Ed Friedlander, M.D., Pathologist

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Welcome to Ed's Pathology Notes, placed here originally for the convenience of medical students at my school. You need to check the accuracy of any information, from any source, against other credible sources. I cannot diagnose or treat over the web, I cannot comment on the health care you have already received, and these notes cannot substitute for your own doctor's care. I am good at helping people find resources and answers. If you need me, send me an E-mail at Your confidentiality is completely respected. No texting or chat messages, please. Ordinary e-mails are welcome. is a larger, full-time service. There is also a fee site at

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I'm still doing my best to answer everybody. Sometimes I get backlogged, sometimes my E-mail crashes, and sometimes my literature search software crashes. If you've not heard from me in a week, post me again. I send my most challenging questions to the medical student pathology interest group, minus the name, but with your E-mail where you can receive a reply.

Numbers in {curly braces} are from the magnificent Slice of Life videodisk. No medical student should be without access to this wonderful resource.

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Freely have you received, freely give. -- Matthew 10:8. My site receives an enormous amount of traffic, and I'm still handling dozens of requests for information weekly, all as a public service.

Pathology's modern founder, Rudolf Virchow M.D., left a legacy of realism and social conscience for the discipline. I am a mainstream Christian, a man of science, and a proponent of common sense and common kindness. I am an outspoken enemy of all the make-believe and bunk that interfere with peoples' health, reasonable freedom, and happiness. I talk and write straight, and without apology.

Throughout these notes, I am speaking only for myself, and not for any employer, organization, or associate.

Special thanks to my friend and colleague, Charles Wheeler M.D., pathologist and former Kansas City mayor. Thanks also to the real Patch Adams M.D., who wrote me encouragement when we were both beginning our unusual medical careers.

If you're a private individual who's enjoyed this site, and want to say, "Thank you, Ed!", then what I'd like best is a contribution to the Episcopalian home for abandoned, neglected, and abused kids in Nevada:

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Especially if you're looking for information on a disease with a name that you know, here are a couple of great places for you to go right now and use Medline, which will allow you to find every relevant current scientific publication. You owe it to yourself to learn to use this invaluable internet resource. Not only will you find some information immediately, but you'll have references to journal articles that you can obtain by interlibrary loan, plus the names of the world's foremost experts and their institutions.

Alternative (complementary) medicine has made real progress since my generally-unfavorable 1983 review. If you are interested in complementary medicine, then I would urge you to visit my new Alternative Medicine page. If you are looking for something on complementary medicine, please go first to the American Association of Naturopathic Physicians. And for your enjoyment... here are some of my old pathology exams for medical school undergraduates.

I cannot examine every claim that my correspondents share with me. Sometimes the independent thinkers prove to be correct, and paradigms shift as a result. You also know that extraordinary claims require extraordinary evidence. When a discovery proves to square with the observable world, scientists make reputations by confirming it, and corporations are soon making profits from it. When a decades-old claim by a "persecuted genius" finds no acceptance from mainstream science, it probably failed some basic experimental tests designed to eliminate self-deception. If you ask me about something like this, I will simply invite you to do some tests yourself, perhaps as a high-school science project. Who knows? Perhaps it'll be you who makes the next great discovery!

Our world is full of people who have found peace, fulfillment, and friendship by suspending their own reasoning and simply accepting a single authority that seems wise and good. I've learned that they leave the movements when, and only when, they discover they have been maliciously deceived. In the meantime, nothing that I can say or do will convince such people that I am a decent human being. I no longer answer my crank mail.

This site is my hobby, and I do not accept donations, though I appreciate those who have offered to help.

During the fourteen years my site has been online, it's proved to be one of the most popular of all internet sites for undergraduate physician and allied-health education. It is so well-known that I'm not worried about borrowers. I never refuse requests from colleagues for permission to adapt or duplicate it for their own courses... and many do. So, fellow-teachers, help yourselves. Don't sell it for a profit, don't use it for a bad purpose, and at some time in your course, mention me as author and KCUMB as my institution. Drop me a note about your successes. And special thanks to everyone who's helped and encouraged me, and especially the people at KCUMB for making it possible, and my teaching assistants over the years.

Whatever you're looking for on the web, I hope you find it, here or elsewhere. Health and friendship!



More of Ed's Notes: Ed's Medical Terminology Page

Perspectives on Disease
Cell Injury and Death
Accumulations and Deposits
What is Cancer?
Cancer: Causes and Effects
Immune Injury
Other Immune
HIV infections
The Anti-Immunization Activists
Infancy and Childhood
Environmental Lung Disease
Violence, Accidents, Poisoning
Red Cells
White Cells
Oral Cavity
GI Tract
Pancreas (including Diabetes)
Adrenal and Thymus
Nervous System
Lab Profiling
Blood Component Therapy
Serum Proteins
Renal Function Tests
Adrenal Testing
Arthritis Labs
Glucose Testing
Liver Testing
Spinal Fluid
Lab Problem
Alternative Medicine (current)
Preventing "F"'s: For Teachers!
Medical Dictionary

Courtesy of CancerWEB


Define the following terms:

Recognize the ways in which the growth properties of cancer cells differ from normal. Explain the Nowell multi-step clonal evolution model for tumorigenesis, and cite evidence that it is true.

Briefly describe how the classic transforming viruses caused cancer in experimental animals. Explain why cancers produced by a particular transforming virus in a particular experiment will, as a rule, be antigenically identical.

Tell the features common to most or all genuine chemical carcinogens. Explain why cancers produced by a particular chemical carcinogen in a particular experiment will, as a rule, be antigenically dissimilar.

Give the evidence for radiation carcinogenesis in humans, and the resulting tumors.

Discuss oncogenes in some detail. Explain how we believe certain mutations make ras oncogenic. Explain the importance of myc oncogenes in certain cancers, and the two ways myc is activated.

Describe tumor-suppressor genes (anti-oncogenes) in considerable detail, and explain why tumors tend to show loss of heterozygosity at their loci. Explain the Knudson two-hit model.

Recognize the important tumor viruses for humans. Tell how they differ from the transforming viruses of the classic animal experiments. Tell how they effect their damage.

Recognize the major known and suspected human chemical carcinogens and the tumors they produce. Describe the Delaney Clause and its repeal.

Evaluate media and government claims about "things that cause cancer" intelligently and honestly.

Critique the following statement, overheard in a supermarket check-out line: "Cancers are continually forming in our bodies, but our immune system destroys them. The natural way to cure cancer is by strengthening the immune system."

Give the overall cure rate for newly-diagnosed cancers in the US today. Identify cancers that are increasing and decreasing in the U.S., and suggest reasons why. Identify cancers that are common in some countries and rare in others. Suggest reasons why.

Distinguish "benign" and "malignant" tumors. Explain how certain benign tumors cause serious disease.

Explain the various mechanisms by which cancer causes pain, disability, and death.

Explain how paraneoplastic syndromes happen (tumor products, tumor immunity). Given the name of a paraneoplastic syndrome, tell its effect on the patient.

Explain the concept of "tumor markers", substances produced by the tumor that appear in the bloodstream and assist diagnosis. Explain what is meant by an "oncofetal antigen".

Describe the common tumor-suppressor gene deletion syndromes ("autosomal dominant tumor susceptibility syndromes") in principle.

Recognize each of the following tumor-family syndromes by physical signs:

Recognize cancer quackery and its methods. Recognize why a scientific physician must not "keep an open mind" toward obvious untruths, or "debate / dialogue" with these people.

Appreciate the devastating impact of a cancer diagnosis to a patient, and the need for intelligent, humane care of the whole person.

RECOMMENDED READING: The "Neoplasia" chapters in Big or Pocket Robbins. or R&F. All are pretty good. I've followed the sequence in Big Robbins.


Photo Library of Pathology
U. of Tokushima

Growth Disturbances / Neoplasia
Iowa Virtual Microscopy
Have fun

Tulane Pathology Course
Great for this unit
Exact links are always changing

Disseminated breast cancer
Pittsburgh Pathology Cases




CHEMICAL CARCINOGENESIS (JAMA 266: 681, 1991; Science 250: 1644, 1990; Science 251: 10 & 387, 1991; little has changed since and this is no longer "cutting edge"; update for the truly-hardcore Mut. Res. 489: 17, 2001)

    Classic carcinogenesis experiments disclosed that key steps are often the INDUCTION AND PROMOTION of cancer by chemicals.

    The historic DELANEY CLAUSE from the 1950's forbade the presence of any "cancer-producing chemical" in any concentration in U.S. food. The selective enforcement of this unrealistic (obsolete, frankly silly nowadays) ideal was highly political and kept lawyers busy: Nature 358: 181, 1992.

      The Delaney Clause was finally modified in 1996 to a "no harm" requirement. (Thanks for once, Newt.) But the whole business of government regulation of what can and cannot be in food remains arcane.

    Now is a good time to learn the following associations:

      Soot: Cancer of the scrotum ("chimney sweep's cancer" -- * discovered by Percival Pott)

      Cancer chemoRx: Acute leukemia (* the bad ones include cyclophosphamide, chlorambucil, busulfan, melphalan, others -- the alkylating agents)

      Cyclophosphamide: Transitional epithelial (mostly bladder) cancers

      Other alkylaters: Many cancers (remember nitrogen mustard, bischloromethyl ether, benzyl chloride)

      Polycyclic hydrocarbons: Tobacco smoking-related cancers (lung, larynx, mouth, throat, esophagus, pancreas, bladder, kidney -- * if someone asks you at a party what the chemicals are, say "3-methylcholanthrene, benz(a)anthracene and benzo(a)pyrene for starters"). Flintstones
      Classic TV ad

      Azo dyes: Bladder cancer (old dye factory workers, ?? red-M&M eaters, etc., etc. -- remember "butter yellow" in margarine, "scarlet red" in maraschino cherries, and beta-naphthylamine). Azo dye workers still have a tremendous increase in urothelial cancer, even many years after exposure: Cancer 76: 1445, 1995; also J. Occup. Env. Med. 42: 762, 2000; Am. J. Ind. Med. 46: 505, 2004. Today, we prefer to use the non-water-soluble dyes, which aren't carcinogens (Tox. Let. 151: 203, 2004).

      Aflatoxin: Eaters of moldy grain and peanuts (hepatocellular carcinoma, endemic in Africa; the mold is aspergillus species); the region's farmers are now taking effective measures to control it (Lancet 365: 1950, 2005).

      Betel nut: Mouth and throat cancer (addictive substance chewed in India and elsewhere; despite older reports the betel nut itself is probably a carcinogen: Lancet Onc. 4: 587, 2003).

      * Maté : Uruguayan herbal concoction; with black tobacco, takes blame for Uruguayan epidemic of esophageal and bladder cancer (Cancer 67: 536, 1991; Cancer Ep. 12: 508, 2003.)

      * Safrole: Sassafras (epidemiologic links to stomach cancer? liver cancer? other cancers?; contains safrole, which binds to DNA (CMAJ 162: 359, 2000). Taiwanese betel nut in particular is loaded with safrole, and Taiwan's molecular biologists are isolating safrole-DNA adducts from their esophageal cancer patients (Mut. Res. 565: 121, 2005). Despite warnings from the FDA, politics still allows the tea to be peddled extensively as a "complementary holistic remedy".

      Aristolochia: A "holistic" herbal remedy that has caused end-stage renal disease in hundreds of people, many of whom went on to develop transitional cell kidney and bladder cancers (J. Ethnopharmacology 94: 245, 2004; Food Chem. Tox. 41: 29, 2003).

      Vinyl chloride: Angiosarcoma of the liver (factory workers)

      Chromium, nickel: Lung cancer (factory workers -- scramble chromosomes and somehow enhance the effectiveness of real mutagens: Tox. Let. 127: 63, 2002). Cr+6 is the worst known mutagen among the metals.

      Cadmium (tin smelters, nickel-cadmium battery factory workers): Well, maybe. Lung cancer (Yes! Cancer Causes & Control 18: 7, 2007; No! Occ. Env. Med. 61: 108, 2004; Occ. Env. Med. 61: 108, 2004) and prostate cancer (No! J. Tox. Env. 6: 227, 2003)

      Asbestos: Lung cancer, mesothelioma (how it causes cancer remains unknown)

      Silica / Sand: Lung cancer. Yes, sand is now an "official" EPA carcinogen (Am. J. Epidemiol. 153: 695, 2001 shares my skepticism). The numbers are very soft and there is no easy-to-believe mechanism.

      Arsenic: Arsenic given as a medication for syphilis was famous for causing skin cancers (amplifies genes -- see Science 241: 79, 1988). Some arsenic occurs naturally in ground water, and this has been a major concern recently. Especially, bladder cancers might have something to do with arsenic in US drinking water (Am. J. Epidem. 153: 411, 2001), and arsenic is generally regarded as contributing to lung cancer (Cancer Causes & Control 18: 7, 2007).

        The business about arsenic in drinking water in the US is extremely politicized, which is easy to do in the absence of hard scientific data: Science 291: 2533, 2001; CA 51: 254, 2001; CMAJ 166: 69, 2002.

        By contrast with the questionable risk in the US, there is no question that the epidemic of arsenic exposure in Bangladesh due to deep wells is increasing cancer rates there (Am. J. Pub. Health 94: 741, 2004).

      PCB's: Polychlorinated biphenyls (pollutants, perennially accused of causing human cancers; hard evidence, i.e., increased cancer in people who actually WORK with the stuff and are heavily exposed, is conspicuous by its absence, which must be why only the World Health Organization is still writing about them (J. Tox. 40: 457, 2002)

      Saccharin: Bladder cancer (in huge doses given to animals, but epidemiologically NOT a significant risk to human users). Saccharin was banned in the 1970's for political reasons.

      Cyclamates: Same story as saccharin.

        * We'll talk later about the obviously-false aspartame claims, the work of a single internet activist who has avoided civil and criminal penalties only because his/her true identity has never been discovered.

      Human feces: Several known carcinogens, including those derived from bile salts (* try and ban feces, Senator Delaney!)

      Benzene: Leukemias and related problems.

        * Vitamin C can decarboxylate sodium benzoate to benzene in warm, light-exposed soda pop, increasing levels above what is considered "safe" for drinking water. This occasionally gets government and media attention, though it's never more than a very few lots that are found to be tainted.

      Phenacetin: Transitional epithelial (mostly bladder) cancers

      Anabolic steroids: Liver cancer (this particular risk is relatively small; more about "roids" later)

      Estrogen: Endometrial hyperplasias and carcinomas. Some promotion of post-menopausal breast cancer, maybe. More about this later.

        * "Green" claims about estrogens in the enviroment as health risks are ever-changing, never scientifically based, and your patients will ask you about them. It's bizarre to see a "leading environmentalist" inveighing against pesticide residues or factory farming practices that supposedly are damaging our hormonal milieu while eating a tofu sandwich -- tofu being famously full of phytoestrogens.

      Ferric ion: Liver cancer (hemochromatosis patients); perhaps many other cancers ("free radical generator")

      * Herbicides & pesticides: Chlorophenol herbicides occasionally show small statistical links to some of the soft tissue sarcomas, which are fairly rare anyway: Epidemiology 10: 788, 1999; Am. J. Epidem. 145: 1061, 1997; the numbers aren't very impressive; this has been tossed around for years. There's still study after study after study in the minor journals, always with small numbers and variable weak correlations between this-and-that or negative results. But no major study has linked herbicide or pesticide exposure to any cancer for the past ten years -- i.e., the science community knows this is a dead-end. For the original dioxin-and-lymphoma epidemiologist's personal memoir after forty years, see Acta Onc. 47: 347, 2008 (good read).

    Some environmental carcinogens are DIRECT-ACTING ("activation-independent"), and exert their effect directly. However, the majority (PROCARCINOGENS) require metabolic conversion (ACTIVATION) to produce carcinogenic molecules (ULTIMATE CARCINOGENS).

      Famous direct-acting carcinogens include the alkylating agents (cancer chemotherapeutic agents) and a few acylators. Some heavy metals actually depolymerize DNA.

      All the others, including polycyclic hydrocarbons (smoke), aromatic amines, amides, and azo dyes, natural plant products, and nitrosamines all require activation to ultimate carcinogens. Often (but not always) the carcinogen is activated by the hepatic P-450 mixed function oxidase system.

      Probably all chemicals that really induce cancer are mutagens ("genotoxic carcinogens"). You don't want any more exposure to these than is practical.

      The non-mutagens ("non-genotoxic carcinogens") act by promoting cell division ("promoters"); these are clearly dose-dependent and the effect is reversible when the promoter is eliminated. These are a lot less dangerous and include lots of common substances -- hence the absurdity of banning "all traces of anything that causes cancer".

      A rule that works most of the time is that the actual carcinogen either damages DNA directly (the alkylating and acylating agents) or is a potent electrophile (* the epoxide ultimate carcinogens derived from polycyclic hydrocarbons, vinyl chloride, and aflatoxins; the N-hydroxylated dye metabolites; the alkyldiazonium ions derived from nitrosamines, etc., etc. etc.: best review article is still Cancer 47: 2327, 1981.)

      Review of how environmental carcinogens produce mutations: JAMA 266: 681, 1991 (still good).

    When (not "if") you, the physician, are asked about media and government claims that something causes cancer, please bear in mind that the relationships that have held up have been striking, apply to animals too, and make sense biologically.


      • THE RELATIONSHIP IS STRIKING, and not just the result of selective memory (i.e., hype any "cause of cancer", and cancer patients and their families, seeking to know "why me?", will remember being exposed to more of it than do controls; real relationships hold up in prospective studies);
      • THERE IS A DOSE-RESPONSE CURVE that makes sense (as you read more and more "scare articles", you'll be amazed how seldom this is present)
      • THERE IS A GOOD ANIMAL MODEL, and not just huge amounts of some substance that are probably acting as a promoter (see below);
      • IT MAKES SENSE BIOLOGICALLY (i.e., you are dealing with something you can demonstrate to be a mutagen / something that interacts with DNA).

      The most dubious "carcinogen" in the public eye in the 1990's was high-tension electric lines. Only in deeply flawed "epidemiologic studies" have "statistical risks" been identified. There is no theoretical mechanism, no one has been able to induce cancer in animals this way, fields orders of magnitude higher have no apparent effect on bio-molecules or cells, and the "electromagnetic field exposure" from the body's own beating heart is far greater. The newer epidemiologic studies haven't shown an effect, either (Br. Med. J. 307: 895, 1993). See also JAMA 265: 1438, 1991; Cancer 68: 455, 1991; Pediatrics 88: 630, 1991; Br. Med. J. 313: 1047, 1996; NEJM 337: 1, 1997. The major article claiming a link was finally branded a fake by Br. Med. J. 319: 337, 1999. The business seems to have ended. (The "cellular phone" business was even sillier. Ask a tort lawyer.)

      * In June 2005 there was a pronouncement by the EPA that they were gravely concerned about the safety of teflon, one of the most inert substances in existence, because a chemical used in its manufacture was a carcinogen. My search of the NIH database did not show a single publication supporting this claim.

* Agent Orange (which was sprayed on the Vietnam jungles to make the enemy more visible) was contaminated by the experimental carcinogen 2,3,7,8-tetrachlorodibenzoparadioxin (TCDD), which remains present in measurable quantities in some veterans even now (Am. J. Ind. Med. 30: 647, 1996). Today, there is apparently total agreement now that Agent Orange is not a mutagen / initiator. Even the folks who use it as an experimental carcinogen say it's apparently just a mitogen (Exp. Tox. Path. 51: 555, 1999). Despite the decision by politicians to compensate Vietnam veterans with lymphoma (the son of Admiral Zumwaldt, who ordered the spraying of agent orange, got lymphoma...) and (1993) tobacco-induced lung cancer (I'm not making this up), any link between agent orange (dioxin) and a plethora of alleged health problems (cancers, birth defects) remains very soft. So is evidence that most of our soldiers were even exposed. See JAMA 265: 898, 1991; Am. J. Pub. Health 81: 289 & 344, 1991; Arch. Env. Health 53: 199, 1998 (Air Force; no chloracne or noted increase in common acne in veterans who sprayed it during Operation Ranch Hand); Am. J. Epidem. 148: 786, 1998 (no increased mortality; no increase in total cancer); J. Occ. Env. Med. 39: 740, 1997 (VA study finds lung cancer claim fails totally); Arch. Env. Health 51: 368, 1996 (gestational trophoblastic disease claim fails); Epidemiology 7: 454, 1996; Ann. Epidem. 5: 414, 1995 (VA; Hodgkin's claim fails completely); Epidemiology 6: 17, 1995 (claims of more stillbirths and birth defects fails completely). No link to prostate cancer: J. Urol. 166: 100, 2001. No link to trophoblastic disease in the Vietnamese people: Arch. Env. Health 41: 368, 1996. People heavily exposed in industry have only a slight increase in overall cancer risk, even assuming that the effect isn't due to confounding variables (Occ. Env. Med. 53: 606, 1996; Env. Health Perspect. 106 S2: 663, 1998); one epidemiologist actually showed how to juggle the statistics, including studies the EPA chose to ignore, to claim dioxin protects against cancer (sort of like broccoli sprouts, I guess; Reg. Tox. Pharm. 26: 134, 1997.) Nevertheless, in 1994, the Environmental Protection Agency issued a report concluding that dioxin as among the "greatest threat[s] to public health", i.e., was a grave danger that could be the cause of 1.3 out of every 100 American cancer deaths. Of course, its own Science Advisory Board refused to accept this groundless claim, both in 1995 and after the EPA's 2000 revision (Tox. Sci. 64: 7, 2001 points out even the EPA is not allowed to divide by zero; also Reg. Tox. 36: 211, 2002, which considers among other strange things the EPA's willingness to believe in "U-shaped dose-response curves"). In 1997 the government decided to compensate Vietnam vets whose children have neural tube defects; again this is politics rather than science. Of course, the Hanoi government claims a tremendous increase in birth defects "caused by Agent Orange"; there was a conference in 2001 (Nature 413: 442, 2001) that produced the expected agreement for joint study (Nature 416: 252, 2002). The fiasco continues: One group estimates "dioxin body burden" in survivors of "Operation Ranch Hand", and discovers that the "most heavily exposed" people have 50% LESS cancer than controls (Exotoxicity and Env. Saf. 50: 167, 2001); they come up with a weird explanation ("both a promoter blocker and a cancer causation agent...") for this. As the population ages, one study found no effect on prostate cancer (J. Urol. 166: 100, 2001; another found that these veterans seem to come in with more and higher-grade prostate cancers (Cancer 113: 2464, 2008); whether this is real or an artifact remains to be seen.

      * John Travolta's "A Civil Action" popularized the idea that the Woburn cluster of childhood leukemia cases resulted from trichloroethylene from a tannery entering the drinking water. I could not find the details of the case, but trichloroethylene-exposed workers are not coming down with more leukemia themselves (Epidemiology 9: 424, 1998; Int. J. Occup. Med. 11: 81, 1998; Cancer Causes & Control 8: 406, 1997). Whatever really happened; I have thought that perhaps trichlorophenol (which has been used in tanning and which is an animal carcinogen) is more suspect.
A Civil Action


    Exposure to high-energy photons (ultraviolet, ionizing radiation) is well-known as a cause of cancer.

      From 1928-1955, "Thorotrast", a complex of thorium dioxide and a carrier dextran, was used to image the livers and spleens of a few million humans. This was monumentally stupid. The long-lived isotope stays in the body, emitting radiation, for the rest of your life, and cancers followed years or decades later (J. Tox. 35: 199, 1997).

      Atomic bomb survivors (Japan, Marshall Islands) have greatly increased incidences of all the common leukemias (except CLL; the incubation time is a few years), and minor increases in many (but not most) solid tumors (remember thyroid, breast, salivary gland, lung).

        Chernobyl's children (thyroid cancer from radioactive iodine, other problems have been less prominent): Nature 359: 21, 1992; update Lancet 358: 1965, 2001. To date, it seems that only thyroid cancers are popping up among even those near the site. Despite claims by anti-nuclear activists that hundreds of thousands of people have died / will die as a result of Chernobyl, no one has been able to show anything plausable, and "investigators estimate that the population exposure that resulted from the Chernobyl fallout is in the range of natural background radiation for most European countries" (Arch. Env. Health 56: 478, 2001).

        Interestingly, children conceived after their parents were exposed to radiation at Hiroshima and Nagasaki do not exhibit any measurable increase in any identified health problem so far. This "non-news" is very important scientifically (Am. J. Hum. Genet. 52: April 1993).

      On the average, 14% of your annual radiation exposure is from your diagnositic x-rays. The cancer risk that this poses is unknown.

        * A group in 2004 made the unjustifiable assumptions that (1) there is a linear relationship with the atomic bomb survivors, and (2) countries that do more x-rays don't find more cancers. They estimated the diagnostic x-rays cause 700 extra cancer deaths annually in the UK (Lancet 363: 344, 2004).

      We'll talk a little about "radon in your home causes lung cancer" later -- the verdict's not fully in. In any case, it's no measurable risk for anything else important; Lancet 341: 1127, 1993; more Lancet 355: 1888, 2000. Since the early 1990's there has been amazingly little work on radon despite the ongoing political stuff and statistics-juggling. The one major study that actually looked at what happens to folks who have a lot of radon in their homes found a slightly increased risk for smokers and ex-smokers (BMJ 330: 223, 2005).

      Nobody's shown an increased risk from living near nuclear power plants (JAMA 265: 1438, 1991).

    Occupational radiation carcinogenesis:

      Old-time radiologists who tested their fluoroscopes using their own hands developed lots of leukemias, Hodgkin's disease, and skin cancer.

      Radium paint workers who put their brushes in their mouths developed bone and nose cancers.

      Uranium miners have a greatly increased incidence of lung cancer, supposedly even if they do not smoke.

        * In the US, the worst harm was done to Navajo miners. Historians see Am. J. Pub. Health 92: 1410, 2002. New series: Cancer 89: 2613, 2000 (almost all the miners with cancer smoked.)

    Iatrogenic radiation carcinogenesis:

      People given high doses of radiation for ankylosing spondylitis (x-rays) or polycythemia vera (radiophosphorus) have greatly increased incidences of all the common leukemias (* except CLL).

      Patients treated with radiation therapy for acne (!) develop multiple skin cancers.

      Newborns treated for mythical "enlarged thymus" developed many thyroid cancers as young adults.

    Ultraviolet radiation is the principal risk factor in most skin cancers (basal cell, squamous cell, malignant melanoma).

      Suntanning offers only modest protection from the wavelengths that cause cancer and elastosis ("aging of the skin").

    Radiation appears to initiate cancer just as chemical carcinogens do -- by causing mutations.

      * The trademark ultraviolet light mutation is CC->TT (Proc. Nat. Acad. Sci. 90: 4216, 1993; now solid).


    Viral (RNA, DNA) causation of cancer is well-documented in the lab, and is important in some (but probably not most) human cancers.

      Polyoma virus and SV40 are linked to a variety of animal tumors.

        * There is perennial discussion of whether exposure to SV40 in contaminated polio vaccines has caused an increase in the rate of all cancers, or any particular cancer. When people exposed to the virus get certain of the less-common cancers (ependymomas, mesotheliomas, osteosarcomas), the cancer cells express the virus, but if there is any increased risk among these people, it is relatively small (Anticancer Res. 19(3B): 2173, 1999), and numbers still differ tremendously from various centers. Most recently, it seems that SV40 is often expressed in particular cancers, but even after 25 years of worrying, cause-and-effect is hard to show (Am. J. Med. 114: 675, 2003). Intersetingly, even the authors of the last paper make no attempt to show that the involved cancers are more common in recipients of the tainted polio vaccine batches.

      Mouse mammary tumor virus is transmitted from mother to child in the milk.

      Feline leukemia virus causes a contagious leukemia in cats.

      Closer to home: Wart virus ("human papilloma virus", HPV) causes warts ("benign tumors") in humans, and certain strains cause cancer of the uterine cervix, vulva, and penis in humans (Nature 336: 765, 1988 was the breakthrough article).

        Now well-established and general knowledge: HPV oncogenic protein E7 inactivates the product of tumor-suppressor gene RB, while E6 inactivates tumor-suppressor gene p53 product and prevents it from repairing damaged DNA (original work: Proc. Nat. Acad. Sci. 90: 3988, 1993; Proc. Nat. Acad. Sci. 91: 2436, 1994.

      Epstein-Barr virus ("infectious mononucleosis virus") is necessary (but not sufficient) to cause African Burkitt's lymphoma, and is etiologic in Chinese nasopharyngeal cancer, immunoblastic lymphoma, and * Eskimo/Inuit endemic salivary gland adenocarcinoma.

        * Using Epstein-Barr as a tumor marker for prognosticating Chinese nasopharyngeal carcinoma: NEJM 350: 2461, 2004.

      Hepatitis B virus has been known for decades to be a major cause of hepatocellular carcinoma. It became clear in the 1990's that hepatitis C virus is also important (NEJM 325: 675 & 729, 1991; lots more). They probably effect this by acting as mitogens, allowing special opportunities for genetic damage (PNAS 86: 8852, 1989; PNAS 87: 6791, 1990; Cancer Res. 51: 1278, 1991). Hepatitis B (and perhaps C) also inserts itself randomly in the genome, with a range of possible effects (Ult. Path. 25: 497, 2001).

      HTLV-I causes epidemic leukemia in Japanese humans.

    Despite all this, the common human cancers (except as noted) do not seem to be contagious. Viral carcinogenesis promises to be an area of continuing interest.



      There is almost nothing to suggest that foreign implants cause cancer. (The breast implant hype and fiasco: NEJM 326: 1649, 1992.) Cancers caused by bile duct flukes or schistosome eggs probably are due to their effects as promoters. Joint replacement doesn't cause cancer at the joint or elsewhere: Cancer 94: 3057, 2002.

      The weight of evidence is that mechanical injuries do not cause cancer, though this is often alleged in lawsuits.

      The only likely exception is fibromatosis / fibrosarcoma where there was massive soft-tissue injury (AMFJP 19: 152, 1998; also Surg. Gyn. Ob. 169; 104, 1989; J. Ped. Surg. 34: 1130, 1999) Both make sense -- cells that do not ordinarily divide will have divided in response to the trauma, letting Nowell's Law operate and producing a tumor with the phenotype of the dividing cell.

      * The traditional wisdom is that head trauma places people at risk for meningiomas, for some unknown reason. If this is the case, the effect is not striking (Cancer Causes & Control 9; 109, 1998; Int. J. Epidem. 27: 579, 1998; Neurology 58: 1849, 2002). Occasionally, head injuries that result in arachnoid cap cells being displaced into the soft tissues of the head and face are followed by meningiomas arising from these cells; perhaps this is the explanation.

      MARJOLIN'S ULCER is well-differentiated squamous cell carcinoma arising in skin that has been badly traumatized (i.e., burn, chronic ulcer), where ongonig regeneration has provided the opportunity for mutated cells to overgrow.

    There is a great deal of speculation and anecdotal evidence connecting carcinogenesis and prognosis of cancers to MENTAL ATTITUDES.

      So far, the best work has failed to support the connection made by folklore, and nowadays real scientists have pretty much stopped examining these claims. The "stress and breast cancer recurrence" claims (Br. Med. J. 304: 1295, 1992; Br. Med. J. 304: 1078, 1992) were finally laid to rest by a huge study (Br. Med. J. 324: 1420, 2002). "Psychic vulnerability" is not a risk for cancer either (Cancer 94: 3299, 2002, twenty-year prospective study; yes really). "Fighting spirit" does not correlate with survival, but being depressed does; I suspect that the latter effect means the cancer has gotten farther and is causing an organic depression (Lancet 354: 138, 1999).

      But the relationship between mind and body is clearly a very potent one, and the whole field cries out for more study.

ONCOGENES (review NEJM 358: 502, 2008; older cancer genetics update: Nat. Genet. 33S: 238, 2003.)

    ONCOGENES are mutated DNA sequences within eukaryotic cells direct the synthesis of proteins that help transform a benign host cell into a cancer cell.

      Oncogenes are slightly altered forms of PROTO-ONCOGENES ("mitogenes") that are essential genes that govern normal tissue growth, differentiation, and apoptosis.

        By now, about 200 different proto-oncogenes are known.

        Many proto-oncogenes are the genes for hormone or vitamin receptors or the proteins to which they talk, while others seem to be general turn-ons.

        When a proto-oncogene is altered to become an oncogene, we speak of its being ACTIVATED. This is by one of three mechanisms:

        • POINT MUTATION: The gene product is stuck on the "on" position.
        • TRANSLOCATION: The gene product is under the control of the wrong promoter, or a FUSION GENE (half-one gene, half-another) produces a product that promotes cell division.

        • AMPLIFICATION: There are too many copies of the gene. Sometimes there are so many copies that "double minute" chromosomes are formed from them

    Oncogenes were originally discovered in TRANSFORMING RETROVIRUSES ("the RNA tumor viruses").

      Retroviruses are ubiquitous, generally harmless RNA viruses (HIV is obviously an exception). The RNA code is transcribed onto DNA, which is then integrated into the host genome.

      The old cancer researchers ground up actual animal tumors and extracted viruses that just happened to contain the genes for malignancy. Bishop and Varmus won the 1989 Nobel Prize for clarifying this. Thankfully, there's nothing to suggest retroviral transmission of activated cancer genes as a cause of cancer, at least among humans.

      "Viral oncogenes" turned out to be cancer-producing genes that the viruses had just happened to pick up ("TRANSDUCED") while growing in established tumors. In fact, the proto-oncogenes were originally discovered as counterparts in the normal genome to the deadly viral oncogenes.

      Typically a "viral oncogene" is a proto-oncogene minus its regulatory sequences, or with a characteristic mutation, or in an excessive number of copies ("amplification"). They are capable of causing cancer by themselves, and hence are VERY different from their normal counterparts (i.e., have been damaged several times).

      As we have noted, a proto-oncogene that has acquired the ability to cause cancer (i.e., has become an oncogene) is said to be ACTIVATED.

  • Receptor tyrosine kinase proto-oncogenes (RTK's)
    • These are signal-transducers, proteins that are fixed firmly across membranes. They are present in all eukaryotes. You met them in "Biochemistry", and learned that they are activated by the ligand joining the outer surfaces of two adjacent receptors. A variety of effects (mostly turn-ons) result within the cell itself. (You can read on your own about these, or review what you have already learned about inositol triphosphate, diacylglycerol, signalling ras, etc., etc.) The stimulated receptor must be engulfed and destroyed ("receptor mediated endocytosis").

      The first tyrosine kinase to be studied extensively was src, well-known in its oncogene form from a transforming virus. It has not proved much of a player in human tumors. (* We still don't know what it does for us in health.)

      c-abl is translocated from chromosome 9 to the breakpoint cluster region of chromosome 22 in most cases of chronic myelogenous leukemia, and this is part of the "Philadelphia chromosome" phenomenon. Much more about this later!

      fms, which codes for MACROPHAGE COLONY-STIMULATING FACTOR RECEPTOR, is mutated in some hematopoietic neoplasms (update Br. J. Haem. 123: 749, 2003), and so is its relative fms-like tyrosine kinase 3 (FLT3).

      The EPIDERMAL GROWTH FACTOR RECEPTOR family (EGFR/HER1, neu/HER2/erb2, erbB-2, erbB-3) (erbB discovered Science 249: 1552, 1990) are now very prominent because of the new biotechnology treatments.

        As with other tyrosine kinase oncogenes, erbB mutants are those that are locked in the "on" position ("constitutively activated"). erbB-related cancers are mostly squamous cell carcinomas, and fms-related cancers are mostly hematopoietic cancers.

        The related neu (once erb2, now HER2) is amplified in many carcinomas, notably adenocarcinomas, especially of the breast. Today, the degree of amplification is a guide to both prognosis and therapy.

        Likewise, EGFR evaluations by anatomic pathologists are now increasing dramatically, and there are competing techniques (J. Clin. Path. 62: 314, 2009).

      met (HGF-receptor) tyrosine kinase proto-oncogene seems to be what produces lumens in mesenchyme and its tumors (synoviosarcomas, mesotheliomas, kidney tubules, liver tubules, others): Science 257: 1258, 1992; Cancer 82: 1513, 1998; Proc. Nat. Acad. Sci. 95: 14417, 1998; it codes for the hepatocyte growth factor receptor and is emerging as a major player (J. Urol. 170: 2163, 2003).

        * Unlike most other activated proto-oncogenes, mutated met can be passed parent-to-child (hereditary papillary kidney cancer) and also marks the aggressive "tall-cell" variant of thyroid cancer.

      RET is a proto-oncogene tyrosine kinase (Nature 363: 458, 1993; NEJM 335: 943, 1996), and was the first activated oncogene that was discovered being passed from parent to child (Science 267: 381, 1995). Depending on the allele, there may be various endocrine tumors, mucosal neuromas, and/or Hirschsprung's disease of the colon.

      kit, the receptor for mast-cell growth factor, is yet another tyrosine kinase activated particularly in GI stromal tumors and some hematopoietic tumors (big review J. Allerg. 114: 13, 2004). As with RET and met, there are germline mutations that cause familial disease (Gastroent. 129: 1042, 2005).

      Flk-1, a VEGF receptor (activated in glioblastoma, etc., must be why they elaborate those odd blood vessels; Nature 367: 525, 1994; J. Path. 207: 224, 2005).

      PDGFRalpha is one of the receptors for platelet-derived growth factor. Mutations are common in medulloblastoma (Eur. J. Cancer 42: 646, 2006); a familial syndrome features GI stromal tumors (Lancet 369: 1731, 2007).

  • GTP-binding protein proto-oncogenes
    • This includes the ras family, present in all eukaryotes. They code for the signal-transducing G-proteins that modulate various transmembrane signals (* for example, turning fibroblasts into fat cells; Science 253: 565, 1991). Each codes for a p21 protein that binds GTP, and the healthy ones hydrolyze it (i.e., they are GTP-ases). They seem to be involved in initiation of mitosis as well as in differentiation. What ras does: Science 264: 1413, 1994. All about the G-proteins: NEJM 332: 406, 1995 (* Nobel prize 1994 Gilman and Rodbell).

      Most oncogenic ras are mutations with a single base pair change that alters an amino acid at position 12, 13, or 61 in the protein product. This destroys GTP-ase activity but retains GTP-binding activity, and current thinking is that these stay locked "on", telling the transformed cell, "Keep dividing!"

      Several of the best-known chemical carcinogens produce a specific mutation specifically at one of the three hot spots. For example, aflatoxin regularly mutates * codon 12 in K-ras (GGT to AGT or GAT).

      ras oncogenes clearly help cause a large percentage of human cancers. The large majority of oncogenes isolated from human tumors have been hot-spot ras mutants. Almost all pancreatic cancers, and many other cancers (especially adenocarcinomas) have mutations in codon 12 of K-ras (update Arch. Path. Lab. Med. 126: 1096, 2002). ras activation precedes malignant expression: Science 248: 1101, 1990.

      * A favorite pathology research subject in the late 1980's was immunostaining for ras p21 and seeing its effect on diagnosis and prognosis. For example, staining for K-ras p21 was reported to differentiate malignant from benign prostate epithelium; unfortunately, this has not held up on closer examination.

      * We can hope for better success with new attempts to screen patients for colon polyps/cancer by checking stools for oncogenic ras; despite much discussion over the past decade, it's still too costly (Gastroenterology 119: 1219, 2000).

      gsp is the activated form of Gs(alpha), a ras-related gene that occasionally shows up altered in endocrine adenomas. More about this when we talk about the pseudohypoparathyroidism family of illnesses.

  • DNA-binding protein proto-oncogenes
    • This is the myc family, present in all eukaryotes, whose protein products are intranuclear and bind to DNA itself. They enable DNA synthesis.

      myc activation is usually by amplification (excess copies of a gene) and/or translocation rather than by mutation.

      In Burkitt's lymphoma of B-cells, c-myc (chromosome 8) is moved next to the immunoglobulin gene (chromosome 14), i.e., the cell decides to multiply like crazy every time it is told to make antibodies.

      myc genes are much amplified in neuroblastomas and oat cell lung carcinomas.

      myb is a related proto-oncogene involved both in human cancer and in the proliferation of cells in human atheromas.

      * The Ewing's sarcoma 11:22 translocation joins FLI1, a myc-like proto-oncogene, to EWS, producing an aberrant transcription factor EWS-FTI1 (Proc. Nat. Acad. Sci. 90: 5752, 1993); much since.

  • Growth factor proteins themselves
    • The prototype Is c-sis, which codes for the beta chain of platelet-derived growth factor (PDGF), the stuff that tells fibroblasts to divide in wound healing.

        Probably sis-induced cancers grow by autocrine self-stimulation by PDGF. Not surprisingly, PDGF is greatly over-expressed in many sarcomas, and only transforms cells with the PDGF receptor.

      int-2, the second site where the mouse mammary tumor virus integrates, is the gene for FIBROBLAST GROWTH FACTOR #3 (FGF3; J. Path. 170: 219, 1993; J. Neurosurg. 76: 792, 1992), a gene with many relatives, including proto-oncogenes flg (FGF1) and bck (FGF2).

  • More oncogenes that are worth knowing.
    • raf, a family of serine-threonine kinases, is part of the signaling pathway that links most of the tyrosine kinases to the ras family. BRAF is mutated in around 15% of human cancers (Am. J. Clin. Path. 123: 256, 2005); famously, mutated BRAF appears in the most comon type of thyroid cancer, and in the "serrated pathway" of colon carcinogenesis (Gastroent. 138: 2088, 2010).

      bcl-2, activated in most B-cell lymphomas, and its relative bcl-X, tell the cell not to undergo apoptosis, but to divide if told to do so. The molecular biology of this important molecule, and its family including bax, is being worked out. (Nat. Med. 3: 614, 1997; Nat. Med. 274: 2002).

      erbA / TRalpha1 codes for the human THYROID HORMONE RECEPTOR. It is linked to a variety of animal cancers (Onc. Rep. 9: 863, 2002; Gastroent. 138: 1863, 2010.

      jun is the factor that initiates transcription of DNA at a particular sequence. Present in all eukaryotes. fos apparently turns short-term stimulation into long-term DIFFERENTIATION, and fos mutants help immortalize cell cultures. fos and jun: Science 254: 1210, 1991. Both are known from the transforming retroviruses (v-fos and v-jun). It was expected that these would turn up mutated in human tumors, but so far there's been no major findings.

      Cyclin D1 itself (11q13, bcl-1, the PRAD-1 locus) is involved in the oldest known lymphoma translocation, in most parathyroid adenomas, and is amplified in around 20% of breast cancers, and the knockout mice get breast tumors (Nature 369: 669, 1994). Review Oncogene 25: 1620, 2006.

      The HIGH MOBILITY GROUP (HMG/HMGI -- many are known) genes are often scrambled specifically in benign tumors with near-zero malignant potential (lipomas, uterine polyps, uterine leiomyomas -- Am. J. Clin. Path. 109: 251, 1998; Am. J. Path. 155: 1535, 1999; lots more from the 1990's). This suggests that these mutations are the single major step to producing benign tumors, which do not turn malignant because there aren't a lot of mutations accumulated.

DNA IN-SITU HYBRIDIZATION has been used occasionally during the past ten years as an adjunct for cancer diagnosis (Am. J. Clin. Path. 112(S1): S11, 1999). For several tumors, it is now used routinely for every newly-diagnosed case.

    Instead of old-fashioned karyotyping, today's techniques count chromosomes instead by fluorescent means, which stain each pair a different color.

    It is now standard to stain paraffin sections of breast cancers with probes for erb-B2 (HER2/neu). Cancers without amplification will show only two loci; those with amplification will show huge numbers of loci, usually in big clumps.

    When there's suspicion that a particular gene is split by translocation, two probes can be used, of different colors. If they remain together, there is no translocation; if they are separated, translocation has occurred. This is very helpful in diagnosing Ewing's sarcoma.

TUMOR SUPPRESSOR GENES (anti-oncogenes): Many reviews; Knudson himself in Proc. Nat. Acad. Sci. 90: 10914, 1993; at the bedside Lancet 349-S2: 16, 1997; kids Ped. Clin. N.A. 49: 1393, 2002; adults Arch. Path. Lab. Med. 125: 85, 2001.

    Tumor-suppressor genes keep cells from overgrowing, even when the oncogenes are activated. To lose their anti-cancer effect, BOTH copies must be altered. (Contrast the proto-oncogenes, which exert their effect when a single copy is activated to an oncogene.)


        ONE HIT: You have a cell with a much increased propensity to turn neoplastic

        TWO HITS: You have a tumor cell.

        If you inherited one copy of the damaged tumor suppressor gene, you have the anti-oncogene deletion syndrome, with a greatly increased risk for the corresponding tumor(s). If you have the corresponding tumor(s) but do not have the germ-line mutation (i.e., your tumor was sporadic), both mutations are somatic. If you don't understand this, stop now and think about it until you do.

        Please don't ask whether the mutated allele is "dominant" or "recessive". It is dominant with respect to the tumor-family syndrome, recessive with respect to the tumor itself. If you are reading this, you already understand.

        If you derive from a mutation-bearing sperm or egg, or were hit at conception, you have one of the autosomal dominant tumor suppressor gene deletion ("tumor-susceptibility") syndromes. The malignant phenotype requires both copies to be bad, so it is autosomal recessive.

      * EPIGENETICS is the study of changes in the genome that are transmitted from parent to daughter cell but do NOT involve changes in the nucleotide sequence. For example, tumor suppressor genes are often "mutated" by loss of methylation of their promoters: Nat. Genet. 21: 163, 1999; Nat. Rev. Genet. 3: 415, 2002; Ann. Rev. Med. 59: 267, 2008. Relaxation of imprinting in the pathogenesis of Wilms tumor: Nature 362: 747 & 749, 1993; Cancer Res. 60: 2356, 2000. microRNA alterations: Int. J. Cancer 122: 963, 2008. No therapies yet, but much to interest basic biologists.

    The prototype Is RETINOBLASTOMA, a hereditary cancer.

      The tendency to retinoblastoma (* and osteosarcomas, in survivors) is inherited as an autosomal dominant trait, i.e., there is one chromosome lacking a particular tumor suppressor gene.

      Retinoblastoma results when a mutation damages BOTH COPIES the healthy tumor-suppressor gene in a single cell (the Knudson "two-hit" phenomenon). The cell now lacks any copy of the tumor suppressor gene, and is transformed.

      The retinoblastoma susceptibility locus is RB1 at 13q14. The protein is central to cell cycling (classic Nature 374: 114, 1995).

        The most important finding in cancer research in the late 1980's was the discovery that many (if not most) DNA-containing tumor viruses (including human papilloma virus) bind to, and inactivate, the normal product of RB1 (Cell 56: 1, 1989). The ability to do this correlates with tumorigenicity (Science 248: 70, 1990); virus protein blocks the binding of Rb to its target among the nucleoproteins (Nature 351: 406, 1991), etc. This has held up, though to date it has not resulted in any new therapeutic strategies.

    The most common known genetic injury in human cancer is damage to the p53 (TP53) gene.

      *  "Molecule of the year" cover story Science Dec. 24, 1993; a tremendous literature exists. Stains for the tumor product are now routinely used in cancer prognosticating: Am. J. Clin. Path. 113(5S1): S84, 2001; Arch. Path. Lab. Med. 124: 966, 2000; lots more).

      Mutations vary; the one well-known "trademark" p53 mutation is the hepatocellular carcinoma mutation due to aflatoxin (codon 249).

      The p53 gene product is a sequence-specific binder to DNA that prevents mitosis during times of cell injury, so that there will be more time for DNA repair. Sometimes (gamete, lymphocyte, chemotherapy) p53 even tells an injured cell to undergo apoptosis.

        * The protein binds as a tetramers, making it easier to understand the oncogene-anti-oncogene duality. The defective unit handcuffs the others. See Science 256: 827, 1992; Nature 358: 15, 1992.

      A famous link is to hepatocellular carcinomas (* those from the aflatoxin-hepatitis B belt have a distinctive mutation in codon 249: Science 253: 49, 1991; the mutagen is aflatoxin: Lancet 338: 1356, 1991).

      The primacy of p53 in cancer progression was first highlighted by the discovery that astrocytomas (low-grade brain cancer) turn into glioblastomas (high-grade brain cancer) upon acquiring a mutated p53 (Nature 355: 846, 1992). There has been much more work since.

      The tumor-suppressor gene p53 product is also inhibited by the proteins of human papilloma virus (see above; p53 and cervix cancer Lancet 340: 140, 1992), SV40, and adenovirus 5 (Science 248: 76, 1990).

    There are many other tumor-suppressor genes.

      As noted above, p16INK4a (was CDNK2A or MTS1), on 9p21, is an inhibitor of cyclin-dependent kinase (i.e., inhibitor of mitosis) which is very commonly deleted in lots of cancers (Proc. Nat. Acad. Sci. 91: 11045, 1994); it may function either an oncogene or a tumor suppressor gene. See also Nature 370: 180, 1994; Nat. Med. 5: 731, 1999; lots more. This now identifies a familial melanoma syndrome: NEJM 338: 879, 1998. Classic work on cell-cycle screwups in cancer: Science 266: 1821, 1994.

      Classic renal cell carcinomas have lost the Von Hippel-Landau locus (Nature 332: 268, 1988; more below). Oat cell carcinomas also lack a portion of 3p; almost all other lung cancers lack a smaller chunk in the same place.

      People heterozygous for a deletion of a bit of 11p have aniridia, and they develop Wilms' tumors that are homozygous for the deletion (as are spontaneous Wilms' tumors: Proc. Nat. Acad. Sci. 90: 1416, 1993).

        This is the famous WT-1 (formerly WAGR) locus, producing a nuclear binding protein that seems to be involved in mesenchymal-epithelial transitions in general, and kidney and urogenital ridge development in particular (Nature 346: 194, 1990; Nature 353: 431, 1991; Proc. Nat. Acad. Sci. 90: 5828, 1993). * Biology jocks: the adjacent aniridia gene is homologous to the drosophila homeobox PAX6.

      Von Recklinghausen's neurofibromatosis type I patients are heterozygous for a mutation on chromosome 17; the locus is "NF-1", and its protein product, "neurofibromin" characterized as a facilitator of hydrolysis of GTP by normal ras p21 (Nature 351: 576, 1991).

      Von Recklinghausen's neurofibromatosis type II patients are heterozygous for a mutation on chromosome 22 (product is * schwannomin or * merlin), and their tumors (and many spontaneous meningiomas and other nerve tumors: Am. J. Hum. Genet. 47: 823, 1990) are homozygous for this loss. See below.

      Colon cancers typically become homozygous for deletions of 5p (early) and 5q21 ("APC", "adenomatous polyposis coli", "familial polyposis locus".

        In any case, the study of colon cancer progression has provided strong support for the Nowell multi-step clonal evolution model of carcinogenesis (no surprise). The colon is a handy organ since pre-cancerous polyps often make it to the lab.

      The familial non-polyposis ("Lynch") family of tumor-suppressor genes are responsible for repair of DNA mismatches.

        * The genes are hMSH2, hMLH1, hPMS1 hPMS2, and so forth; MLH1 can be inherited as a mutant with normal sequence but abnormal methylation NEJM 356: 697, 2007.

        We now screen for the entire family using microsatellite instability assays. See below.

      * Despite a huge amount of study, the mitochondrial genome seems to have little to do with tumorgenesis (PLoS Med 2(11): e401, 2005). The one sporadic tumor in which changes in mitochondrial DNA seems causal is renal "oncocytomas", i.e., tumors made up of cells with preposterous numbers of mitochondria. More about this under "Kidney". We'll look later at the succinic acid dehydrogenase and fumarate hydratase mutations that cause hereditary cancer syndromes.

    During tumor progression, the second anti-oncogene is lost by nondisjunction and loss of heterozygosity when an extra chromosome is randomly eliminated. The phenomenon enabled the discovery of many of these genes.

    * Actually, we've known for decades that tumor suppressor genes must exist. A classic finding is that when a cancer cell and a non-cancer cell are fused, the product is often a non-cancer cell.


    THE subject in basic cancer research right now.

    Once its growth genes have been mutated and its genome perhaps destabilized, cancer is still not a threat until it has developed the ability to invade, to induce its own blood supply, and (usually) to spread to distant sites.

    We are just now unravelling the additional accumulated mutations that allow these things, and they will be the targets of new cancer therapies.

    A major mystery of medicine is why some cancers (notably metastatic breast carcinoma and metastatic melanoma) lie dormant and hidden for years (even decades).

    For that matter, it's puzzling why cancer metastases will thrive in one locale and not in another.

      * Virchow actually doubted that cells travelling from the cancer are responsible for metastases, since lung metastases were less common than liver metastases in breast cancer.

    MICROSATELLITE INSTABILITY means the presence of abnormally long stretches of DNA with repeating motifs of 1-5 base pairs (i.e., a long string of "A"'s or "AC"'s or whatever), indicating defective DNA repair. This can actually be present quite early, before there are any visible histologic changes.

      Today, pathologists routinely get microsatellite instability assays on certain cancers (colon -- Gastroenterology 138: 2059 & 2073, 2010 -- endometrium, ovary; especially certain histologic types and those occurring in the young.) A tissue stain for the mismatch repair proteins seems to be almost as good as the actual genetic assay: Cancer 95: 2422, 2002; Arch. Path. Lab. Med. 127: 694, 2003. The purpose is to screen for Lynch's syndrome / Lynch-like new mutations, and (at least for colon) as a guide for prognosis (better than the rest) and treatment: NEJM 349: 247, 2003. Lynch cells are "RER-positive" (replication error positive).

    CHROMOSOMAL INSTABILITY of course means there have been problems with the mitotic spindles and non-disjunction will become commonplace. Cells without the necessary chromosomes die and don't contribute to progression; cells with extra copies may possess a growth advantage. Eventually this leads to those variably-sized and often huge nuclei that are familiar from conventional histology of cancers (Am. J. Path. 161: 391, 2002; many others).

    MICRO-RNA GENES ("gene silencers" -- no "household names" yet, but Fire and Mello received the 2006 Nobel Prize for discovering the phenomenon) do not code for proteins, but produce RNA's that bind to messenger RNA sequences of proto-oncogenes (Am. J. Clin. Path. 128: 830, 2007; Am. J. Path. 171: 728, 2007; JAMA 297: 1293, 2007). Knocked out, they function as do lost anti-oncogenes. (For example, advancing colon cancers are often with altered microRNA genes, with miR-21 in particular as a bad prognosticator: JAMA 299: 324, 2008). This, plus what cytosines are methylated, are part of the growing field of "epigenetics in cancer": NEJM 358: 1148, 2008.

TUMOR IMMUNOLOGY (mega-review NEJM 358: 2704, 2008)

    Despite a great deal of data and the fact that lymphocytes are usually abundant in advancing cancers, study of the immune system's attack on tumors has yielded little useful information.

      For some cancers (breast cancer, maybe melanoma, etc., etc.), a dense infiltration of lymphocytes imparts a slightly better prognosis, but this is hardly decisive. (The most impressive link so far is for ovarian epithelial carcinoma: NEJM 348: 203, 2003).

      By and large, cancer treatments that focus on strengthening the immune system (BCG, cytokines) have failed to help most cancer patients.

      * In the early 1990's, there was considerable interest in cultivating and re-infusing lymphocytes found in tumors (i.e., lymphocytes that are presumably attacking the tumor). This "autologous mature lymphocyte transfer" sometimes resulted in some regression of the tumor (Cancer Res. 51(S): 5074, 1991). The main problem was that the re-infused lymphocytes tended to just die. It's still done occasionally, especially for melanoma (J. Immuno. 173: 7125 & 7622, 2004; apparent triumph with a new strategy 358: 2664 & 2698, 2008).

    Despite the widespread belief (medical, folk, certain pathology textbooks) that "our immune system is our main defense against cancer", evidence in support of the "immune surveillance theory" is not very convincing.

      People who are immune-crippled (hereditary immunodeficiency, AIDS, immunosuppressive therapy) simply don't have increased rates for any of the common cancers. See, for example, Chest 103: 862, 1993; review in AIDS: JAMA 285: 3090, 2001; JNCI 28: 5-9, 2001; update Lancet 370: 59, 2007 (the cancers that aren't caused by infectious agents just aren't increased in AIDS or iatrogenic immunosuppression).

      The malignant lymphomas that are result from immunosuppression (AIDS, transplant patients) arise from cells that are already undergoing compensatory hyperplasia because of the immune suppression. Actually many of these are not even tumors, but hyperplasias that regress when good immune function is restored.

      Kaposi's "sarcoma", seen in AIDS and transplant patients, is actually a viral hyperplasia, not a real tumor.

        This has been obvious for decades. It arises multifocally, lacks anaplasia, is common among the immunosuppressed, and is epidemic in parts of the world.

        * Knowing "it's not a true cancer" is probably little comfort to patients who die of Kaposi's choking off the viscera. The cause of the cellular overgrowth is Kaposi's "latent nuclear antigen" (LANA) interacting with the Rb-E2F pathways (Nat. Med. 6: 1121, 2000).

      Patients with ataxia-telangiectasia (cancers plus immunodeficiency) have "fragile chromosomes" as the basic problem; even carriers are at extra cancer risk.

      Carcinomas of the skin and lower lip are common in transplant patients and they tend to be aggressive. This is not true of other carcinomas, and rather than invoking "escape from immune surveillance", the usual suspects are known and unknown viruses (Cancer 85: 1758, 1999).

      Nude mice have no cell-mediated immunity but are no more susceptible to spontaneous cancers than any other mice.

      Today, there are about a dozen strains of genetically modified immunodeficient mice that get increased numbers of particular cancers. However, in every case, we don't see the increased susceptibility to overall cancers that the classic "immune surveillance theory" predicts.

        In most strains, the tumors are malignant lymphomas, just as one would expect -- when part of the immune system is deficent, other portions must overgrow and thus have any mutations promoted.

        The Rag2-negative strains develop adenocarciomas of the bowel ... but only if they are inoculated with the bacterium that causes it in mice (Am. J. Path. 162: 691, 2003).

        Read the stuff from the remaining true-believers and decide for yourself: J. Clin. Invest. 117: 1137, 2007;

      People with autoimmune diseases triggered by the known anti-tumor antibodies do not self-cure their tumors (though there may be modest regressions), nor do these diseases pop up in the absence of the tumors known to cause them (Lancet 341: 21, 1993).

    Frankly, tumor immunology is only starting to get interesting to patient-care physicians. Although "cancer is not other, it is us", a few known antigens are distinctive (though not unique) for individual cancers, and it is against these that any effective immunotherapy will probably be directed. Further, the immune response to these known tmor-associated antigens is weak despite the fact that the same patients have no trouble mounting immune responses to microbes. Despite failure after failure, "novel strategies" to get the immune system to take notice are still being put forward (J. Allerg. Clin. Imm. 125: S272, 2010) -- and sooner or later, something may work.

      * Today, people talk about "immune escape", which happens quickly once the genome is destabilized: Nat. Immuno. 3: 999, 2002 (acknowledges that the classic "immune surveillance" hypothesis is completely discarded); Nat. Immuno. 3: 991, 2002. Immune surveillance updates: Nat. Rev. Cancer 2: 850, 2002.

      * One very well-known phenomenon is that in allogenic bone marrow transplantation to cure cancer, a strong graft-vs.-host response increases the likelihood of an actual cure. It seems most likely that the donor cells are attacking the last of the cancer cells because they are slightly different from the rest of the host's minor incompatibility antigens, to which they have tolerized. Update on hematopoietic stem cell transplantation: NEJM 354: 1813, 2006.

      * One interesting approach tags antibodies against such antigens with pseudomonas exotoxin ("immunotoxins"), selectively destroying cancer cells. Minimal side effects. So far it's proved helpful for a few human cancers (notably hairy cell leukemia): Blood 94: 3340, 1999; Nat. Biotech. 16: 449, 1998; however, progress is held up by the tendency to make antibodies against the agent (J. Imm. 177: 8822, 2006).

      Melanoma has a couple of antigens that are attacked by the immune system ("MART" -- "melanoma antigen recognized by T-cells"; also HMB-45/gp100 which is a popular stain to diagnose melanoma, Cancer 93: 409, 2001). Neither expressed much in health, but comes out in activated and malignant melanocytes. There are some others too (J. Imm. 168: 951, 2002). Melanoma and renal cell carcinoma are unusual in that generalized immune stimulation (i.e., by interleukin 2) actually helps a little bit sometimes (Cancer 91: 806, 2001).

    Despite the near-total failure of tumor immunology itself to help cancer patients, the era of magic bullets (targeted therapies, i.e., specific monoclonal antibodies and specific oncogene product inhibitors) in the treatment of cancer has arrived. Today's arsenal includes:

    • rituximab ("Rituxan", anti CD20 monoclonal antibody; now standard for non-Hodgkin B-cell lymphomas)
    • ibritumomab tiuxetan ("Zevalin"; anti-CD20 that may have a radioactive tag; for non-Hodgkin's lymphomas)
    • gemtuzumab ozogamicin ("Mylotarg", anti-CD33 with an attached poison for acute myeloid lymphomas)
    • cetuximab ("Erbitux"; anti-EGFR monoclonal antibody; especially colorectal and head-and-neck cancer; seems to help if the colorectal cancers have wile-type KRAS: NEJM 360: 1408, 2009)
    • panitumumab ("ABX-EGF"; anti-EGFR monoclonal antibody; colorectal cancer monoclonal antibody)
    • trastuzumab ("Herceptin"; anti-HER-2/neu monoclonal antibody; much-used especially for breast cancers)
    • pertuzumab ("Omnitarg"; anti-HER-2/neu monoclonal antibody that, unlike others, prevents the receptors from dimerizing)
    • bevacizumab ("Avastin"; anti-VEGF monoclonal antibody; now used especially in colorectal, non-small cell lung cancer, breast cancer, and renal cell carcinoma; update NEJM 358: 2066, 2008; Lancet 370: 2103, 2007)
    • imatinib ("Gleevic"; small molecule that inhibits abl-specific phosphorylation, PDFG receptors and certain kit; "miracle drug" for classic chronic myelogenous leukemia; remember also GI stromal tumors and chordomas)
    • gefitinib ("Iressa", an oral EGFR-tyrosine kinase inhibitor, the drug that actually worked for non-small-cell lung cancer: JAMA 290: 2149, 2003; Science 304: 1497, 2004; update and others JAMA 298: 70, 2007; wonder drug for a few types of lung cancer NEJM 361: 947, 2009; how cancers become resistant Nat. Med. 15: 718, 2009.)
    • erlotinib ("Tarceva", similar to gefitinib, claims made for non-small-cell lung and pancreatic cancer)
    • sorafenib ("Nexavar", inhibits raf kinase, PDFG, and VEGF receptor kinase; modest results for renal cell carcinoma)
    • sunitinib ("Sutnet", yet another oral multi-kinase inhibitor; modest results in advanced renal cell carcinoma)
    • bortezomib ("Velcade"), proteosome inhibitor and hence apoptosis enhancer that seems also to allow the local immune cells to become sensitized to tumor antigens (JAMA 297: 1423, 2007).
    • denileukin difitox ("Ontak", an interleukin-2 bound to diphtheria toxin, for T-cell lymphomas)
    • I131-tositumomab ("Bexxar", radioactive anti-CD20 -- the radioimmunoconjugate "magic-bullet" for the once-incurable low-grade lymphomas. NEJM 352: 441, 2005; Update Cancer 106: 616, 2006.)
    • There are plenty more on the way. Older reviews Am. J. Clin. Path. 119: 472, 2003; Am. J. Clin. Path. 122: 598, 2004. Update Lancet 373: 1033, 2009. Watch for future applications of monoclonal antibodies tagged with toxins like ricin, staph exotoxin A, others.


    Despite pop claims, the overall rates of new cancers adjusted for age and smoking are about the same as always in the United States. Current talk about "a tremendous increase in cancer due to pollution and our unhealthy diet of processed foods" merely reflects the facts that (1) we are not dying as children or young adults from violence, infection, malnutrition, or obstetrical catastrophes, but are living long enough to get cancer; (2) primitive societies do not always make the diagnosis of cancer when it strikes, and (3) people's fear of cancer makes them willing to believe obvious untruths. The myth of a "cancer epidemic": Lancet 340: 399, 1992; Br. Med. J. 308: 705, 1994. How "cancer clusters" usually result from chance: CA 54: 273, 2004.

    However, rates for individual cancers are changing. The reasons must have to do with environment and/or lifestyle.

    • BREAST CANCER is on the increase, explainable by an aging population and the fact that women are having fewer children, having their first child later in life, and are more obese. Despite massive efforts and an agitprop industry, nobody has been able to link breast cancer to a single environmental toxin (Cancer 97 1S: 289, 2003).
    • LUNG CANCER seems to be explainable by smoking. The rates for men have been dropping for over a decade, and now the rates for women are dropping as well (CDC 2004).
    • STOMACH CANCER rates have dropped by about 80% from the late 1800's, probably because we have chemicals and refrigerators rather than smoke to preserve our food and there's better drinking water and less helicobacter.
    • SKIN CANCERS including melanoma correlate with sunlight exposure.
    • CERVICAL CANCER is a sexually-transmitted disease and its epidemiology has followed the course of the sexual revolution.
    • ENDOMETRIAL CANCER is up some probably because of estrogen supplementation.
    • COLON CANCER is pretty much stable since it's mostly genetic and the American diet hasn't really changed so much as we've heard.
    • The incidence of PROSTATE CANCER is hard to estimate from year to year because of changing methods of making the diagnosis; the death rate hasn't changed much over the decades.
    • I remain openminded on the possibility that pollutants contribute to CANCER OF THE PANCREAS, as the risk factors (other than heredity and smoking) seem elusive and there's a trademark mutation, but attempts to link it to known chemicals (the usual suspects are chlorinated hydrocarbons) don't even show an exposure-response trend (Am. J. Epid. 153: 841, 2001).

    • The rates for MALIGNANT LYMPHOMA are going up. This is a major mystery.

    • * For some unknown reason, the once-rare ADENOCARCINOMA OF THE ESOPHAGUS is becoming much more common in the USA. (Since these occur low, perhaps the reason is that pathologists aren't calling them stomach cancers. Or our fatter society, which has more reflux, is also more affected with its malignant complication. See Dig. Dis. Sci. 53: 2307, 2008.)
    If you get a cancer in the United States (and we're not counting the little skin cancers), what are your odds?

    • 1950: Around two of six patients cured
    • 1970: Three of six patients cured
    • 2004: Four of six patients cured
        • (CDC, 2004)

    The improved prognosis is more the result of earlier detection than anything else. As physicians, you will devote much effort to SCREENING for treatable cancers.

      Every health care system will have perverse incentives. Under managed care in the US, the typical provider has a disincentive to do cancer prevention. It cuts into the provider's current profits, and years later when expensive cancer occurs, the patient will probably be covered by a different company's plan.

CANCER AROUND THE WORLD: Science 254: 1114, 1991 is still good

    Cancer is an ancient disease among humans, is ubiquitous in human societies, and is common in wild animals as well.

      * In the 1960's and 1970's, the Bantu (Africa) and Hunza (Himalayan) people were portrayed by laetrile proponents as "cancer free societies, because their diets are rich in laetrile." This was just another bold lie (though it has become part of both "conservative-pious" and "liberal-green" mythology). Both malnutrition and cancer were very common in both societies.

    Around the world, different cancers are common in different countries, and in different ethnic groups. And these numbers are changing.

      Breast cancer is much less common in the Third World than in the developed countries. Its incidence is highest in the U.S., and immigrants acquire the U.S. risk after a generation or so. According to some people, if a woman becomes pregnant just after menarche, she is practically immune to breast cancer for the rest of her life.

      Hepatocellular carcinoma is most common where hepatitis B infection is common (the Far East, sub-saharan Africa), regardless of race. In the same region, iron overload and aflatoxin also must contribute.

      Japan has a tremendously high incidence of atrophic gastritis and stomach cancer, as does Chile and many of the poor nations. The reasons are obscure. Japanese who immigrated to the U.S. have the same high rate, while their children have the same low rate as other native-born U.S. citizens.

      The U.S. leads the world in incidence of colon cancer ("because of our low-fiber diet"). Immigrants have increased risk, and their children have the same high rate as other native-born U.S. citizens.

      Japanese men, and men in the poor nations, seldom get prostate cancer. The incidence is somewhat increased in Japanese who move to the U.S. The incidence of prostate cancer is highest in African-Americans (MMWR 41: 401, 1992).

      In parts of China and the southeastern USSR, cancer of the esophagus is the leading killer. This may have to do with nitrosamines and/or something else in the environment Generally, cancer of the esophagus is many times more common in the poor nations than in the developed world. In addition to alcohol and tobacco, risk factors also include super-hot drinks and carcinogen-loaded ethic delicacies.

      Epstein-Barr virus is ubiquitous around the world, but Burkitt's lymphoma is an African disease, and its distribution corresponds to regions where malaria is endemic. Immigrants to Africa are susceptible just as are the native Black peoples.

      Skin cancers, notably melanomas, are commonest in light-skinned people who have heavy sun exposure at low latitudes and/or high altitudes. The author's old home area, East Tennessee (fair-skinned Scotch-Irish people, high altitudes, outdoor work), has an appallingly high rate of skin cancer.

      Cancer of the uterine cervix is supposedly less common where men are circumcised (which interferes some with the growth of HPV); otherwise it has the typical epidemiology of a sexually transmitted disease.

        Cervix cancer kills about 500,000 women per year worldwide; typically young mothers. (A new estimate has the number down to 260,000, but this is still very high: BMJ 336: 751, 2008).

      Choriocarcinoma is most common in the Far East, where molar pregnancies are so common.

      African-American men almost never get cancer of the testis.

      Squamous cell carcinoma is caused by bladder schistosomiasis. This is a terrible problem where the infestation is common, especially in Egypt.

      Under the Romanian tyranny, transitional cell carcinoma of the renal pelvis (a component of Balkan nephropathy) was the major cancer killer. More on this later.

    IT IS HARD TO BELIEVE THAT DIET DOESN'T HAVE SOMETHING TO DO WITH RISKS FOR PARTICULAR CANCERS, and there is plenty of data, but convincing conclusions have been elusive.

      During the past two decades, there has been much less interest than before in the "diet and cancer" business in the developed nations. Update Lancet 360: 861, 2002.

      Despite the mass of conflicting results from past studies, the current work suggests that "the Western diet" just isn't the great cancer risk we've been told. For example, a huge study of from Oxford showed no real differences between carnivores and vegetarians in any major category of fatal disease (Am. J. Clin. Nutr. 78(3S): 533S, 2003).

      There is some interest in carotene as an agent to prevent various squamous cell carcinomas. High levels do seem to correlate with lower risk of breast cancer (yes! Am. J. Clin. Nutr. 79: 857, 2004; no! Am. J. Clin. Nutr. 76: 883, 2002), urothelial cancer (J. Urol. 173: 1502, 2005), etc., etc.; there are also negative studies. Just to add to the confusion, a 2008 study from Florida had findings similar to some earlier studies... supplementing with beta-carotene produced a 25% INCREASE in the rate of lung cancer among current smokers (Cancer 113: 150, 2008). The much touted flavenoid polyphenols fail to affect cancer risk: Am. J. Clin. Nutr. 81(s1): 317-S, 2005.

      One of the "exciting new discoveries" of the 1990's that's still a subject of considerable interest is the finding that isothiocyanates like sulforaphane in broccoli and other brassica vegetables promote apoptosis and thus "help prevent cancer", especially in folks with certain enzyme variants. Update Cancer Caus. Control 15: 977, 2004.

      Obesity does seem to increase the risk of esophageal, colorectal, breast, endometrial, and kidney cancers. Alcohol abuse is well-known to increase the risk for mouth, throat, laryngeal, and esophageal cancer and (to a lesser extent) liver cancer (Lancet 360: 861, 2002).

      Later on, I'll talk some about the sub-science and politics behind Corporate America's / Uncle Sam's ever-changing directives on how to eat right. "Based on current epidemiologic knowledge, public health recommendations to decreased total fat intake for the prevention of cancer appear largely unwarranted" (Am. J. Med. 133 S9B: 63S, 2002). Any additional claims you hear about diet and cancer are much more dubious, and since people have been looking at this intensively for decades, I can't recommend getting overly concerned about "red meat", "fiber", "vitamins", and so forth.


    Some benign tumors cause serious problems because of their location (one unfortunate expression is "malignant by location"). These include:

    • pituitary adenomas crushing the normal pituitary and optic nerves
    • craniopharyngiomas destroying the hypothalamus
    • atrial myxoma blocking the flow of blood through the heart
    • meningiomas compressing the brain
    • colloid cysts blocking the flow of cerebrospinal fluid
    • pleomorphic adenoma of the salivary gland encasing the facial nerve

    Other benign tumors cause serious problems by other means. These include:

    • too many tumors (innumerable painful lipomas in "adiposis dolorosa"; innumerable nerve tumors in Von Recklinghausen's; innumerable hamartomas in tuberous sclerosis, etc.)
    • hormone production (some thyroid adenomas, most pituitary adenomas, a few adrenal adenomas, and of course insulinomas, vipomas, glucagonomas, reninomas, others)
    • GI problems (bleeding, obstruction, telescoping, or potassium wasting)
    • large size (100 pound ovarian mucinous cystadenomas, etc.)
    • torsion and infarction (famously, ovarian tumors... why?)


{07562} neglected breast cancer

    These are numerous. Remember that any cancer, unless successfully treated, will eventually kill the patient.

    Many of the effects of cancer result from invasion of normal structures. For example:

      BRAIN DAMAGE AND HERNIATION results from growing tumors (primary, metastatic) inside the brain

      PULMONARY EDEMA results from cancer blocking pulmonary lymphatics (* "pulmonary carcinomatous lymphangiosis" or "lymphatic carcinomatosis")

      BONE FRACTURES result from cancerous destruction of bone

{21118} bone fracture secondary to osteosarcoma

      THROMBOCYTOPENIA, GRANULOCYTOPENIA, and even ANEMIA result from bone marrow replacement by tumor. HEMORRHAGE at many locations results from thrombocytopenia and/or vascular invasion.

{07138} exsanguination, larynx cancer (probably a jugular-esophageal fistula in neck)

      BOWEL OBSTRUCTION is as bad as it sounds and is a common problem with large tumors.

      PLEURAL EFFUSIONS result from cancer growing on the pleural surfaces. They prevent lungs from expanding as they should. PERICARDIAL EFFUSIONS (AJR 194: W489, 2010) are even more vicious, as they compromise blood flow back to the heart. Both types of effusion are quite common.

      ULCERS and FISTULAS (the latter is an abnormal communication between two epithelial surfaces) result from tumor growth.

    Regardless of type, advanced malignant tumors usually cause CACHEXIA, which is a poorly-understood syndrome of weakness, malaise, anorexia, and wasting.

      Nutrient uptake by the cancer, tumor products ("tumor necrosis factor alpha" used to be called "cachectin", and other familiar cytokines make people feel terrible too), the acute phase reaction, and psychological factors causing folks not to eat are all implicated.

      Simply not eating (for whatever reason) is also a life-shortener (review Ca 48: 69, March-April 1998).

    PARANEOPLASTIC SYNDROMES result from (known or presumed) elaboration of substances by the tumor, and occur remote from the tumor. The harder you look for them, the more you will find:

      FEVER is a common presentation for some cancers (mostly Hodgkin's and non-Hodgkin's lymphomas), and many of your "fever of unknown origin" patients -- especially the ones who seem most baffling -- will turn out to have malignant lymphoma.

        Nowadays, it's commonplace to find one cytokine over-produced by cancers that cause fever (for example, interleukins 1-6 or one of the tumor necrosis factors: Case Gastroent. 107: 543, 1994).

      CUSHING'S SYNDROME (too much cortisol, with all that this implies) is common in benign and malignant tumors of the adrenal cortex, and in oat cell carcinoma of the lung and occasionally other apudomas (produces ACTH).

{25669} Cushing's, before and after
{25670} Cushing's
{49426} Cushing's

      MASCULINIZATION (too much male hormone) is common in certain ovarian and adrenal tumors. Obviously, this is easier to spot in a child or woman. FEMINIZATION (estrogen production) means breast development in a child or man, recurrence of uterine bleeding after menopause. It is seen most often with testicular or ovarian tumors.

      LOW SERUM SODIUM caused by hypersecretion of hADH is a major problem in oat cell carcinoma. In cachexia from any cause, the "osmostat may be reset" by protein wasting, and sodium lowered for this reason.

      LOW SERUM POTASSIUM is an infamous effect of villous adenoma of the colon, which overperforms the colon's natural job of removing extra potassium from the body.

      HIGH SERUM CALCIUM can be due to bony metastases from any tumor, or from parathormone-like substances produced by squamous cell carcinoma of the lungs (parathyroid-like hormone) and * HTLV-I induced malignant T-cell lymphoma (nobody knows why). Patients lapse into coma and die.

      * RENAL PHOSPHATE WASTING is caused by the production of a hormone (usually fibroblast growth factor 23) that blocks the renal resorption of phosphate. The result is PARANEOPLASTIC OSTEOMALACIA ("oncogenic osteomalacia"), the demineralization of bone (NEJM 330: 1645, 1996; NEJM 348: 1656 & 1705, 2003; J. Clin. Endo. Metab. 85: 549, 2000). The usual culprit is the "phosphaturic mesenchymal tumor" (Am. J. Surg. Path. 28: 1, 2004, usually benign but can be a sarcoma.) Blood assay of FGF-23 is now available and enables a confident diagnosis of paraneoplastic osteomalacia (J. Clin. Endo. Metab. 89: 3979, 2004).

      LOW SERUM CALCIUM is uncommon as a side-effect of cancer but you need to recognize it, because it is the least-understood component of the dreaded TUMOR LYSIS SYNDROME (high serum potassium, uric acid, and phosphate, low serum calcium) seen especially in chemotherapy of lymphomas and leukemias (updates Mayo Clin. Proc. 77: 722, 2002; Am. J. Med. 116: 546, 2004; plenty more) or in very large tumors that undergo watershed necrosis (Am. J. Med. Sci. 325: 38, 2003). I suspect the cause of the low calcium is precipitation of calcium phosphate in the tissues. Ed on Electrolytes

      HYPOGLYCEMIA can result from insulinomas and rarely from other tumors. It causes obesity, feels terrible, and can kill people.

      CARCINOID SYNDROME (paroxysms of flushing, wheezing, and diarrhea) results from production of serotonin and kinins by certain apudomas.

      ERYTHROCYTOSIS (excessively high red cell mass) is seen whenever a renal cell carcinoma produces excessive erythropoietin. It can cause the blood to become more viscous when the hematocrit rises above around 60%.

      THROMBOCYTOSIS is a poorly-understood, common finding in cancer. Usually the increase in platelets is mild.

      AUTOIMMUNE HEMOLYTIC ANEMIA affects a large percentage of patients with malignant lymphoma.

      HYPERVISCOSITY SYNDROME results from cancers that elaborate IgM. The very thick plasma sludges in the brain and death results.

      PERIPHERAL NEUROPATHY is a very common paraneoplastic syndrome, and when it appears in an adult without an obvious explanation, a search for cancer might be a good idea.

      NERVOUS SYSTEM SYNDROMES may result from metastases, electrolyte disturbances, infections (remember progressive multifocal leukoencephalopathy), or autoimmunity. Several of the latter have turned out to be mediated by antibodies that are directed again tumor antigens but that cross-react with healthy antigens (Clin. Lab. Med. 12: 61, 1992; the ONCONEURAL ANTIGENS).

        * ANTI-YO DISEASE is a paraneoplastic cerebellar degeneration seen with several different cancers (Neurology 55: 713, 2000; others can do the same thing; update Brain 126: 1409, 2003).

        * ANTI-RI DISEASE is opsoclonus secondary to breast cancer or oat-cell lung cancer (Neurology 41(S): 363, 1991; Lancet 341: 21, 1993; Brain 124: 437, 2001).

        * ANTI-RETINA ANTIBODY DISEASE causes blindness in patients with oat-cell lung cancer (NEJM 321: 1589, 1989). One antigen is recoverin (Am. J. Ophth. 126: 230, 1998.)

        * ANTI-HU DISEASE (anti-ANNA1, or anti-neuronal nuclear antibody 1 disease) is family of peripheral neuropathy and/or encephalopathy diseases usually from oat cell lung cancer (Mayo Clin. Proc. 68: 278, 1993; Mayo Clin. Proc. 66: 1209, 1991; Lancet 341: 21, 1993; still the most common cause of limbic encephalopathy Brain 123: 1481, 2000).

        * ANTI-Ma2 DISEASE is a limbic and brainstem encephalopathy of testicular cancer patients (NEJM 340: 1788, 1999).

        * ANTI-Ma1: Brain 122: 27, 1999.

        * ANTI-AMPHYPHYSIN: Stiff person syndrome: Neurology 61: 195, 2003; Ann. Neuro. 55: 286, 2004.

        * ANTI-VGKC: limbic encephalitis Brain 127: 701, 2004.

        SPINAL CORD DISEASE ("myelopathy"; update Arch. Neuro. 67: 298, 2010) is devastating and common. Perhaps 5% of cancer patients will get extradural cord compression; metastases to the cord are also fairly common, and paraneoplastic destrction of cord neurons (Nat. Clin. Pract. Neuro. 4: 284, 2008) is less common but just as horrendous.

        EATON-LAMBERT SYNDROME is a myasthenia-gravis-like NMJ problem seen in many patients with oat-cell lung cancer. Patients make an autoantibody against calcium channels that blocks release of acetylcholine (Science 239: 405, 1988; NEJM 332: 1467, 1995).

      ACANTHOSIS NIGRICANS is an accumulation of black hyperkeratotic papules in the armpits and groin. If it first appears in an adult, suspect adenocarcinoma somewhere.

      * HYPERTRICHOSIS LANUGINOSUM ("dog-faced boy syndrome"): new growth of long, dark, fine hairs on the body, is a rare phenomenon that often heralds cancer (Arch. Int. Med. 149: 273, 1989)

      DERMATOMYOSITIS-POLYMYOSITIS is often a marker of occult cancer.

      SKIN SIGNS include the eruption of multiple seborrheic keratosis ("sign of Leser-Trelat"), sebaceous gland tumors / keratoacanthomas (* "Muir-Torre syndrome"), and the bizarre "erythema gyratum repens", snakelike red lines like Jar Jar Binks's skin.

        * The molecular biology of Leser-Trelat remains mysterious; the Mayo group reaffirms an older idea that it's a response to transforming growth factor alpha produced by the tumor (J. Am. Acad. Derm. 43: 386, 2000).

        * The ability to get Muir-Torre requires a Lynch mutation, i.e., antioncogene deletion syndrome (MSH2; Ann. Int. Med. 90: 119, 539, 1993; Am. J. Surg. 173: 37, 1997).

      CLUBBING OF THE DIGITS ("Hippocratic change"; "hypertrophic osteoarthropathy" when it is extremely severe and involves more joints) commonly results from lung cancer, but is nonspecific (and seen in many non-cancerous diseases, notably those that cause extensive lung damage or right-to-left cardiac shunts).

        Long-mysterious, the cause of clubbing is apparently embolization of megakaryocyte remnants, bypassing the lungs. See Am. J. Card. 86: 1198, 2000.

{16598} clubbing
{46265} clubbing
{12337} clubbing

      VENOUS THROMBOSIS, not just in the legs, is a marker for pancreatic cancer ("Trousseau's other sign") and (less famously but still importantly) for many other cancers (NEJM 349: 109, 2003; JAMA 293: 715, 2005).

      DISSEMINATED INTRAVASCULAR COAGULATION is common in advanced cancer, especially when the blood vessels have been invaded

      MARANTIC ENDOCARDITIS is little fibrin vegetations on the heart valves seen in patients with any wasting disorder, but especially in adenocarcinoma patients and especially when the adenocarcinoma arises in the pancreas. They are prone to embolize.


      PLUGGING OF THE RENAL TUBULES by immunoglobulin light chains is common in cancer of the plasma cells.

      GLOMERULAR PROTEIN LEAKAGE ("the nephrotic syndrome") is a troublesome remote effect of various cancers.

      * PARANEOPLASTIC PEMPHIGUS: autoantibodies against the desmosomes in the epidermis cause blistering and loss: NEJM 323: 1729, 1990.

      * BOWEN'S DISEASE OF THE SKIN: a carcinoma-in-situ once thought to herald internal malignancy, probably doesn't (JAMA 266: 842, 1991).

    What causes cancer pain?

      INVASION OF BONE, CAUSING MICROFRACTURES is probably the most common mechanism of cancer pain.

      OBSTRUCTION OF A HOLLOW ORGAN (ureter, gut) causes colicky pain, and is usually worth treating even when the cancer is advanced.

      INFILTRATION OF NERVE PLEXUSES is less common, and the most familiar example is pancreatic cancer invading the celiac plexus. (* This isn't simply a mechanical process; perineural invasion is now known to be a complex interaction between cancer and nerve: Gastroent. 107: 219, 1994).

      AFTER SURGERY: Post-surgical analgesia is often still inadequate; surgeons are lawyer-shy (Lancet 341: 27, 1993).

      PSYCHOLOGICAL DISTRESS has various causes you will not want to overlook.

        Even nowadays, cancer patients are still neglected by physicians, family, and friends. The reasons are complex. In my experience, most cancer patients want to be touched.

        Some (most?) cancer patients and their families think the disease is contagious. (When I was caring for cancer patients, I made it a point to tell them it was not. This seemed to surprise most of them.)

        Some cancer patients have other attitudes that most of us would consider superstitious. The best way to deal with all of these is frank discussion -- raise the subject if necessary.

        Wrong-headed as it seems to most of us today, in the early part of the 20th century (up through the 1960's or thereabouts), it was not just routine to lie to cancer patients about their diagnosis -- it was considered the ethical thing to do. Today, you cannot conceal the diagnosis of cancer from the patient (JAMA 266: 2550, 1991, and probably we never really could).

        You said it yourself, Big Daddy, mendacity is a system we live in.

            -- Brick Pollitt, in "Cat on a Hot Tin Roof"

        In the U.S. and around the world, "opiophobic" laws designed "to help control drug addiction" (they don't) make it very difficult to provide adequate morphine for the terminal cancer patient. This was already old news years ago: Lancet 341: 1061 & 1075, 1993. Thankfully, education of physicians (including those on state licensure boards) is helping the problem, and increased use of opiates is helping people die with greater comfort and dignity, without evident harm to them or to society (JAMA 283: 1710, 2000.) Nowadays pharmacies in predominantly nonwhite (their term) neighborhoods in the US usually do not stock opiates (NEJM 342: 1023, 2000).

        Despite all the talk about "autonomy and accurate informed consent are the cornerstones of US medical ethics", there's still plenty of oncologists pushing their chemotherapy without being fully honest with their patients. Others are great about getting the palliative-care folks involved early. Even the JAMA (299: 2667, 2008), which is not noted for doctor-bashing, is straight-up about this.

        Survivors have their own special problems, including difficulty getting or keeping jobs (Ann. Int. Med. 111: 517, 1989).

        As a result of radiation or chemotherapy, the risk of second primaries may be increased. For children cured of leukemia, the risk seems to progress linearly over time, with 12% at 30 years (JAMA 297: 1257, 2007.)

        The scientific community is also coming to recognize that chemotherapy often causes brain damage (often subtle, but sometimes sudden and horrorific appearing months after the cessation of chemotherapy). Stem cell transplant recipients usually return to normal cognition (Cancer 110: 1560, 2007), but the whole subject is very complicated and hard to study. Update see JAMA 299: 2494, 2008; Lancet 374: 1639, 2009.

      Managing cancer pain: Lancet 353: 1695, 1999. This is highly political in the U.S. and elsewhere because of Kafkaesque bureaucracies.

        The inadequacy of pain management among outpatients: NEJM 330: 592, 1994 (ECOG study, horrifying). Update on how inadequate things still are in the US: Hosp. Pract. 35: 101, April 15, 2000. Managing cancer pain in France: Br. Med. J. 310: 1034, 1995 (French physicians exhibit stoical indifference to their patients' pain.) The government of India had made opiate analgesia very difficult to prescribe or obtain, again because of the "war on drugs" (Lancet 358: 139, 2001). The fact that there are still serious problems in the industrialized nations is showcased by the fact that you still have to do a prospective study to see if a shot of morphine works (Cancer 94: 3049, 2002).

        * Mother Teresa, who rightly received acclaim for getting dying people off the streets of Calcutta, refused to use anything stronger than aspirin even for cancer patients in severe pain (Lancet 344: 807, 1994, others). It can't be that she and her team didn't have the resources. I've ready that her refusal was for philosophical (i.e., ideological) reasons -- does anyone have direct knowledge about this?

        * On the evidence, cancer patients in the Netherlands very much appreciate being allowed to smoke marijuana legally for relief of pain and anorexia (Neurology 64: 917, 2005).

        Cancer pain task force recommendations: Arch. Int. Med. 165: 1574, 2005. Pain control is among the cheapest and easiest of medical interventions, and future generations will look on our policies as barbaric. More on this under "The War on Drugs".

    What finally kills the cancer patient?

      Pneumonia (bacterial lung infection) is the common pathway out of life for many (most?) cancer patients. Part of the problem is NEUTROPENIA (bone marrow replacement by tumor) and/or NON-SPECIFIC IMMUNOSUPPRESSION caused by cancer. Also, tumor in the lung OBSTRUCTS THE AIRWAYS, pleural effusions and just lying in bed cause ATELECTASIS (collapse of alveoli, which get infected easily), cachectic patients are TOO WEAK TO COUGH to keep their airways clean, bedridden patients ASPIRATE FOOD AND VOMITUS, and NARCOTICS SUPPRESS RESPIRATORY DRIVE AND COUGH ("the drugs we gave for pain shortened his life-span"; actually they probably don't: Cancer 86: 871, 1999).

      SEPSIS, especially gram-negative, leading to shock, is also common. There may or may not be an obvious source -- lung, bladder, necrotic tumor, stercoraceous ulcer from constipation (remember that last one), etc.

      HEMORRHAGE (brain, gut, elsewhere) is common in the thrombocytopenic patient (i.e., the patient with bone marrow replacement).

      PULMONARY THROMBOEMBOLI kill many bedridden (and even ambulatory) cancer patients.

      RENAL FAILURE (tumor infiltration, ureteral obstruction)

      Certain PARANEOPLASTIC SYNDROMES (see below) are highly lethal.

      IATROGENIC DISEASE is to be expected in patients receiving surgery, radiation, chemotherapy. Some damage is likely to persist following cure. Major review of iatrogenic disease in cancer survivors: Ann. Int. Med. 111: 411, 1989 (still good). Please remember that platinum chemotherapy is likely to damage your hearing for the rest of your long life (Pediatrics 125: e938, 2010), and that survivors of pediatric cancers have maybe a 28% excess mortality as adults (Ann. Int. Med. 152: 409, 2010).

        People started talking about "economically unjustifiable cancer therapy": J. Roy. Soc. Med. 83: 25, 1990; JAMA 269: 837, 1993 as managed care loomed. Now third-party payers are simply refusing to pay for costly, horrible treatments that might prolong life -- though this is still what many people demand. The situation will keep changing.

        US oncologists have long been criticized for continuing chemotherapy in very sick people when it is obviously not working (big meeting Br. Med. J. 322: 1267, 2001). You'll need to decide how much of this is merely the result of the common demand to "do everything possible."

      Cancer filling the pleural spaces kills by preventing the lungs from expanding. Cancer filling the pericardial cavity interferes with filling and expansion of the heart. Obstruction of the biliary tree invites bacterial infection of the liver.

      SUICIDE and ACTIVE EUTHANASIA account for an unknown percentage of deaths in cancer patients (Lancet 335: 718, 1990).

        By the time you are in practice, active euthanasia will almost certainly be lawful under some circumstances throughout most or all of the U.S. Federal appeals judge Stephen Reinhardt said it's not the government's business to interfere with it; the British Medical Journal (not a bunch of radicals) called Jack Kevorikain a "hero" (Br. Med. J. 312: 1431, 1996), and so forth.

        Today, putting someone who is near death and in severe pain under heavy sedation ("SFTID -- sedation for the imminently dying") is "controversial" (slippery slope to active euthanasia). I can't see why, and neither could the vast majority of neurologists polled in 2010 (Neurology 74: 1303, 2010).

        Before euthanizing a cancer patient, please recall that almost all cancer pain can be controlled adequately if you know how (and are allowed to do so by whoever is writing the laws). Strangely, the subject of pain control often gets overlooked in a young physician's training, and crazy thinking is still commonplace ("I won't increase her morphine because she will die addicted", etc.)

      For a review of the most important molecular players ("the molecular basis of death due to malignancy") in wasting, thrombosis, "total body failure" and so forth, see CA 57: 225, 2010.

TUMOR MARKERS (nice review: Am. Fam. Phys. 68: 1075, 2003)

    Substances produced by cancer cells, which when elevated in the serum assist in the diagnosis of cancer. Worth learning now:

      Ig Light chains: Plasma cell myeloma, other B-cell tumors

        Good to know: In a proliferation of B-cells or plasma cells, if all express the same light chain (i.e., there's not a mix of kappa-makers and lambda-makers), it's proof of clonality and therefore neoplasia. Be sure you understand.

      Carcinoembryonic antigen (CEA): Various carcinomas (mostly adenocarcinomas and high-grade transitional cell carcinomas; most often this is used to detect recurrence of colon cancer)

      Alpha-fetoprotein (AFP): Hepatocellular carcinoma, embryonal cell carcinoma of testis / ovary

      hCG: Placental and certain testicular carcinomas; it is also the mainstay of monitoring benign gestational trophoblastic disease

      Calcitonin: Medullary carcinoma of the thyroid

      Prostate specific antigen: Prostate cancer (review Mayo Clin. Proc. 69: 69, 1994; more about this under "Lab Testing"!) This is the only tumor marker that is has come into widespread use for population screening. Whether it saves enough lives to be worth it is still very much in question. Stay tuned as the recommendations seem to be changing.

      CA15-3: various carcinomas, usually run as part of a panel with some other more obscure tumor markers

      CA-125: Ovary cancer

      CA-19-9: Stomach, colon, pancreas cancer; elevation suggests malignancy especially in a questionable pancreatic mass

      Note that carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP) are "oncofetal antigens" -- they are major proteins that the body stops making around the time of birth.


      Certain well-known cancers usually seem to arise within a pre-existing, slow-growing tumor. This is entirely in keeping with what we have already learned about the nature and development of cancers.

        GLIOBLASTOMA MULTIFORME arises from low-grade astrocytomas.

        COLON CANCER usually arises from a benign colonic polyp.

        POORLY-DIFFERENTIATED GRANULOCYTIC LEUKEMIA is the typical fatal event in well-differentiated granulocytic leukemia ("chronic myelogenous leukemia"). This is the infamous "blast crisis".

        AGGRESSIVE LEUKEMIA/LYMPHOMA supervening on that most indolent of systemic cancers, chronic lymphocytic leukemia, is the infamous "Richter's syndrome". And aggressive lymphomas often arise from low-grade, indolent, follicular B-cell lymphomas.

        PLASMA CELL MYELOMA ("multiple myeloma") often arises in the setting of longstanding "benign monoclonal gammopathy" ("monoclonal gammopathy of uncertain significance"). The latter is a quasi-benign clonal plasma-cell proliferation.

        ANAPLASTIC CARCINOMA OF THE THYROID GLAND arises from papillary or follicular thyroid cancer (update Cancer 103: 2261, 2005).

        YOLK-SAC CANCER often arises in a benign teratoma (especially the familiar sacrococcygeal teratomas of newborns).


      Some cancers have strong or weak hereditary tendencies.

        For example, the ability to get adenocarcinoma of the colon easily is an autosomal dominant trait (NEJM 319: 533, 1988; NEJM 322: 904, 1990) at several loci. These include weak alleles of the syndromes below.

        Hereditary pancreatic cancer is usually caused by mutated trypsinogen, which causes the pancreas to auto-digest and regenerate continually. It's one of the few cancer syndromes not caused by a mutated proto-oncogene or tumor suppressor gene. Update Gut 58: 97, 2009.

      There are a variety of genetic cancer syndromes that are common enough for you to learn now.

        * Screening for each one will cost "somebody" around $400 (Am. J. Clin. Path. 112(S1): S7-S10, 1999.)

(i.e., you inherited the first mutation in your germline)

  • Familial polyposis coli (colon polyps and cancer; locus APC)

    Familial colonic polyposis
    WebPath Photo

  • Gardner's syndrome (colon cancers, bone cancers, epidermoid cysts; same locus as familial polyposis coli, with a different mutation: Lancet 338: 1363, 1991)
  • * CDH1/cadherin (diffuse stomach cancer and lobular breast cancer: JAMA 297: 2360, 2007; they're best to have their stomachs removed prophylactically Cancer 112: 2655, 2008)
  • Multiple endocrine neoplasia syndromes:
    • Type I: pituitary, parathyroids, pancreatic islets (MEN-I "menin": update J. Clin. Endo. Metab. 88: 3845, 2003)

      Type II: parathyroids, medullary thyroid CA, pheochromocytoma (RET)

      Type IIb: like II, but parathyroid involvement is less common, and ganglioneuromas stud the GI tract (RET; different allele)

  • Peutz-Jeghers (small and large bowel polyps, mostly benign, spots on lips; overall cancer risk is much increased at many sites (Gastroent. 119: 1447, 2000); gene STK11/LKB1 identified as a novel serine kinase (Nat. Gen. 18: 38, 1998), now classed as an anti-oncogene (J. Clin. Path. 54: 126, 2001; Am. J. Path. 159: 2017, 2001).
  • Retinoblastoma (locus Rb, see above)
  • Von Hippel-Lindau syndrome (pheochromocytoma, renal cell carcinoma, cerebellar hemangioblastoma, retinal angiomas, * pancreatic cysts and islet cell adenomas, * epididymal cystadenomas) (review Medicine 76: 381, 1997, including how the gene works, also Mayo Clin. Proc. 75: 265, 2000).
  • Tuberous sclerosis (mostly benign tumors / hamartomas).
  • Von Recklinghausen's neurofibromatosis (nerve tumors, pheochromocytoma)
  • Li-Fraumeni syndrome (cancer-family syndrome, breast cancer and sarcomas). The mutation is in tumor-suppressor gene p53. Making the link: Science 250: 1233, 1990; Lancet 338: 1490, 1991. Suspect a p53 mutation whenever a young person has developed two different cancers (NEJM 326: 1039, 1992); multi-family studies Am. J. Path. 150: 1, 1997.
    • * Li-Fraumeni with hCHK2 mutated: Science 286: 2433, 1999.

  • Breast-and-ovary cancer family (BRCA1 tumor-suppressor gene deletion of * 17q; 60% of have one or the other by age 50): Very common, big news. Lancet 341: 1060, 1993; Am. J. Hum. Genet. 51(4): issue, April 1993. BRCA-2: Nature 378: 762 & 789, 1995. It's also common; alleles Nature Genetics 15: 103, 1997.

      * These are the ones that Mr. Rifkin and Mss. Abzug, Steinham and Frieden campaigned against screening for entirely in 1996. This prompted the Clinton administration's successful effort to get the presence of these tumor-suppressor gene deletions removed as "pre-exists" for insurance -- destroying these extremists' case.

      A woman with BRCA1 or BRCA2 has an 85% lifetime risk of getting a breast cancer (vs. 4% for other women). BRCA1 also gives a 40% lifetime risk for ovarian cancer (1% for other women), and increases the colon and prostate cancer risks as well. Reportedly it does not increase a man's breast cancer risk.

      Despite earlier reports, BRCA2 gives a 25% or so lifetime risk for ovarian cancer; it also gives a man a few percent risk for breast cancer (Cancer 86: 821, 1999).

      Removing the ovaries prophylactically seems like a good idea, and is quite acceptable nowadays: NEJM 346: 1609, 2002.

  • HPC1/RNASEL is a familial prostate cancer locus (JAMA 278: 1251, 1997; Nature Genetics 30: 181, 2002)
  • Lynch's familial non-polyposis colon cancer: Science May 7, 1993; several different genes cloned Nature 366: 722, 1994 (1 person in 200; excess colon, ovary, uterus, and kidney cancer, problem repairing DNA mismatches; * this gene family goes back to prokaryotes)
    • * Turcot's (colon polyps, brain tumors) usually arises from a Lynch locus (NEJM 332: 839, 1995; Ann. Med. 36: 379, 2004).

  • * Tylosis: thick keratin on palms and soles, esophageal cancer. Gene TOC ("tylosis / oesophageal cancer") Gastrotent. 114: 1206, 1998; thankfully rare
  • Familial melanoma / dysplastic nevus syndrome (* several purported loci are still questionable Clin. Exp. Derm. 30: 68, 2005, most people have normal CDKN2A and RAF, and I expect at least one major gene remains undiscovered; pheomelanin itself, which abounds in dysplastic nevi, generates free radicals instead of protecting from sunlight)
  • * CDKN2 and P16-1NK4 (CDKN2A / CDK4) are for pancreatic cancer and melanoma NEJM 333: 940 & 975, 1995; Proc. Nat. Acad. Sci. 94: 669, 1997; NEJM 338: 879, 1998. Cyclin inhibitors; keeps cells from turning off their growth cycle when they should.
  • * Cowden's (hamartomas, odd cancers; Cancer 70: 869, 1992; Am. J. Clin. Path. 97: 705, 1992); the gene PTEN turns out to be a Proteus locus (Am. J. Med. Genet. 70: 829, 2002)
  • * Hereditary Multiple Exostoses: cartilage cap things (like little bonus condyles); genes EXT1, EXT2, and EXTL are now characterized: Genome Res. 7: 359, 1997, others.
  • * Carney complex (atrial myxomas, lentigos, calcified sertoliomas, others; gene is often but not always PRKAR1A, J. Clin. Endo. Metab. 86: 4041, 2001.)
  • * LEOPARD syndrome (lentigos, eyes far apart, pulmonic stenosis, nerve deafness, more)
  • * Familial cylindromas (the infamous "turban tumors", named CYLD; Nature Genetics 25: 160, 2000; the actual spectrum of the illnesses is quite broad and this does not represent different alleles: J. Inv. Derm. 142: 919, 2005)
  • * Familial diffuse gastric adenocarcinoma and (?) breast cancer (E-cadherin; Cancer 94: 1443, 2002; NEJM 344: 1904, 2001)
  • * Familial paragangliomas/pheochromocytomas map to the succinate dehydrogenase genes (!): J. Clin. Endo. Metab. 86: 2890, 2001
  • * Juvenile polyposis coli (a minority are caused by mutated SMAD4/DPC4; Hum. Gen. 7: 1907, 1998; Bioch. Bioph. Res. Com. 306: 799, 2003)
  • * Rhabdoid tumor syndrome (hSNF5/INI1): JNCI 92: 648, 2000.
  • * Gorlin's basal cell nevus syndrome (on 9q, homologous to the drosophila "patched" gene PTCH Science 272: 1668, 1996; Am. J. Med. Genet. 73: 304, 1997; Cancer 85: 2662, 1999; Gorlin mouse Nat. Med. 4: 559 & 619, 1998; NEJM 358: 393, 2008.) It's now considered a "must know" for primary care physicians: Am. Fam. Phys. 65: 2501, 2002 (nice photos).
  • * Familial papillary renal cell carcinomas (mutated MET, the hepatocyte growth factor receptor gene, a tyrosine kinase; Int. J. Cancer 82: 640, 1999; Nat. Genet. 20: 66, 1998)
  • * PALB2, which makes a protein that binds to BRCA2's product, produces familial pancreatic and breast cancer (Science 324: 217, 2009).
  • NOTE: Most of these are still tumor-suppressor gene deletion syndromes ("hereditary preneoplasia"); there are only a few known activated oncogenes (MEN-II/RET, MET, kit, a few others) that are not lethal to the embryo.

(i.e., your genes tend to mutate more)

  • Ataxia-telagiectasia (see below)
  • Fanconi's anemia (pancytopenia, multiple birth defects, white cell tumors, other cancers; chromosomes easily broken when stressed in the lab.

      The syndrome can result from defective gene pairs at any of at least 11 different loci (Cancer 97: 425, 2003; Nat. Genet. 35: 165, 2003). The best-known was discovered in 2002 to be another allele of BRCA2 (Science 297: 606, 2002; Science 302: 591, 2003; Blood 103: 3226, 2004). Simple screening: Blood 100: 4649, 2002.

      * Telomere shortening seems to explain the aplastic anemia: Blood 91: 3582, 1998.

      Fanconi review Cancer 97: 425, 2003.

  • Bloom's syndrome (carcinomas, leukemias; * subtotal DNA helicase (BLM) deficiency
  • * Rothmond-Thomson, another DNA-helicase deficiency RECQL4
  • Xeroderma pigmentosum (skin cancers -- cannot repair DNA; genes Nature 350: 190, 1991; Nature 359: 70, 1992; update Neurology 55: 1442, 2000; there are at least seven different loci)
  • Werner's syndrome (sarcomas; this is a supposed "accelerated aging" syndrome, gene WRN; more later)
  • NOTE: A-T, Fanconi's, and Bloom's are fragile-chromosome syndromes (* radiation therapists take note!).


    VON RECKLINGHAUSEN'S NEUROFIBROMATOSIS is covered in "Big Robbins" under genetic disorders.

      This is quite a common (1 person in 3000) autosomal dominant trait, with variable expressivity but nearly complete penetrance.

        Type I neurofibromatosis (Mayo Clin. Proc. 73: 1071, 1998; Arch. Neurol. 56: 364, 1999) is caused by loss of an effective tumor-suppressor gene on chromosome * 17 (NF-1, codes for neurofibromin). Several subtypes exist, depending on the allele.

        Type II (in which acoustic neuromas are the worst problem) is caused by loss of a similar gene on chromosome * 22 (NF-2, gene cloned Nature 363: 515, 1993, homologous to proteins that link cytoskeleton and plasma membrane). Review Lancet 373: 1974, 2009.

          * Don't confuse these with the mucosal neuromas of MEN-IIb/III.

      Patients have nerve tumors anywhere, and pigmented skin lesions ("café au lait", i.e., coffee with milk, spots; look around the armpits; supposedly six big smooth ones clinches the diagnosis).

        Nerve tumors include schwannomas ("neurilemmomas"; especially common on the eighth cranial nerves) and plexiform neurofibromas (tumors that turn the body's nerves into thick, sausage-like structures and that have around a 3% chance of turning malignant, a serious problem when one has lots of them). These are the major life-shortener for the disease (Arch. Path. Lab. Med. 121: 139, 1997).

        The "elephant skin", sometimes seen in these people, is caused by epidermal and dermal hyperplasia overlying neurofibromas.

        Pheochromocytomas are tumors of the adrenal medulla or similar masses of chromaffin, neuron-like tissue.

        * Patients may also have a range of skeletal deformities, "medullary" C-cell carcinoma of the thyroid, pheochromocytoma, neurofibromas/ganglioneuromas often impinge on the renal arteries or cause GI bleeding, more myeloid leukemia in childhood (NEJM 330: 597, 1994. showcases NF-1 as a tumor-suppressor gene), etc.

        * Future geneticists: look for "Lisch nodules" on the iris in type I patients. "Café au lait" spots in neurofibromatosis have smooth borders, while those in Albright's disease have irregular borders. Freckles in the armpits is also typical of neurofibromatosis.

        Often the diagnosis of neurofibromatosis is not obvious at birth. Given time, however, it will declare itself.

        * There is a common mimic, with the cafe au lait spots and sometimes freckles and big head, but none of the nerve tumors at SPRED1 ("Legius neurofibromatosis-1 like syndrome"; JAMA 302: 2111, 2009).

{27883} neurofibromatosis, many neurofibromas
{27886} neurofibromatosis
{37725} neurofibromatosis
{53742} neurofibromatosis, note café au lait spots, elephant skin on right elbow
{53743} neurofibromatosis, elephant skin over large neurofibroma
{13474} neurofibromatosis, armpit freckles
{37735} neurofibromatosis, cauda equina; all nerves seem thickened by neurofibromatous change

Patient photo
Brazilian Medical Students

Patient skin
KU Collection

Patient photo
Brazilian Medical Students

Joseph Merrick * Joseph Merrick, "the elephant man" (the name "John" is propagated error), had Proteus syndrome, not von Recklinghausen's neurofibromatosis (Br. Med. J. 293: 683, 1986). Proteus syndrome is now clearly the result of post-zygotic mutation, as pathologists have thought for decades. It features hemihypertrophy (especially of half the face and the corresponding hand; look at this photo of Mr. Merrick), rib thickening (observed in his skeleton), and various hamartomas. Review JAMA 285: 2240, 2001. More on its being a post-zygotic mutation: Nature 417: 10, 2002, Arch. Derm. 140: 947, 2004; occasionally it's PTEN, the Cowden's locus (Lancet 358: 210, 2001); other times it's not (Am. J. Med. Genet. 130: 123, 2004).

    VON HIPPEL-LINDAU DISEASE is also covered in "Big Robbins" under "genetic disorders".

      The deleted tumor-suppressor gene seems is at 3p25, which is regularly deleted in renal cell carcinomas. The locus is large and complex; it's been isolated (Science 260: 1317, 1993) and named VHL.

      Classically, the classic tumors are retinal hemangiomas and/or cerebellar hemangioblastomas. More familiar tumors are renal adenomas and carcinomas, and pheochromocytomas.

      These patients may have a variety of other curious tumors and cysts.

    TUBEROUS SCLEROSIS ("epiloia", "Bourneville's disease"; now "hereditary multisystem hamartomatosis"): Ann. N.Y. Acad. Sci. 615, 1991 (whole issue); J. Derm 19: 914, 1992; J. Urol. 169: 1635, 2003; Lancet 372: 657, 2008

      A relatively common (maybe 1/6000 people or even more if you look really close) syndrome with multiple tumors (most are really hamartomas) and widely variable penetrance.

        About 2/3 of cases are new mutations.

        Notable "tumors" include:

        • angiofibromas on the maxillary region, nose, and chin (* misnamed "adenoma sebaceum")
        • "candle gutterings" (benign glial nodules on the walls of the cerebral ventricles)
        • "rhabdomyomas" of the heart
        • "angiomyolipomas" of the kidney
        • various brain tumors

        • patches of cerebral cortex that are hard and white ("tubers", or potatoes), with scrambled neurons
        • fibromas under the nails

      Most patients are dull or mentally retarded, and many have seizure disorders.

      Ask a pediatrician to show you a child with ash-leaf depigmented spots on the skin (ultraviolet light makes these stand out).

      Long considered "autosomal dominant with variable penetrance" and a high rate of sporadic cases (i.e., new mutations), the genetics of tuberous sclerosis was finally worked out in the 1990's.

        There are two TS loci, TSC1 and TSC2, with products that work together. The product of the former is hamartin, the product of the latter is tuberin, a GTP-ase (Am. J. Path. 150: 43, 1997; Proc. Nat. Acad. Sci. 95: 15629, 1998); Neurology 53: 1384, 1999. Update on the molecular biology of the tubers: Neurology 74: 1716, 2010.

        * The new drug serolimus targets a pathway involved in tumor formation in tuberous sclerosis, and has found use in treating lymphangiomyomatosis and angiomyolipomas: NEJM 358: 140, 2008).

{11975} "adenoma sebaceum", mild
{37746} "adenoma sebaceum"
{11976} ash-leaf spot
{11977} ash-leaf spot, as seen under ultraviolet "Woods lamp"
{12190} ash-leaf spot
{27946} tuberous sclerosis, brain, showing tubers (like little white potatoes)
{01828} candle gutterings, walls of ventricles
{01830} candle gutterings, walls of ventricles
{01872} candle guttering, histopathology (don't worry about it)

      * THE PHAKOMATOSES is a term for the tumor-suppressor gene deletion syndromes that can affect the brain, i.e., Von Hippel-Lindau, neurofibromatosis, Sturge-Weber (we may suppose), tuberous sclerosis, and Cowden's.

    ATAXIA-TELANGIECTASIA (immunodeficiency, serpiginous blood vessels on the eyes, tumors (outstandingly leukemia and lymphomas), extra tumor risk and radiosensitivity even in heterozygotes)

      This is a hot topic right now. Telomeres shorten too rapidly in these people; in health, the gene Atm allows production of p53 and other "don't divide until we're fixed" gene products following genetic injury. Mouse model Proc. Nat. Acad. Sci. 97: 3336, 2000). Clinical picture and its correlation to the molecular pathology: J. Clin. Path. 58: 1009, 2005.

CANCER QUACKERY (update CA: 54: 110, 2004)

    Fraud is easily recognized by the human warmth it exudes.

          -- Paul Veyne

    A sorry monument to human greed and stupidity (mostly the latter). As a nation, we spend more money on health frauds every year than we do on medical research.

    * The major cancer frauds of the past hundred years:

    • (KNOW:) apricot pits ("Laetrile" -- generated >100 new millionaires). This peaked in the 1970's and was the most massive cancer fraud of all time. Proponents targeted "conservative" conspiracy buffs with fabricated "scientific findings" -- some were book-length, legitimate-looking collections of lies that only someone who knows medicine well would recognize as such. Cancer was supposedly trophoblast that persisted because of deficient chymotrypsin and would respond to "vitamin B17" (laetrile), that contained cyanide that only normal cells could detoxify. The Supreme Court ("Rutherford vs. US") made a landmark decision that the government can indeed protect even the terminally sick against cynical health frauds; the public turned against laetrile only after seeing it fail in their neighbors, and especially in the high-profile deaths of two children. It's illegal but is still around ("Apricots from God", etc.)
    • coffee enemas (several regimens)
    • cryptococcus ("Glover serum")
    • distilled water ("Koch antitoxins")
    • fecal bacteria ("Hett serum")
    • grapes ("Brandt Harmony Healing nature cure")
    • magic box ("Orgone energy" -- collected "cosmic blue bions")
    • magic raw-liver-and-fruit chopper ("Gerson cure")
    • Luigi di Bella cure -- melatonin, vitamins, and so forth in a secret mix. Italian far-right-wing politics. Br. Med. J. 317: 366, 1998 reported that out of his 3000 patients, 1500 never had cancer, and of the ones who did, he had four possible responders, all of whom had received other therapy. The Italian government was forced by public pressure to run a huge study, which showed no effect (Cancer 86: 2143, 1999). All of this strongly recalls the laetrile business in the United States.
    • (KNOW:) mineral oil and creatine ("Krebiozen")
    • mistletoe ("Iscador" -- collection times based on astrology)
    • mucor and rhizopus bread molds ("Mucorhicin")
    • novocaine ("Gerovital")
    • pepsin, cascara, herbs ("Hoxsey cure" -- packaged in the 1930's along with rabid anti-Semitism, today a sweetness-and-love "holistic" therapy available in Mexico)
    • placenta extract ("Bahamas cure" -- Science 241: 1285, 1988)
    • powdered diamonds ("Ayur-Vedic diamond carbon compound")
    • shark cartilage (this one is really cynical; sharks do so get cancer FDA Consumer July-August 2000, p. 7)
    • KNOW: phenylacetic acid and other simple molecules ("antineoplastons"; JAMA 267: 2924, 1992). They were obviously worthless, but for political reasons, the NCI began a study in 1992, culminating in Mayo Clin. Proc. 74: 137, 1999. The stuff had no effect on the cancers and proved capable of causing horrendous brain damage. I have a real ethical problem with our government giving in to "alternative medicine" pressure groups like this. The inventor and some allies in Japan are still publishing (2006).
    • unknown substance ("Greek cure")
    • unknown substance, tooth extractions ("Issels cure")
    • (KNOW:) unknown substances ("Maharishi Ayur-Vedic medicine"; no relation to mainstream Hinduism)
    • Venus fly-trap extract ("Carnivora")
    • warts ground up in sour milk ("Sanders cure")

    • zeolite (the clay used in water softeners -- a multi-level marketing scheme promoted primarily in "social conservative" circles, your lecturer is proud of his persoenal role in discrediting this scam in 2006.)
    • (KNOW:) weird diet to prevent and treat cancer ("Zen macrobiotics"; no relation to real Zen or any other Buddhist school. Its chief proponent in the 1980's, anesthesiologist Anthony J. Sattilaro, died of cancer in 1989. Its chief proponent in the 1990's, Aveline Kushi, died of cancer in 2001.)
    • "Nemenhah Band", a pseudo-Native American anti-medical healing cult founded by ex-con Philip Landis ("Chief Cloudpiler"), who outraged the Nez-Perce Indians by falsely claiming to be the grandson of the great Chief Joseph. You can become a medicine man for $250, with maintenance fee of $100/year plus paying Landis for the "natural medicines". "It's a religion", and the reason behind the unfortunate business of 13 year old Daniel Hauser, whose mom kidnapped and hid him to prevent him from receiving chemotherapy for his Hodgkin's disease.

    In my opinion, after careful review, today's claims that "cancer is caused by negative attitudes, and meditation helps the body fight cancer" are groundless.

      * New Age guru Carl Simonton, M.D., a "Silva Mind Control" buff, based his claim that "negative emotions cause cancer" on his study of his radiation therapy patients. He told his patients they were "responsible for having cancer", but promised each patient a good result if the patient practiced "visualization" to enhance treatment effects. Afterwards, the patients who got good results "had good attitudes", while the treatment failures acted bitter, hurt, and angry. Dr. Simonton and team concluded, therefore, that bitterness, hurt, and anger cause poor responses to treatment. Read Dr. Simonton's own account in "The Holistic Health Handbook", 1977.

      * Simonton's cruel travesty is still the basis for most current pop-culture claims that "a positive mental attitude helps fight cancer", etc., etc. Don't confuse this stuff with honest studies of the mind-body link. These do exist (and generally fail to support New Age "whole person", "you create your own reality" claims). Dr. Simonton's book, "Getting Well Again", contains a grisly account of his asking each new patient, "Why did you want to die? Why did you need to have cancer?"

    One perennial scam is Mexican clinics that offer "the same chemotherapy and immunotherapy as you would get in the States, plus natural healing remedies that both fight the cancer and prevent chemotherapy side effects." In fact the "methotrexate", "interferon", etc., etc., administered here are placebos -- explaining the marvelous lack of side effects!

    * Another disturbing event in recent memory was the planting of a series of false research reports by the Maharishi's people ("transcendental meditation") in refereed medical journals. (Suckers included "Lancet" and "JAMA".) The pattern of deception by this particular group was massive. (Stealing university department stationery was just the beginning....) As one former participant put it, "We thought we weren't doing anything wrong, because we were told it was often necessary to deceive the unenlightened to advance our guru's plan to save the world." See JAMA 266: 1471 & 1749, 1991. Perennial health guru Deepak Chopra was one of the physicians who touted the quack remedies, and submitted a blatantly false statement that he had no financial interest in the stuff (JAMA 265: 2633, 1991 and 266: 798, 1991); when caught, he responded with the usual "persecuted humanitarian / I'm so spiritual" stuff. Deepak Chopra
    Deepak Chopra

    * A popular book called "The China Study" advocates the vegan diet for cancer prevention. Your lecturer examined the author's actual publications, and they simply did not support his claim. Curiously, he also co-authored a paper about the great health benefits of eating fish, which is odd for a vegan. More when we talk about "nutrition".

    Quacks are convincing because they:

    • tell people what they want to hear
    • use the terminology of science (though not its methods, i.e., no quack ever does an honest blind-controlled clinical-equipoise study)
    • quote honest papers out of context, or even present fictitious data referenced to published papers where no such data appears; oddly, this technique, also a mainstay of the classic right-wing and left-wing pseudosciences, violates no U.S. law, and the public will not believe anyone would lie so grossly, especially people who are "spiritual";
    • make many statements that are obviously true (commonplaces of preventive medicine, statements about the limits of conventional cancer therapy)
    • phrase their grandiose, false claims as true statements or rhetorical questions ("If laetrile cures your cancer, you avoid the side-effects of surgery, radiation, and chemotherapy." "It is better to treat the real causes of disease rather than just the symptoms." "You should treat disease early, before it become symptomatic." "Doctors should focus on the whole person, not just treating the disease." "Has the OTHER shoulder started hurting yet?")
    • pretend to love their clients, and share their values (especially "family values", "freedom", "positive wellness", "treat the whole person", "taking part in your own care", "natural healing", "New Age mysticism", various religious faiths, and various right-wing and left-wing political ideologies)
    • claim their remedy is "natural" (how else could substances exert a real physiological effect without ever producing side effects?!)
    • present themselves as reasonable humanitarians, and their critics as ignorant monsters ("Liar!" "Conspiracy!" "Nazi!", "Murderer!", "Genocide!" "You're unspiritual!" etc., etc.; I get subjected to this kind of abuse occasionally)
    • allege that all claims by physicians and scientists (and even "reality itself") are entirely motivated by politics and dogma (the "social causation" model, a far-left New Age / postmodernism spinoff; read Science 255: 613, 1992, then either laugh or cry)
    • peddle paranoia (it can be highly profitable to tell the public that there is a "huge conspiracy" against them, that familiar things are deadly, etc., etc.) and ridicule the hated "medical establishment"

    The cancer quack cannot lose. Whenever a patient

    • seems to get well: "We cured you"
    • seems to improve: "We helped you"
    • seems to stay the same: "We stabilized you"
    • dies: "If only you had come here sooner / hadn't gone to the greedy, wicked AMA physicians / hadn't eaten those Twinkies"

    AS A PHYSICIAN, YOU ARE BETRAYING THE PUBLIC'S TRUST IF YOU "KEEP AN OPEN MIND" OR "RESPECT THE VIEWS OF OTHERS" WHEN THE DISTINCTION BETWEEN TRUTH AND LIES IS SO OBVIOUS. There are many things in life about which reasonable people can reach different conclusions. This isn't one of them. If you possess basic integrity and choose to become involved with these people, you will be bitterly disappointed. If you are already a scientific physician and you try to "dialogue" or "reason" with these people, they will smear you. Don't play their game. You can't win, and you don't want to be the target of a letter-writing campaign to the licensure board or the university president's office. Yes, this happens -- their attorneys even instruct them in how to harrass honest physicians and scientists (NEJM 336: 1176, 1997.) It is of no consequence whatever if some quacks are "sincere". (Some are cynical criminals. Others are decent, altruistic, scientifically-illiterate people who are misguided. Suspect a pathological grief reaction when a scientifically-trained person becomes the staunch advocate of a bunko campaign -- Linus Pauling, the krebiozen testimonials).

    The best response that you, as an ethical medical student, can make to quackery is to practice honest, informed medicine while making full use the quack's main techniques:

    • take time with your patient, listen carefully, and show a real interest and affection
    • explain the pathologic process and what you are doing
    • let the patient take as active a role as possible in his or her health care
    • tell the truth but give hope (thoughtful article Cancer 113: 442, 2008)
    • try to be kind to everybody, even when this is most difficult.

    You can find a guide to NON-QUACK COMPLEMENTARY CANCER MEDICINE -- such things as diet, massage, meditation, acupuncture, aromatherapy, and so forth -- in Curr. Opin. Onc. 9: 327, 1997; CA 49(6): 362, 1999; and Med. J. Aust. 174: 88, 2001 ("Our knowledge regarding the potential benefit and harm of complementary and alternative medicine is insufficient.") Less friendly: West. J. Med. 163: 463, 1995. The similarities to, and differences from, what's listed above are obvious. Note that unlike quacks, decent complementary practitioners talk about helping rather than curing, and do not offer radical new ideas about the body or cosmos.

SLICE OF LIFE REVIEW: In response to student requests, I have chosen a grab-bag of "normal" pictures of material from the Year I curriculum content for some of the upcoming units. This will appear at the end. For each unit, the order is by picture number. As per my "make 'em think, 'cause they have too much to read already" policy, no long explanations will be provided. Viewing this is STRICTLY OPTIONAL.

{03680} mediastinum, normal
{06227} pulmonary arteries, normal
{09130} cilia, normal
{09131} cilia, abnormal
{13424} karyotype, normal
{13425} karyotype, normal
{13426} karyotype, normal
{14270} immunoelectrophoresis, normal
{14536} umbilical cord, normal, trichrome stain
{14541} loose connective tissue, normal
{14545} loose connective tissue, normal
{14546} loose connective tissue, normal
{14565} tendon, normal
{14687} capillary, normal
{14688} arteriole-venule, normal
{14689} arteriole-venule, normal
{14690} capillary (or venule), normal
{14691} capillary (or venule), normal
{14902} olfactory epithelium, normal
{14941} transitional epithelium, normal
{14952} microtubles, cell biology
{14954} microtubles microfilaments, cell biology
{14960} cytoskeleton membrane interactions, cell biology
{15115} adipose tissue, normal
{15116} connective tissue, loose
{15117} mast cell in loose connective tissue, #3
{15118} fibroblast, in loose connective tissue
{15402} desmosome
{15926} nerve, normal
{16497} mesothelial cells, normal
{16499} mesothelial cells, normal
{17336} neutrophilic wbc, normal em
{20234} ecg, normal
{20255} chest, normal x-ray
{20621} CT, normal CT
{20622} CT, normal CT
{20623} CT, normal CT
{20624} CT, normal CT
{20625} CT, normal CT
{20626} CT, normal CT
{20627} CT, normal CT
{20628} CT, normal CT
{20629} CT, normal CT
{20630} CT, normal CT
{20631} CT, normal CT
{20632} CT, normal CT
{20633} CT, normal CT
{20634} CT, normal CT
{20635} CT, normal CT
{20636} CT, normal CT
{20637} CT, normal CT
{20638} CT, normal CT
{20639} CT, normal CT
{20640} CT, normal CT
{20641} CT, normal CT
{20642} CT, normal CT
{20643} CT, normal CT
{20644} CT, normal CT
{20645} CT, normal CT
{20646} CT, normal CT
{20647} CT, normal CT
{20648} CT, normal CT
{20649} CT, normal CT
{20650} CT, normal CT for orientation
{20717} epithelium, stratified squamous
{20718} epithelium, stratified squamous
{20719} epithelium, transitional
{20720} epithelium, pseudostratified
{20721} epithelium, simple columnar
{20730} adipose tissue, normal
{20730} adipose tissue, normal
{20731} adipose tissue, arrow on nucleus
{20732} connective tissue, loose
{20733} mast cell, connective tissue
{20734} fibroblast, connective tissue
{20735} connective tissue, dense
{20736} connective tissue, dense
{20772} nerve, peripheral
{20773} nerve, peripheral
{20776} nerve, perineurium
{20777} nerve, longitudinal section
{20778} basophil
{20779} lymphocyte, small
{20780} red blood cell, erythrocyte
{20781} lymphocyte, large
{20782} polymorphonuclear leukocyte, normal
{20783} monocyte
{20784} platelets
{20792} epithelium, stratified squamous
{22910} capillary, normal
{24630} joint, normal
{25798} urothelium, normal
{25800} basophilic cytoplasm, urothelium - normal
{26078} urothelial cells, normal
{29914} spine, normal - cryosection
{29915} spine, normal
{29916} spine, normal - cryosection
{29917} spine, normal
{29918} spine, normal - cryosection
{29919} spine, normal
{29920} spine, normal - cryosection
{29921} spine, normal
{29922} spine, normal - cryosection
{29923} spine, normal
{29924} spine, normal - cryosection
{29925} spine, normal
{29926} spine, normal
{29927} spine, normal
{29928} spine, normal
{29929} spine, normal
{29930} spine, normal
{29931} spine, normal
{29932} spine, normal cryosection
{29933} spine, normal
{29934} spine, normal
{29935} spine, normal
{29936} spine, normal cryosection
{29937} spine, normal
{29938} spine, normal
{29939} spine, normal
{29940} spine, normal
{29941} spine, normal
{29942} spine, normal
{29943} spine, normal
{41522} glycogen stores, normal and depleted
{46429} plasma cell, normal
{46431} secretory granules, normal
{46432} nucleolus, normal
{46433} mitosis, normal
{46436} mitochondria, normal
{46437} mitochondria and rough ER, normal
{46550} karyotype, normal

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Teaching Pathology

Pathological Chess

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7:26 min