Oncology General Principles Continued
Most cancers may occur because of environmental factors.
This conclusion takes into account findings that:
(a) specific cancer incidence rates are not constant
(b) cancer rates, even within populations, change and are affected by migration.6
Within the framework of environmental factors one should consider:
sun exposure (skin cancers such as melanoma)
In addition to these factors, underlying risk may occur as a result of hereditary predispositions.
Hereditary effects could influence the sequential processes involved in transformation of normal cell biology to cancer cell biology.6
Epidemiological analysis has suggested that cancers which present in middle and old age might be reduced by as much as 80% to 90% with overall risk, worldwide, reduced by 50%.
Along with this suggestion is the realization that attainment of this result might require approaches not considered socially acceptable.
In this epidemiological study considering behavioral and environmental impacts on human cancer risk, proportions of fatal cancers associated with different causes were examined under 17 categories, some noted below.6,7
|smoking||alcohol use||pharmaceutical products||infections including parasitic, viral, and bacterial|
|Radiation including ionizing, ultraviolet, and lower frequency||industrial products||pollution in the air, water, and food sources||physical inactivity|
Smoking was determined to be the most important consideration.
Smoking was an identifiable factor in the development of seven cancer types in addition to eight recognized earlier by the International Agency for Research on Cancer (1986).
Smoking was likely responsible for 38% of cancers in men and 6% in women in Germany.
Probably the above noted factors act in a synergistic way with the ultimate risk of developing a particular cancer type modifiable in accord with changing risk factor profiles.7
Carcinogens: The definition of carcinogen includes chemical agents, biological agents, and physical factors, such as ionizing radiation, that can cause cancer in animals or humans.
(a) Cutaneous melanoma, which is a melanoma starting in the skin rather than the eye or an internal organ.
(b) Basal cell carcinoma, a skin cancer involving cells in the lower part or base of the outer layer of skin (epidermis).
(c) Squamous cell carcinoma.
This type of skin cancer occurs in the principal cells of the epidermis (squamous cells).
Higher intensity, ionizing radiation, can produce6:
(a) Sarcomas (Sarcomas refer to malignant tumors associated with connective tissue, e.g. cartilage, or bone.)
(b) Leukemias (Leukemia refers to blood cell cancer. Blood cell growth and development are abnormal and this abnormality is principally associated with leukocytes, i.e. white blood cells. Often leukemia can be used in a more general way to reference cancer associated with any cell in blood or bone marrow. An example would be erythroleukemia.)
Cancer as a result of ionizing radiation was described over 400 years ago when it was noted that miners in the Black Forest regions in Eastern Europe exhibited premature death.
The explanation for these deaths was likely radon gas which accumulated to high concentration in relatively unventilated mine tunnels.
Probably about 3% of all cancers may be attributable to radiation exposure, most of the time this exposure is from natural sources such as radon and cosmic rays (cosmic rays, which are high-energy radiation originating beyond the Earth’s atmosphere, include protons, alpha particles which consist of positively charged helium nuclei, 2 protons and 2 neutrons, and other atomic nuclei).8
Carcinogenic effects from radiation have been assessed mainly in populations exposed to > 20 cGy. (20 rad, 1 rad equals a dose of 0.01 Joules of energy/kilogram; 1 rad = 0.01 Gray).8
In order to compare higher exposures to more commonly encountered references, a chest x-ray exposes bone marrow to about 0.026 cGy, whereas a mammogram exposes breast tissue to about 0.3 cGy.
Naturally occurring background radiation contributes about 0.1 to 0.3 cGy per year in whole body radiation.
By contrast, workplace or occupational radiation limits are set at 5 cGy per year.
The LD50 for radiation (lethal dose for 50% of the population in one month) would be about 400 cGy.
In radiation cancer treatment (radiation oncology treatment), targeted exposure would range between 1000 to 6000 cGy.8
Significant occupational exposure is associated with underground mining, medical technologies, as well as involvement in nuclear fuel/activities.8
Although current physicians are probably not at increased risk from radiation used in their practices, early radiologists were likely exposed over time to large levels which were reflected in increased incidence of skin cancer and leukemia.
Many years ago, long before the “digital” age, analog watch dials were painted with radium, allowing illumination in the dark.
Unfortunately, this practice exposed these workers to very high radiation dosages, probably resulting in bone and sinus sarcomas.
Underground miners exposed to radon exhibit at increases in lung cancer incidence.8
Hazards possibly associated with radon exposure, at low levels, found in the home have been of recent concern since indoor radon may account for over 50% of all general population radiation exposure.
Based on analysis of extrapolated data from high-dose exposure, indoor radon exposure may increase lung cancer deaths per year by an amount in a range between 6000 to 36,000.8
Ultraviolet Radiation: Sunlight emits electromagnetic (photon) radiation at wavelengths encompassing a range of 11 orders of magnitude [10-4 nm (nanometers) to 1012 nm). DNA exhibits an absorption maximum at 260 nm and is probably the primary chromophore for UV radiation (UVR).
The relationship between radio waves on one hand and gamma rays on the other as well as the intermediate energies in electromagnetic spectrum is noted below:
UVR is subdivided into three regions, UVC (240 to 290 nm), UVB (290 to 320 nm) and UVA (320 to 400 nm).
UVC radiation is absorbed by atmospheric (stratospheric) ozone resulting in limited wavelengths < 300 nm reaching the Earth’s surface.
Most pathological effects of the sun are due to UVB radiation; however, UVR, overall is responsible for a significant proportion of skin cancer in humans.
The most common types of cancer on the face and trunk (men) and face and legs (women) include basal and squamous cell carcinomas.
Increased skin pigmentation tends to decrease skin cancer risk; moreover, certain genetic diseases can increase risk of sunlight-induced skin cancer.
These genetic dysfunctions relate to diminished UVR damage and repair system efficacy.
One such disease exhibiting attenuated DNA repair is xeroderma pigmentosum, associated with increases not only in squamous and basal cell carcinoma frequencies but also increased melanoma incidence.
Following exposure to radiation with wavelengths consistent with the DNA absorbance spectrum, DNA can be altered by photon absorption.
One such alteration involves a conversion of a pyrimidine based to an excited state.
The excited state transitions back to the ground state in one scenario by non-radiative transition or fluorescence (heat or light being liberated).
Another possibility is that the excited pyrimidine state will react with other molecules forming either unstable or stable photoproducts.
One less likely scenario but one which increases the likelihood of photoproduct formation depends on transition of the pyrimidine from an excited singlet state to an excited triplet state which exhibits a longer half-life, thus increasing the likelihood of subsequent photoproduct formation.21
Many chemicals have been demonstrated in carcinogenic in humans and are responsible for leukemias, carcinomas, and sarcomas.6
Viruses: In addition to chemicals, viruses are also causative agents for cancer6:
Hepatitis B and C virus have been implicated in oncogenesis for those patients with liver cancer.
Hepatitis B (HBV) is a circular DNA virus consisting of about 3200 base pairs.
HBV codes for 4 sets of viral products. Hepatitis C virus, by contrast, is a linear, single-strand RNA virus.9
Chronic hepatitis B, especially in patients infected in early childhood or infancy and patients with the HBeAg envelope protein and/or high levels of HBV DNA, may be associated with increased hepatocellular carcinoma risk.
Patients with chronic hepatitis C are also at increased risk for hepatocellular carcinoma and, in this context, the patients probably have cirrhosis and have had hepatitis C typically for least 30 years.9
By way of background, symptoms exhibited by hepatocellular carcinoma (HCC) may include:
abdominal fullness and
The most common physical sign is hepatomegaly, occurring in between 50% and 90% of patients.
Human papillomavirus (HPV) subtypes16 and 18 have been associated with anal cancer.
The Epstein Barr virus has been implicated in nasopharyngeal cancer and in certain lymphomas.
Epstein-Barr virus (EBV) is typically transmitted by infected saliva and results in oropharynx infection.
Pharynx and salivary gland epithelial cells host viral replication.
Surface B lymphocytes may also host the infection.
Infected B cells promote the spread of infection from a oropharynx initiation site throughout the rest of the body.
In addition to nasopharyngeal carcinoma, EBV is a causative agent of Burkett's lymphoma and Hodgkin's disease as well as certain other lymphomas.
Serum samples from patients with Burkett's lymphoma or nasopharyngeal carcinoma exhibit high antibodies levels of virus-specific antigens; furthermore, EBV DNA is found in tumor tissue and viral gene expression occurs in tumor samples.
With respect to Burkett's lymphoma, a jaw tumor in African children and young adults, EBV DNA and the tumor-expressed EBNA1 antigen are found.
By contrast, outside of Africa, only about 1/5 of Burkett's lymphoma contain the EBV viral DNA. Malaria is a recognized cofactor.12
Human herpesvirus type 8 and Kaposi sarcoma6 .
Four cancers are associated with AIDS so much so that they are included in the CDC classification.
primary lymphoma of the brain, and
invasive cervical carcinoma.
Kaposi's sarcoma lesions can be located anywhere and appear as a purplish, nonblanching and maybe either papular or nodular.
About 40% of patients ultimately develop visceral disease for example, gastrointestinal and pulmonary, although the initial manifestations were dermatologic.
There are four forms of Kaposi's sarcoma:
The first form of Kaposi's sarcoma, classic or Mediterranean which is found in elderly men of Mediterranean, Jewish, or Eastern European descent. (This form is unlikely to be seen in the US.)
These lesions are typically limited to extremities, often lower extremities and the lesions would be characterized as a benign and associated with minimal pain.
The second form of Kaposi's sarcoma occurs in the post-transplant setting.
This form is described as iatrogenic Kaposi's sarcoma and occurs following kidney transplant in some patients who are also receiving cephalosporin.
The disorder develops after a number of months of immunosuppressive treatment and the disease may regress if immunosuppressive therapy is discontinued.
The third type of Kaposi's sarcoma is considered endemic or "African Kaposi's".
This form tends to be more aggressive than those mentioned earlier affecting both the skin and internal organs.
Further, endemic Kaposi's sarcoma is associated with significant morbidity and, in African children, there is a variant of endemic Kaposi's that targets lymph nodes and maybe rapidly fatal.
The fourth type of Kaposi's sarcoma is AIDS-associated. This form is very aggressive, disseminating to internal organs, often with fatal outcomes.13
In terms of the differential at least in so far as superficial appearance, Kaposi's lesions might be confused with other lesions (vascular) including angiomas and pyogenic granulomas.
Pyogenic granuloma (Medline Plus; U.S. NLM and NIH), [http://www.nlm.nih.gov/medlineplus/ency/imagepages/2465.htm]
Pyogenic granuloma (Medline Plus; U.S. NLM and NIH), [http://www.nlm.nih.gov/medlineplus/ency/imagepages/2517.htm]
Kaposi's sarcoma was identified early on in the AIDS pandemic as an important marker.
Although HIV infection can predispose to Kaposi's sarcoma (KS), KS tumor cells were not found to contain the HIV genome.
However, factors released from HIV-infected cells were noted to promote KS tumor cell growth.
Epidemiologic studies suggested that a sexually transmitted factor different from HIV was important in KS tumorigenesis.
The likelihood of KS development was enhanced by the presence of concurrent sexually transmitted diseases, number of sex partners, and various sexual behaviors.
Several factors, taken together research focused on identification of other factors than HIV, i.e. exogenous pathogens in KS tumors.
In 1994, utilizing polymerase chain reaction technology (PCR), two small DNA fragments were found present in AIDS-KS specimens yet absent in most non-KS sites.
Nucleotide sequencing indicated that these two fragments exhibited homology to two known gamma-(lymphotropic) herpesviruses.
This finding suggested that the fragments were derived from a herpes viral genome.
The sequence can also be found not only in nearly all AIDS-KS tumor sources but also in KS specimens from HIV-negative patients.
The novel herpes viral genome ultimately led to human herpesvirus 8.
Most AIDS-related B-cell lymphomas do not appear associated with HHV-8 except for "primary effusion lymphoma" (cavity-based lymphoma).14
HIV infection may predispose to adult T-cell leukemia/lymphoma.6
Intermediate-or high-grade B-cell HIV-related lymphoma (HRL) was designated as an AIDS-defining disease in 1985.
AIDS defining illnesses eventually included recurrent bacterial infection, cervical cancer, and tuberculosis to name a few.
Overall incidence declined with the introduction of highly active antiviral therapies (HAART).
The HIV virus is not likely directly involved in malignant T cell transformations; moreover, HIV nucleotide sequences are not always detectable in lymphoma tissue or in reactive B-cell hyperplasia seen in generalized, persistent lymphadenopathy, a condition preceding lymphoma development about a third of the time.
In this context PCR (polymerase chain reaction) investigations describe HIV presents only in infiltrating T cells.
What seems to be more important than the HIV infection itself and lymphoma development is HIV-infection-induced immune dysregulation.15
HIV-infected cells synthesize and release multiple cytokines; furthermore, some of these cytokines promote T cell proliferation as well as differentiation. IL-6 is an example of a cytokine, actually an autocrine growth factor for B-cell cancers, such as multiple myeloma and chronic lymphocytic leukemia. Other HIV-infection-induced cytokines include IL-1, IL-2, IL-4, IL-7, IL-10, IFN-γ, lymphotoxin, tumor-necrosis factor, and B-cell growth factor. The HIV virus itself can promote directly polyclonal B-cell activation.15
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