be examined by:
(a) Standard histological techniques: Paraffin section - approximately 24 hours to process; or frozen section - approximately 20 minutes while the patient is on the operating table.
(b) Immunohistochemical techniques: use of antibodies to a range of antigens that are typical of particular tumour types and have implications for prognosis e.g. intermediate filaments, cell surface markers in lymphomas.
(c) Chromosomal analysis: e.g. Philadelphia chromosome in CML, aneuploidy (uneven multiple of the basic number of chromosomes) in a number of common carcinomas, diploidy in neuroblastoma.
(d) Molecular diagnosis: an examination of the genes being expressed in a tumour, by hybridisation with DNA or RNA, either isolated or on the tumour section. Not in routine use at present, but will assume greater importance with time.
(e) Flow cytometry: for the quantitation of cell surface antigens and DNA content. Especially useful for leukaemias and lymphomas.
Note that sometimes a tumour may be difficult or impossible to diagnose accurately (e.g. tissue of origin e.g. some amelanotic melanoma metastases; benign or malignant e.g. some bone tumours). A diagnosis is always an opinion, which sometimes may be wrong or inaccurate, simply because the laboratory tests used can not differentiate the possibilities.
Females: New cases: breast, colon, melanoma, lung
Mortality: breast colon, unspecified, lung, ovary
Male: New cases: lung, prostate, colon, melanoma
Mortality: lung, prostate, unspecified, colon
30 years ago, cancer of the cervix was the most common cancer in females; today it is the seventh most common, presumably due to Pap smear screening. On the other hand, ovarian cancer usually presents quite late (after metastasis) due to its location making it difficult to detect early.
40% of all cancers have metastasised at the time of presentation, due to late detection e.g. lung, prostate and GIT. There are no good, cheap screening tests for these cancers.
Age for highest incidence of cancer: Males: 45-54, Females: 30-64
(ii) Geographic and racial factors
Japanese have the highest incidence of cancer of the stomach (? dietary); malignant melanoma is more common in northern versus southern Australia (? sun exposure); cancer of the colon is more common in Western countries than in Asian countries (? dietary); there is a high incidence of cancer of the liver in South East Asia (due Hepatitis B infection, leading to cirrhosis). The observed "geographic" differences in cancers is almost certainly mainly due to environmental influences.
(iii) Environmental and cultural
Smoking is related to certain jobs and is associated with cancers of the mouth, larynx, oesophagus, pancreas, bladder and cervix.
Asbestos exposure in miners, pipe laggers etc. can cause mesothelioma of the pleura.
(iv) Age
Cancers occur mainly in older age groups; presumably cells have had a longer opportunity to mutate (probably due to chronic low grade exposure to carcinogens and/or deterioration in immunosurveillance with age).
Some cancers occur mainly in children (e.g. certain leukaemias, neurological tumours and renal tumours).
(v) Heredity
A clear inherited risk for cancer, following classic Mendelian genetics, occurs in very few cancers e.g. the rare retinoblastoma of infancy, and the rare familial polyposis coli.
However, an increased risk of a particular cancer has been detected for a wide range of cancers if several blood relatives have had that cancer e.g. there is an increased risk (~5 x) of breast cancer if close female blood relatives have had breast cancer. Thus, probably a predisposition to cancer is inherited, but for cancer to develop a range of, often unknown, environmental factors presumably have to come into play.
(vi) Acquired pre-neoplastic disease
Certain disease changes pre-dispose to cancer, e.g. cervical dysplasia, cirrhosis (especially from Hepatitis B infection), solar keratosis of the skin, ulcerative colitis, villous adenoma of the colon. Note that most benign tumours remain benign e.g. leiomyoma of the uterus rarely, if ever, becomes malignant.
G. Aetiology of Cancer
(i) Radiation
All forms of radiation are carcinogenic.
UV light induces skin cancers (c.f. melanoma Ý near equator).
Ionising radiation causes a range of cancers. Leukaemias are most common, followed by thyroid cancer in children (? due to uptake of radioactive iodine isotopes from radioactive fall-out, but also from direct irradiation of the thyroid), breast, lung and salivary glands, with gastrointestinal and skin (excluding high UV areas) and bone being relatively resistant to radiation induction.
Classic examples are the increase in leukaemias (7 years) and solid tumours (longer) in survivors of the Hiroshima and Nagasaki bomb blasts; or the 10 x increase in lung cancer in uranium mine workers.
Carcinogenic potential is dose dependent and additive.
Radiation damaged cells are more susceptible to other carcinogens (e.g. chemical).
Radiation damages DNA and may also affect genes involved in DNA repair.
Note that rapidly dividing cells (e.g. bone marrow) are more susceptible to radiation damage and, if the dose is high enough, to radiation induced death. Thus, leukaemia (originating in rapidly dividing bone marrow cells) is a common "early" cancer strongly associated with radiation carcinogenesis. However, radiation can also be used as a treatment for cancer; it kills rapidly dividing cancer cells selectively, leaving the normal adjacent cells alive.
(ii) Chemicals
Chemical carcinogens are very diverse. They may be both natural and synthetic substances.
Chemical carcinogens cause cell damage because they are highly reactive electrophiles that remove electrons from DNA, RNA or proteins.
Chemical carcinogenesis proceeds in essentially two steps:
(1) Initiation: a chemical carcinogen causes permanent DNA damage, which is "remembered" but will not of itself cause neoplastic change.
(2) Promotion: a second chemical carcinogen causes reversible damage to the initiated cell, which induces neoplastic change. However, application of the promoter does not cause neoplastic change in cells that have not been exposed to the initiator.
Note that some chemicals possess both initiator and promoter capabilities; they are "complete carcinogens".
Chemical carcinogens may act on cells:
(1) Directly, without modification: e.g. chlorambucil (and other anticancer chemotherapeutic agents), an alkylating agent that is used to treat cancer. If the patient survives for any length of time after treatment, then the patient may develop other cancers!
(2) Indirectly, requiring the cell to first metabolise the chemical into another product: e.g. polycyclic hydrocarbons (cigarette smoke), aromatic amines (dyes use in the clothing and rubber industries), azo dyes (in margarine), microsamines and amides, which form nitrosamine compounds (preservatives and cigarettes), aflatoxin B produced by fungus on nuts and cause hepatic cancer, asbestos, chromium, nickel and vinyl chloride.
(iii) Oncogenic viruses
There is clear evidence for viruses being oncogenic in animals but the evidence is slightly more circumstantial in humans.
Two categories of oncogenic viruses: DNA and RNA viruses.
(1) DNA oncogenic viruses:
Transforming DNA viruses form stable associations with the host cell genome and some of the early viral genes are expressed in transformed cells. Three examples are:
(a) Human Papilloma virus (HPV): definitely causes benign genital warts and strongly implicated in cervical carcinoma. Probably acts as a promoter, additional genetic events are required for carcinogenesis. Note that HPV is usually sexually transmitted.
(b) Epstein-Barr virus (EBV): a herpes virus, first implicated in the African form of Burkitt's lymphoma, but now also believed to be involved in some other types of lymphoma, Hodgkin's disease and nasopharyngeal carcinoma. EBV infection of B-cells immortalises them (EBV forms an episome in the cell nucleus). Apoptosis is prevented, in part by an interaction with the bcl-2 gene (see later). EBV infects nearly all adults in the world but few get lymphoma, suggesting other genetic or environmental factors are involved. In Africa, one factor is probably chronic infection with malaria.
(c) Chronic hepatitis B virus (HBV) infection: implicated in hepatocellular carcinoma. A high incidence of HBV infection and hepatocellular carcinoma is geographically coincident in South East Asia. The mechanisms involved are unclear.
(2) RNA oncogenic viruses (retroviruses):
Reverse transcriptase from the virus converts viral RNA into DNA which can be incorporated into the cell genome. There are clear associations between cancer and these viruses in animals, but only one virus has been clearly implicated in human disease:
Human T-cell leukaemia virus type 1 (HTLV-1): which is associated with T-cell leukaemia and lymphoma. HTLV-1 is related to the AIDS virus and has a tropism for CD4+ T-cells. Leukaemia develops in 1% of infected individuals after a 20-30 year latent period! The mechanisms involved are unclear.
(iv) Others
* chronic inflammation: may be involved in cervical and hepatocellular carcinoma.
* hormones: oestrogen may be involved in endometrial and breast carcinomas.
* physical substances: asbestos and mesothelioma
* organisms: schistosomiasis (a disease caused by a water fluke or helminth) can cause bladder cancer in its endemic areas (mainly China).
(v) Summary of Carcinogenesis
Neoplastic transformation is believed to almost always be multifactorial, with a series of cellular events adding to each other.
90% of carcinogenic factors are thought to be environmental, 10% a genetic predisposition.
Essentially, changes in the genome of somatic cells result in:
* the cell activates oncogenes and/or deactivates cancer suppressors genes;
* the altered cell then changes its phenotypic characteristics (particularly its growth pattern);
* additional events resulting in further changes to the genome occur, and
* eventually the cell undergoes neoplastic transformation.
Thus, carcinogenesis is a multistep process.
Retroviral Oncogenes (partial list)
Oncogene (v-onc)
|
Prototype Retrovirus
|
Species of Origin
|
 |
src
|
Rous sarcoma virus
|
Chicken
|
myc
|
Avian myelocytomatosis virus
|
Chicken
|
erb A, erb B
|
Avian erythroblastosis virus
|
Chicken
|
myb
|
Avian myeloblastosis virus
|
Chicken
|
H-ras
|
Harvey rat sarcoma virus
|
Rat
|
K-ras
|
Kirsten murine sarcoma virus
|
Mouse
|
abl
|
Abelson murine leukemia virus
|
Mouse
|
fes
|
Feline sarcoma virus
|
Cat
|
sis
|
Simian sarcoma virus
|
Monkey
|
|
Activation of Cellular Proto-oncogenes in Human Cancers
Proto-oncogene
|
Activation by
|
Chromosomal Change
|
Associated Cancer
|
|
c-myc
|
Genetic rearrangement
|
Translocation: 8-14, 8-2, or 8-22
|
Burkitt's lymphoma
|
c-abl
|
Genetic rearrangement
|
Translocation: 9-22
|
Chronic myeloid leukemia
|
c-H-ras
|
Point mutation
|
|
Bladder carcinoma
|
c-K-ras
|
Point mutation
|
|
Lung and colon carcinoma
|
N-myc
|
Gene amplification
|
|
Neuroblastoma
|
Proteins Encoded by Proto-oncogenes and DNA Tumor Viruses
Localization
|
Proteins Encoded by
|
|
Cellular Proto-oncogene
|
DNA Tumor Virus
|
|
Nuclear
|
myc
|
SV40 large T
|
|
N-myc
|
Polyoma large T
|
|
myb
|
Adenovirus E1a
|
Cytoplasmic
|
ras
|
Polyoma middle T
|
|
abl
|
|
|
src
|
|
|
erb B
|
|
|
sis
|
|
Conversion of Cellular Proto-oncogenes to Oncogenes
The known mechanisms of proto-oncogene activation and well-studied examples include:
translocation: c-myc, c-abl; promotor insertion: c-myc, c-erb B;
point mutation: c-ras;
deletional mutation: c-erb B;
amplification: c-myc.
Cellular Functions of Protooncogene Encoded Proteins
Function
|
Protein
|
Protoonco-
gene
|
Associated Human Cancers
|
|
Growth factor
|
PDGF
|
sis
|
Osteosarcoma
|
Growth-factor receptor
|
EGF receptor
|
erb B
|
Breast, lung, ovarian cancer
|
Post-receptor signal transduction
|
GTP-binding protein
|
ras
|
Lung, colon, pancreatic cancer
|
Nuclear transcription regulator
|
myc protein
|
myc
|
Breast, colon, lung cancer, Burkitt's lymphoma
|
Tumor Markers
Marker
|
Tumor
|
|
Resulting from tumor-cell dedifferentiation
|
|
Carcinoembryonic antigen (CEA)
|
Carcinomas of gastrointestinal tract, pancreas, breast, lung
|
Alpha-fetoprotein
|
Hepatocellular carcinoma, yolk-sac tumor of testis
|
Alkaline phosphatase isoenzyme
(Regan enzyme)
|
Various tumors
|
Ectopic hormones
|
Refer to: Paraneoplastic syndromes
|
|
Resulting from over-production by tumor cells
|
|
Prostate-specific antigen (PSA)
|
Prostate carcinoma
|
Choriogonadotropic hormone
(beta subunit)
|
Choriocarcinoma, hydatidiform mole, embryonal carcinoma of testis
|
Calcitonin
|
Medullary carcinoma of thyroid
|
Other Hormones
|
Refer to: Endocrine tumors
|
Myeloma and Bence-Jones proteins
|
Multiple myeloma
|
Monoclonal macroglobulinemia
|
Waldenstrom's macroglobulinemia
|
|
|
[Aberrations in the normal process of transmembrane signaling involving growth factors (GFs), GF receptors, post-receptor "transducer" proteins, and nuclear controls may be caused by activated oncogenes and result in the abnormal growth characteristics of neoplastic cells.
Growth factors (GFs) are ubiquitous polypeptides that are produced and secreted by cells locally and that stimulate cell proliferation by binding to specific cell-surface receptors on the same cells (autocrine or autostimulation) or on neighboring cells (paracrine stimulation). Conceptually, uncontrolled autostimulation from the persistent over-production of GFs may convert a cell to the neoplastic state. Human platelet-derived growth factor (PDGF), so named because it is released from platelets during blood clotting, is a major growth factor recoverable from serum. PDGF is apparently encoded by c-sis, the normal analog of v-sis which is the transforming gene of simian sarcoma virus (SSV). Cultured cells infected with SSV produce a PDGF-like mitogen which binds to PDGF receptors and stimulates the cells to proliferate in an uncontrolled manner, resulting in transformation.
Structural changes or amplification of GF receptors may promote neoplastic transformation. If GF receptors are changed in a way that continually presents cells with growth stimulatory signals, even in the absence of GFs, cells may respond as though high levels of GFs were present. One of several examples, all in the group of cytoplasmic oncogenes, can be mentioned. A portion of the human epidermal growth factor (EGF) receptor protein is almost identical with the erb B protein.
Autonomy to GFs may be produced by changes in post-receptor "transducer" proteins that enable them to transmit growth stimulatory signals without prompting by a GF receptor. Ras-encoded proteins are guanosine triphosphate (GTP)-binding proteins that function as post-receptor signal transducers (cyclic Œon-off¹ switches) for growth stimulatory signals.. Ras proteins are located in the plasma membrane and mediate the passage of growth signals from outside to inside the cell and to the cell nucleus, thus initiatiating the cell cycle and DNA synthesis. Mutations in ras proteins, potentially associated with a continuous growth signal that cannot be deactivated, are found in about 30% of human cancers (Wittinghofer, F., Nature 394: 317, 1998).
The cell division cycle is normally monitored at critical check points along the mitogenic signaling pathway and is also regulated by the myc gene protein product and related nuclear regulatory proteins. Transcriptional amplification of myc and related nuclear proteins is associated with unregulated cell proliferation and transformation.
In summary, the activation of proto-oncogenes to cancer-associated oncogenes represents a "gain of gene function" (dominant allele) mutation involving pathways of transmission and transduction of mitogenic signals from cell to cell and from cell surface to nucleus and the activation of certain nuclear genes, culminating in DNA synthesis, unregulated cell division, and neoplastic transformation. ]
p53 Tumor Suppressor Gene
A normal (wild-type) nuclear protein of 53 kilodaltons called p53 protein is the product of the p53 tumor suppressor gene on human chromosome 17(p13). As previously noted with the Rb gene, mutated or deleted tumor suppressor genes such as mutant p53, while heritable as a dominant allele, are recessive to the normal (wild-type) allele in somatic cells, and mutations or deletions in both p53 alleles ("two hits") are required for loss of function. Patients with germline mutations at the p53 locus are at very high risk for cancer development, as seen in the Li-Fraumeni hereditary cancer syndrome characterized by early onset of breast carcinoma, childhood sarcomas, and other tumors.
Somatic mutations at the p53 locus, usually point mutations substituting one amino acid for another and inactivating suppressor activity, are the most common genetic change in human cancers and occur in about 50% of them, including carcinoma of breast, colon, stomach, bladder, and testis, melanoma, and soft-part sarcoma.
Normal p53 protein is a transcription factor (increases gene expression) and mediates several cellular functions: regulation of the cell division cycle, DNA repair, and programmed cell death. In response to various forms of genomic DNA damage (caused by oncogene activation, radiation, cytotoxic drugs, hypoxia, certain viruses), the p53 protein can arrest the cell cycle at the G1 to S transition point, thus affording time for DNA repair and preventing duplication of a mutant cell or, alternatively, failing DNA repair, p53 protein can implement programmed cell death (apoptosis). Accordingly, p53 has been dubbed the "guardian of the genome." The cellular process of DNA replication is initiated by the formation of complexes between proteins called cyclins and enzymes termed cyclin-dependent kinases (CDKs). The formation of cyclin-CDK complexes is inhibited by p53 protein and other cell-growth inhibitors.
As previuosly noted, mutated or deleted tumor suppressor genes, such as mutant p53 or mutant Rb, while heritable as a dominant allele are recessive to the normal (wild-type) allele in somatic cells, and mutations or deletions in both alleles are required for loss of gene function.
DNA Mismatch-Repair Genes
A new class of cancer susceptibility genes was recently identified in hereditary non-polyposis colorectal cancer (HNPCC):a defective hMSH2 gene located on human chromosome 2p and a defective hMLH1 gene located on chromosome 3p. These defective genes are associated with widespread instability of microsatellite DNA and other short repeat sequences in HNPCC cells and with the accumulation of mutations, both germ line and somatic, throughout the genome of some HNPCC patients (Peltomaki,P.,et al., Science 260: 810-812, 1993; Ionov,Y.,et al.,Nature 363:558-561, 1993).Other studies indicate that natural (wild-type) hMSH2 and hMLH1 are human homologs, respectively, of a bacterial gene and a yeast gene that encode a base-binding enzyme involved in DNA mismatch repair.Genetic defects in DNA repair genes not only contribute to the development of HNPCC but may also be involved in other hereditary cancer syndromes as well as in the genetic instability (heterogeneity) commonly shown by cancer cells.
It is estimated that about 0.5% of the general population (~ 1 million Americans) may carry this or other mutator genes, along with a greatly increased risk of colorectal carcinoma or other cancers, such as, ovarian, uterine, and renal.
Apoptosis
Apoptosis (Gr. apo, away; ptosis, falling) is a normal process of non-random cell death that occurs in many biological conditions, among them: embryological development; perinatal thymus selection and deletion of self-responsive T-cells; normal cell turnover throughout life; and in response to abnormal stimuli, such as genomic DNA damage, but without concurrent pathological necrosis and inflammation.
Apoptosis (programmed cell death) is an active, energy-dependent process characterized by the rapid occurrence of distinctive morphological and biochemical changes in the cell. These changes include: the formation of cytoplasmic blebs; chromatin condensation at the nuclear membrane; and cleavage of chromatin by an endonuclease that is exclusively activated in apoptosis and that yields a distinctive 'chromatin ladder' pattern of DNA fragments, as shown by gel electrophoresis. Specialized proteases called caspases (cysteine aspartases), associated with mitochondria and the cytochrome C respiratory pathway, accelerate the cell-death response (Earnshaw, W. C., Nature 397: 387-389, 1999).
As noted elsewhere (see: p53 Tumor suppressor gene), p53 protein expression in response to genomic DNA damage can arrest the cell cycle (at G1) for DNA repair, thus preventing duplication of a mutant cell or, alternatively, failing DNA repair, implement cell suicide through programmed cell death.
If oncogenes are likened to an "accelerator" of cell proliferation or transformation and tumor suppressor genes to a "brake", then apoptosis is a final "suicidal crash". Thus, at least two signals ( and obviously multiple genetic controls) are required for cell proliferation or transformation: one that drives cell proliferation; and one that blocks cell death. Surprisingly, the protein product of the myc proto-oncogene has one domain that mediates cell proliferation and another one that, in the absence of required growth factors, nutrients, or other gene products, induces apoptosis. On the other hand, the bcl-2 proto-oncogene (known to be activated by chromosomal translocation in a variety of B-cell lymphomas) encodes an antiapoptosis protein; the bcl-2 protein product functions as an inhibitor of apoptotic cell death.
Human Cancer Cells Created with Defined Genetic Elements
Sequential mutations or inappropriate expressions of different classes of cellular genes (oncogenes, tumor suppressor genes, mismatch repair genes, and genes that mediate apoptosis) are involved in the usually multiple-step process that leads to human cancer.
This concept was put to critical test in a recent landmark study: normal human epithelial cells (and fibroblasts) in culture were transformed into cancer cells by the insertion of defined genetic elements (Hahn, W.C., Counter, C. M., et al., Nature 400: 464-468, 1999). The three necessary genetic elements were serially inserted and included: a subunit of the telomerase gene, to immortalize the cells by telomere maintenance, i.e., preventing telomere shortening at each cell division (see: Neoplasia VIII. Chromosomal Abnormalities: Telomeres)); an activated ras oncogene, known to be mutated in many kinds of human cancers; and a viral oncoprotein gene (SV 40 large T), known to inhibit the tumor suppressor proteins p53 and pRb.
When injected into immunodeficient mice, the transformed cells formed malignant tumors having similar identifying cellular and molecular genetic characteristics as the injected cells, thus suggesting that the tumorigenic growth was not the consequence of some other rare random event occurring in vivo after inoculation of these cells. Telomere maintenance appeared to be essential for the formation of human cancer cells.
Cancer Susceptibility Genes - Summary
The following table gives only a short list of the ever increasing number of cellular genes that, through inherited or somatic mutations and a gain (dominant allele) or loss (recessive allele) of function, are associated with the development of certain forms of human cancer. Prototype examples of affected genes and associated cancers were previously discussed.
Activating (gain of function) somatic mutations of proto-oncogenes (such as ras, myc, abl, etc.,) are present in a variety of sporadic human cancers (Table). Surprisingly, inherited mutations of proto-oncogenes are not regularly found in hereditary cancers with the following notable exception: inherited germ line mutation in the ret (RET) proto-oncogene confers a genetic predisposition to multiple endocrine neoplasia.
Germ line and subsequently somatic (loss of function) mutations associated with human cancer susceptibility and expression (see Table) mainly involve tumor suppressor genes (established examples include: APC, Rb,& p53 which is mutated in many forms of cancer; BRCA1, BRCA2, NF1, WT1, and DNA repair genes (such as hMSH2).In familial breast cancer, an inherited germ line mutation of the BRCA1 gene located on chromosome 17(q21) confers a predisposition to early-onset (~ premenopausal) breast cancer and ovarian cancer; and an inherited mutation of the BRCA2 gene located on chromosome 13(q12-13 is also linked to early-onset breast cancer. Mutations in BRCA1 and BRCA2 are each estimated to account for less than 5% of the total of all female breast cancer cases (~180,000) occurring annually in the U.S.
Table: Cellular Genes Associated with Human Cancer Susceptibility and Expression
Human Genes Associated with Cancer Susceptibility and Expressions
Affected Gene
|
Chromosome
|
Associated Cancer
|
|
Oncogenes:
|
|
|
abl
|
9(q24)
|
Chronic myeloid leukemia
|
c-myc
|
8(q24)
|
Burkitt's lymphoma
|
ras
|
12(p)
|
Variety of cancers: colon, lung, pancreas, leukemia
|
N-myc
|
2(p)
|
Neuroblastoma, small cell cancer of lunh
|
RET
|
10(q11)
|
Medullary thyroid carcinoma, multiple endocrine neoplasias
|
PML/RAR-alpha
|
t(15;17)
|
Acute promyelocytic leukemia
|
Tumor Suppressor Genes:
|
|
|
APC
|
5(q21)
|
Colon carcinoma
|
BRCA 1
|
17(q21)
|
Breast and ovarian carcinoma
|
BRCA 2
|
13(q12-13)
|
Breast carcinoma
|
p53
|
17(p13)
|
Variety of cancers, Li-Fraumeni syndrome
|
NF1
|
17(q11)
|
Neurofibromatosis type 1
|
RB
|
13(q14)
|
Retinoblastoma, osteosarcoma
|
WT1
|
11(p13)
|
Wilms' tumor
|
Mismatch Repair Genes:
|
|
|
hMSH2
|
2(p16)
|
Colon carcinoma
|
|
Chemical and Physical Carcinogenesis
Introduction
The discovery of chemical carcinogenesis was made by Sir Percival Pott (1713-1788), English surgeon, who related the cause of scrotal skin cancer in a number of his patients to a common history of occupational exposure to large amounts of coal soot as chimney sweepers when they were boys. Industrial development, which began in the 18th century and continues to this day, has exposed many workers to the hazards of carcinogenic agents. The accompanying table lists many of the physical and chemical agents that have been established over time as causes of occupational cancers.
Table: Occupational Cancers
Agent
|
Occupation
|
Cancer Site
|
|
Ionizing radiations
|
|
|
radon
|
certain underground miners (uranium, fluorspar,etc.)
|
bronchus
|
X-rays, radium
|
radiologists, radiographers
|
skin
|
radium
|
luminous dial painters
|
bone
|
Ultraviolet radiation
|
farmers, sailors, etc.
|
skin
|
Polycyclic hydrocarbons in soot, tar, oil
|
chimney sweepers, manufacturers of coal gas, many other groups of exposed industrial workers
|
scrotum, skin, bronchus
|
2-Naphthylamine; 1-naph-thylamine
|
chemical workers, rubber workers, manufacturers of coal gas
|
bladder
|
Benzidine; 4-aminobiphenyl
|
chemical workers
|
bladder
|
Asbestos
|
asbestos workers, shipyard and insulation workers
|
bronchus, pleura, and peritoneum
|
Arsenic
|
sheep dip manufacturers, gold miners, some vineyard workers and ore smelters
|
skin and bronchus
|
Bis(chloromethyl) ether
|
makers of ion-exchange resins
|
bronchus
|
Benzene
|
workers with glues, varnishes, etc.
|
marrow (leukemia)
|
Mustard gas
|
poison gas makers
|
bronchus, larynx, nasal sinuses
|
Vinyl chloride
|
PVC manufacturers
|
liver (angio-sarcoma
|
An occupational cancer in a radium dial painter. Neoplastic osteocytes embedded in malignant osteoid matrix (the homogeneous substance between tumor cells).
In addition to occupational exposure to carcinogens, medical treatment with agents such as ionizing radiations and natural exposure to solar ultraviolet radiation were early recognized as causes of human cancers. Occupational cancers comprise a small but preventable part of the worldwide incidence of human cancers. It is paradoxical that, more than two centuries after the discovery of the carcinogenic hazards of coal soot, a smoke product of another source, associated with life-style rather than occupation, is etiologically related to one of the most prevalent human cancers today, namely, bronchogenic carcinoma of tobacco smokers.
Classification of Chemical Carcinogens
Chemical carcinogens are of synthetic ("man made") or natural origin, are extremely diverse in structure without any common feature, and are classified into two categories:
direct-acting (DNA-reactive, activation independent, genotoxic) carcinogens that bind covalently to cellular genomic DNA and are mutagens;
procarcinogens (activation dependent) that require metabolic conversion to metabolites ("ultimate carcinogens") capable of transforming cells and inducing tumors.
Procarcinogens are among the most potent chemical carcinogens.
Table: Major Chemical Carcinogens
Pro-carcinogens (require metabolic activation to "ultimate carcinogens")
Polycyclic aromatic hydrocarbons
benzanthracene (first pure carcinogen)
3,4-benzpyrene (isolated from coal tar)
3-methylcholanthrene (prepared from a steroid, deoxycholic acid)
7,12-dimethylbenzanthracene (most potent carcinogen)
Aromatic Amines and Azo Dyes
2-naphtylamine (produces bladder carcinoma)
benzidine (produces bladder carcinoma)
2-acetylaminofluorene
4-dimethylaminoazobenzene (produces liver tumors)
Natural Products
aflatoxin B1 (potent hepatocarcinogen produced by mold contamination of food)
mitomycin C
Other
nitrosamine (can be formed by action of nitrites on foods)
some insecticides (chlordane and others)
some metals (chromium and nickel)
carbon tetrachloride
Direct-Acting Carcinogens (DNA-reactive)
Alkylating agents
anticancer chemotherapeutic drugs (cyclophosphamide, busulfan, chlorambucil)
beta-propiolactone
bis(chloromethyl)ether
Acetylating agents
1-acetylimidazole
Biological Aspects of Chemical Carcinogenesis
Carcinogenesis is a multiple step process. One of the characteristics of chemical or physical carcinogenesis is the usually extended period of time (latent period) between contact with the carcinogen and the appearance of a tumor. The latent periods of occupational cancers may extend from one to several years and commonly to several decades, as noted in the accompanying table.
Table: Latent Periods of Representative Occupational Cancers
|
|
|
LatentPeriod (years)
|
Site of Cancer
|
Type of Cancer
|
Agent
|
Average
|
Range
|
|
Skin
|
Epidermoid and basal cell carcinomas
|
Arsenic
Coal tar & pitch
Ionizing radiation
Solar radiation
|
25
20-24
7
20-30
|
4-46
1-50
1-12
15-40
|
Lung
|
Bronchogenic carcinoma
|
Asbestos
Ionizing radiation
|
18
25-35
|
15-48
7-50
|
Bone marrow
|
Leukemia
|
Benzene
Ionizing radiation
|
|
3-19
3-15
|
Bladder
|
Squamous cell carcinoma
|
Aromatic amines
|
11-15
|
2-40
|
Bone
|
Osteogenic sarcoma
|
Ionizing radiation
|
|
10-25
|
|
The latency between exposure to a carcinogen and cancer formation is explained in part by the results of animal experiments which show that skin carcinogenesis in the rabbit and mouse is divisible into two stages, tumor initiation and promotion. Following single exposure to a subcarcinogenic dose of a carcinogen ("initiation"), the latent period can be shortened and the tumor yield increased by treatment with certain "promoting agents" (croton oil, phorbol esters, others) which are not carcinogenic in themselves, or very weakly so, but cause vigorous cell proliferation in target tissue, a process that may be necessary for the "fixation" or expression of tumor initiation. Wound healing also has a tumor promoting effect: wounding of an area of skin treated with a carcinogen brings out tumors along the edge of the wound.
A scheme of tumor initiation-promotion phases is given in the following diagram.
Table: Initiation-Promotion Phases of Experimental Carcinogenesis of Mouse Skin
I________________________________________> No Tumors
I____________P_P_P_P_P_P_________________> Tumors
I______________________P_P_P_P_P_P_______> Tumors
P_P_P_P_P_P_P____________________________> No Tumors
P_P_P_P_P_P_P_I__________________________> No Tumors
Time_____> (15-70 weeks)
I, initiation by single application of subcarcinogenic dose of polycyclic hydrocarbon.
P, promotion by spaced applications of promoting agent, such as phorbol ester.
Tumors are skin papillomas and carcinomas.
Initiation and promotion are two stages in the development of tumors. Initiation is caused by chemical, physical, or biological agents which irreversibly and heritably alter the cell genome.
The mechanism of promotion is not well understood. There are many kinds of promoting agents with diverse molecular structures: phorbol esters, estrogen, prolactin, other endogenous hormones, drugs, and others. Some of the promotors exhibit specific interaction with cell receptors. For example, phorbol esters bind with a surface receptor identified as protein kinase C which also mediates the effect of platelet derived growth factor (PDGF), a mitogen encoded by the proto-oncogene c-sis. The protein kinase becomes activated and in turn causes a change in Pi metabolism, an increase in intracellular Ca++, and a rise in intracellular pH. These changes trigger cell proliferation, an apparently necessary process in the "fixation" or expression of tumor initiation.
Progression
Tumor promotion as studied in the animal model of skin carcinogenesis results mainly in the formation of papillomas and occasionally in the progression of papillomas to carcinomas. Progression, the third definable stage of neoplastic development, is separable from promotion. To illustrate, phorbol esters are strong promotors but weak progressing agents. Furthermore, following the initiation-promotion stages of induction of skin carcinogenesis, a high incidence of carcinomas can be produced by subsequent applications of a different initiating agent, suggesting a second event ("second hit") in the induction of carcinomas. As previously noted, molecular genetic mechanisms are implicated in tumor progression, among them, chromosomal rearrangements or mutations that activate proto-oncogenes.
Thus, it appears that of the three stages of carcinogenesis - initiation, promotion, and progression - initiation, most certainly, and progression, most likely, involve molecular genetic changes.
Biochemical Aspects of Chemical Carcinogenesis
Most chemical carcinogens are , or are metabolically converted into, electrophilic reactants (electron-attracting chemicals) that cause their biological effects by covalent binding with cellular proteins and nucleic acids, particularly chromosomal DNA. The most frequent reaction sites in DNA are with guanine.
The majority of chemical carcinogens are procarcinogens and require metabolic conversion into chemically reactive forms (ultimate carcinogens). Many chemical pathways (oxidation, reduction, hydroxylation, hydrolysis, conjugation, etc.) lead to metabolic conversion of procarcinogens to intermediate metabolites (proximate carcinogens) and finally to ultimate carcinogens which react with cellular DNA to cause neoplastic transformation.
Most procarcinogens are activated by microsomal enzymes in the endoplasmic reticulum. The conversion of polycyclic aromatic hydrocarbons to ultimate carcinogens is initiated by aryl hydrocarbon hydroxylase (AHH). Cytochrome P-450, a terminal component of an electron transport system present in liver microsomes, is also involved in the metabolic activation of procarcinogens.
Tests for mutagenicity indicate that virtually all ultimate carcinogens are mutagenic. Conversely, most mutagens show carcinogenic activity. In the Ames screening test for mutagenicity, a putative carcinogen is incubated with liver microsomes and an indicator microorganism. An increase in the frequency of specific mutants above control levels is scored as a positive result .
Modifying Factors in Carcinogenesis
Host factors (genetics, gender, hormones, aging) and environmental factors may have a modifying role in increasing, or decreasing, the susceptibility to carcinogens. With procarcinogens, activating enzyme systems must be present or inducible in target cells. This genetically determined activity explains the organ and species specificity of some procarcinogens.
Microsomal enzymes in the liver degrade (detoxify) a large part of a procarcinogen to non-carcinogenic products. Enzymes can be induced which accelerate detoxification. A variety of naturally occurring compounds, such as indole, flavones, and related compounds that occur in vegetables (brussels sprouts, cabbage, broccoli, cauliflower) have a protective action in animals exposed to carcinogenic polycyclic hydrocarbons.
Endogenous (and exogenous) sex hormones are important factors apparently in the promotion stage of human carcinomas of breast, endometrium, and prostate. Additionally, a history of exposure in-utero to the synthetic estrogen diethylstilbestrol (DES) is strongly associated with the development of carcinoma of the vagina and cervix in some young women.
Other exogenous factors in human carcinogenesis include dietary excesses and deficiencies and, most notably, tobacco smoking which is a major factor associated with lung carcinoma.
Non-genotoxic Carcinogens
The actions previously described are those of agents which react with cellular DNA and cause genomic alterations. As more and more chemicals are tested for carcinogenicity, a number are now being recognized as "non-genotoxic". These chemicals do not form stable covalent bonds with cellular DNA or other macromolecules. Solid state materials (asbestos) are an example.
DNA Damage and Repair
Ultimate carcinogens are mutagens and cause point mutations (base-pair substitutions) and frame-shift mutations. The activation of ras proto-oncogenes by point mutations is associated with chemical carcinogenesis in experimental animals and with many types of human cancers. Ultraviolet and ionizing radiations are also mutagenic and produce several types of lesions (strand breaks, cross-links, base alterations) in cellular DNA. Ultraviolet radiation also produces dimers between adjacent thymidines.
Excision repair of damaged DNA occurs to a greater or lesser extent and involves the excision of the damaged strand, synthesis of a patch, and rejoining of the strand by a DNA ligase.
Several autosomal recessive disorders associated with an increased incidence of cancer exhibit defects in the repair and maintenance of DNA. Notably, the repair of damage caused by ultraviolet radiation is defective in patients with xeroderma pigmentosa (autosomal recessive) who have a high incidence of skin cancer in areas exposed to sunlight. Bloom's syndrome, a condition characterized by multiple chromosomal breaks and a high incidence of leukemia or intestinal cancer, is associated with a defect in a DNA ligase.
Concept of Neoplasia as a Disease of Cell Differentiation
The discussion of carcinogenesis thus far has emphasized carcinogenic agents which cause irreversible, heritable genomic change (somatic mutations) in the neoplastic cell. Also alluded to previously was the extremely rare, but clinically and pathologically documented, occurrence of spontaneous regression of some malignant tumors, such as neuroblastoma of childhood which, remarkably, in a small proportion of cases regresses by differentiation to a benign ganglioneuroma or disappears.
Experimental studies have shown that mouse teratocarcinoma cells with normal karyotypes, when injected into early mouse embryos (blastulas), differentiate along with host cells into "normal" cells, tissues, and organs and result in normal-appearing mice at birth and as adults. While, embryos injected with aneuploid teratocarcinoma cells also appear normal at birth, they developed many teratocarcinomas and die subsequently. These studies suggest that neoplastic cells with apparently normal genomes may, under defined conditions, lose their neoplastic characteristics and differentiate as do normal cells. Therapeutic strategies to induce "terminal differentiation" of neoplastic cells are under investigation.
Therapeutic strategies to induce "terminal differentiation" of tumor cells are under investigation. Clinical remissions produced in patients with acute promyelocytic leukemia (PML) by treatment with all-trans-retinoic acid are associated with drug-induced differentiation of leukemia cells (Warrell, R.P., et al., N. Engl. J. Med., 329: 177-189, 1993).
Hormone Production by Human Tumors
Tissue
|
Tumor
|
Hormone
|
Clinical Features
|
|
Hormones appropriate for the tumor tissue of origin (endocrine tumors):
|
Adrenal Cortex
|
Adenoma,
carcinoma
|
Cortisol
Aldosterone
Androgen
|
Cushing's syndrome
Conn's syndrome
Adrenogenital syndrome
|
Adrenal Medulla
|
Pheochromo-cytoma
|
Norepinephrine,
epinephrine
|
Hypertension
|
Pancreas Islet
|
Adenoma
|
Insulin
|
Hypoglycemia, to 1492
hyperinsulinism
|
Enterochromaffin
|
Carcinoid
|
Serotonin
|
Carcinoid syndrome
|
Placenta
|
Choriocarcinoma,
hydatidiform mole
|
Gonadatropin
|
|
Ectopic hormones, inappropriate for tumor tissue of origin (non-endocrine tumors):
|
Lung
|
Oat cell carcinoma
Squamous cell
|
ACTH
ADH
PTH-like
|
Cushing's syndrome
Inappropriate diuresis
Hypercalcemia
|
Kidney
|
Adenocarcinoma
|
PTH-like
|
Hypercalcemia
|
Liver
|
Hepatoma
|
Gonadatropin
|
Precocious puberty,
gynecomastia
|
Lung
|
Oat cell carcinoma
|
Gonadotropin
|
Gynecomastia
|
|
Symbols: ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone; PTH-like, parathyroid hormone-like.
http://edcenter.med.cornell.edu/CUMC_PathNotes/Neoplasia/Neoplasia_05.html
Growth factors have a number of characteristics in common:
they are all polypeptides which bind to specific high affinity membrane receptors;
they are produced and act on cells at "short range", unlike endocrine action;
each cell has receptors for multiple factors;
some factors, such as interleukin 2 (IL2) act on very few cell types, while others, for example, epidermal growth factor (EGF), act on many;
factors vary in the point of the cell cycle in which they act;
factors may, according to cell type, inhibit cell division and cause differentiation.
Cellular Growth Factors
Factor
|
Full Name
|
Size (kD)
|
Source
|
Target Cell
|
|
EGF
|
Epidermal
|
6
|
Salivary gland
GI cells
|
Many epithelial and mesenchymal cells
|
TGF-A
|
Transforming
|
5.6
|
Tumor cells
Placenta & embryos
|
Same
|
PDGF
|
Platelet derived
|
32
|
Platelets
Endothelium
Placenta
|
Mesenchymal cells
Smooth muscle
Trophoblast
|
TGF-B
|
Transforming
|
25
|
Platelets
Tumor cells
Kidney
|
Fibroblasts
Keratinocytes
Mammary cells
Carcinoma cells
|
IGF1
|
Insulin-like (Somatomedin C)
|
7
|
Liver
Smooth muscle
|
Epithelial and mesenchymal cells
|
IGF2
|
Insulin-like (Somatomedin A)
|
7
|
Fetal liver
Placenta
|
Same
|
IL2
|
Interleukin
|
15
|
T-helper cells
|
T-lymphocytes
|
FGF
|
Fibroblast
|
16
|
Brain, Tumors,
Salivary gland
|
Endothelial cells
Fibroblasts
|
CSF1
|
Colony Stimulating (macrophage)
|
70
|
L-cells
|
Macrophage precursors
|
CSF2
|
(macrophage-granulocytic)
|
15-28
|
Lung
Placenta
|
Macrophage & granulocyte precursors
|
CSF3
|
MultiCSF (IL3)
|
28
|
T-lymphocytes
|
Many types of leukocytes
|
|
Bombesin
|
2
|
Brain
GI cells
|
CNS, GI tract
Oat cell carcinoma
|
Hereditary Cancers and Inherited Disease Syndromes Associated with a High Incidence of Cancer (Short List)
Disease/Syndrome
|
Associated Neoplasm
|
Inheritance
|
|
Breast/Ovarian
Cancer Syndrome
|
Early onset breast cancer/
ovarian cancer
|
D
|
Chromosomal Instability Syndromes:
|
Bloom's syndrome
|
Leukemia, intestinal cancer
|
R
|
Fanconi's anemia
|
Leukemia, squamous carcinoma
|
R
|
|
|
|
Hereditary Skin Diseases:
|
Xeroderma pigmentosa
|
Skin cancers
|
R
|
|
|
|
Endocrine System:
|
Multiple endocrine neoplasia
|
Adenomas of endocrine glands
|
D
|
Zollinger-Ellison syndrome
|
Pancreatic & duodenal gastrinomas
|
D
|
|
|
|
Nervous System:
|
Retinoblastoma
|
Retinoblastoma, bilateral
|
D
|
Neuroblastoma
|
Pheochromocytoma
|
R
|
Neurofibromatosis
(von Recklinghausen's)
|
Fibrosarcoma, meningioma
|
D
|
|
|
|
Gastrointestinal System:
|
|
|
Familial polyposis coli
|
Interstinal polyps and carcinomas
|
D
|
Gardener's syndrome
|
Intestinal polyps & cancers, osteomas
|
D
|
|
|
|
Vascular System:
|
Osler-Weber-Rendu syndrome
|
Angioma
|
D
|
Ataxia-telangiectasia
|
Lymphoma, leukemia, gastric cancer
|
R
|
|
|
|
Urogenital System:
|
Wilms' tumor
|
|
D & R
|
Stein-Leventhal syndrome
|
Endometrial carcinoma
|
D
|
|
|
|
Immunologic Syndromes:
|
Agammaglobulinemia (Swiss type)
|
Lymphoma, leukemia
|
R
|
X-linked agammaglobulin-
|
Lymphoma, leukemia
|
XR
|
DiGeorge syndrome
|
Squamous carcinoma of upper respiratory tract
|
D
|
|
Mode of inheritance: D, autosomal dominant; R, autosomal recessive; XR, X-linked recessive.
|
Common Cancers •
Bladder Cancer• Breast Cancer
• Colon Cancer
• Endometrial Cancer
• Head and Neck Cancer • Lung Cancer
• Melanoma
• Non-Hodgkin's Lymphoma
• Prostate Cancer
• Rectal Cancer
TUMORS OF THE SPLEEN
Chronic myelogenous leukemia
Chronic lymphocytic leukemia
Malignant lymphoma
Benign tumors
Schwannoma Leiomyoma of uterus
Meningioma
Adenomatous polyp of colon, gross
Adenomatous polyp of colon, micro
Teratoma
Fibroma of maxilla
Malignant tumors
Squamous cell carcinoma, gross
Squamous cell carcinoma, micro
Adenocarcinoma
Teratocarcinoma
Melanoma, gross
Burkitt Lymphoma
Acute Myelogenous Leukemia, peripheral blood
IN ALL OF THIS DON'T FORGET THE PARANEOPLASIC SYNDROME THAT APPEAR WITH ALL THE APUDOMAS TUMORS [EMBRYONIC SAME ORIGIN OF SOME TUMORAL CELLS] [A SPECIAL CHAPTER WILL BE DONE IN MY SURGICAL WEB PAGE]
A paraneoplastic syndrome occurs when a neoplasm elaborates a substance that results in an effect that is not directly related to growth, invasion, or metastasis.
Most paraneoplastic syndromes result from elaboration of hormone-like substances, but a variety of effects are possible. Sometimes the paraneoplastic syndrome may precede diagnosis of the neoplasm and may give a clue to its presence.
Paraneoplastic syndromes
|
Syndrome
|
Mechanism
|
Example
|
Cushing's Syndrome
|
ACTH-like substance
|
Lung (oat cell) carcinoma
|
Hypercalcemia
|
Parathormone-like substance
|
Lung (squamous cell) carcinoma
|
Hyponatremia
|
Inappropriate ADH secretion
|
Lung (oat cell) carcinoma
|
Polycythemia
|
Erythropoietin-like substance
|
Renal cell carcinoma
|
Trousseau's Syndrome
|
Hypercoagulable state
|
Various carcinomas
|
Hypoglycemia
|
Insulin-like substance
|
Various carcinomas and sarcomas
|
Carcinoid Syndrome
|
5-hydroxy-indoleacetic acid (5-HIAA)
|
Metastatic malignant carcinoid tumors
|
