U.S. Cancer Death Rates: The Crude Reality

There is a rising sense that, thanks to modern medical therapies, we are finally beginning to win the War on Cancer (officially begun under President Nixon, in 1971). Since 1991, the age-adjusted rate of cancer deaths in the U.S. has been dropping. If you simply look at the graphed trend, you might assume that we can eradicate cancer in one or two more generations.

Here is the age-adjusted cancer death rate, in the U.S. for the period 1969 to 2005.



Well, reality is not exactly as it seems. First off, the data is age-adjusted. Age-adjustment is a legitimate precedure, performed by statisticians who are comparing disease rates in different populations (or in one general population at different times in history). Age-adjustment normalizes changes in disease rated caused entirely by shifts in the ages of people in the population. If a disease exclusively strikes people over the age of 60, and the population has a large increase in the over-60 population, then it would necessarily have an increase in the incidence of disease, on this basis, even when there are no medical or biological causes for the increase. To rectify this effect, statisticians "adjust" the data to normalize the distribution of ages against a standard age distribution (now, the year 2000 age distribution determined by the U.S. Census bureau).

If you want to know the impact of a disease on a population, you need to use the crude data, not the age-adjusted data (because the impact of a disease on healthcare resources and on society cannot be sensibly "adjusted").

Here is a graph of the crude death rate data for all cancers, in the United States, between 1969 and 2005



The rate of deaths per hundred thousand population, is getting worse and worse, despite a relative respite in the past decade or so.

Now, if you want to know the true burden of cancer on the population, you need to look at the total number of people dying from cancer (not the rate of cancer deaths). To find the total number of deaths from cancer, you multiply the crude death rate for each year, by the population of the U.S. during that year (obtained from the U.S. Census bureau), expressed as 100s of thousands.

Here is is the total number of cancer deaths, in the U.S. for each year from 1969-2005.



The number of people dying from cancer, in the U.S., just gets higher and higher. Again, towards the end of the graph, there are a few years where there the total number of deaths seems to have leveled off or even improved slightly.

I hope to discuss, in much more detail in a future blog, how these graphs were generated directly (the first two graphs) or indirectly (the third graph) from the NCI's SEER (National Cancer Institute's Surveillance Epidemilogy and End Results) database.

What is going on at the tail end of the graph? Is this leveling of cancer deaths due to improved treatments for cancer? We'll discuss this in a future blog.

- © 2008 Jules Berman

key words: neoplasms, cancers, tumor, tumour, epidemiology, cancer rates, cancer news, cancer trends

---

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.

Neoplasms: Book discussion

Has science helped us to understand and defeat cancer?

In the past few decades, we've learned a great deal about the genetic alterations that play key roles in carcinogenesis (the biological process that leads to cancer). Have these scientific breakthroughs reduced the cancer death rate from cancer? Have they lessened our confusion about this terrible disease?

There are literally hundreds of distinct types of cancer. Pathologists can distinguish all these cancers by their clinical, gross (the morphology of the tumor visible to the unaided eye), anatomic (location of the tumor) and histologic (the morphology of the tumor cell visualized with a microscope) features. In some cases, genetic studies further enhance our ability to distinguish one cancer from another.

Why are there different kinds of tumors? If cancer is a single disease, why is there not one single kind of cancer, representing the end-point of carcinogenesis? Every person is a unique individual, with unique genes. Why do cancers, of a specific type, have the same features when they occur in different individuals? We are told that cancers have genetic instability. If the genes in a cancer are constantly changing, should there not be an infinite number of different cancers? In fact, wouldn't you expect a single cancer to change its type, morphing from one kind of cancer into another kind of cancer, as its genes alter.

When we learn that a specific oncogene (activated cancer-causing gene) is found in a specific type of tumor, what does that tell us about cancer, in general, when other tumors do not contain the same oncogene? Can we be certain that all tumors are caused by oncogenes? What controls, or reverses, the carcinogenic process? Can we draw any conclusions about the general development of cancer, by studying a single type of cancer?

It is all very confusing.

If you want to learn something about cancer, you have a choice of two types of books. There is the basic cell biology book, that tells you about oncogenes and tumor suppressor genes and treats cancer as though it were one disease, with one biological process. Yes, the oncogene for one tumor may be a different gene than the oncogene for another type of tumor, but it is generally assumed that the same principles of cancer development apply to any tumor. There are other books that list all the different types of cancer, supplying the clinical, anatomic and histologic features that distinguish one tumor from another. Both these books fail to organize scientific and pathologic information in a manner that helps us to understand the differences and the unifying principles that apply to biological classes of human tumors.

I wrote Neoplasms: Principles of Development and Diversity, to provide the biological and clinical connections between between different types of cancers. Many of the lessons in Neoplasms come from observations that have not appeared in other books. The book begins by exploring tumor speciation (why we encounter a diversity of cancers). This is followed by employing the principles of tumor speciation to develop a useful and comprehensive tumor classification. Nothing we learn about cancer means anything if it cannot be used to reduce the number of deaths due to cancer. The third and final part of Neoplasms is devoted to cancer eradication.

Since publication of Neoplasms: Principles of Development and Diversity, on Oct 1, 2008, I've been including excerpts of this book in my blog. I'll continue to include short excerpts over the next several weeks. After that, I plan to go back to writing may random thoughts about the organization, annotation, retrieval, and analysis of biomedical information.

-Jules Berman

Neoplasms: Excerpt 9

Neoplasms: principles of development and diversity was published October 1, 2008. In the next few blogs, I will provide some short excerpts from the book.

Excerpt from CHAPTER 23 Class-Dependent Cancer Prevention, Diagnosis, and Treatment: 23.3 Why Are There So Few Tumors that We Can Now Cure?

Currently, there are just a handful of cancers that can often be cured when the cancer is discovered at an advanced stage.

Choriocarcinoma
Acute lymphocytic leukemia of childhood
Burkitt lymphoma
Hodgkin disease
Acute promyelocytic leukemia
Large follicular center cell (diffuse histiocytic) lymphoma
Carcinoma of testis
Hairy cell leukemia (probable)]

Today, all potential cancer cures are tested in clinical trials. The term clinical trial is virtually synonymous with prospective randomized clinical trial. Randomization refers to the random assignment of patients to the treated or to the untreated (or standard treatment) group. In addition to being randomized, many clinical trials are blinded so that neither the treating physician nor the patients know the assignment group during the trial.

Modern clinical trials are long and expensive. The process of testing a prospective new drug can take many years. For example, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, NIH/NCI trial NO1 CN25512) serves as an example. The PLCO is a randomized controlled cancer trial. Between 1992, when the trial opened, and 2001, when enrollment ended, 155,000 women and men between the ages of 55 and 74 joined PLCO. Screening of participants and the collection of follow-up data will end around 2016. The purpose of the study is to determine whether screening will reduce mortality from prostate, lung, colon, or ovarian cancers (302). There are thousands of different tumors, and it is unlikely (actually impossible) that we will ever come up with effective, tested treatments for each and every type of cancer. Although prospective trials are considered the only way of determining the efficacy and safety of new treatments, the public may ask whether society has the time, money, and patience to continue our current course (303).

In Chapter 15, we surveyed the six major classes of neoplasms:

1. Tumors of Class Endoderm/Ectoderm
2. Tumors of Class Mesoderm
3. Tumors of Class Neuroectoderm
4. Tumors of Class Neural Crest
5. Tumors of Class Germ Cell
6. Tumors of Class Trophectoderm

The neoplasms within each class of tumor use inherited cellular pathways to achieve the neoplastic phenotype, and many of these inherited pathways are shared among the members of a tumor class. Controlling class-dependent pathways may lead to methods of cancer treatment that will be effective for most or all of the tumors within a class. We can start to think about approaches to preventing, diagnosing and treating neoplasms that are based on the range of neoplasms that occur within a neoplasm classification.

Here are 9 prioritized strategies that use class-based methods to lower the cancer death rate [discussed at length in Neoplasms]:

1. Develop of relatively nontoxic drugs that will enhance the natural tendency of precancers to regress.

2. Continue to develop strategies to prevent cancers.

3. Continue to develop effective treatments for stem cell tumors, almost all of which are tumors of childhood and almost all of which operate through simple pathways that can be targeted by relatively nontoxic drugs.

4. Continue to develop vaccines against viral carcinogens.

5. Develop epigenomic drugs that will target germ cell tumors.

6. Develop effective treatments for tumors of mesoderm, neuroectoderm, and neural crest tumors.

7. Develop effective nonsurgical treatment for benign neoplasms.

8. Develop new diagnostic and predictive markers for cancers.

9. Use experience obtained from items 1, 3, 6, and 7 to develop targeted drug treatments for endoderm/ectoderm tumors.

(to be continued)

The full Table of Contents and Index are now available from Amazon's Neoplasms book site. In the next few days, I will continue to discuss content from Neoplasms in my blogs.

-Jules Berman

Key words: tumors, tumour, neoplasms, neoplasia, carcinogenesis, tumor development, cancer research, neoplastic development, precancer preneoplasia, preneoplastic

Neoplasms: Excerpt 8

Neoplasms: principles of development and diversity was published October 1, 2008. In the next few blogs, I will provide some short excerpts from the book.

Excerpt from the Introduction to Chapter 5, "What Can We Learn About Human Neoplasms by Studying Animals, Plants, Fish, and Insects?"

Bacteria, protoctists, fungi, plants, and animals all share constitutive molecules and pathways, and they all derive from the same primordial organism.

Unicellular organisms, bacteria and protoctists, do not develop cancer. There are bacterial mutants that grow more rapidly than their wild-type counterparts, but there are no instances of cancerous bacteria that dominate the bacterial world, replacing all bacterial flora in a biological system (such as the gut) with an unregulated mutant clone. Presumably this is because unregulated growth is not a particularly useful feature for a single-cell organism. Organisms need to know when to become quiescent. Unregulated growth, occurring when food supply is limited or when growth conditions are suboptimal, does not provide a survival advantage.

The kingdoms of plants (Plantae) and animals (Animalia) share a susceptibility to cancer. In both of these kingdoms, organisms consist of growing amalgams of different kinds of cells. The cells in plants and animals become specialized, with particular cells differentiating along particular developmental lineages due to epigenomic programming. It seems that these features (growth, multicellularity, and differentiated cell types) provide the necessary setting for the occurrence of neoplasms.

The question posed in the chapter title,"What can we learn about human neoplasms by studying animals, plants, fish, and insects?" is often misconstrued to mean, "What are the animal models for human cancer?" Sadly, much of the history of cancer research has involved the search for cancers in rodents and other animals that closely mimic some human cancer. Traditionally, if an animal tumor has a similar morphology and biological behavior to a human cancer, it is thought to be suitable for human cancer studies (testing for potential human carcinogens, developing human tumor markers, or developing new therapeutic agents). Although progress has been achieved through the "animal model" approach of comparative pathology, many detractors believe that animal models are wasteful, time consuming, and cruel. A large community of animal activists has become repulsed by large-scale testing studies on rodents and other animals and has called for the cessation of many experiments that subject animals to toxic agents and surgical procedures.

The purpose of chapter 5 is to show that we can learn a great deal about human cancer simply by observing the natural occurrences of neoplasms in plants and animals. A naturalist's approach to comparative pathology will show that we learn more by observing differences between one organism and another than by observing similarities. We see in Chapters 6 and 14 that the methods of animal classification serve as the basis for the classification of human neoplasms.

(to be continued)

The full table of contents is available. In the next few days, I will continue to discuss content from Neoplasms in my blogs.

-Jules Berman

Key words: tumors, tumour, neoplasms, neoplasia, carcinogenesis, tumor development, cancer research, neoplastic development, precancer preneoplasia, preneoplastic

Neoplasms: Excerpt 7

Neoplasms: principles of development and diversity was published October 1, 2008. In the next few blogs, I will provide some short excerpts from the book.

Excerpt from Chapter 4 Section 4.6. Precancers

Precancers are neoplastic growths that precede the development of cancers. The precancers are extremely common lesions that can often be biopsied (excised as a tissue sample) and diagnosed by pathologists. In most cases, clear-cut morphological features distinguish precancers from cancers.

Suppose this were not the case. Suppose we lived in a world wherein precancers could not be distinguished from cancers, and suppose that we had no means by which we could study the biology of these important lesions. Even if we had no physical examples of precancers,we could infer the existence of these lesions from simple observations of tumor biology.

Here is an example. In the New York Times of December 15, 2006, there was a provocative article by Gina Kolata (70). Ms. Kolata wrote:

"Rates of the most common form of breast cancer dropped a startling 15 percent from August 2002 to December 2003, researchers reported yesterday. . . . The reason, they believe,may be because during that time, millions of women abandoned hormone treatment for the symptoms of menopause after a large national study concluded that the hormones slightly increased breast cancer risk."

Here is the problem with this news. The 15% drop in breast cancer rates occurred in the interval between August 2002 and December 2003, immediately after the large drop of hormone use among the population at risk for breast cancer. For most other diseases, this might lead you to suspect causality, but carcinogenesis is a multistep process that extends over many years. Based on our understanding of carcinogenesis, there is no reason to think that a decision to discontinue a drug could possibly result in a measurable drop in cancer incidence observed the following month!

It is commonly accepted that breast carcinogenesis takes about 15 years (from initiating event to tumor detection). Let us pretend that the 15-year number is good. Then if there is a large drop of cancers beginning in August 2002, would not it make sense to look for some change in carcinogen exposure that occurred starting in August 1987? The only way around this objection is to assume that the women who opted out of hormone treatment in August 2002 (and who may have accounted for the drop in breast cancer incidence starting the following month) harbored a lesion that was not quite cancer but that could develop into cancer. The “not quite cancerous” lesions are called precancers. The observations raise the question,“Has the reduction in hormone treatment in menopausal women resulted in a decrease in the progression of precancerous breast lesions?

Decades ago, epidemiologists closely studied the effects of smoking cessation on the incidence of lung cancer. The mathematical models for smoking-induced lung cancer did not fit the observed rates in lung cancer incidence in people who had ceased smoking. Epidemiologists inferred the there must be some phase of cancer development, independent of the continuing presence of the carcinogen, that transitions to cancer when smoking stops.

These lesions, that occur after initiation and that preceded the development of cancers are called precancers. Almost every cancer occurring in humans is preceded by an obligatory precancer. Understanding and controlling these lesions are among the most important goals in cancer research.

(to be continued)

The full table of contents is available. In the next few days, I will continue to discuss content from Neoplasms in my blogs.

-Jules Berman

Key words: tumors, tumour, neoplasms, neoplasia, carcinogenesis, tumor development, cancer research, neoplastic development, precancer preneoplasia, preneoplastic

Neoplasms: Excerpt 6

Neoplasms: principles of development and diversity was published October 1, 2008. In the next few blogs, I will provide some short excerpts from the book.

Excerpt from Chapter 2 Section 2.13. Why Do Chemical Carcinogens Need to be Activated by Cells in our Bodies Before They Can Cause Cancer?

The active moieties of most chemical carcinogens will react with virtually any molecule in their vicinity: air, water, cell membrane, proteins, cytoplasm, or anything. For this reason, chemicals that are chemically reactive in their natural state are almost never carcinogens: they expend all their reactivity on nongenetic molecules before reaching the nucleus! A potent carcinogen is a molecule that can pass through membranes and through the interior of a cell without reacting with other molecules. An effective carcinogen waits until it gets near to its target molecule (DNA) before it activates. In most cases, activation is achieved within the smooth endoplasmic reticulum. In the endoplasmic reticulum are a variety of enzymes that can activate some molecules and deactivate others. Carcinogens are activated to a highly reactive species. Reactive species formed deep within a cell may find their way to DNA. Some of the DNA alterations may lead to mutations that are passed to progeny cells. Some of those mutations may lead to cancer.

There are exceptions. Some unstable molecules spontaneously achieve an active state (without the participation of cellular enzymes), but the rate at which the reactive species are generated is sufficiently slow to give the nonreactive form enough time to gain proximity to the nucleus. This is the case for several carcinogenic alkylating agents.

Other agents produce mutations in DNA without chemically reacting with bases. Intercalating agents (such as ethidium bromide) are examples of carcinogens that are not activated within cells. Silicates and so-called foreign body carcinogens and a range of inert fibers (including asbestos) do not require enzymatic activation. Still, most of the carcinogens delivered in food, air, and water are chemical carcinogens that require intracellular activation.

(to be continued)

The full table of contents is available. In the next few days, I will continue to discuss content from Neoplasms in my blogs.

-Jules Berman

Key words: tumors, tumour, neoplasms, neoplasia, carcinogenesis, tumor development, cancer research, neoplastic development, precancer preneoplasia, preneoplastic

Neoplasms: Excerpt 5

Neoplasms: principles of development and diversity was published October 1, 2008. In the next few blogs, I will provide some short excerpts from the book.

Excerpt from Chapter 2 Carcinogenesis (Section 2.9: Tumor Dormancy):

Dormancy occurs when an established cancer (one that has passed through the stages of initiation, latency, and precancer) stops growing for a period of time. When people use the word dormancy, they are usually referring to one of three situations

Examples of tumor dormancy.

1. A patient has an invasive brain tumor and has refused any form of therapy. The tumor is followed by radiologic imaging at regular intervals. The tumor that had been growing suddenly ceases to grow, for several years, before resuming growth.

2. An invasive primary tumor is excised. There is no evidence at the time of excision that the tumor has metastasized. Several years later, the patient develops clinically obvious metastatic lesions in multiple organs.

3. A patient with carcinoma is diagnosed with cancer. The cancer is staged. Several regional lymph nodes (near the primary cancer) are found to have small deposits of metastatic cancer. The patient is treated with excision of the primary tumor followed by intensive chemotherapy. Several years later, the patient develops clinically obvious metastatic lesions in multiple organs.

In each of these cases, the tumor undergoes a period of dormancy. Biologically, each instance of dormancy is a distinctly different process. In the first instance, an entire tumor ceased growth. In the second instance, occult metastases (i.e., metastases that were not evident at the time of diagnosis) persisted without noticeable growth for some period of time before becoming clinically obvious. In third instance, a patient with known metastatic cancer was treated with systemic chemotherapy. The metastatic lesions survived chemotherapy and eventually grew to become clinically detectable masses.

The phenomenon known as tumor dormancy probably represents several different processes that have the same observed outcome: growth cessation and growth renewal of a formerly growing neoplasm. In the case of the second instance (occult metastases growing after a period of time), we can speculate that the process of metastasis selected for a cell that escaped from a primary tumor and settled in a distant anatomic site. The selection process for a metastatic cell may not have favored a cell that was particularly well equipped to grow into a thriving clone. It is likely that most metastatic cells die without producing clinically detectable metastatic lesions. The emergence of a growing metastatic subclone may have required multiple successful generations of very slow growth, during which a fast-growing descendant cell was selected.

(to be continued)

The full table of contents is available. In the next few days, I will continue to discuss content from Neoplasms in my blogs.

-Jules Berman

Key words: tumors, tumour, neoplasms, neoplasia, carcinogenesis, tumor development, cancer research, neoplastic development, precancer preneoplasia, preneoplastic

Neoplasms: Excerpt 4

Neoplasms: principles of development and diversity was published October 1, 2008. In the next few blogs, I will provide some short excerpts from the book.

Excerpt from Chapter 2 Carcinogenesis (Section 2.8: Latency):

The latency period is the time between exposure to a carcinogen (the initiating event) and the emergence of a detectable neoplasm. The latency period is one of the least understood aspects of carcinogenesis.

We know that in some experimental systems, after initiation, the initiated cells look like normal cells and can participate in normal differentiation. Gestl and coworkers used a transgenic mouse strain containing the Wnt oncogene, but in which Wnt expression is doxycycline dependent (30). These transgenic mice, when provided with doxycycline in their diet, will almost always develop Wnt-initiated mammary adenocarcinomas.

In this system, the process of postinitiation carcinogenesis can be interrupted by simply withdrawing doxycycline from the diet of the mice. Initiated mammary tissue can be transplanted into cleared fat pads of uninitiated transgenic mice (that have not had doxycycline in their diets) and then observed. The initiated mammary tissue, now growing without the influence of the Wnt oncogene, grows as normal mammary explants, producing ducts and lobules that are indistinguishable from the ducts and lobules of normal mammary tissue. If doxycycline is added to the diet of the mice receiving the transplants, the initiated tissue resumes its carcinogenic pathway to quickly yield multiple synchronous carcinomas. This tells us that initiated cells can look and behave like normal cells, under experimental conditions. Because tumors arose rapidly after doxycycline-dependent Wnt expression was restored, it suggests that the growth of initiated (but latent) cancer foci can be manipulated. This means that we may be able to develop new therapeutic interventions that stop the growth of latent cancers.

Currently, nobody knows all the conditions that lengthen or shorten the latency period. Because carcinogenesis is a multistep process, we can guess that very condition that modifies early steps in carcinogenesis will have some effect on the latency period.

In carcinogenesis experiments, we can expose a large number of rodents of a single strain, gender, and age to a single carcinogen at the same dose. In the 1970s, cancer researchers used this approach to investigate whether the initiating dose of a carcinogen would modify the latency period. Specifically, they wanted to determine whether low doses of a carcinogen would result in a latency period that exceeded the life expectancy of the animal. If this were the case, there would be no practical problem with exposing animals (or people) to doses of carcinogen that produce a longer-thanlifetime latency.

Many rodent trials ensued. Latency was measured as the time between initiation and the time that the first tumor occurred. It is not surprising that high doses of carcinogen produced short latency periods. Low doses of carcinogen resulted in long latency periods. Very low doses of carcinogen produced very long latency periods. Extremely low doses of carcinogens usually produced no more tumors than no carcinogen at all.

In a mathematical analysis conducted in 1977,Guess and Hoel showed that these prior measurements of tumor latency were simply manifestations of dose-dependent changes in tumor incidence. If a high-dose drug produces many more tumors than a low-dose drug, and if the tumor latency period is random (i.e., not determined by the dose of drug), you would see that tumors occurred earlier in the high-dose subjects.Why? The more tumors that occur, the likelier it would be that some tumors will occur early rather than late. If a low-dose carcinogen produces very few tumors, the time before the first tumor develops will likely be longer, simply because there are fewer tumors (31). Today, low-dose risk extrapolations take into account dose-dependent changes in tumor incidence.

Despite decades of research, tumor latency remains one of the murkiest areas of carcinogenesis.We do not know whether there is a safe dose for carcinogen exposure.

(to be continued)

The full table of contents is available. In the next few days, I will continue to discuss content from Neoplasms in my blogs.

-Jules Berman

Key words: tumors, tumour, neoplasms, neoplasia, carcinogenesis, tumor development, cancer research, neoplastic development, precancer preneoplasia, preneoplastic

---

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.

Neoplasms: Excerpts 3

Neoplasms: principles of development and diversity was published last week. In the next few blogs, I will provide some short excerpts from the book.

Excerpt:

In metastasis, tumor cells leave the primary tumor site and travel to some anatomically distant (or at least noncontiguous) location, where they form a growing mass. There are many steps involved in metastasis, and it is no wonder that metastasis is a late event in carcinogenesis that follows the acquisition of invasiveness.

Steps in Metatastasis

1. A tumor cell must invade through the wall of a lymph vessel or a blood vessel.

2. Once inside the vessel, the tumor cell must be carried away from the primary tumor to another site, still within the vessel, where it may reside for some indeterminate time.

3. The tumor cells residing inside the lymphatic vessel must invade through the vascular endothelium into the surrounding tissue.

4. The invading cell or cells must begin to grow.

5. The growing colony must adjust to its new microenvironment and must eventually attract the growth of vessels from which it can derive oxygen and other external nutrients.

Each of the steps of metastasis provides opportunities for a fledgling clone of tumor cells to die, and each step may take time (days, months, or years) while the clone acquires the biological prerequisites for the next step. The time between the seeding of a tumor cell into the lymphatic circulation (the small vessels that lead to lymph nodes), and the clinical observation of a metastatic growth, is called dormancy. Dormancy is discussed in depth in Chapter 2. The time between tumor seeding and the appearance of a metastatic lesion can depend on a great many factors. If the seeded tumor cells have all of the properties necessary to complete the steps of metastasis, then a metastasis may become clinically apparent soon after the primary tumor has begun to invade. For example, if cells were seeded by a metastatic lesion (not from the primary tumor), then the second generation metastatic cells might arrive at their metastatic site pre-equipped for successful growth. In this case, metastases might occur quickly. Alternately, host factors (properties of the non-tumorous cells of the organism) may provide barriers to tumor metastasis. For example, tumor cells that have seeded into the lymphatics might be filtered, trapped, and destroyed in lymph nodes through an immunologic reaction.

Given the complexity of metastasis, you might think that only malignant cells could manage the task. Surprisingly, metastasis is also seen in normal tissues. All blood cells move through the circulation through a process indistinguishable from metastasis. White bloods cells (leukocytes), in response to inflammatory chemokines, will attach to a vessel wall, move through the wall, and proceed to invade local tissues until they arrive at the site of inflammation (the site of highest chemokine concentration). Leukocytes are all highly invasive and metastatic. The only feature that distinguishes normal leukocytes from cancer cells is their controlled growth. The growth of the leukocyte population in response to an infectious process is self-limited. Growth stops when the infection ceases. The most significant clinical property that distinguishes physiological neutrophilia (increase in neutrophils, the most common type of leukocyte) from chronic myelogenous leukemia (the neoplasm caused by an increase in neutrophils) is growth persistence. Chronic myelogenous leukemia gets worse and worse over time. Physiologic neutrophilia eventually plateaus or returns to normal levels.

In Chapter 9, we examine some nonmalignant proliferative disorders of myeloid and lymphoid cells, all of which have clinical features that closely resemble leukemias and lymphomas.

In chinchillas, the normal placenta both invades and metastasizes (5). Trophoblastic tissue invades into uterine vessels, passes into the general circulation, and seeds the lungs. It is normal for a chinchilla mother to harbor pulmonary placental nodules that persist for up to 2 months after delivery. In humans, trophoblastic invasion of the myometrium must be well controlled. Otherwise, harm can come to fetus and mother. Placenta accreta occurs when the placenta attaches directly to the myometrium with deficient development of decidual (maternally-derived) cells between the invading trophoblasts and the myometrium. If the placenta invades deeply into the myometrium, this is called placenta increta. If the placenta invades through the myometrium, this is called placenta percreta. All three conditions are associated with medical risks to baby and mother. We discuss human gestational trophoblastic disease in Chapter 20.

(to be continued)

Chapter 1 Table of Contents:

1 What Properties Are Shared by All Cancers? 3

1.1 Background 3

1.2 Are There Any Properties of Neoplasms that Are Not Found in Normal Cells? 4

1.3 Persistent Growth in Normal Cells 4

1.4 Invasion by Normal Cells 5

1.5 Metastasis by Normal Cells 5

1.6 Is There a Common Temporal Sequence Leading to the Development of Cancer? 7

1.7 Why Is It Important to Treat Cancers Early? 7

1.8 Cancer Morphology 8

1.9 General Rules for Naming Neoplasms 8

1.10 What Is a Cytologic Diagnosis? 9

1.11 Morphology of Malignant Cells 10

1.12 Cancerous Atypia and Reactive Atypia 12

1.13 How Can You Distinguish Reactive Atypia from Cancerous Atypia? 13

1.14 Dysplastic Cells and How They Differ from Cancer Cells 14

1.15 Nuclear Atypia in Cancer Cells 15

1.16 Why Are the Nuclei of Malignant Cells Different from Nuclei of Normal Cells? 15

1.17 Tumor Monoclonality 15

1.18 Monoclonal Proliferative Lesions 16

1.19 Clonal Expansion in Paroxysmal Nocturnal Hemoglobinuria 17

1.20 Clonal Expansions of Normal Cells that May Not Lead to Cancer 18

1.21 Polyclonal Expansions that May Lead to Monoclonal Cancer 18

1.22 Tumor Growth Regulation and Tumor Autonomy 18

1.23 Limits on Tumor Autonomy 19

Summary 19

The full table of contents is available. In the next few days, I will continue to discuss content from Neoplasms in my blogs.

-Jules Berman

Key words: tumors, tumour, neoplasms, neoplasia, carcinogenesis, tumor development, cancer research, neoplastic development, precancer preneoplasia, preneoplastic

Neoplasms: Excerpts 2

Neoplasms: principles of development and diversity was published last week. In the next few blogs, I will provide some short excerpts from the book.

Excerpts:

Cancer cells do not create new biological properties. They use the same properties that normal cells use, only they tie them all together in a package that nobody wants to receive.

....

Invasion is a biological property that is shared by neoplastic and certain normal tissues.An example of an extreme formof normal tissue invasion is found in gestational implantation and placentation. In implantation, the blastocyst (the early embryo) attaches to the endometrium (the lining of the uterus) and invades into the uterine wall. In placentation, the uterine spiral arteries (of the mother) are invaded by trophoblast cells of the embryo. Implantation and placentation occur quickly. Normal trophoblastic invasion matches or exceeds the most aggressive invasion seen in neoplasms.

(to be continued)

Chapter 1 Table of Contents:

1 What Properties Are Shared by All Cancers? 3

1.1 Background 3

1.2 Are There Any Properties of Neoplasms that Are Not Found in Normal Cells? 4

1.3 Persistent Growth in Normal Cells 4

1.4 Invasion by Normal Cells 5

1.5 Metastasis by Normal Cells 5

1.6 Is There a Common Temporal Sequence Leading to the Development of Cancer? 7

1.7 Why Is It Important to Treat Cancers Early? 7

1.8 Cancer Morphology 8

1.9 General Rules for Naming Neoplasms 8

1.10 What Is a Cytologic Diagnosis? 9

1.11 Morphology of Malignant Cells 10

1.12 Cancerous Atypia and Reactive Atypia 12

1.13 How Can You Distinguish Reactive Atypia from Cancerous Atypia? 13

1.14 Dysplastic Cells and How They Differ from Cancer Cells 14

1.15 Nuclear Atypia in Cancer Cells 15

1.16 Why Are the Nuclei of Malignant Cells Different from Nuclei of Normal Cells? 15

1.17 Tumor Monoclonality 15

1.18 Monoclonal Proliferative Lesions 16

1.19 Clonal Expansion in Paroxysmal Nocturnal Hemoglobinuria 17

1.20 Clonal Expansions of Normal Cells that May Not Lead to Cancer 18

1.21 Polyclonal Expansions that May Lead to Monoclonal Cancer 18

1.22 Tumor Growth Regulation and Tumor Autonomy 18

1.23 Limits on Tumor Autonomy 19

Summary 19

The full table of contents is available. In the next few days, I will continue to discuss content from Neoplasms in my blogs.

-Jules Berman

Key words: tumors, tumour, neoplasms, neoplasia, carcinogenesis, tumor development, cancer research, neoplastic development, precancer preneoplasia, preneoplastic