Principles of Tumors

USA

Preface and Acknowledgments

Tumors comprise a large number of complex diseases. Understanding their natures and developing adequate therapies for them have long been recognized as among the greatest challenges to medical science.

In recent decades, there has been enormous growth in our knowledge of all aspects of tumors. These include, particularly, the basic biological abnormalities in tumors, the genomic disturbances in tumor cells, as well as the ways in which tumors may be diagnosed, treated, and prevented.

With this progress almost every area of research and practice relating to tumors has acquired new concepts, which in many instances are supported by their own extensive literature.

It has become difficult for students intending on a career in one or other of the disciplines relating to cancer research or practice—as well as established practitioners and research workers involved with tumors—to approach easily many of the basic issues in areas outside their primary area of activity.

This book has been written as a guide to the principles of the issues in the major areas of cancer research and practice. The emphases have been threefold:

i. To explain the principles, terminology, and concepts in the major areas of tumor research and practice. The overall readability of the overall work has been enhanced by arranging the topics in the traditional order of history, definition, incidence, classifications, etiology and pathogenesis, morphology, therapy, and prevention.

ii. To give accounts of interfaces between different areas where translational approaches may be most valuable. A major example of these is the relationships between the complex morphologies of tumors and their genomic disturbances. Another is the application of appropriate statistical methods to the many different areas of tumor research and practice, especially epidemiology and classification, etiology, therapy, and prevention.

iii. To provide up-to-date references for reviews and further reading in the areas discussed. This has been possible only through the databases accessible through the World Wide Web, especially PubMed, provided by the National Library of Medicine, Washington, DC.

The editors, Cassie van der Laan and Lisa Eppich, are thanked for their patience with what has been a long process of preparing the book.

Familiarity with the works of the early German pathologists and tumor theorists is owed to Emeritus Professor Brian Coghlan and Associate Professor Hubertus Jersmann. Previous collaborations with them have produced translations of works of the nineteenth century pathologists, especially those of David Paul von Hansemann (1858–1920) and Rudolf Virchow (1821–1901).

The University of Adelaide has provided access to the Barr-Smith Library, and the staff there has been of great assistance in retrieving older and recent material on tumors from its collection. The staff of the Library of the Royal Adelaide Hospital and SA Pathology is also thanked for the prompt retrieval of many less-common references.

Many of the photographs have been prepared by the Department of Photography, SA Pathology.

Others who have provided advice and assistance include James Bignold, Monica Bignold, Maria Collis, Peter Dent, Peter Gillam, Soula Grech, Douglas Handley, Wolfgang von Hansemann, Damien Harkin, Sarah Moore, Mary Peterson, Warwick Ruse, Mark Stevens and Peter Sutton-Smith.

Chapter 1

Introduction

This chapter is designed for readers who have little or no prior knowledge of tumors. It summarizes in plain English the main, fundamental topics in the other chapters, excluding Chapter 10. The sections of the chapter are in the same order as the chapters in the book. Thus Section 1.1 summarizes Chapters 1–3. Section 1.2 summarizes Chapters 4–7. Section 1.3 summarizes Chapters 8 and 9. Section 1.4 summarizes Chapters 11–13. Section 1.5 summarizes Chapter 14.

Keywords

Tumors; causation; molecular pathology; micro-metastases; clinical features; treatments

Outline

1.1 Essential Aspects of the Nature, Types, and Rates of Incidence of Tumors 2

1.1.1 Tumors Used in the Sense of True Tumors 2

1.1.2 Classifications and Terminology of the Tumor Types 3

1.1.3 Incidences Especially of Malignant Tumor Types 5

(a) General 5

(b) Influence of Ageing Populations 5

(c) Incidences of Tumor Types According to Kind of Parent Cell 5

(d) Use in Medical Practice 6

1.1.4 Epidemiology of Tumors 7

1.1.5 Uses of Animals in Research into the Aspects of Human Tumors 8

1.2 Basic Aspects of Etiopathogenesis 9

1.2.1 Etiological Factors 9

1.2.2 Pathogenesis: DNA Damage 10

1.2.3 Cancer Genes in Pathogenesis 11

(a) When the Genomic Events Occur Entirely in the Somatic Cell (i.e., Without Germ-Line Genomic Alteration) 12

(b) Requiring Germ-Line Alteration as Well as a Somatic Alteration in the Genome 12

(c) Cell Signaling in Normal Growth Control 13

1.3 Abnormalities in Morphology and Molecular Pathology 15

1.3.1 Background 15

1.3.2 Grading of Tumors 15

(a) General 15

(b) Grading of Carcinomas of the Lung 16

(c) Grading of Carcinomas of the Breast 16

(d) Grading of Carcinomas of the Large Bowel (Colon and Rectum) 16

(e) Grading of Carcinomas of the Prostate 16

1.3.3 Staging of Cases of Tumor 16

(a) General 16

(b) Staging of Carcinoma of the Lung 17

(c) Staging of Carcinoma of the Breast 17

(d) Staging of Carcinoma of the Large Bowel (Colon and Rectum) 17

(e) Staging of Carcinoma of the Prostate 17

1.3.4 Importance of Micro-Metastases 17

1.3.5 Molecular Pathology and Other Nonmorphological Features of Tumor Cells 18

1.4 Fundamental Aspects of Clinical Features and Treatments 18

1.4.1 Principles of Symptoms and Signs of Tumors 18

(a) Skin 19

(b) Respiratory Tract 21

(c) Female Breast 21

(d) Alimentary System 22

(e) Hematopoietic and Lymphoid Systems 22

(f) Female Genital 22

(g) Male Genital 23

(h) Nervous System 23

(i) Urinary System 23

(j) Skeletal System 23

(k) Other Systems: Including Endocrine and Special Senses 23

(l) Progression 23

(m) Miscellaneous Clinical Features of Tumors 24

1.4.2 Diagnosing Suspected Cases of Tumor 24

1.4.3 Surgery 24

1.4.4 General Aspects of Nonsurgical Treatments 26

1.4.5 Radiation Therapies 26

1.4.6 Anticancer Drug Therapies 27

1.4.7 Relapses 27

1.4.8 Common Side Effects of Nonsurgical Anticancer Therapies 28

1.4.9 Lifetime Limits of Doses of Certain Anticancer Therapies 28

1.5 Prevention 29

References 29

Tumors are autonomously growing accumulations of cells which occur in types characterized by distinct, variable combinations of variable differences from their respective kinds of cell of origin. The natures and causes of most of the types of tumors are not well understood. The types which invade adjacent tissues and metastasize to other parts of the body are liable to cause death if untreated.

This chapter summarizes the fundamental aspects of tumors as a basis for the discussions of topics in the following chapters. Much of the material will be at familiar to medical students, as well as to many bioscience students in disciplines such as molecular biology, cell biology, and genetics.

The general principles of normal histology which are relevant to tumors are outlined in Appendix 1. The general aspects of the human genome are described in Appendix 2.

1.1 Essential Aspects of the Nature, Types, and Rates of Incidence of Tumors

1.1.1 Tumors Used in the Sense of True Tumors

In its most general sense, a tumor is any swelling in the body. The term can be applied to a wide variety of conditions including physiological swellings such as a normal pregnant uterus, as well as to pathological swellings such as inflammations (see Section 11.1). In this book, as in most medical situations, the term tumor is used as a synonym for neoplasm or true tumor.

All tumor cells are irreversibly modified normal cells. As a result, tumor cells have two sorts of hereditary characteristics [1]:

i. Those which are particular features of their parent cell and are retained to greater or lesser extents.

ii. Those which are effects of the genomic event associated with tumor.

Tumor cells usually have the following characteristics:

i. The cells have morphological and behavioral abnormalities in comparison with the parent kind of normal cell. They also have different and variable life spans compared to their parent kinds of cells.

ii. While tumor cells individually are not immortal, the cell population of each case of tumor is immortal, in the sense that the population almost invariably continues to grow without any tendency to regress or heal.

iii. In many cases, with time, tumor cell populations show progressive increases in morphological and other abnormalities. The populations virtually never spontaneously revert to less malignant populations.

The degrees of retention of parental features and the degrees of intensity of the acquired abnormalities are highly variable between different tumors. The variability is seen at three levels: between different types of tumors, between different cases of the same kind of tumor, and between different foci in individual cases of tumor.

While the distinction between tumors and nontumorous lesions is usually easy, pathologists recognize many clinicopathological conditions as tumor-like. Examples include benign hyperplasias of the breast and prostate gland.

1.1.2 Classifications and Terminology of the Tumor Types

Tumors comprise a thousand or so different types. How these types are recognized and the differences between them are described in multivolume works such as the Armed Forces Institute of Pathology’s Atlas of Tumor Pathology [2] and the World Health Organization Classification of Tumours [3]. The diversity of the tumor types also applies to their clinical behavior and responses to therapies. This is the basis of the complexities which are apparent in clinical oncology [4–7].

The different types of tumors are classified according to three main criteria:

i. The first criterion is the broad category of parent cell of origin as listed in Appendix 1 (Section A1.2.1). The categories are mainly epithelial cells, hematopoietic and lymphoid cells, nervous system cells, melanocytes, soft tissue cells, hard tissue cells, etc.

ii. The second criterion for classification is the exact kind of parent cell within the organ system from which the tumor arose. All of the broad categories of cells (Section A1.2.1) comprise more than one kind of cell. Thus the epithelial cells of the epidermis, mucosa of the intestine, kidney tubules, and thyroid follicles have significant differences, one from another. The cells in almost all types of tumors resemble only a single particular kind of normal cell which is located at the site of the tumor.

iii. The third criterion is according to whether the tumor is benign or malignant (Figure 1.1). Clinically, this is the most significant division of tumors, as has been understood for several centuries [8].

Figure 1.1 Main differences between benign and malignant tumors.

Benign types of tumors:

i. Grow slowly.

ii. Have well-circumscribed margins and bulge or displace, but do not invade, local vessels or adjacent organs. No metastases occur.

iii. May compress adjacent structures, but otherwise do little anatomical damage.

Thus benign tumors usually do not harm the individual and are relatively easily removed by surgery.

In contrast, malignant types of tumors are extremely serious because they commonly grow rapidly. They tend to have irregular margins, and they frequently invade and destroy adjacent structures. These structures often include nearby blood vessels and lymphatic vessels. Via the lumina of these vessels and occasionally other avenues, tumor cells often then spread to distant sites as micro-metastases, which, with time, may grow into macro-metastases.

Many cases of malignant tumors are not removable by surgery, because at the time of diagnosis, they have already invaded a structure in the body which cannot be cut. The tumor is said to be unresectable.

Because of all these features, malignant tumors are liable to cause the death of the patient.

These criteria of classification are the basis of the general terminology of tumors. The solid tumor types (i.e., excluding hematopoietic tumors) are named primarily by their site, their parent cell, and then as benign or malignant. By convention, benign tumors of epithelial cells are usually called adenomas, and malignant tumors carcinomas. Benign tumors of soft and hard tissue cells are referred to by the kind of cell of origin with the suffix -oma. Malignant tumors of such cells are indicated by the suffix -sarcoma.

Thus a tumor might:

i. occur in the uterus (uterine);

ii. arise from a smooth muscle cell (leiomy-);

iii. behave in a benign fashion (-oma).

Such a tumor is called a uterine leiomyoma.

Another tumor might:

i. occur in the stomach (gastric);

ii. arise from a glandular epithelial parent cell (adeno-);

iii. behave in a malignant fashion (-carcinoma).

Such a tumor thus is named a gastric adenocarcinoma.

By way of exceptions, leukemias are generally named according to kind of leukocyte involved and the stage of specialization which the majority of leukemic cells appear to have achieved [9]. This is discussed further in Section 8.6.

Within the group of tumors arising from lymphocytes in lymph nodes, the major division is between Hodgkin’s and non-Hodgkin’s lymphomas. The further classification of these tumors is complex and has been revised frequently in the last few decades (see Section 3.4 and Refs. [9–11]).

Tumors of cells of the nervous system and melanocytes have complex terminologies and classifications, which can be found in relevant special texts [12,13].

1.1.3 Incidences Especially of Malignant Tumor Types

(a) General

If all benign and malignant tumors of all organs including naevi and other benign skin tumors are taken into account, then the majority of people in the world will develop one or other kind of tumor in their lifetime. However, only data on malignant tumors excluding the epidermal malignancies are collected by national agencies such as the Centers for Disease Control [14], and internationally, by the World Health Organization (WHO) [15] in association with the International Agency for Research on Cancer (IARC). Major differences in incidences of tumors occur according to geographical region (Figure 1.2) and by type of tumor (Figure 1.3).

Figure 1.2 Incidences and mortality of malignant tumors according to geographical region. The data show significant differences in reported incidence of all cancers combined in different parts of the world. The differences in reported mortality are much less marked than are the differences in incidences. ASR (W) = Age-Standardized Rate (World). Reproduced with permission from the IARC.

Figure 1.3 World incidence and mortality rates of malignant tumors by type. The data show significant differences in the reported incidence of the different types of cancer world-wide. The differences in reported mortality are much less marked than are the differences in incidences. Reproduced with permission from the IARC.

Worldwide, malignant tumors account for approximately 12% of all deaths [15,16], while in the United States, the proportion of deaths due to malignant tumors is approximately 23% [17].

(b) Influence of Ageing Populations

In the last century, tumors of almost all types have become more common in most populations in the world. This is mainly explained by declines in deaths due to infectious, cardiovascular, and other nontumorous diseases. These declines have resulted in longer average life spans of individuals in these populations. Hence more people are living to the ages at which tumors become most frequent (30–70 years) and so the incidence of tumors has risen. The association of the increased incidence of tumors with modern living conditions can be explained on this basis of increasing longevity. No evidence of any general age-adjusted increase for most types of tumors has been established [18].

(c) Incidences of Tumor Types According to Kind of Parent Cell

An obvious, but puzzling, point about the tumor types is that their incidences differ enormously according to their kind of cell of origin. For example, skeletal muscle fibers—which contain a large proportion of all the cell nuclei in the entire body, and which are capable of mitosis in healing or reactive nontumorous pathological conditions—very rarely give rise to benign tumors (rhabdomyomas) and only slightly more commonly to malignant tumors (rhabdomyosarcomas). However, the adipocytes and fibrocytes—which are located between the muscle fibers and presumably exposed to carcinogens in similar amounts—much more frequently give rise to both benign and malignant tumors of various types, although their nuclei are much fewer in number than are those of the skeletal muscle fibers.

Another slightly more complicated example is that tumors of smooth muscle cells are much more common in the uterus than in the intestine. There is much more smooth muscle in the latter organ than the former. Both kinds of smooth muscle are subject to the progestogen hormones, but the intestinal smooth muscle is insensitive to them physiologically. Hence the difference between the two organs may be associated with sensitivities to these hormones. Nevertheless, pregnancy is not the cause of uterine leiomyomas; in fact child-bearing protects against these tumors [19].

(d) Use in Medical Practice

Knowledge of the incidences of tumor types is important in everyday medical practice. The different types of tumors occur at markedly different rates not only according to the kind of parent cell (Section 1.1.3), but also by age and gender of the patient. For example, certain tumors such as retinoblastoma occur only in children. Others such as osteogenic sarcoma are commonest in young adults. This particular type of tumor, however, may complicate Paget’s disease of bone, such that a second peak of its incidence occurs in old age. Carcinomas of the thyroid gland are more common in females than in males, while the reverse applies to carcinomas of the esophagus.

These facts assist the process of medical diagnosis because the practitioner can have a good idea of what the type of tumor is likely to be simply on the basis of these features of site, age, and gender.

1.1.4 Epidemiology of Tumors

Epidemiology is the scientific discipline concerned with collecting and analyzing data—usually involving statistical methods—of the incidences and related issues of the different types of diseases, including tumors.

The incidences of tumors in most Western countries are assessed through reports of diagnoses of malignant tumors to national- or state-based cancer registries (see Chapter 3). The data collected are essential for the planning of provision of health services. This is because government and private agencies must make decisions concerning allocation of resources between services for all the different categories of diseases, such as neurodegenerative, cardiovascular, and infectious disorders, as well as to tumors.

Epidemiological methods are also often used to assess:

i. possible hereditary factors in tumor causation (Chapter 7);

ii. possible environmental carcinogens and hence lead to appropriate preventative measures (Chapter 14);

iii. the efficacies of methods of treatments of the different types of tumors (Chapters 11–13). This is becoming increasingly important in all countries, because the costs of best practice care for cases of malignant tumors are threatening to become unaffordable in many countries.

1.1.5 Uses of Animals in Research into the Aspects of Human Tumors

Understanding all the complex issues in human tumors represents one of the major challenges of biomedical science. Certain kinds of research, especially experiments, obviously cannot be conducted in humans. As a result, for over a century, experiments have been conducted using experimental animals as surrogates for humans.

The experiments in which animals can be used include understanding the etiology and pathogenesis of carcinogens, the efficacies or otherwise of anticancer therapies, and the value or otherwise of putative preventative measures (Figure 1.4A). A particular valuable feature of experimental studies is that the growth of tumors can be monitored in the animals by the same techniques (Figure 1.4B) as are used in clinical practice for cancer patients. This also adds the dimension that tumors in animals may be used to test the qualities of imaging technologies in ways which would otherwise not be possible.

Figure 1.4 (A) General uses of animals in research into human tumors. (B-D) Techniques which allow also imaging of growth of a tumor in an experimental animal.

1.2 Basic Aspects of Etiopathogenesis

Causation of a disease involves two parts: etiology and pathogenesis (Figure 1.5).

i. Etiology is concerned with the causative factors

ii. Pathogenesis is how the etiological factors cause the lesions in the body.

Figure 1.5 General scheme of etiology and pathogenesis applicable to all diseases.

Considerations of these two parts frequently become intertwined so that the term etiopathogenesis is used.

1.2.1 Etiological Factors

This aspect of tumors receives enormous attention in the public arena as well as in scientific circles. Answers to the question what things cause tumors? are of great general interest, as can be seen almost daily in the newspapers and other mass media platforms. The scale of the problem is enormous because in this relative vacuum of reliable information—which determines the advice a clinician might give concerning preventative action—there are many suggestions for causes of these diseases. New findings regarding possible causes of these latter kinds of tumors are reported not just in the biomedical literature but in the lay media as well. Almost every aspect of the general environment, diets, occupations, socioeconomic levels, and lifestyles of humans has at one time or another been reported as associated with—and hence identified as a possible risk factor for—causation of tumors.

As one indication of the information given to the public, a search in a leading New York newspaper in the 2013 calendar year for references to causes of cancer retrieved 2,330 results [20] including suggestions that using cell phones may cause brain cancer; breast implants and estrogen therapy may contribute to breast cancer; particular bacteria may cause colon cancer; formaldehyde may cause myeloid leukemia; and as well, that ethanol, hormones, tungsten particles, sugar, and many other diverse substances or activities may cause cancers of various types.

Various etiological agents for tumors are established, but most of them are relevant to only one or a few types of tumors [21–23] (Table 1.1). For example, ultraviolet B (UVB) radiations cause carcinomas of the epidermis and melanomas (UVA is noncarcinogenic). Some chemicals in tobacco cause carcinoma of the bronchi. A few particular viruses contribute to a small number of types of tumors in humans. For example, the Epstein–Barr virus is associated with Burkitt’s lymphoma, human herpes virus 8 with Kaposi’s sarcoma in the acquired immunodeficiency syndrome (AIDS), and some strains of human papilloma virus (HPV) with carcinoma of the uterine cervix.

Table 1.1

Common Etiopathogenetic Factors for Common Tumors

Certain hereditary predispositions to specific types of tumors, such as to neurofibromatosis and retinoblastoma, are known. Inheritance of predispositions to all types of tumors—i.e., a generalized susceptibility to all tumor types—has been suggested for centuries, but has never been confirmed [24,25].

Generally, it must be recognized that, except for carcinoma of the lung and epidermis, the causes of many of the other common malignancies, e.g., of the colon and rectum, the breast, prostate, and pancreas, are largely unknown.

1.2.2 Pathogenesis: DNA Damage

The pathogenesis of tumors attracts much less public attention than etiological factors, but is nevertheless an essential part in the causation of tumors. The fundamental concept in pathogenesis is that if an agent causes a change in a cell, then first, the agent must affect some chemical structure in the cell such that the function of the structure is changed. Then, second, the change in function of the target structure must then result in the observable changes in the cell.

For most pathological processes, the change caused by the etiological factor is usually one of reduction or loss of one or other metabolic capacity. However, in tumors, the change is characteristically a gain in the function of cell multiplication.

In relation to carcinogens and tumors, the most widely accepted idea of pathogenesis is that carcinogens react with the DNA in the normal cells (Figure 1.6). The major kinds of damage to DNA are shown in Figure 1.7. Damage to individual sites on nucleobases is discussed in Section 5.1. The damage to DNA is thought to cause alterations in the nucleotide sequences during repairs of existing DNA or synthesis of new DNA (see Sections 5.1 and A2.1.4). These altered sequences then cause the phenotypic changes which characterize tumor cells.

Figure 1.6 Overview of the major theory of tumor formation by carcinogens.

Figure 1.7 Major categories of damage to DNA. For intercalations see Figure 4.8, and for nucleobase changes and modifications see Figures 5.2 and 5.3.

There are many kinds of genomic events (see Chapter 5) which can result in errors in nucleotide sequence. First there are substitutions, insertions, and deletions affecting one or two nucleotides. Of note here is that an insertion or deletion of any number of nucleotides, which is not a multiple of three, results in a frameshift event, which affects up to thousands of consecutive nucleotides in one section of DNA. Second, there are deletions, insertions, amplifications, transpositions, and inversions of parts of chromosomes from tens or a few hundreds of nucleotides to microscopically visible parts of chromosomes (chromosomal aberrations).

1.2.3 Cancer Genes in Pathogenesis

The next step—exactly what part of the genome, when altered, causes tumors—has been pursued mainly in terms of genomic events in exons of genes. Broadly, these occur in two groups (Figure 1.8).

Figure 1.8 In-principle differences between growth factor–oncogenes and tumor suppressor genes.

(a) When the Genomic Events Occur Entirely in the Somatic Cell (i.e., Without Germ-Line Genomic Alteration)

The genes in this category are often referred to collectively as oncogenes [26]. They include:

i. Insertion of viral DNA into the genome of a somatic cell. These viral oncogenes have been identified in extracts of the human tumors, e.g., the Epstein–Bar virus in Burkitt’s lymphoma [27].

ii. Induced hyperactivation of one or more endogenous genes. An example of this is the Rous sarcoma virus [28].

All of these genes have been identified mainly on the basis that, when transfected into cells cultured in vitro, they induce a change known as malignant transformation (Section 14.2.3).

(b) Requiring Germ-Line Alteration as Well as a Somatic Alteration in the Genome

These are less common than the oncogenes and number approximately 20. These are usually referred to as tumor suppressor genes (Section 6.5) on the basis that they are genes which normally keep the proliferation of cells under control in physiological and nontumorous pathological conditions [29]. They include the genes in which:

i. The germ-line alteration is in one allele (copy of the gene), and the somatic event is necessarily on the other allele as in retinoblastoma [30]. These genes have been identified by studies of the genomes of patients and of the genomes of the tumors which occur in them.

ii. Germ-line alterations are required in both alleles of the same gene—i.e., inheritance is Mendelian recessive. In these patients, one (if not more) additional somatic event, usually in other genes, is required for the tumor [31]. An example of this is xeroderma pigmentosum [32] in which biallelic germ-line genomic events in the particular XP gene result in reduced capacity to repair UVB damage to DNA. The skin tumors which are common in the condition are due to the additional genomic events in the epidermal cells resulting from the damage to DNA.

Genes which require germ-line events in both alleles also include many low-penetrance genomic events which may have their phenotypic effect in adult life [33].

(c) Cell Signaling in Normal Growth Control

The next step in the pathogenesis of tumors concerns the functional roles in cells of the protein products of cancer genes. Most studies have been directed at whether or not they are part of, or affect, biochemical signaling pathways which are involved in proliferation of cells [34–36].

The principle of signaling (Figure 1.9) is that an extracellular factor binds to a specific surface receptor site on a protein. This protein extends through the membrane and has an enzymatic site on its intracellular end. Binding of the factor to the surface receptor activates the intracellular site. The active enzyme site is usually a kinase (an enzyme which adds phosphates to proteins). The signaling usually involves sequential activation of additional phosphorylating enzymes. Ultimately, transcription factors are produced which lead to the production of final effector proteins which induce the relevant effect in the cell. For growth-related signaling pathways, the final effector proteins are cyclins and others involved in cell division (see Section A1.3).

Figure 1.9 Cascade/pathway model of intracellular signaling.

The protein products of oncogenes are mainly one or other component in these cascades, i.e.,

i. membrane proteins;

ii. intermediary kinases;

iii. transcription factors;

iv. apparent regulators of the cell cycle or cell death;

v. the final effector protein of the cascade.

Signaling pathways are generally named by the oncogene/membrane receptor protein, and/or the principle kinase(s) involved.

The functions of products of tumor suppressor genes in normal biology and nontumor pathology are assumed to be prevention of excessive growth of cells (Section A1.3). An early idea was that their primary function was to inhibit the activation of oncogenes (hence the term anti-oncogenes [37]). At least some products of suppressor genes may act as inhibitors of transcription factors for the components of the signaling cascades (see Section 6.3.3). However currently, the functions of the protein products of many tumor suppressor genes are unknown [38].

Activations of certain pathways tend to be particularly associated with particular types of tumors. However, activations of only a few pathways are individually specific for a single tumor types, and few activations are identifiable in every case of any tumor type (see Section 9.4).

1.3 Abnormalities in Morphology and Molecular Pathology

1.3.1 Background

The morphological abnormalities of tumors are the bases on which pathologists make most of their diagnoses of tumor types [1,2]. The cells in the different tumor types show different degrees of abnormalities, and no individual abnormality, except accumulation of cells, is shown by all tumor types. No abnormality is seen exclusively in true tumors and not in any other nontumorous condition.

The morphological abnormalities include:

i. Alterations in specialized activity of tumor cells.

ii. Changes in the internal structure of the cells. This is seen especially in nuclear size and in the relative proportions of nucleus to cytoplasm seen in the parent cell.

iii. Abnormal micro-anatomical spatial arrangements. This is seen both in the tumor cells to one another and in the tumor cells to the supporting/connective tissue cells of the tumor mass. Invasion of connective tissue by tumor cells is an extreme example of the latter and is a major indicator of malignancy.

iv. More numerous mitotic figures are seen in the parent cells.

v. Abnormalities in mitotic figures, including unequal distributions of chromosomes during ana(sub)phase (see Section A1.3.4).

1.3.2 Grading of Tumors

(a) General

For most tumor types, the greater degrees of morphological abnormalities of a case are associated with greater degrees of malignancy (aggressiveness) of the particular case (Figure 1.10). The severity of particular abnormal histological features can be graded. These grades are of value for assessing prognosis in the individual case and also can be used to guide treatment. High-grade tumors may be frequently treated differently to low-grade tumors of the same type.

Figure 1.10 Relationship between degree of cytostructural instability and cell behavior in colonic epithelial tumors.

There are different grading systems for different tumor types. For most tumor types, new grading systems have been drawn up from time to time.

(b) Grading of Carcinomas of the Lung

There are four major types of lung carcinoma, of which adenocarcinomas and squamous cell carcinomas may be assessed according to their degree of specialization (differentiation—see Section 8.1.2). No other grading scheme is widely used.

(c) Grading of Carcinomas of the Breast

Grading has considerable significance for prognosis for carcinoma of the breast and is almost universally used. The main protocol is the Elston–Ellis modification of the Scarff–Bloom–Richardson grading system [39]. Tumor cells are assessed according to three criteria: (i) glandular/tubule formation, (ii) nuclear pleomorphism, and (iii) numbers of mitotic figures. Adding the individual counts gives a range of 3–9, with the higher numbers indicating worse prognosis.

This grading of tumors is taken together with the results of molecular studies (especially of estrogen and progesterone receptors, and HER-2 gene expression), to plan particular components of treatment of the individual case [40].

(d) Grading of Carcinomas of the Large Bowel (Colon and Rectum)

More than 90% of these tumors are adenocarcinomas, and most of these are well (Grade 1), moderately (Grade 2) differentiated/specialized. Only 5–10% of cases are poorly differentiated (grade 3). Cases of Grades 1 and 2 are commonly grouped together as low grade. Poorly differentiated/high-grade/Grade 3 tumors are diagnosed when less than 50% of the cells form tubules. Undifferentiated carcinoma shows no glandular, mucus, neuroendocrine, squamous, or sarcomatoid specialization [41].

(e) Grading of Carcinomas of the Prostate

The main grading system for this tumor was devised by Gleason in 1975 and is based entirely on architecture of the tumor masses. Initially, the assessment was intended to include nuclear pleomorphism and stage of the case of tumor. However, nuclear abnormalities were found not to affect outcomes, and assessments of stages were too complicated to include [42].

Most systems of grading for other types of tumors include assessments of the abnormalities listed above, together with abnormalities in antigen expressions and genomic alterations where appropriate (see Chapter 9).

It should be noted that grading systems have only been validated by empirical observations. The biological basis for the association of cytostructural abnormalities—such as loss of specialized activity, loss of spatial regularity, pleomorphism of nuclei, and abnormal mitotic figures—with tendency to invade and metastasize is unknown.

1.3.3 Staging of Cases of Tumor

(a) General

The stage of the tumor is the anatomical extent to which the tumor has already spread in the patient’s body at the time of diagnosis. The rationale for documenting the stage of a case is that a tumor which has already spread to, for example, local lymph nodes is more likely to have spread more widely in the body than a tumor which has not already spread to lymph nodes.

As in grading systems, there are various staging systems described for the different types of malignant tumors. In the widely accepted TNM scheme, stage is assessed in three components:

i. The degree of local spread of tumor—the T number.

ii. The presence or absence of metastases in lymph nodes—the N number.

iii. The presence or absence of metastases to other organs—the M number. Usually M0 is for no metastases, and M1 indicates distant metastases are present.

For many purposes, a single number for each letter is sufficient. However, there has been a trend to greater and more complex subdivision of each stage. The subdivisions are usually indicated as A, B, etc.

The criteria for these subdivisions of the T and N numbers differ according to the type of malignant tumor. The details are given in publications of the International Union Against Cancer (UICC), the American Joint Committee on Cancer and Cancer Research UK [43–45], as well as other organizations. A summary is as follows.

(b) Staging of Carcinoma of the Lung

In stage 1, the tumor is confined to the lung and is divided into A and B according to size up to 5 cm across. Stage 2 is divided into A and B, referring to sizes 7 cm across or growing into certain thoracic structures (five situations) such as bronchial or hilar lymph nodes. Stage 3 is divided into A and B, referring to a number of possible combinations of (i) size greater than 7 cm, (ii) spread directly to another structure such as the mediastinum, and (iii) metastasis to the other lung, the spine, or lymph nodes of the neck. A tumor is stage 4 if it has already spread to other parts of the body. Further details are given in Ref. [46].

(c) Staging of Carcinoma of the Breast

The system in general use is complicated because it gives emphasis to the size of the primary tumor (especially the measurement of 2 cm) at diagnosis and relatively less weight to a few cells in local lymph nodes (which would be within an actual or potential simple mastectomy specimen). Stages 1–3 are divided into two or more substages (A, B ± C), with up to three alternative situations within each subcategory. Stage 4 indicates spread to distant organs. Details of the stages are given in Refs. [47,48].

(d) Staging of Carcinoma of the Large Bowel (Colon and Rectum)

Stage 0 is in situ tumor and stage 1 indicates that slight invasion of the main muscle layer of the bowel. Stage 2 is divided into A, B, and C depending on degree of local invasion. Stage 3 is divided into A, B, and C, with each having two or more alternatives. These are determined by combinations of the depth of invasion by primary tumor and the number of local lymph nodes containing tumor. Stage 4 is when distant metastases are identified. This stage is divided into A and B according to the number of distant organs involved [49].

(e) Staging of Carcinoma of the Prostate

Current schemes for staging these tumors include not only the actual spread of tumor cells in the body, but also the criteria of the histological grade (Gleason score, see Section 1.3.2), as well as the serum prostate-specific antigen (PSA) level. Stage 1 is a tumor which is too small to be detected by clinical examination or imaging. The tumor has a low Gleason grade, and the PSA is low. Stage 2 refers to tumors which have not extended beyond the capsule of the gland. It is divided into A (five alternative combinations of features) and B (three alternative combinations of features). Stage 3 tumors have spread through the capsule of the gland and may have invaded the seminal vesicles. Stage 4 refers to cases in which greater spread of tumor has occurred: three alternative combinations of features [50].

1.3.4 Importance of Micro-Metastases

There is a considerable literature on the prognostic significance of small collections of tumor cells which are identified adjacent to the main mass in a resection specimen [51]. However, it is important to remember that the techniques used for imaging in the patient (see Section 1.4.2), as well as for microscopic examination of cells in the pathological specimen, do not detect all the malignant cells which have spread in the body before diagnosis and therapy.

These undetectable micro-metastases are the basis of at least some of the secondary tumors which become apparent only during or posttherapy. If these micro-metastases are present just outside the surgical margin—and thus cannot be seen in microscopy sections—a local regrowth of tumor (recurrence) is possible. If the micro-metastases are present in a distant organ, then new metastases will develop. These situations are sometimes called relapses.

1.3.5 Molecular Pathology and Other Nonmorphological Features of Tumor Cells

The term molecular pathology [3,52], when it is applied to tumors, refers to the expressions of antigens, as well as changes in DNA, RNA, and other molecular features in tumor cell populations. In tumors, these aspects are often qualitatively and quantitatively abnormal. Many of these studies are mainly related to oncogenes and proteins of signaling pathways (see Section 1.2.2).

Other nonmorphological abnormalities are mainly the cell turnovers (cytodynamics/cell kinetics) [53] of tumor cell populations. Although the field is little studied at the present time, it is important because the tumor cell populations are significantly different to those of the parent kinds of cells. In tumors, cells may be produced at variable rates and independently die at variable rates. Further, and unlike normal cells, tumor cells may enter a vegetative state in which they remain partly specialized, but do not divide. There are many mechanisms involved in these rate changes of tumor cell life spans (see Sections 6.1, 11.4.2, and A1.3.3).

1.4 Fundamental Aspects of Clinical Features and Treatments

1.4.1 Principles of Symptoms and Signs of Tumors

The clinical features of tumors taken together may cause almost every symptom and sign which is known in clinical medicine [4–6]. This is because they can arise in—and in the case of malignant tumors, metastasize to—almost any part of the body.

Both benign and malignant tumors can cause the symptoms and signs through their presence alone, or via their complications (Figure 1.11). In principle, the complications arise because the tumor may:

i. compress or

ii. obstruct an organ or adjacent structure in the body.

Malignant tumors in addition can:

iii. destroy adjacent structures,

iv. bleed and/or

v. create holes in the part of the organ in which they form.

Figure 1.11 Complications of malignant solid tumors in approximate order of frequency.

Malignant tumors can cause the same phenomena in any adjacent organ or tissue which they invade or in which they grow as a metastasis. Also, metastases can develop in more symptom-critical part of the body than the site where the primary tumor arises. Moreover, in some cases, the metastases seem to grow faster than the primary tumor.

The result is that the signs and symptoms of the secondary tumors may appear before those arising from the primary tumor. For example, lung carcinomas can metastasize to the central nervous system and produce symptoms and signs such as epileptic seizures, headaches, and palsies, before any respiratory-tract symptom has appeared.

As another example, carcinomas of the large bowel can metastasize to the liver causing enlargement and pain in that organ, before the primary tumor in the bowel has caused any symptom of a bowel lesion.

Thus, in principle, complications are the bases of most of the clinical features of tumors of noncutaneous (i.e., internal) organs.

The main tumor types and their symptoms and features in each organ system are as follows and are summarized in Table 1.2. Some general references for this section are given in Refs. [4–6].

Table 1.2

Features of the Commonest Types of Malignant Tumors

aThe first clinical manifestation of some cases of malignant tumor may be via metastases.

bParticular causes are known for a few cases.

cHereditary predispositions in some cases.

dSee Chapter 3.

Ca, carcinoma

(a) Skin

The most important tumors of this organ are epidermal and melanocytic. Epidermal tumors include many benign types. Of the malignancies, squamous cell carcinomas are mainly low grade, and basal cell carcinomas invade but hardly ever metastasize.

Benign melanocytic tumors comprise naevi of various kinds and are common. Malignant melanomas are less common. The outcome of the particular case of melanoma depends mainly on the size of the primary tumor.

Most types of tumors of epidermal cells or melanocytes produce an abnormality of the surface—e.g., a projection, roughness, discoloration, ulceration, and even bleeding. Cases of tumor types arising from cells in the dermis sometimes break the surface, but otherwise appear as thickenings of the skin.

(b) Respiratory Tract

Benign tumors of these organs are uncommon. Most are of connective tissue cells. All carcinomas of the lung/bronchi have poor prognosis. For small cell anaplastic carcinoma, nonsurgical therapies are the main mode of therapy. Nonsmall cell carcinomas—squamous, adeno- and large cell anaplastic types—are of more or less equal malignancy and susceptibility to therapies.

Tumors of the lungs may cause coughing in general, and coughing blood in the sputum in particular. Also, shortness of breath and chest pain (usually on one side) are common. Tumors of the pleura (mainly mesothelioma) almost always cause pain on the side of the tumor and later shortness of breath.

(c) Female Breast

A benign condition known as mammary dysplasia or fibrocystic disease is very common. It does not tether to skin or other structure, but produces firm areas in the breast tissue which sometimes cannot be distinguished from carcinomas without pathological examination.

Apart from this, the main benign tumor type is the fibroadenoma. This usually occurs in young women. It does not tether to skin or any other structure.

Carcinoma of the female breast is common and highly variable, both in age of onset and aggressiveness. Carcinomas may be found at screening, if available, or by the discovery of a mass. Tethering to the skin may occur with superficially placed tumors. Tethering to the underlying skeletal muscles may occur with deeply placed tumors. Some tumors are not palpable because of the amount of surrounding breast tissue, especially if that tissue is fibroadenomatous. These tumors may only manifest through metastases, which are common in local lymph nodes, pleura, and bone as well as liver, lungs, and other organs.

Carcinomas in young women tend to be more aggressive than those in older women. Pathological examination for grade and staging gives valuable prognostic information.

(d) Alimentary System

In the esophagus, benign tumors are rare. Malignancies include squamous cell carcinomas and adenocarcinomas near the esophago-gastric junction. These generally have a poor prognosis because they invade deeply before they cause any symptoms.

In the stomach, benign polyps occur but are less common than in the colon. Adenocarcinomas of the stomach have a generally poor prognosis because of their usual high invasiveness.

Tumors of the small intestine are uncommon.

In the colon and rectum, several kinds of benign epithelial tumors (polyps) occur quite frequently. Adenocarcinomas are common and are of intermediate malignancy (approximately 30% 10-year survival