Non-seminomatous germ cell tumors

In yesterday's blog, we examined the enormous increase in the incidence of seminomatous germ cell tumors occurring in white non-Hispanic males.

There are two categories of germ cell tumors: seminomatous and non-seminomatous.

The seminomatous tumors are tumors composed predominantly of a single cell type, the gonocyte. The non-neoplastic gonocyte would normally produce sperm cell in the testis. Seminomas are permitted to contain a few neoplastic trophoblasts, but otherwise, seminomas are composed of a population of large, round, monomorphic cells.

The other type of germ cell tumors is the non-seminomatous tumors, and these tumors are composed of malignant cells resembling those of the pluripotent primitive embryonic (from the early embryo) or extra-embryonic (from the placenta) malignant cells. Consequently, the non-seminomatous germ cell tumors may be teratomatous, primative embryonic, choriocarcinomatous, or some mixture of these. Non-seminomatous germ cell tumors may even contain foci of seminoma! The key characteristic of non-seminomatous germ cell tumors of the testis is that they must have a component of primitive neoplastic cells that are not seminoma cells.

Can we observe the same increased incidence of non-seminomatous germ cell tumors as we saw (yesterday) in the seminomatous germ cell tumors.

NO. Here are the numbers, computed from the SEER (the U.S. National Cancer Institute's Surveillance Epidemiology and End Results) public use data files. The first column is the crude number of occurrences of non-seminomatous germ cell tumors of testes in white, non-Hispanic males. The second column is the number of occurrences expressed as a proportion of all of the seer cases for the year examined, and the third column is the number of occurrences expressed as a proportion of the U.S. population for the year examined.

       crude   of SEER  of U.S. Pop
1973   000109   000196   000051
1974   000147   000218   000068
1975   000157   000213   000072
1976   000165   000218   000075
1977   000189   000246   000085
1978   000167   000214   000075
1979   000182   000226   000080
1980   000216   000260   000095
1981   000222   000259   000096
1982   000203   000234   000087
1983   000226   000251   000096
1984   000219   000234   000092
1985   000238   000243   000100
1986   000233   000232   000097
1987   000253   000238   000104
1988   000222   000206   000090
1989   000263   000238   000106
1990   000243   000209   000097
1991   000237   000192   000094
1992   000237   000185   000092
1993   000245   000194   000095
1994   000222   000176   000085
1995   000216   000169   000082
1996   000247   000202   000093
1997   000225   000178   000084
1998   000234   000180   000086
1999   000245   000185   000089
2000   000237   000177   000084
2001   000223   000162   000078
2002   000258   000185   000089
2003   000230   000166   000079
2004   000278   000192   000094
2005   000275   000188   000092
2006   000251   000169   000084
2007   000277   000182   000091

Here's the graph. The blue columns are the crude occurrences. The maroon columns are the numbers as a proportion of the year's seer records, and the white column are the numbers as a porportion of the U.S. population in the examined year.



There's a small increase since 1973, but much of the increase is accounted for by the increase in the SEER population and the increase in the U.S. population for the same years. The relative (population adjusted) rate of occurrence of non-seminomatous germ cell tumors has not increased by much; certainly nothing like the increase seen yesterday, for the seminomatous germ cell tumors.

What about the germ cell tumors that occur outside the gonads? Are they increasing in occurrence since 1973? Though germ cell tumors can occur outside the gonads, they are very rare. Here are the SEER numbers for non-seminomatous non-testicular germ cell tumors in white non-Hispanic males.

       crude   of SEER  of U.S. Pop
1973   000011   000019   000005
1974   000008   000011   000003
1975   000014   000019   000006
1976   000011   000014   000005
1977   000011   000014   000004
1978   000011   000014   000004
1979   000019   000023   000008
1980   000021   000025   000009
1981   000016   000018   000006
1982   000019   000021   000008
1983   000018   000020   000007
1984   000012   000012   000005
1985   000019   000019   000007
1986   000014   000013   000005
1987   000025   000023   000010
1988   000016   000014   000006
1989   000020   000018   000008
1990   000011   000009   000004
1991   000023   000018   000009
1992   000011   000008   000004
1993   000018   000014   000006
1994   000012   000009   000004
1995   000010   000007   000003
1996   000009   000007   000003
1997   000018   000014   000006
1998   000010   000007   000003
1999   000013   000009   000004
2000   000005   000003   000001
2001   000015   000010   000005
2002   000013   000009   000004
2003   000010   000007   000003
2004   000017   000011   000005
2005   000020   000013   000006
2006   000011   000007   000003
2007   000012   000007   000003

Here are the numbers for seminomatous non-testicular germ cell tumors in white non-Hispanic males.

       crude   of SEER  of U.S. Pop
1973   000002   000003   000000
1974   000001   000001   000000
1975   000005   000006   000002
1976   000004   000005   000001
1977   000010   000013   000004
1978   000008   000010   000003
1979   000004   000004   000001
1980   000014   000016   000006
1981   000016   000018   000006
1982   000011   000012   000004
1983   000011   000012   000004
1984   000011   000011   000004
1985   000013   000013   000005
1986   000016   000015   000006
1987   000014   000013   000005
1988   000011   000010   000004
1989   000016   000014   000006
1990   000010   000008   000004
1991   000011   000008   000004
1992   000014   000010   000005
1993   000013   000010   000005
1994   000023   000018   000008
1995   000017   000013   000006
1996   000020   000016   000007
1997   000018   000014   000006
1998   000010   000007   000003
1999   000009   000006   000003
2000   000016   000012   000005
2001   000014   000010   000004
2002   000017   000012   000005
2003   000016   000011   000005
2004   000022   000015   000007
2005   000026   000017   000008
2006   000014   000009   000004
2007   000017   000011   000005

Non-testicular germ cell tumors represent a tiny fraction of the germ cell tumors occurring in men. For the purposes of analysis, there's not much you can do with these tumors. They're not going to give you statistically significant results when you try to test a hypothesis; some of them may represent misdiagnoses (e.g., colon cancer mistaken for monomorphic teratoma in a peri-testicular appendage), or a conservative topographic assignment (peri-testicular metastasis from a regressed primary germ cell tumor).

So, for the purposes of this blog, where we're trying to find a biological explanation for the rise in seminomas in non-Hispanic white males, we'll ignore the non-testicular germ cell tumors.

Jump to Tomorrow's Blog

- © 2010 Jules Berman

key words: carcinogenesis, neoplasia, neoplasms, tumor development, tumour development, germ cell tumor, germ cell tumour, tumor epidemiology, increasing germ cell cancer rates, germ cell cancer, seminomas, seminomatous, common disease, orphan disease, orphan drugs, genetics of disease, disease genetics, rules of disease biology, rare disease, pathology

---

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

I urge you to read more about my book. There's a generous preview of the book at the Google Books site.

Germ cell tumors: the problems

Germ cell tumors are very rare neoplasms that occur most often in young adults and children.

For a variety of reasons, which I'll try to explain in the next few blog posts, much of what we think we understand about these tumors is highly confusing and probably wrong.

Considering that these are rare tumors, you might accept a certain degree of ignorance, but sometimes the mysteries that surround rare tumors must be solved before we can make any headway understanding the more common tumors.

Also, for some strange reason, the incidence of seminomatous germ cell tumors of the testes, in the white population, has been increasing over the past 35 years (at least).

Here are the numbers, computed from the SEER (the U.S. National Cancer Institute's Surveillance Epidemiology and End Results) public use data files. The first column is the crude number of occurrences of seminomatous germ cell tumors of testes in white, non-hispanic males. The second column is the number of occurrences expressed as a proportion of all of the seer cases for the year examined, and the third column is the number of occurrences expressed as a proportion of the U.S. population for the year examined.

       crude   of SEER  of U.S. Pop
1973   000036   000064   000016
1974   000026   000038   000012
1975   000044   000059   000020
1976   000069   000091   000031
1977   000197   000257   000089
1978   000169   000216   000075
1979   000192   000239   000085
1980   000225   000271   000099
1981   000200   000234   000087
1982   000240   000277   000103
1983   000257   000286   000109
1984   000252   000270   000106
1985   000256   000262   000107
1986   000293   000292   000122
1987   000302   000285   000124
1988   000299   000278   000122
1989   000343   000311   000138
1990   000338   000290   000135
1991   000303   000245   000120
1992   000352   000274   000138
1993   000340   000269   000131
1994   000385   000305   000147
1995   000303   000237   000115
1996   000371   000304   000139
1997   000379   000300   000141
1998   000408   000315   000150
1999   000363   000274   000133
2000   000413   000310   000146
2001   000409   000297   000143
2002   000398   000285   000138
2003   000371   000268   000127
2004   000400   000277   000136
2005   000382   000262   000129
2006   000374   000252   000125
2007   000378   000249   000125

Here's the graph. The blue columns are the crude numbers. The maroon columns are the numbers as a proportion of the year's seer records, and the white column are the numbers as a porportion of the U.S. population in the examined year.


When the incidence of a tumor increases almost every year, and we're clueless to explain the increase, it's probably worth thinking about the problem.

Jump to Tomorrow's Blog

- © 2010 Jules Berman

key words: carcinogenesis, neoplasia, neoplasms, tumor development, tumour development, germ cell tumor, germ cell tumour, tumor epidemiology, increasing germ cell cancer rates, germ cell cancer, seminomas, seminomatous, common disease, orphan disease, orphan drugs, genetics of disease, disease genetics, rules of disease biology, rare disease, pathology

---

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

I urge you to read more about my book. There's a generous preview of the book at the Google Books site.

Tumor speciation revisited

"Things that are new are wont to be set forward rudely and formlessly, and then must be polished and perfected in succeeding centuries."
  - Pappus, a Helenistic mathematician (circa 350-300 B.C.E.)

Regular readers of this blog all know that I have a keen interest in the tumor speciation (why we encounter a the set of tumor types that are familiar to all pathologists, and no others). Some examples of different types of tumors are: follicular lymphomas, glioblastomas, oligodendrogliomas, seminomas, hepatocellular carcinomas, etc.)

I find the question of tumor speciation to be profound for the following reason: Research in the genetics of tumors has found that tumors are incredibly complex, with some tumors having thousands of genetic mutations, making each tumor unique from every other tumor that has ever occurred in humans. If every tumor is unique, and if many tumors are genetically complex (many mutations) and internally heterogeneous (a tumor cell may be genetically separable from another tumor cell from the same tumor), then why are there only a finite number of different kinds of tumors? Shouldn't there be a near-infinite number of tumor types?

In a prior post, I tried to answer this question, drawing an analogy from animal speciation, and though the argument seems valid, I can see how it might confuse readers. I spent much of a chapter in my Neoplasms book explaining tumor speciation, but I can't help but wonder if there's a shorter explanation.

Here's my third try:

Basically, cancer is caused by alterations in the genome. Tumor speciation is restricted to a relatively small set of patterns in the epigenome.

That's it! Here's the explanation of what it means and why it makes sense.

When oncogenic mutations occur in cells, a malignant phenotype can only arise in cells that have a specific type of differentiation. The type of differentiation that a cell manifests is determined by the epigenome (the non-sequence modifications to DNA). There are about 200 different cell types in the body. Each cell type within an individual animal has the same exact genome (DNA sequence) as every other cell type in the same animal. Neutrophils, enterocytes, neurons, thyroid cells differ from one another because of differences in their epigenomes.

Because we only observe about 200 different cell types in the body, it's likely that only a finite set of epigenomic patterns "work"; i.e., sustain cell viability. In the case of cancer, the cancer genotype can only manifest itself within a finite set of epigenomic patterns. Specific types of genetic alterations are found in specific types of epigenomic patterns (e.g., the bcr/abl mutation is seen in myeloid lineage cells). Even when cancer mutations become complex, their malignant phenotype can only occur in a restricted epigenomic background.

What happens during the process of carcinogenesis (the period following a carcinogenic mutation and leading to the emergence of an invasive cancer, often years later)? Maybe carcinogenesis requires epigenomic accommodation of the cancer genotype. Over multiple cell generations, the epigenome continuously changes until a stable epigenomic pattern is selected. Because most epigenomic patterns are not viable, most cancer mutations never lead to the emergence of a tumor.

This argument hardly constitutes proof of anything, but in my Neoplasms book, I provide many examples of how tumors develop within the constraints of allowable epigenomic patterns (i.e., the observed differentiated cell types).

Jump to the next Specified Life blog

- © 2010 Jules Berman

---

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

I urge you to read more about my book. There's a generous preview of the book at the Google Books site.

tags: biology of rare diseases, common diseases, genetic disease, disease genetics, orphan diseases, orphan drugs, rare disease organizations, rare disease research, rare diseases, rare disease funding, rare disease research, funding for rare diseases, importance of rare diseases, funding opportunities, books about rare diseases, books about orphan drugs, orphan drug development, pathology of rare diseases, complex diseases, carcinogenesis, neoplasia, neoplasms, oncogenes, cancer development, epigenome, genome, cancer diversity, cancer phenotype, cancer genotype, cancer epigenotype, tumor development, tumour development

Melanoma and the precancer time machine

In an earlier post, I explained the precancer time machine phenomenon. Basically, when you successfully treat precancers, you don't see an immediate drop in the incidence of invasive cancers; you see a drop in invasive cancers at some point in the future, corresponding to the time at which the treated precancers would have developed into invasive cancers.

In the earlier post, I demonstrated that the precancer time machine seemed to apply in the case of dcis and invasive breast cancer.

In today's post, I've used the latest SEER (The U.S. National Cancer Institute's Surveillance Epidemiology and End Results) cancer data to show that there seems to be the same phenomenon going on for melanoma precancers.

The topic of treating melanoma precancers has been somewhat controversial. It would seem to be a no-brainer that we can reduce the incidence of invasive melanomas by treating melanoma precancers (dysplastic nevi and in situ melanomas). Unfortunately, there is no epidemilogiic evidence to support this assertion. Basically, the incidence of invasive melanoma seems to be rising every year, despite our best efforts to stem the tide (through the use of sunscreens, avoiding exposure to strong sunlight, and treating precancers).

The latest SEER data (which covers cancer cases from 1973 to 2007) seems to offer some hope that conditions might be improving.

Here's the graph of invasive melanome incidence in the U.S. SEER population.



The tallest bars (blue) are the crude numbers of occurrences of invasive malignant melanoma. The middle bars (maroon) are the occurrences of invasive melanoma expressed as a proportion of the total number of SEER cases. The bottom bars (white), are the occurrences of melanoma expressed as a proprotion of the total population of the U.S. in the perspective years.

Here are the numbers:

       crude   of SEER  of U.S. Pop
1973   001062   001916   000501
1974   001305   001938   000610
1975   001559   002116   000721
1976   001601   002116   000734
1977   001791   002337   000813
1978   001829   002347   000821
1979   001973   002460   000876
1980   002190   002645   000963
1981   002298   002690   001001
1982   002352   002714   001015
1983   002350   002617   001005
1984   002462   002638   001043
1985   002795   002864   001174
1986   002947   002942   001227
1987   003050   002879   001258
1988   002948   002743   001205
1989   003194   002896   001294
1990   003272   002816   001311
1991   003518   002853   001395
1992   003569   002786   001399
1993   003611   002860   001400
1994   003904   003097   001499
1995   004189   003283   001594
1996   004438   003641   001673
1997   004627   003668   001728
1998   004739   003663   001753
1999   004893   003704   001794
2000   005105   003832   001814
2001   005380   003911   001886
2002   005377   003857   001867
2003   005514   003993   001898
2004   005859   004062   001998
2005   006451   004431   002180
2006   006431   004335   002152
2007   006325   004172   002097

In the last two years studied (2006, 2007), the incidence of invasive malignant melanoma has dropped. Is this just a fluke, or does it indicate a real trend? There's no way to be sure, but inspection of the graph would indicate that it's the first time since 1973 when incidence has dropped two years running.

What about the corresponding incidence of in situ melanoma (the non-invasive precursor for invasive melanoma)?

Here's the graph for in situ melanoma.


Here are the numbers.

       crude   of SEER  of U.S. Pop
1973   000035   000063   000016
1974   000059   000087   000027
1975   000081   000109   000037
1976   000096   000126   000044
1977   000155   000202   000070
1978   000177   000227   000079
1979   000177   000220   000078
1980   000263   000317   000115
1981   000276   000323   000120
1982   000326   000376   000140
1983   000384   000427   000164
1984   000466   000499   000197
1985   000638   000653   000268
1986   000723   000721   000301
1987   000782   000738   000322
1988   000824   000766   000337
1989   000976   000885   000395
1990   001127   000970   000451
1991   001192   000966   000472
1992   001373   001072   000538
1993   001375   001089   000533
1994   001599   001268   000614
1995   001920   001504   000730
1996   002091   001715   000788
1997   002258   001790   000843
1998   002533   001957   000937
1999   002765   002093   001013
2000   003202   002404   001137
2001   003508   002550   001230
2002   003656   002622   001269
2003   003429   002483   001180
2004   003604   002499   001229
2005   004060   002788   001372
2006   004048   002728   001354
2007   004291   002831   001422

The incidence of in situ melanoma keeps going up and up. That's as it should be. When we successfully cure more and more in situ melanomas, we reduce the incidence of invasive melanomas.

The lag between the rise in incidence of the in situ lesions and the drop in incidence of the invasive lesions is due to the precancer time machine phenomenon.

Can we be sure? Not yet. Hopefully, over the next five years or so, the data will become a little more convincing.

- © 2010 Jules Berman

key words: precancer, precancerous, skin cancer, dysplastic nevi, dysplastic nevus, dysplastic naevus, dysplastic naevi, cancer mortality, cancer prevention, carcinogenesis

---

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

I urge you to read more about my book. There's a generous preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

Methods in Medical Informatics

My new book, Methods in Medical Informatics: Fundamentals of Healthcare Programming in Perl, Python,and Ruby, was published yesterday by CRC Press.

I've prepared web pages with a book description and the Table of Contents for anyone interested.

- Jules Berman

Naming rocks, minerals, and gems

Rocks, minerals, and gems have a rich vocabulary. There seems to be only one naming rule: no uppercase letters. This might be intended to simplify the nomenclature, but it can be confusing when you encounter a name such as "childrenite." You assume that name was inspired by a child, but the name comes from an adult; J.G. Children. The practice of using lowercase for eponyms is different from anatomic nomenclatures, wherein capitalization is preserved (e.g., Eustachian tube, not eustachian tube, after Bartolomeo Eustachio).

Similarly, you would think that "greenockite" must be a green rock (it's most often yellow, not green). It gets its name from Lord Greenock.

Likewise, biotite does not derive from a biologic precursor. It's named after Jean Biot.

Contrarily, rocks are sometimes named for lowercase (common) nouns.

Sepiolite is named for the cuttlefish bone, sepia.

Serpentine is named after the snake.

Where rocks get names from people, it's usually the surname. But not always.

Torbernite is named for Torbern Olaf Bergmann (the given name).

But don't get carried away. Bruceite was not named after someone whose given name was Bruce. It was named for a surname (Archibald Bruce). Likewise, Vivianite was not named after a woman named Vivian. It also came from the surname: J.G. Vivian

Perhaps the final solution for naming rocks after mineralogists was solved with the naming of frankhawthorneite after Professor Frank Hawthorne, of the University of Manitoba.

Here are a few more surprises:

If a gem is given a name, you'd think that it must be distinguishable from other gems with different names. No. Sapphire and ruby are the same gem, with different colorations (due to impurities in the stone). They're color-variants of corundum. Similarly, amethyst is just a color variant (purple) of common quartz.

Color in a mineral's name can be highly misleading. Glaucodot (greek for "blue"), is a gray to white mineral; never blue. Glaucodot is, however, used in the manufacture of blue glass, but you'd never know that by looking at the mineral.

Some rocks are named after the place where it was discovered or mined.

For example bytownite is named for Bytown, the former name for what is now called Ottawa.

This can be confusing, as franklinite is not named for Ben Franklin. It's named for Franklin, New Jersey. The city was named for Ben Franklin, but not the rock.

Consider Trona, California, where trona (sodium bicarbonate, and variously called tron) is mined. The mineral was not named for the city. The city was named for the mineral, which took it's name from tron, a shortened form of natron, the Arabic word for sodium.

Some rocks are named for their taste:

Calomel (probably from ancient Greek, meaning honey-taste)

or odor:

Scorodite (garlic-like, in Greek)

Some rocks are named after their included elements.

Bismuthinite contains bismuth, as you would expect. Zincote (a zinc dispersion) contains zinc, as does zincite (a true mineral).

But

Zinkenite contains no zinc (named after JKL Zinken, a German mineralogist).

Similarly, selenite, a clear crystal form of gypsum, contains no selenium.

If you're interested in the names of rocks, you must really know your Latin. Septarian concretions have complex internal structures, with multiple branches. You might think that the term comes from the latin septem (seven) referring to the number of branches. You'd be wrong. The name comes from the latin septum (partition).

It's also good to know your mythology. Pollucite was named for Pollux, the twin of Castor. The name has a certain inevitability. Pollucite is often found alongside petalite, previously known as castorite.

Some rocks are named for their geometry. There's tetrahedrite (tetrahedral crystals), triplite, clinoclase, microcline, and anorthoclase. But you can never generalize in mineralogy. Anglesite is not named for the angles in the crystal. It's named for Anglesey, Wales, where it is mined.

Sometimes, the relationship between a rock and it's name can be the opposite of what you might imagine. Fluorite is a rock that fluoresces. You might imagine that it was named because it had the property of fluorescence. Wrong. Fluorite was named for fluorine, from which it is composed (CaF2). The mineral fluorite was found to change color under UV light. The phenomenon was called fluorescence, after the first mineral shown to produce the effect. Today, every mineral that changes it's emission color under UV light is said to be fluorescent, whether it contains fluorine or not.

Sometimes you're sure a rock's name has been misspelled. Surely goethite should be geothite. Alas, no. Goethite is named for the polymath Wolfgang van Goethe.

In summary, if you're interested in the semiotics of rocks, you (unlike the rocks) will need to be flexible.

- © 2010 Jules Berman tags: nomenclature, specification, geology, rocks and minerals, hobbyists, semiotics, logophiles

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Science is not a collection of facts. Science is what facts teach us; what we can learn about our universe, and ourselves, by deductive thinking. From observations of the night sky, made without the aid of telescopes, we can deduce that the universe is expanding, that the universe is not infinitely old, and why black holes exist. Without resorting to experimentation or mathematical analysis, we can deduce that gravity is a curvature in space-time, that the particles that compose light have no mass, that there is a theoretical limit to the number of different elements in the universe, and that the earth is billions of years old. Likewise, simple observations on animals tell us much about the migration of continents, the evolutionary relationships among classes of animals, why the nuclei of cells contain our genetic material, why certain animals are long-lived, why the gestation period of humans is 9 months, and why some diseases are rare and other diseases are common. In “Armchair Science”, the reader is confronted with 129 scientific mysteries, in cosmology, particle physics, chemistry, biology, and medicine. Beginning with simple observations, step-by-step analyses guide the reader toward solutions that are sometimes startling, and always entertaining. “Armchair Science” is written for general readers who are curious about science, and who want to sharpen their deductive skills.

Precancer time machine

In the previous post , we discussed breast precancer. We saw that as mammography picked up earlier and earlier lesions (precancers and early breast cancers), deaths from breast cancer dropped, along with the incidence of invasive breast cancer.


In this graph, which covers the years 1975 to 2007, the top line of bars (blue) represent the incidence of breast cancers (including invasive and non-invasice lesions). The next lower line of bars (maroon) is the incidence of the invasive breast cancers (the kind that account for breast cancer deaths), and the bottom line of bars represents the rate of precancers (ductal carcinoma in situ) collected by SEER.

As you recall from the previous blog , the big drop in cancer death rates did not occur until about 1990, well after there was a rise in the number of diagosed breast precancers.

Why didn't the precancers diagnosed in the 1980s produce an immediate drop in the rate of breast cancer deaths or in the incidence of invasive cancers?

Precancer treatment works like a time machine. When you cure a precancer today, you don't see a reduction in the number of cancers that would arise that same day. You see a reduction in the number of cancers that will arise in some future date (if the precancer had been allowed to develop into a cancer, over time).

If a precancer would ordinarily require 5 years to develop invasive features (i.e., become a cancer), and you diagnose and treat the precancer in 2010, then you will eliminate a cancer that would have occurred in 2015. This explains the delay in the decrease in cancer mortality that you can always expect to see with successful precancer treatment initiatives.

- © 2010 Jules Berman

key words: precancer, precancerous, dcis, ductal carcinoma in situ, breast cancer, breast cancer mortality, cancer prevention, carcinogenesis

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About my book, Precancer: The Beginning and the End of Cancer. Nearly every type of cancer passes through a precancer phase, during which it cannot metastasize or invade other tissues. While medicine is not always successful in treating or curing advanced stages of cancers, recent advances in our understanding of carcinogenesis have helped us to develop strategies to prevent, diagnose, and treat many cancers at the precancer stage. Research in this field is escalating rapidly as the evidence increasingly shows that the number of annual cancer deaths could be drastically reduced through the effective treatment and cure of precancer lesions. This book begins by explaining why it has been so difficult to cure cancers, followed by a review of precancer biology, with descriptions of the most common precancer lesions. The final chapters provide practical socio-political and medical goals for precancer treatment, including discussions of the economics and politics of treating precancers.

I urge you to read more about this important topic. Google Books has provided a generous preview of this book.

Treating breast precancers saves lives

Breast cancer deaths rose through the '70s and '80s, but declined in the '90s. For nearly the past 20 years, American women have had about a 2% annual drop in the breast cancer death rate.

Here is the mortality graph provided by the U.S. National Cancer Institutes SEER (Surveillance, Epidemiology and End Results) program.



Though nobody wants to take the blame for the rise in breast cancer deaths in the '70s and '80s, lots of people want credit for the fall of breast cancer deaths that began in the '90s. Was it due to a reduction to the exposure of carcinogens, or to better treatment, or to earlier diagnosis?

The fall in breast cancer deaths does not seem to be due to cancer prevention. While the deaths from breast cancer were falling, there was an apparent rise in the incidence of breast cancer cases. Here is the SEER graph for the incidence in breast cancer in the U.S.



Since the breast cancer incidence rose while the deaths from breast cancer dropped, it seemed as though the benefit must have come from better treatment or earlier detection.

A major study, attempting to resolve this issue, was published in the New England Journal of Medicine, in 2005:

Berry DA, Cronin KA, Plevritis SK, Fryback DG, Clarke L, Zelen M, Mandelblatt JS, Yakovlev AY, Habbema JD, Feuer EJ. Effect of screening and adjuvant therapy on mortality from breast cancer. Cancer Intervention and Surveillance Modeling Network (CISNET) Collaborators. N Engl J Med 353:1784-1792, 2005.

They concluded that that 28 to 65 percent of the sharp decrease in breast cancer deaths from 1990 to 2000 was due to mammograms. The remainder of the improvement was was attributed improved breast cancer treatment.

The study did not take into account the great contribution of precancer treatment to the reduction of breast cancer deaths.

Let's review this SEER data, this time taking into account the diagnosis of DCIS (ductal carcinoma in situ) a precancer that precedes the development of invasive breast cancer. Here is the SEER data for the incidence of all breast cancer and of DCIS (the precancer for breast cancer).



In the past few decades, there has been a huge rise in the number of diagnosed cases of breast precancers. This is due largely to the use of mammography, which can detect lesions that cannot be found by palpation. When a precancer is detected and removed, the patient does not develop invasive cancer.

The total number of breast cancer cases includes cases of DCIS. If we subtract the number of breast precancer cases (DCIS) from the total number of breast cancer cases, we get the incidence of invasive breast cancer cases. Here is the SEER data.



In this graph, which covers the years 1975 to 2007, the top line of bars (blue) represent the incidence of breast cancers (including invasive and non-invasice lesions). The next lower line of bars (maroon) is the incidence of the invasive breast cancers (the kind that account for breast cancer deaths), and the bottom line of bars represents the rate of DCIS.

Look carefully at the middle bars (maroon), representing the incidence of invasive breast cancers. The graph shows that incidence of invasive breast cancers has actually dropped since the early '90s, as the diagnosis and treatment of DCIS has risen.

Much of the decrease in breast cancer mortality can be accounted for by the diagnosis and treatment of breast precancers. In fact the drop in breast cancer deaths follows the same slope, and has about the same magnitude, as the drop in invasive breast cancers that follows the increase in breast precancer treatments.

- © 2010 Jules Berman tags: cancer prevention, cancer treatment, early treatment, precancer, precancer treatment, preneoplasia, preneoplastic

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About my book, Precancer: The Beginning and the End of Cancer. Nearly every type of cancer passes through a precancer phase, during which it cannot metastasize or invade other tissues. While medicine is not always successful in treating or curing advanced stages of cancers, recent advances in our understanding of carcinogenesis have helped us to develop strategies to prevent, diagnose, and treat many cancers at the precancer stage. Research in this field is escalating rapidly as the evidence increasingly shows that the number of annual cancer deaths could be drastically reduced through the effective treatment and cure of precancer lesions. This book begins by explaining why it has been so difficult to cure cancers, followed by a review of precancer biology, with descriptions of the most common precancer lesions. The final chapters provide practical socio-political and medical goals for precancer treatment, including discussions of the economics and politics of treating precancers.

I urge you to read more about this important topic. Google Books has provided a generous preview of this book.

Mystery of the missing prelymphomas

A large problem in pathology is the lack of any consistent nomenclature for the precancers. Consequently, many precancerous lesions are simply not recognized as such, and cannot be included in clinical trials that assess the effectiveness of precancer treatments.

For example, lymphoma experts do not use the terms "precancer" or "prelymphoma" [prelymphomas are lesions that precede the development of lymphomas].

In a recent article, Elaine Jaffe discussed a condition that can be detected by flow cytometry in which monoclonal populations of CD5+ B-cells are found in 3% of healthy adults over the age of 40.

Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Am Soc Hematol Educ Program 523-531, 2009.

Many of these clones have the same marker chromosomes found in chronic lymphocytic leukemia (CLL). A small percentage of patients with these lesions will progress to CLL. This lesion is a precancer for CLL; and is strictly analogous to MGUS (monocloncal gammopathy of undetermined significance) a condition that precedes virtually every case of multiple myeloma (MGUS was discussed in a prior blog entry).

The condition has been given a name: monoclonal B-cell lymphocytosis. This is the only name by which the lesion is addressed in the WHO (World Health Organization) lymphoma classification.

Monoclonal B-cell lymphocytosis has all of the biological properties of a precancer It should be recognized as such (in this specific case, as the prelymphoma for CLL). If it were, it could be included in clinical trials for precancers.

The WHO has grappled with several different proliferative lymphoid lesions that can precede the development of lymphomas. They have used, or currently use, terms such as "proliferations of uncertain malignant potential" or "intrafollicular neoplasia", or "in situ follicular neoplasia." Why bother? There is an accepted term for lesions that precede cancers of every cell type of origin: precancers. The word "precancer" does not appear anywhere in the WHO classification or in Dr. Jaffe's discussion of the WHO classification. It would be very helpful if hematopathologists climbed aboard on this issue.

Though we are currently treating only a few of the different kinds of precancers in man, there is ample evidence that precancer treatment effectively reduces the number of people who die from cancer. In the next blog, I'll expand the topic of precancer treatment.

- © 2010 Jules Berman

key words: lymphoma, lymphoma classification, prelymphoma, pre-lymphoma, precancer, lymphocytosis, precancer treatment

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About Precancer: The Beginning and the End of Cancer. Nearly every type of cancer passes through a precancer phase, during which it cannot metastasize or invade other tissues. While medicine is not always successful in treating or curing advanced stages of cancers, recent advances in our understanding of carcinogenesis have helped us to develop strategies to prevent, diagnose, and treat many cancers at the precancer stage. Research in this field is escalating rapidly as the evidence increasingly shows that the number of annual cancer deaths could be drastically reduced through the effective treatment and cure of precancer lesions. This book begins by explaining why it has been so difficult to cure cancers, followed by a review of precancer biology, with descriptions of the most common precancer lesions. The final chapters provide practical socio-political and medical goals for precancer treatment, including discussions of the economics and politics of treating precancers.

Precancer: missed opportunities for diagnosis

"And what physicians say about disease is applicable here: that at the beginning a disease is easy to cure but difficult to diagnose; but as time passes, not having been treated or recognized at the
outset, it becomes easy to diagnose but difficult to cure. The same thing occurs in affairs of state; for by recognizing from afar the diseases that are spreading in the state (which is a gift given only to a prudent ruler), they can be cured quickly; but when they are not recognized and are left to grow to the extent that everyone recognizes them, there is no longer any cure."

- Niccolo Machiavelli

Today's blog continues yesterday's discussion of the precancers. The theme of all these blogs is that precancers, the lesions that precede the development of cancers, can be easily treated. Treatment of all precancers will lead to the eradication of all human cancers.

One of the obstacles in the treatment of the precancers comes from the reluctance of many pathologists and oncologists to recognize precancers when they see them. If you don't recognize the precancers, the clinical trials for new cancer chemotherapeutic agents becomes virtually uninterpretable.

Here's an example:

Suppose you have a new drug that targets a specific gene that is altered in a particular type of cancer. You collect a group of patients with the cancer, and you treat them with your drug, comparing their response to a group of cancer patients who are treated with conventional chemotherapy. You find that 10% of your patients respond well to the drug, and 90% don't respond at all. On average, the group of people who received the new drug had a shorter survival than the group who received conventional chemotherapy. You abandon your new drug.

Now suppose that your population of patients did not all have the same cancer. Suppose that 10% of them actually had a precancerous lesion, and this population accounted for the good responders in your experimental treatment group. In this case, your new therapy failed miserably as a treatment for people with developed cancers, but it succeeded remarkably well as a treatment for precancers.

Unless you have a way of distinguishing the precancers from the cancers, you cannot adequately assess the results of a clinical trial that includes a subset of people who have the precancerous lesion!

If you are a pathologist or an oncologist, you might be thinking that this cannot occur. Patients accrued to clinical trials are carefully evaluated to ensure that they all have the same cancer and have not been misdiganosed [with precancers]. In tomorrow's blog I will show that this is not always the case. In fact, the blurring of precancers with cancers is a prevalent, but avoidable, obstacle to progress against cancer.

- © 2010 Jules Berman

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About Precancer: The Beginning and the End of Cancer. Nearly every type of cancer passes through a precancer phase, during which it cannot metastasize or invade other tissues. While medicine is not always successful in treating or curing advanced stages of cancers, recent advances in our understanding of carcinogenesis have helped us to develop strategies to prevent, diagnose, and treat many cancers at the precancer stage. Research in this field is escalating rapidly as the evidence increasingly shows that the number of annual cancer deaths could be drastically reduced through the effective treatment and cure of precancer lesions. This book begins by explaining why it has been so difficult to cure cancers, followed by a review of precancer biology, with descriptions of the most common precancer lesions. The final chapters provide practical socio-political and medical goals for precancer treatment, including discussions of the economics and politics of treating precancers.

Precancer properties

Readers of this blog know that I have a keen interest in precancers. Precancers are the lesions that precede the development of cancers. Unlike cancers, precancers are easy to treat. If we successfully treated precancers, we would stop cancers from developing.

Why are cancers so easy to treat? There are several reasons. First, precancers are fragile lesions. Spontaneous regression is common in precancers. It is easier to treat a localized lesion that is always skirting-on-the-edge of its existence, than to treat fully developed cancers, that virtually never regress spontaneously and that have metastasized to throughout the body.

In addition, fully developed cancers are biologically complex, with many different genetic and epigenetic alterations that confer their malignant phenotype (properties). When a cell has many different genetic lesions, you would expect it to be difficult (or impossible) to effectively treat cancers by targeting any single molecular alteration. This has proven to be the case. Most of the new chemotherapeutic drugs, that target specific molecules, have not proven effective at curing the common cancers (i.e., epithelial cancers of lung, colon, prostate, pancreas). However, there has been remarkable success using the newer, targeted agents, against cancers that have simple genetic alterations (such as chronic myelogenous leukemia, GIST, and a variety of rare cancers).

Because the molecular targeted therapies work best against cancers with simple genetic alterations, you can expect them to work better against the precancers than against the cancers. This is because during carcinogenesis (cancer development), genetic alterations are continuously increasing in number. Precancers will never have as many genetic alterations as the cancers into which they eventually develop. Therefore, precancers, like the tumors that respond best to molecularly targeted agents, are genetically simpler than the common epithelial cancers that account for the majority of cancer deaths.

In the next few blogs, I will discuss some of the issues related to the precancers that were not discussed in my recently published book on the subject.

- © 2010 Jules Berman

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About Precancer: The Beginning and the End of Cancer. Nearly every type of cancer passes through a precancer phase, during which it cannot metastasize or invade other tissues. While medicine is not always successful in treating or curing advanced stages of cancers, recent advances in our understanding of carcinogenesis have helped us to develop strategies to prevent, diagnose, and treat many cancers at the precancer stage. Research in this field is escalating rapidly as the evidence increasingly shows that the number of annual cancer deaths could be drastically reduced through the effective treatment and cure of precancer lesions. This book begins by explaining why it has been so difficult to cure cancers, followed by a review of precancer biology, with descriptions of the most common precancer lesions. The final chapters provide practical socio-political and medical goals for precancer treatment, including discussions of the economics and politics of treating precancers.