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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 scalpel_blade@yahoo.com Your confidentiality is completely respected. No texting or chat messages, please. Ordinary e-mails are welcome.
I am active in HealthTap, which provides free medical guidance from your cell phone. There is also a fee site at www.afraidtoask.com.
If you have a Second Life account, please visit my teammates and me at the Medical Examiner's office. |
With one of four large boxes of "Pathguy" replies. |
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.
I am presently adding clickable links to images in these notes. Let me know about good online sources in addition to these:
Public Database of Human Cancers -- World Health Organization
Stanford Surgical Pathology Criteria -- probably the best resource for the practicing surgical pathologist in an increasingly difficult specialty
Medscape Pathology -- mostly clinical medicine, the best "daily news" of the medical world
Pathology Resident Wiki
Human Pathlogy -- growing resource
Surgical Pathology Atlas -- lots of photos
Pathology Education Instructional Resource -- U. of Alabama; includes a digital library
Pathopic -- Swiss site; great resource for the truly hard-core
Alabama's Interactive Pathology Lab
Chilean Image Bank -- General Pathology -- en Español
Chilean Image Bank -- Systemic Pathology -- en Español
Connecticut
Virtual Pathology Museum
Australian
Interactive Pathology Museum
Loyola
Dermatology
History of Medicine -- National Library of Medicine
KU
Pathology Home
Page -- friends of mine
The Medical Algorithms Project -- not so much pathology, but worth a visit
Telmeds -- brilliant site by the medical students of Panama (Spanish language)
U of
Iowa Dermatology Images
U Wash
Cytogenetics Image Gallery
Urbana
Atlas of Pathology -- great site
Visible
Human Project at NLM
Karolinska Institutet -- pathology links
Johns Hopkins CPC's
Oklahoma Teaching Cases
Indiana U. Teaching Cases
SUNY Histopathology
West Virginia Case of the Month
Society for ultrastructural pathology -- electron microscope cases
PathologyPics -- where pathologists share favorite images. Thanks!
WebPath:
Internet Pathology
Laboratory -- great site
pathology.org -- my cyberfriends, great for current news and browsing for the general public
EnjoyPath -- a great resource for everyone, from beginning medical students to pathologists with years of experience
Medmark Pathology -- massive listing of pathology sites
Estimating the Time of Death -- computer program right on a webpage
Pathology Field Guide -- recognizing anatomic lesions, no pictures
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:
My home page
More of my notes
My medical students
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 eighteen 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 William Carey 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 William Carey for making it still 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!
BIBLIOGRAPHY / FURTHER READING
I urge anyone interested in learning more about cancer pathology to consult these standard textbooks.
In my notes, the most helpful current journal references are embedded in the text. Students using these during lecture strongly prefer this. And because the site is constantly being updated, numbered endnotes would be unmanageable. What's available online, and for whom, is always changing. Most public libraries will be happy to help you get an article that you need. Good luck on your own searches, and again, if there is any way in which I can help you, please contact me at scalpel_blade@yahoo.com. No texting or chat messages, please. Ordinary e-mails are welcome. Health and friendship!
Define the following terms and use them appropriately:
activation (of oncogene)
activation (of carcinogen)
Ames test
amplification
carcinogenesis
chromosomal instability
clonal selection
complete carcinogen
fusion gene
growth fraction
immortalization
immune surveillance
inducer (genotoxic carcinogen)
Knudson two-hit model
labeling index / proliferative index
microsatellite instability
(mono)clonality
oncogene
procarcinogen
promoter (non-genotoxic carcinogen)
proto-oncogene
retrovirus
transduction
transformation
tumor progression
tumor marker
ultimate carcinogen
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.
KCUMB Students
"Big Robbins" -- Neoplasia
Lectures follow Textbook
QUIZBANK
Cell growth #'s 1-21, 31-147
Neoplasia
|
Growth Disturbances / Neoplasia
|
LEARN FIRST
If you have gotten this far, you should already know how to recognize benign and malignant tumors grossly and microscopically. Please ask for help if this is still a problem.
Tumors are overgrowths, clones within clones, of cells bearing cumulative genetic injuries, each of which confers growth advantages over the neighbors ("NOWELL'S LAW" is my term). Tumor cells typically have failure of division control, failure of senescence ("immortalization"), and failure of proper apoptosis (cell suicide). At least some of these have already gone bad in the seemingly-normal cells from which tumors arise.
Among the many hundreds of known kinds of tumors evidently, many have patterns of genetic injury that are distinctive for that particular tumor type. Risk factors are known for various kinds of genetic injury, and various kinds of cancer.
Oncogenes are slightly altered (ACTIVATED) versions of normal genes involved in cell division (proto-oncogenes). Activation may occur by point mutation, translocation, or increased copy number (amplification). Oncogenes tell the cell to divide when it shouldn't. This message overrides normal instructions from the gene's normal counterpart.
Tumor suppressor genes (anti-oncogenes) are normal genes that tell cells when NOT to divide. Usually the neoplastic phenotype is expressed only when BOTH copies are damaged or missing.
The Knudson two-hit model explains the tremendously high prevalence of certain tumors in people unfortunate enough to have inherited one defective copy of a tumor suppressor gene.
Viral carcinogenesis is probably important in only a few common human tumors. Viruses cause cancer in humans by (1) binding and inactivating the products of normal tumor-suppressor genes, and/or (2) increasing cell turnover, allowing selection of abnormal clones, and/or (3) scrambling the genome. Cancer of the cervix and hepatocellular carcinoma are the most important cancers caused by known infectious agents.
Truly benign tumors are those in which the genome has not and will probably not become destabilized. In cancers, the genome has become destabilized, and new mutations accumulate over time, making the disease more and more aggressive.
People with cancer do not die of the disease itself, but of secondary effects of the tumor or its treatment.
INTRODUCTION
This will be a whirlwind tour of cancer biology. Don't worry, you will see most of this material again and again.
There is more erroneous information circulating about cancer than about any other disease (even AIDS and mental illness). Some of this is the result of disinformation campaigns by charlatans. Much of this is due to what I hope you know by now: "EPIDEMIOLOGY IS PARTICULARLY PRONE TO THE GENERATION OF FALSE-POSITIVE RESULTS" (J. Nat. Cancer Inst. 100: 988, 2008 -- a great read; one of the most annoying aspects of the practice of pediatrics in particular is that you will be questioned daily about the latest bad study reported in the media Ped. Clin. N.A. 48: 1215, 2001.) And some results from our failure as physicians simply to explain things to our patients.
THE ESSENTIAL "CAUSE OF CANCER", ONCE MYSTERIOUS, IS NOW CLEAR. BOTH BENIGN AND MALIGNANT TUMORS ARE CLONAL OVERGROWTHS OF CELLS BEARING MULTIPLE GENETIC INJURIES. The visible tumor is the result of the overgrowth of clones within clones within clones. This is as well-established as anything in science. We are now simply filling in the details. Cancer is the great acquired genetic disease of humankind. Understand this.
Caring for a cancer patient requires a combination of great knowledge (of cancer biology, of therapeutics, of community resources, of the human heart), total integrity, and real compassion and love. When the time comes, I know you'll all be ready.
Cancers often sit and "smolder" for years -- for example, in forensic autopsies, 7% of bodies had unsuspected cancer, and 3% were dead from undiagnosed cancer (Arch. Path. Lab. Med. 133: 1923, 2009).
For updates on cancer genetics, see Surg. Clin. N.A. 88: 681, 2008; Nat. Med. 10: 849, 2004 and CA 55(1):45-54, Jan.-Feb. 2005. Only in 2008 did Congress finally pass a bill that would prevent health insurance companies from denying coverage or benefits based on your carrying genes that might make you more vulnerable to disease ("The Genetic Information Non-discrimination Act", or GINA... thanks, better late than never all you bipartisans; JAMA 299: 2493, 2008). Nowadays, scientists examine huge numbers of loci to find somewhat increased or decreased risks posed by different alleles at each; for now, simply be aware of this (JAMA 299: 2423, 2008). This information will become more important as individuals start getting extensive routine genetic profiling.
ATTRIBUTES OF CANCER CELLS
CARCINOGENESIS is a generic term for a series of events leading up to expression of full malignant potential. TRANSFORMATION is the term for this process as applied to cells themselves.
Much of the material in "Big Robbins" in loc. is primarily of research interest. Worth remembering:
Tumors are CLONAL OVERGROWTHS, generally monoclonal (G6PD marker studies). By the time a tumor is visible, the changes have been underway for a long time (at least months, usually years). The really bad areas represent CLONES THAT HAVE ARISEN FROM CLONES, bearing cumulative genetic injuries. There is now overwhelming evidence that EACH SUCCESSIVE MUTATION CONFERS AN UNFAIR GROWTH ADVANTAGE ON THE CELL LINE THAT BEARS IT. This is the famous NOWELL MULTI-STEP CLONAL EVOLUTION MODEL OF TUMORIGENESIS, first articulated Science 194: 23, 1976. It should probably now be called "Nowell's Law", and is by your lecturer.
If the tumor results from only a few mutations of large effect (perhaps one for cell division and another to induce a stroma), the genome will probably remain stable ("benign tumor"). Otherwise, the genome will be destabilized, and the cells will eventually acquire new abilities, eventually remembering how to invade and spread.
As a destabilized (i.e., malignant) tumor grows, non-disjunction creates cells with extra chromosomes (the deprived cells, of course, die off), and many (but not all) cancers become aneuploid. Especially the study of colon cancer (one route is "the chromosomal instability pathway") has clarified how this happens.
TUMOR PROGRESSION refers both to the growth and distant spread of cancer, and to the way the front-line cells become more aggressive and more resistant to therapy (i.e., by the emergence, and selection for, nasty subclones; "multiple-steps").
It is fundamentally wrong to think of cancer just as "cells growing more rapidly than other cells". Rather, they are less subject to normal controls, have remembered how to do things they shouldn't be doing now, and are growing faster than they are dying off.
GROWTH FRACTION is the percent of cells making nucleic acid at a given time. The monoclonal antibody Ki-67 stains proliferating cells, and is now standard to determine growth fraction; its use as a prognostic marker is now well-established. Another stain is PCNA (proliferating cell nuclear antigen).
"Increased numbers of mitotic figures seen in cancer" represent (at least in part) mitoses that got stuck because of the cell disorganization. A cancer's mitotic figure can perhaps stick around for weeks.
THE ABILITY TO INVADE AND SPREAD:
Benign tumors, with basically stable genomes, simply expand or perhaps reach a stable size. Malignant tumors, however, eventually gain the ability to invade the surrounding tissues. The mechanisms of invasion and metastasis involve binding to laminin of basement membranes, and destruction of type IV collagen (the early work Cancer 73: 22, 1994, Nature 370: 14, 1994) in basement membrane. Until this can happen, a would-be carcinoma cannot get through a basement membrane. Unfortunately, when a single cell acquires these abilities, it has a tremendous growth advantage over its neighbors, and the tumor will progress accordingly.
Please read, at your convenience, the speculative material about metastasis, vascular homing, and so forth in "Big Robbins". It is likely to be important on your licensure exam and in future therapy. Update Clin. Ortho. 451-S: S19, 2003; more recently Lancet 369: 1742, 2007 (much more than you'll need as a clinician, but useful for guessing tomorrow's experimental treatments.)
* By now, there are dozens more known. If you're very curious, see Lancet 369: 1742, 2007. These are continually being updated, and now we can guess where the tumor will go based on microassay arrays: Nat. Med. 9: 999, 2003. The term "epithelial-mesenchymal transition" refers to the changes in the behavior of carcinoma cells that resemble mesenchyme (less adhesion, more mobility, resistance to anoikis) and their molecular correlates, which are now intensively studied (Am. J. Path. 174: 1588, 2009). A profile panel of 186 invasiveness genes now predicts which breast cancers will almost certainly be cured (NEJM 356: 217, 2007).
* The first report of stromal cells bearing mutations that enhance progression of cancer (breast): NEJM 357: 2543, 2007; JAMA 297: 2103, 2007.
Of course, TELOMERASE is required to allow cancer cells to remain immortal. And so the successful clones in a cancer mutate so as to express telomerase. It's a target for anti-cancer therapy today: Nat. Med. 5: 1164, 1999; Anticancer Res. 20: 4419, 2000.
There are actually two different mechanisms by which telomeres lengthen. In the absence of telomerase, an "alternative lengthening of telomeres" mechanism can produce monstrously long ones. See Am. J. Path. 177: 2694, 2010; J. Clin. Inv. 122: 1962, 2012).
And there's more... BENIGN OR MALIGNANT, A TUMOR MUST BE ABLE TO INDUCE ITS OWN BLOOD SUPPLY. After decades of searching for "the" factor that the neoplastic cells must learn to elaborate, we found VEGF ("vascular endothelial growth factor"; Nature 367: 576, 1994).
* In at least some cancers, VEGF and its receptor stimulate one another's production, allowing for very rapid growth J. Clin. Inv. 123: 1732, 2013.
In questionable cases, production of VEGF confirms that a cancer is actually invading (Am. J. Path. 156: 159, 2000; Am. J. Path. 155: 1967, 1999). VEGF can be blocked (the famous monoclonal antibody bevacizumab "Avastin"), or its receptor blocked, and the growth of some (but by no means all) experimental cancers arrested nicely (the early work PNAS 98: 8829, 1998)
For the ultimate hard-core student, about 100 molecular players are catalogued in CA 57: 225, 2007. If there's a single pattern that's emerging, it's that the cytokines (interluekins 1 and 6, TNF-alpha, TGF-beta, and a few others that are responsible for much of the morbidity and mortality.
* During the 1990's, there was much intrerest in prognosticating cancer progression by the extent of neovascularization (MICROVESSEL DENSITY). Brain Cancer 77: 362, 1996; lung: J. Thor. Card. Surg. 115: 652, 1998; and Ann. Thor. Surg. 61: 470, 1996; cervix Am. J. Ob. Gyn. 178: 314, 1998; larynx Am. J. Surg. 174: 523, 1997; prostate Cancer 78: 345, 1996; stomach Surg. 131(S1): S48, 2002; cartilage tumors Clin. Orth. 397: 76, 2002; almost everyplace Anticancer Res 21(6B): 4373, 2001; other head & neck did not show a correlation Arch. Ot. 124: 80, 1998), using Factor VIII antigen (why?) as the marker for the new vessels. This hasn't impacted practice so much as the other markers.
* ANGIOSTATIN, the angiogenesis inhibitor that is a breakdown product of plasminogen, raised the possibility of therapy with the substance and/or the gene (J. Clin. Invest. 101: 1055, 1998; Blood 101: 1857, 2003). This generated much hope, a huge media hype, and then a major disappointment. ENDOSTATIN, a bit of collagen XVIII, is also a potent angiogenesis inhibitor. Again, no great success stories.
Angiostatin and endostatin were discovered as substances that primary tumors produce that inhibit metastases; when primaries are removed surgically, it is relatively common for metastases to bloom luxuriantly.
Despite the disappointing results in humans, both are now being used in animal models and slow the growth of many cancers dramatically -- and so far, resistance has not developed; look for gene therapy to deliver the synthesizers for these substances to the cancer cells themselves. (PNAS 95: 5843, 1998; Canc. Res. 60: 2190, 2000).
Bevacizumab of course eclipsed these substances, though angiostatin and endostatin are still being studied. Antibodies that kill off only the new vessels of tumors (??!) -- Cancer 116: 1859, 2010.
* A variety of other possible targets were identified in the 1990's (Cancer 80(S-12): 2378, 1997). Basic fibroblast growth factor (bFGF) and its receptor (Am. J. Surg. 174: 540, 1997) have not done much yet for cancer, but are used in experimental treatments to healing of non-cancer-related injuries. Also watch mitogen-activated protein kinase (MAPK: Nat. Med. 5: 736, 1999), and the primitive fibronectins laid down in new growths.
Effective metastasis is probably to a site where fibrin has been laid down. The successful cancer cells themselves figure out how to lay fibrin down (Am. J. Pat. 152: 399, 1998), and this too may eventually be targeted by new therapies. The role of platelets: Blood 115: 3427, 2010.
Since the heady days of the late 20th century, interest in the mechanisms of metastasis has waned, especially in the wake of the triumphs of molecular medicine and specific targeted therapies.
ALTERED GROWTH PROPERTIES IN TISSUE CULTURE: "Cancer cells can be characterized as antisocial, fairly autonomous units that appear to be indifferent to the constraints and regulatory signals imposed on normal cells" (Big Robbins). They exhibit:
RELATIVELY UNREGULATED PROLIFERATION -- a feature of cells from both benign and malignant tumors. ("High LABELING INDEX / PROLIFERATIVE INDEX" was the classic measure of the number of cells in S-phase, i.e., those that will label with tritiated thymidine. Today we are more likely to use a marker for "I'm planning to divide", such as MIB-1/Ki-67.).
FAILURE TO MATURE: i.e., they never assume postmitotic forms.
Nobody in pathology was surprised by this -- it's common long after a cancer is cured with radiation or chemotherapy to see anaplastic cells left behind in the scar.
The literature is now filling up with accounts of "killing the CANCER STEM CELLS" (i.e., the ones that are actually capable of division). You'll probably hear the term.
TRANSPLANTABILITY: i.e., they grow easily in culture or syngenic hosts or athymic ("nude") mice.
IMMORTALITY: i.e., the culture won't die out after around fifty generations, like cells from healthy tissues do (i.e., the "Hayflick phenomenon" does not take place because cancer cells can re-grow their telomeres and no longer obey the "do-not-divide" signals even if they are shortened.) The story of the immortal HeLa cells (named for the pseudonymous "Helen Lane", victim of cervical cancer) is fascinating, as is the story of donor.
LOSS OF CONTACT INHIBITION: i.e., cultured cells continue dividing and actually pile up, instead of stopping once they have formed a nice monolayer
* I know a student is faking when my question, "What makes this tumor look malignant?" gets answered: "I can see it has lost contact inhibition."
LOSS OF SERUM AND ANCHORAGE REQUIREMENT: i.e., cancer cells will grow suspended in fluid, and in relatively low concentrations of (presumably growth-factor rich) serum
LOSS OF DENSITY-DEPENDENT GROWTH INHIBITION: i.e., you can grow a lot more of them on just a little medium, presumably because they are less dependent on growth factors, less subject to various inhibitory influences, etc.
RESISTANCE TO ANOIKIS ("death from homelessness"; "live free or die"). Ordinarily, an epithelial cell will undergo apoptosis if deprived of its usual cell-cell interactions (integrins and ligands). This is a big deal right now as the molecular players are discovered: Nature 430: 973 & 1034, 2004; Am. J. Path. 177: 1044, 2012.
MORPHOLOGIC CHANGES ON BIOPSY
These were mostly described in the previous lecture. Very rarely does a tumor that is anatomically "benign" ever metastasize.
KARYOTYPIC CHANGES
Many cancers (as well as benign tumors, even the banal lipoma; Int. J. Cancer 48: 194, 1991) have trademark chromosomal abnormalities (deletions, translocations) that are characteristic for that particular tumor. It seems likely that we will eventually discover one or more such changes ("the genetic fingerprint") for each common cancer.
Ring chromosome 22
Brain tumor also
Pittsburgh Pathology Cases
Good to know (because there is a reason for each):
Microassay microarray technology has made it possible to do elaborate GENE EXPRESSION PROFILING on tumors, examining the levels of expression of thousands of genes at the same time.
ANTIGENIC CHANGES
This is a huge subject of old-time cancer researcn that contributed almost nothing to patient care.
Rules:
1. All tumors evoked by a specific oncogenic retrovirus (in one organ in one species) tend to have the same tumor-specific antigens (Nowell's law; laboratory retroviruses carry extremely potent oncogenes sufficient to transform by themselves).
2. Tumors induced by a specific chemical are all pretty much different antigenically (Nowell's law, the background of other mutations is different in each case).
METABOLIC CHANGES
Another old much-studied subject that ended up showing that "cancer is not other, it is us." Cancer cells do the same biochemical pathways as do normal cells.
* Old ideas about cancer focused on increased aerobic metabolism (Warburg hypothesis), accumulation of polyamines, etc., etc. The fact that cancers tend to do more glycolysis and less oxidative phosphorylation is well-known (proteomics Carcinogenesis 26: 2095, 2005). I suspect it's because cancer cells aren't exactly work-horses and lose interest in doing much oxidative phosphorylation. As tumors progress, some known mutations tend to accumulate in the mitochondria but these merely tend to slow down oxidative phosphorylation (model J. Clin. Inv. 121: 195, 2011). The "persistent trophoblast" business was just a bad guess that was taken up by charlatans. People still look at polyamines, which of course bind to the genes, but there hasn't been anything too interesting.
* CELL SURFACE AND MEMBRANE CHANGES:
Still another historic field that yielded nothing useful. Typical changes include greatly increased lectin agglutinability, loss of such adaptations as microvilli and pseudopods, increased turnover of plasma membrane, and so forth. Go figure -- cells that are mutating and no longer interested in doing things will tend to lose stuff.
NOTE: Despite the "many differences between cancer cells and normal cells", the similarities still predominate. As of this writing, there is still no known antigen unique to any cancer (Nature 369: 357, 1994, still holds). On rotations, you'll see the still-disappointing results of chemotherapy ("drugs that are more toxic to cancer cells than normal cells") for the most common cancers. "Cancer is not 'other', it is 'us'" (to paraphrase Virchow, of course). "To fully understand cancer, we will need to understand all of life."
* One of the most exciting developments in oncology is the discovery that a peptide (HVGGSSV) conjugated to a near-infrared imaging agent distinguishes in days whether a chemotherapy program is working (Nat. Med. 14: 343, 2008).
* mdr-1 (MRP1 / P-gp / P-glycoprotein-1) was the first of several resistance genes for chemotherapy, turned on in many cancer cells. It's a pump that pumps the medicines out of the cells. There is a stain for its presence (i.e., to warn that chemotherapy will probably fail) though its use turned out not to be that helpful (J. Clin. Path. 50: 465, 1997).
NOTE: One apparent problem with Nowell's law as a unified theory for cancer is that CERTAIN CANCERS ARE COMMON IN CHILDREN (acute lymphoblastic leukemias, neuroblastoma, certain distinctive brain tumors, Wilms' tumor, retinoblastoma), BUT NOT IN ADULTS.
Cancers that are distinctive for teens and young adults arise in tissues that have just recently been growing (i.e., Hodgkin's in reactive lymph nodes, osteosarcomas in the knees of tall teens, testicular cancer in the germinal epithelium).
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.
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"). |
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 beverage; with black tobacco, takes blame for Uruguayan epidemic of esophageal and bladder cancer (Cancer 67: 536, 1991; Cancer Ep. 12: 508, 2003; BMC Cancer 7: 57, 2007.)
* 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 has been believed for decades to be the worst known metal mutagen with high rates of nasal and lung cancer in people with massive industrial exposure. It remains intensely politicized as "the Erin Brockovich chemical" -- this environmental activist / legal clerk obtained a $333 million dollar settlement for people in the town of Hinkley, California, whose ground water was accidentally contaminated by a factory. This is the single largest settlement in US history, and happened depsite the facts that the contamination was miniscule, there was no obvious increase in overall cancer in the town during or after the period, and the stuff forms in nature and gets into the ground water naturally. The Environmental Protection Agency (2011) decided to require communities to monitor hexavalent chromium levels in response to militants, but has so far declined to issue standards. You decide. |
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)
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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; I'm convinced now J. Urol. 182: 46, 2009), and arsenic is generally regarded as contributing to lung cancer (Cancer Causes & Control 18: 7, 2007).
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 evidence56497., 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 produces microcrystals in animal urine, but not human urine, and these were promoters. Saccharin was banned in the 1970's for political reasons.
Cyclamates: Same story as saccharin.
Human feces: Several known carcinogens, including those derived from bile salts (* try and ban feces, Senator Delaney!)
Benzene: Leukemias and related problems.
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.
Ferric ion: Liver cancer (hemochromatosis patients); perhaps many other cancers ("free radical generator")
* Herbicides & pesticides: In people who actually spray pesticides, there seems to be some extra cancer risk, though it is not striking, and the numbers are presently being sorted out (CA 63: 120, 2013). 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. For the original dioxin-and-lymphoma epidemiologist's personal memoir after forty years, see Acta Onc. 47: 347, 2008 (good read).
* For decades, the Environmental Protection Agency has claimed that formaldehyde -- the common tissue fixative -- is a carcinogen and regulated it heavily. Most pathologists are skeptical. Sure, it's a promoter in a few systems, like almost everything else; there's an epidemiologic link to the very-rare nasal sinus adenocarcinoma. Apparently it is NOT a genotoxin (rats: Mut. Res. 677: 76, 2009; pathologists Toxicology 252: 40, 2008). Formaldehyde is actually a vital intermediary in some of your metabolic pathways. The right-wing billionaire Koch brothers provide much of the USA's formaldehyde, and the extent to which their problems with the EPA is related to their financing of the "grassroots" tea-party movement will be decided by historians.
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.
WHERE THE LINK HAS PROVED GENUINE:
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* 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 real 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 discovered to be a fake by Br. Med. J. 319: 337, 1999 ("the Liburdy affair").
The business seems to have ended.
(The
"cellular phone" business is even sillier. Ask a tort lawyer or the World Health
Organization, the latter being responsible for the most recent foolishness.)
* 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). This is the stuff that greens call "dioxin" for short, which generates great confusion since real "dioxin" is a common, simple diether solvent. There is apparently total agreement by now that the Agent Orange contaminant is not a mutagen / initiator. Even the folks who use it as an experimental carcinogen say it's 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 (tetrachlorodibenzodioxin) 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 tetrachlorodibenzodioxin 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 tetrachlorodibenzodioxin 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. |
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For the Love Canal episode, in which the population expanded into an ancient toxic-waste dump site that leeched benzene and dioxin (the REAL ether, not the agent-orange stuff) into their homes, see Science 212: 800 & 1404, 1981. There was no higher rate of cancer or anything else here than elsewhere, and the initial claim that "31% of these people have damaged chromosomes compared with 1% of normals" didn't hold up. But not surprisingly, people were upset when chemical waste appeared in their living rooms and on their lawns, and they tended to blame every illness in the community on this. After the "green cure" (money from lawyers) and some awards to "heroic environmentalists", the business passed into history -- and the impact on urban development was serious (you are liable if anybody alleges that the land you want to develop was ever used by anyone else to dispose of any real or imaginary chemical hazard).
* In 1998, there was an E-mail flap about sodium lauryl sulfate (the famous saponifier) causing cancer. Readers were exhorted to shun shampoos, toothpastes, and so forth that contained sodium lauryl sulfate. The truth... Some twit read a couple of articles about mixtures containing sodium lauryl sulfate causing a variety of cancers in laboratory animals. What the author didn't realize was that sodium lauryl sulfate was used as the vehicle to deliver the real carcinogens. Gee whiz!!
* The antiperspirants and breast cancer business is just a lie. The business about tampon manufacturers putting cancer-causing asbestos in tampons to make women bleed more is yet another bald-faced lie. The fact that these persist as internet and contemporary folklore shows how willing people are to believe ugly, obvious untruths that fit with their ideologies.
Cooked meat (including poultry and fish) contains heterocyclic amines that cause cancer in animals models. You've all heard the stuff from the militant vegetarians. Your lecturer remains skeptical about "statistical evidence" that frequent consumption of red meat is a serious cancer risk. See also Br. Med. J. 315: 1018, 1997; Lancet 353: 703, 1999 (heterocyclic amines). The big prospective Oxford study ("EPIC" -- European Prospective Investigation into Cancer and Nutrition") couldn't find measurable differences between vegetarians and omnivores either in longevity or any particular cause of death (Am. J. Clin. Nutr. 89: 1613-S, 2009). In 2009, a much-discussed NIH study with a huge cohort and a really serious attempt to control for all the likely confounding variables found a slight increase in mortality, cancer and heart disease in folks who eat a lot of red / processed meat (Am. J. Med. 169: 562, 2009). For whatever reason, the media did NOT pick up on the same study finding that the more WHITE meat folks ate, the LESS heart disease, cancer, and overall mortality, the numbers being every bit as impressive as those for the supposed dangers of red meat. After reading this over, I decided that all that's required to render this study invalid is for Joe Greaseburger to tell Uncle Sam that he exercises a little bit more or smokes a little bit less than he really does. Take it for what it's worth. A slight increase in cancer risk and overall mortality in heavy red-meat eaters: Arch. Int. Med. 172: 555, 2012.
Here's the basics of what you need to know to evaluate pop / media / Green / EPA claims about cancer risk from chemicals in the environment.
No reasonable person would question the great harm that pollution has done to life in the waters. No reasonable person would question that air pollution is unhealthy, and places people at some increased risk for lung cancer.
The public is often told (by pop writers and even by government agencies) that pollution is the cause of an epidemic either of all cancers, or of particular cancers. You need to evaluate these claims carefully and thoughtfully, knowing that emotion and politics are involved as well as real science.
You already know that it is very easy to lie with statistics in order to frighten people. For example, more people are dying of cancer each year in the US today than in the 1950's... because there are more people. If you control for this and for the effects of increased smoking (Lancet 229: 268, 1992) and an aging population, the incidence of new cases is quite stable and the death rate is actually down by about 30% from 1950 (CDC from 2001). Children's cancers have not changed significantly in incidence over the period (JNCI 91: 1051, 1999), though many fewer of these children die.
* Rachel Carson's book "Silent Spring" blamed insecticides for the increase in the number of cases of childhood leukemia between 1950 and 1960. (Carson's book cites a 43% increase but she chose to ignore the impact of the baby boom on demography so the real increase in incidence was about 13%. Of course, the percentage of all childhood deaths that resulted from leukemia rather than other causes increased tremendously at the time as antibiotics cut the rate of deaths from infections.) It was not unreasonable to think at the time that insecticides might be causing leukemia, and I appreciate that Ms. Carson brought it up, even though she was wrong. And she was wrong. Today's new rates of childhood leukemia are actually lower than they were in 1950. See JNCI 91: 675 1999; Lancet 354: 532, 1999, or check the WHO or NCI databases. Unfortunately, Ms. Carson's calling pesticides "elixirs of death" set an unfortunate tone for Green agitprop that persists today. It seems most likely to me that the 13% increase probably resulted from increased urbanization -- children who grow up around a lot of other children from different communities and their viruses (see for example Lancet 357: 858, 2001), get more leukemia, i.e., there's one or more viruses involved. Recent studies have utterly failed to link childhood leukemia either to growing up next door to the nuclear power plant (Cancer Causes & Control 9: 529, 1998) or chemical landfills (Int. J. Epidem. 29: 391, 2000). Nobody is even writing scientific papers about chemicals in the environment causing childhood leukemia any more; the latest review concluded that "no causal factor has been identified which can explain a single cluster of childhood leukemia" (Eur. J. Epid. 15: 847, 1999). |
Rachel Carson Give her credit. She was right about |
In real life, most risks are either logarithmic or show a threshold below which there is no risk. Today's attempts by governments to "estimate the risk of low exposures" based on animal studies generally assume a linear relationship instead.
If the relationship is really logarithmic... | Do you see the fallacy? |
If there is a threshold for risk... | I thought you would. |
To decide whether a substance is a cancer risk in the absence of an obvious epidemiological link, and if so how much is "safe", it's usual nowadays to give huge doses to a few dozen lab animals. (Lower doses and more animals would produce many fewer tumors and be much more expensive.) When a handful of animals get a particular tumor (and this often does happen), a linear relationship is assumed to exist between dose and risk. This is a stupid assumption (it doesn't even apply for alcohol-and-liver, or tobacco-and-lung; and it's the basis for the asinine claim that "every drink of alcohol kills 500 brain cells".) But it's supposedly the best we can do, i.e., YOU CAN GENERATE ANY SCARE STORY YOU WANT. And that's the beauty. Exactly what is done with the results is up to the politicians. Plants produce their own natural insecticides, some of which cause cancer in lab animals (hydrazine in mushrooms, caffeic acid in many fruits and vegetables, lots of things in pepper.) These naturally-occurring known experimental carcinogens are tolerated in quantities that are orders of magnitude higher than what we allow for pesticide residues, of course for political reasons (see the Ames references below).
The Environmental Protection Agency is charged with setting the allowable limits for various synthetic chemicals in air, food, and water. It is a highly-politicized government body. A recurring pattern has been making pronouncements that are opposite to the consensus of the very scientists who it had hired. During the 1990's, the mainstream scientific community around the world had little or no respect for the EPA (Nature 412: 677, 2001). The politics flip-flops between Left to Right as administrations change (Nature 422: 5, 2003). In 2007, the Supreme Court found AGAINST the Bush EPA ("Massachusetts et al. vs. EPA") and ruled that "the harms associated with climate change are serious and well-recognized." Whatever direction politics swings, there's little chance of things improving until the US public become scientifically literate. As a physician, you may need to reassure your patients about EPA stuff.
Before you decide to ban pesticides "just to be on the safe side", consider the effect on real human beings and what they'd eat. You know you will drive food prices up, and the burden will be borne by the world's poor. It's pretty clear that a good intake of fruits and vegetables seems somewhat protective against several cancers. For now, "organic" methods would make these much more expensive, making a good diet much less available to the poor. Good public policy is a matter of weighing relative risks. Think about it.
The difficulty of finding out the truth about environmental exposures, whatever that truth may be, is made much more difficult by the fact that the parents of children with cancer tend to "overreport" exposures to suspected carcinogens, i.e., people are not always totally honest / accurate. The reality of "reporting bias" / "recall bias" is documented in Am. J. Epidem. 158: 710, 2003.
* There's a "school of independent medical thought" called homeopathy,
which holds that small doses of a substance have the opposite
effects from large doses. If these people really believed their own
claim, they would consider exposures to low levels of carcinogens
to be GOOD for us.
Did you ever think about that?
* As an example of "confounded relationships" --
Arch. Derm. 147: 1379, 2013
published a paper describing how vitamin D
levels are higher in white people with skin cancer than white people without
skin cancer. This is no surprise -- both result from ultraviolet light
exposure -- but they had to discuss whether vitamin D caused the skin cancers.
Two terms from classic studies of chemical carcinogenesis:
INITIATION: The result of exposure of a cell or cells to a carcinogen, which permanently alters its genetic material but not its phenotype (yet). As noted, these are mutagens ("genotoxic carcinogens").
PROMOTION: A substance that causes initiated cells to turn into tumors. Tumors result when the promoter is administered after, but not before, initiation. Promoters are "non-genotoxic carcinogens".
* Long thought to be "nonspecific irritants" or to exert their effects by "increasing the rate of mitosis, therefore causing sequential selection of mutant clones", we now know that some mitogens are much better promoters than others. This will eventually get sorted out; don't worry about it now.
Experimentalists mostly use phorbol esters as promoters. They work by activating protein kinase C (Cancer Res. 58: 1423, 1998).
Hormones are also promoters for particular organs.
And probably many things (Epstein-Barr virus, various non-genotoxic chemicals that have been linked to cancer) do act "by disrupting normal tissue homeostasis". This has always been hard to study (Nature 350: 555, 1991). It does seem now that hepatitis B and C viruses are much more likely to produce hepatocellular carcinoma when they cause rapid, prolonged cell turnover, i.e., making Nowell's law operate more readily (Cancer 73: 1149, 1994).
A COMPLETE CARCINOGEN is a substance that is both initiator and promoter, such as "tobacco smoke" or certain really awful chemicals.
The AMES TEST for mutagenicity (and presumably carcinogenicity) relies on production of mutants in a culture of typhoid bacteria.
* Today's more sophisticated tests include a "micronucleus test", in which mutagens supposedly can be distinguished by their ability to produce tiny nuclei from aberrant anaphases in a strain of lymphocytes. NIOSH uses them to test chemicals (for example, Anesth. Analg. 92: 118, 2001).
"All chemicals that cause cancer in laboratory animals", typically at preposterously high doses, used to be banned (theoretically) from foods in the US ("Delaney clause").
By the late 1980's it was very clear that the vast majority of such chemicals were "non-genotoxic carcinogens", exerting their high-dose effect by causing cell division ("mitogens, not mutagens"), which should not be a realistic concern at lower doses. See Science 236: 271, 1987; Science 249: 970, 1990; Science 250: 1645, 1990; Science 251: 12, 1991. Even Dr. Ames said that animal testing of carcinogens, and fear of "chemicals", had gotten ridiculous (Science 240: 1043, 1988; Science 249: 970, 1990; more recently Mut. Res. 447: 3, 2000: "Even Rachel Carson was made of chemicals.... Putting huge amounts of money into miniscule hypothetical risks damages public health by diverting resources and distracting the public from major risks").
Dr. Ames often points out the fallacy involved in animal carcinogenesis work. About half of chemicals tested produce cancers in rodents if given in ludicrously high doses, by disrupting the environment in which mitosis takes place. The "risk estimate" on which political decisions are based then assumes that the relationship is linear, which is obviously not true. But even if it IS true and you compare the curves, the "risk" from the amount of caffeic acid alone in a cup of coffee or a lettuce salad is commensurate with the hypothetical risk from a month's exposure to DDT during Rachel Carson's era (see Science 236: 271, 1987; Proc. Nat. Acad. Sci. 87: 772, 782 & 787, 1990; Env. Health Per. Sup. 105: 865, 1997; Mut. Res. 447: 3, 2000; all by Bruce Ames).
Long-neglected in practice, the absolute ban was finally eliminated in 1996.
RADIATION CARCINOGENESIS
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) 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).
Exposure of the "atomic veterans" from the USA and Great Britain, and the people of the Marshall Islands, probably did generate a real increase in risk, but it's been hard to demonstrate Lancet 361: 1759, 2003; Health Physics 73: 187, 1997.
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, and how to estimate this (and I'm wondering whether we need to try) is extremely contentious: Br. J. Rad. 85: e1166, 2012.
Diagnostic imaging of the unborn child may perhaps produce a slightly increased risk of childhood cancers; ultrasound does not (BMJ 342: d472, 2011).
A big study finds that radiation to the breast from mammography measurably increases the risk of cancer in women with BRCA1/2 mutations, and recommends non-ionizing radiation instead (BMJ 345: e5600, 2012).
We'll talk a little about "radon in your home causes lung cancer" later -- the verdict's not fully in, but the mandates that homeowners shell out thousands of dollars to radon-proofers before they could sell their homes seems to be ending. 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 two major studies 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) or just a tiny increased for male current smokers and no risk for anybody else(Arch. Env. Health 56: 208, 2001).
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.
Iatrogenic radiation carcinogenesis in the Bad Old Days:
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.
Today, cancers that arise years after therapeutic radiation tend to be sarcomas. More about this later.
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).
ONCOGENIC VIRUSES
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.
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.
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.
OTHER REPUTED CARCINOGENS
FOREIGN-BODY CARCINOGENESIS and CARCINOGENESIS BY REPEATED TRAUMA are possibilities that worry patients.
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.
It is very valuable to the cigarette defense to establish firmly that unsuccessfully managed stress plays a dominating role in the etiology of cancer.
-- Philip Morris Tobacco Vice President Jetson Lincoln, papers made public Am. J. Pub. Health Nov 2012
ONCOGENES (review NEJM 358: 502, 2008; older cancer genetics update: Nat. Genet. 33S: 238, 2003.)
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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.
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:
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.
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").
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).
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).
ALK, anaplastic lymphoma kinase, is important in several tumors we'll meet later. A mutated form causes an autosomal-dominant syndrome with neuroblastoma (Nature 455: 930, 2008).
* 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).
The most important of these oncogenes has proved to be HER2 -- which is routinely assayed in breast cancers to decide the optimum therapy (Arch. Path. Lab. Med. 135: 55, 2011.)
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!
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" ("gain of function"), 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(early attempts 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.
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.
* The Ewing's sarcoma 11:22 translocation joins FLI1, a myc-like proto-oncogene, to EWS, producing an aberrant transcription factor EWS-FLI1 (Proc. Nat. Acad. Sci. 90: 5752, 1993); much since.
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 bearing 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).
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). In melanoma, as in other tumors in which it is mutated, dabrafenib is now being used to treat incurable disease (Lancet 379: 1893, 2012).
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.
* c-jun is the factor that initiates transcription of DNA at a particular sequence. Present in all eukaryotes. Its molecular partner c-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 was developed in the late 1980's and has come into its own 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 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, to mark the two ends of the gene. 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.)
KNUDSON'S LAW FOR TUMOR-SUPPRESSOR GENES
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.
The prototype tumor / tumor family syndrome caused by a mutated tumor suppressor gene is RETINOBLASTOMA.
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.
* And famously, elephants get less cancer because they have backup copies of good TP53. JAMA 314: 1850, 2015.
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 (FAMMM): 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 ("MMR"; "mismatch-repair").
Around 1 person in 440 has Lynch's. We now screen for the entire family using microsatellite instability assays (MSI). 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.
LATE PROGRESSION
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.
MICROSATELLITE INSTABILITY (MSI) 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.
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.
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: updates Ann. Rev. Med. 59: 267, 2008; CA 60: 376, 2010. 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. Update Nat. Med. 17: 330, 2011. There are now several drugs that seem to be active against components of the "epigenetic machineries."
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, ovarian surface 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. Since the discovery of the first cancer antigen in 1991, almost none of the several hundred known antigens have proved useful targets for treatment.
* Beginning in the early 1990's, we've started 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 started showing promise especially for melanoma (J. Immuno. 173: 7125 & 7622, 2004; apparent triumph with a new strategy 358: 2664 & 2698, 2008; now considered likely to cure maybe half of metastatic melanoma cases Clin. Cancer Res. 17: 4550, 2011).
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 significantly in AIDS or iatrogenic immunosuppression -- only a few histologic patterns are up and these aren't even the common ones Cancer 118: 4869, 2012).
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.
* 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).
* 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. Malignant melanoma, the one common cancer in which the patient's immune
response does seem to be an important factor, is somewhat more common
in people who are immunocompromised; the business is being
sorted out: Mayo Clin. Proc. 87: 991, 2012.
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;
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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 tumor-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.
* 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).
Late in some advanced cancers, there are altered clones that have overgrown for some reason and managed to evade the T-cell response. A large minority of a couple of common cancers get a sometimes-dramatic response from anti-PD-L1 (programmed death ligand), which makes it easier for T-cells to kill things. See NEJM 366: 2455, 2012.
You'll learn these terms from other lecturers, but they are worth mentionng here.
TUMOR-ASSOCIATED ANTIGENS are those expressed by particular types of tumors -- for example, many ovarian cancers make a lot of CA125 / mucin 16, but this is also a normal product of other tissues.
Despite the overall-disappointing results of immune-strengthening 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:
There are plenty more immunoconjugates on the way -- maybe someday even for solid tumors (Clin. Pharm. Ther. 89: 513, 2011). 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.
CANCER IN THE UNITED STATES
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.
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.
No reasonable person questions the value of screening colonoscopy in preventing deaths from colon cancer or cervical cytology to prevent deaths from cervix cancer.
* Your lecturer remains skeptical about just how helpful mammography (especially as a substitute for self-examination) is for women and routine prostate blood work screening is for men. More about this down the road.
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 poor nations 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. Helicobacter is part of the story, but otherwise 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" -- or maybe better diagnosis). 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, the southeastern USSR, and especially Mongolia, 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. This continues to be a major mystery of medicine.
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 historically about 500,000 women per year worldwide; typically young mothers. (A new estimate has the number down to 260,000, but this is still unacceptable for a disease in which death is almost 100% preventable: 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.
In the poor nations of the tropics, Hodgkin's disease is usually a childhood cancer, while in the developed world, it most often affects teens and young adults. We must think there's a virus involved.
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.
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 omnivores 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.
EFFECTS OF BENIGN TUMORS ON THE PATIENT
Some benign tumors cause serious problems because of their location (one unfortunate expression is "malignant by location"). These include:
Other benign tumors cause serious problems by other means. These include:
EFFECTS OF MALIGNANT TUMORS ON THE PATIENT
{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 (mega-review Mayo Clin. Proc. 85: 838, 2010) 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).
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; Arch. Neuro. 68: 1073, 2011).
* ANTI-RI DISEASE is opsoclonus secondary to breast cancer (less often 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 common in testicular cancer patients (NEJM 340: 1788, 1999).
* ANTI-Ma1: Brain 122: 27, 1999. Update on anti-Ma1 and anti-Ma2 encephalopathies: Arch. Neuro. 68: 521, 2011.
* ANTI-AMPHYPHYSIN: Stiff person syndrome: Neurology 61: 195, 2003; Ann. Neuro. 55: 286, 2004; Neurology 71: 1955, 2008.
* ANTI-VGKC: limbic encephalitis Brain 127: 701, 2004. Update on this and the other paraneoplastic encephalitis syndromes: Brain 135: 1622, 2012.
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; Neurology 76: 2089, 2011) 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; Ann. Thorac. Surg. 89: 2001, 2010).
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 LANUGINOSA ("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 with acanthosis nigricans ("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 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).
{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.
MYASTHENIA GRAVIS, IMMUNE DESTRUCTION OF NORMOBLASTS, and SUPPRESSION OF PLASMA CELLS are all common in thymomas.
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; Arch. Derm. 147: 67, 2011.
* 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 and most troublesome 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.
You said it yourself, Big Daddy, mendacity is a system we live in. |
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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). Today it's okay to use methadone (Cancer 116: 520, 2010). Update on cancer pain management CA 61: 157, 2011.
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.
The Dutch (who else?) examine the senseless and cruel tendency to give chemotherapy to patients who are obviously terminal -- looking at the psychology and groupthink involved (BMJ 342: d1993, 2011).
By contrast, cancer patients for whom cure is no longer an option but who exercise autonomy to avoid hospitalization / ICU placement, who perceive a therapeutic alliance with their physician, and/or who pray / meditate have the pastor visit now enjoy quite a good quality of life (Arch. Int. Med. 172: 1133, 2012).
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.
* 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. Anecdotes in medical journals claim 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".
When opiates fail or cannot be used for political reasons, destroying the nerves to the area using phenol now seems to provide almost perfect pain relief (Anes. Anal. 110: 216, 2010).
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; also JAMA 309: 2371, 2013 -- pulmonary dysfunction, fertility problems and hearing loss each affect a majority of survivors).
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.
CANCERS ARISING FROM PRE-EXISTING TUMORS:
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.
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)
* 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 a mutant BRCA1 has a much increased breast cancer rsk beginning at age 30; her lifetime risk is maybe 60-70%; her risk for ovarian cancer is maybe 40-50%. A woman with mutant BRCA2 has a lifetime breast cancer risk of 40-50%, ovarian cancer risk around 10%. Breast cancer popping up in men often results from one of these mutations.
Removing the ovaries prophylactically seems like a good idea, and is quite acceptable nowadays: NEJM 346: 1609, 2002.
* Turcot's (colon polyps, brain tumors) usually arises from a Lynch locus (NEJM 332: 839, 1995; Ann. Med. 36: 379, 2004).
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, ALK, a few others) that are not lethal to the embryo. The reason for this is that the mutant genes function nicely when there's only two of them, but the mutant allele tends to amplify in individual cells long after conception.
* Telomere shortening seems to explain the aplastic anemia: Blood 91: 3582, 1998.
Fanconi review Cancer 97: 425, 2003.
NOTE: A-T, Fanconi's, and Bloom's are fragile-chromosome syndromes (* radiation therapists take note!).
LEARN THESE TUMOR FAMILY SYNDROMES NOW:
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 (Am. J. Path. 178: 1932, 2011) 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.
The much less common 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). Patients are also likely to have meningiomas and to a lesser extent other nervous system tumors. Review Lancet 373: 1974, 2009.
Patients with NF1 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, juvenile myelomonocytic leukemia (NEJM 330: 597, 1994, showcases NF-1 as a tumor-suppressor gene), etc.
* Future geneticists: look for "Lisch nodules" of melanocytes 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
* 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); the most common locus may be AKT1 (NEJM 365: 611, 2011). |
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 systemid and/or pulmonary hypertension and/or a variety of other curious tumors and cysts.
* The tyrosine kinase inhibitor sunitinib seems to work especially well for these patients, both for the systemic problems and the tumors (J. Clin. Endo. Metab. 94: 386, 2009).
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.
Notable "tumors" include:
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 drugs serolimus and everolimus target a pathway involved in tumor formation in tuberous sclerosis, and has found use in treating lymphangiomyomatosis and angiomyolipomas: NEJM 358: 140, 2008), brain changes (Neurology 78: 526, 2012) and the tumors of tuberous sclerosis (Pediatrics 127: e1335, 2011; Lancet 38: 125, 2013).
{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 (gene found -- somatic mutation in GNAQ NEJM 368: 1971, 2013), 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). Common genetic syndrome among the Amish.
CANCER QUACKERY (updates CA: 54: 110, 2004; helping victims of expensive fakes NEJM 366: 783, 2012)
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:
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.
* The late 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?"
* Your lecturer was the Simontons' nemesis. The story is quite funny, especially when our battle was played out in a popular magazine. I came away believing that Dr. Simonton and his ex-wife were self-deceived idealists with decent hearts, but still it's simply wrong on multiple levels to tell cancer patients that they caused their own disease by bad attitudes. I'm proud of my role in discrediting them in the eyes of their own "alternative and complementary medicine" community.
* The pop claim that "job stress causes cancer" totally fails an objective study: BMJ 346: f165, 2013.
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 |
* 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:
The cancer quack cannot lose. Whenever a patient
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:
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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