Principles of Tumors: A Translational Approach to Foundations

By Leon P. Bignold

Principles of Tumors: A Translational Approach to Foundations, Second Edition, provides a concise summary of translational/interdisciplinary topics on the various aspects of tumors, especially abnormalities in their cells, their causes and effects on patients. Topics discussed include how genomic abnormalities in tumors may result from the actions of carcinogens and how genomic changes determine the cell biological/morphological abnormalities in tumor cell populations. In addition, the relationships between tumor cell genomics and therapeutic outcomes are described. There are also supporting appendices on general bioscience, including the principles of histology (the cells and tissues of the body), genetics, pathology, radiology and pharmacology.

This book gives a thorough, detailed, yet concise account of the main bioscience, clinical and therapeutic aspects of tumors. It emphasizes the translational aspects of research into tumors with extensive discussions of interdisciplinary issues. The content in this book will be invaluable for researchers and clinicians involved in collaborative projects where it is necessary to understand fundamental issues in other branches of biomedicine.

• Presents content that has been totally updated with the most recent developments of the field, including new chapters on tumor imaging exams, new surgical techniques, immunotherapy, gene therapy, and several novel therapies using natural and synthetic compounds
• Presents translational approaches for every topic to improve conceptual insights for new research projects
• Covers a broad range of subjects, making it easier for the reader to understand related fields
• Includes diagrams for complex topics to aid in understanding for non-specialists

• Language: English
• Publisher: Academic Press
• Release date: Nov 1, 2019
• ISBN: 9780128173299

Leon P. Bignold

Dr. Leon Bignold teaches pathology to medical undergraduates and post graduates and has for the last 30 years. He also works as a diagnostic histopathologist in a hospital environment for the last 30 years. He has published 3 oncology books with Springer in the last 10 years. Leon Bignold is a regularly invited speaker at international oncology conferences.

Book preview

Principles of Tumors

A Translational Approach to Foundations

Second Edition

Leon P. Bignold

Table of Contents

Cover image

Title page

Copyright

Preface to the second edition

Chapter 1. Introduction

1.1. General

1.2. Translational aspects and issues in the study of tumors

Chapter 2. Theories and definitions of tumors

2.1. Historical influences in concepts of tumors

2.2. Deviations in normal biological or nontumorous pathological processes

2.3. Definitions offered by 19th and early 20th century authors

2.4. Early genomic theories, viral carcinogenesis, and definitions

2.5. Theories of limited polyclonalities in tumor cell populations

2. 6. Other theories and concepts of tumors

2.7. Current definitions

Chapter 3. Etiopathogenesis of tumors

3.1. General aspects of tumor formation by known etiological agents

3.2. Specific aspects of radiations

3.3. Specific aspects of chemical carcinogens

3.4. Viruses

3.5. Other microorganisms as carcinogens

3.6. Hormones as carcinogens

3.7. Solid carcinogens in vivo

3.8. Summary of translational issues

Chapter 4. Growth of cells, growth factors, and oncogenes

4.1. General

4.2. Intracellular (intracrine) mechanisms of growth control: cell signaling pathways

4.3. Other aspects of cell signaling, growth factors, and oncogenes

4.4. Summary of the translational issues

Chapter 5. Hereditary predispositions to tumors, tumor suppressor genes, and their clinico-genomic complexities

5.1. General features of high-penetrance hereditary predispositions to tumors in humans

5.2. General aspects of tumor suppressor genes

5.3. Phenotype–genotype relationship I: A single tumor type deriving from one parent cell type with one or more genes involved

5.4. Phenotype–genotype relationship II: several tumor types deriving from one (or closely related) parent cell type with one gene involved

5.5. Phenotype–genotype relationship III: multiple tumor types and even nontumor lesions arising in different kinds of parent cells in the one individual

5.6. Phenotype–genotype relationship IV: multiple tumor types and even nontumor lesions arising in different kinds of parent cells; multiple genes

5.7. Phenotype–genotype relationship V: predispositions to different syndromes according to position of the germline event in the one gene

5.8. Genomic models for the inherited predispositions

5.9. Low-penetrance inherited susceptibility syndromes in humans

5.10. Hereditary predispositions to tumors in experimental animals

5.11. Summary of translational issues in inherited predispositions to tumors

Chapter 6. The tumor types: The complexities in the combinations and variabilities of their traits

6.1. The traits of tumor cells and the complexities of the tumor types

6.2. Further variabilities in tumor traits and types

6.3. Progression in tumor cell populations

6.4. Hematopoietic tumors similar in principle to solid tumors

6.5. Invasion: pathological observations, cell biology, and possible genomic pathogenesis

6.6. Metastasis: pathological observations, cell biology, and possible genomic pathogenesis

6.7. Summary of translational issues in the morphology of tumors

Chapter 7. Epidemiology of tumors

7.1. Data and measures used in epidemiological studies of tumors

7.2. Medical practice factors affecting the reported incidence and mortality data

7.3. Comparative international data on incidences and mortalities of cancers by type

7.4. Significance of overdiagnosis

7.5. Suggested subcategories of incidence to accommodate factors in medical practice

7.6. Summary of translational issues in cancer epidemiology

Chapter 8. Prevention of tumors

8.1. Confirmed human carcinogens: preventative measures

8.2. Identifying and investigating further carcinogens: epidemiological data and methods

8.3. Association does not prove causation

8.4. Other aspects of interpreting cancer-causation epidemiological data

8.5. Problematic issues with low-level or disputed carcinogens and carcinogenic factors

8.6. Laboratory methods in the identification of environmental carcinogens

8.7. Human lesion and genetic screening programs and their efficacies in preventing deaths from tumors

8.8. Cancer-preventative drugs: benefits and potential dangers

8.9. Barriers to prevention

8.10. Summary of translational issues in cancer prevention

Chapter 9. Clinical features of tumors

9.1. General

9.2. Symptoms and signs of the most common malignant tumors

9.3. Symptoms and signs of less common malignant tumors

Chapter 10. Typing, grading, and staging of cases of tumor

10.1. Morphological bases for the typing of tumors

10.2. Molecular and other contributions to the typing of tumors

10.3. Grading of solid tumors for planning therapy

10.4. Staging of cases of solid tumor by examination of the resected specimen

10.5. Prognostic indices using multiple factors

10.6. Sampling artifact in pathological assessments of cases of tumor

10.7. Other difficulties in grading and staging

10.8. Summary notes of translational issues in typing grading, staging, and prognosis

Chapter 11. Endoscopic visualization and imaging assessments of cases of tumor

11.1. Endoscopic and other internal visualizations

11.2. Imaging techniques: physical principles

11.3. Imaging in diagnosis, staging, biopsies, and therapies of particular tumors

11.4. Hazards of imaging

11.5. Other difficulties in imaging

Chapter 12. Principles of surgery for tumors

12.1. Preoperative considerations

12.2. Classification of operations

12.3. Aspects of particular cancer operations and their complications

12.4. Robotic surgery

12.5. Translational notes on surgery in cases of cancer

Chapter 13. Principles of nonsurgical therapies

13.1. General

13.2. Reasons for partial responses and relapses

13.3. Monitoring responses and relapses in the patient

13.4. Summary of translational issues in nonsurgical therapies

Chapter 14. Aspects of radiation therapy

14.1. General

14.2. Aspects of particular forms of radiation therapy

14.3. Recommended regimens for common malignancies

Chapter 15. Specific aspects of cytotoxic and hormonal drug therapies

15.1. General

15.2. Target-selective drugs

15.3. Aspects of personalized medicine

15.4. Chemotherapies for particular malignant tumors

15.5. Antihormone therapies

15.6. Summary of translational issues

Chapter 16. Immunotherapies

16.1. Tumor antigens

16.2. Cytotoxic responses of immune cells

16.3. Possible explanations of tumor growth in the presence of normal immune responses generally

16.4. Therapies specifically or nonspecifically increasing patient's cellular immune responses

16.5. Therapies supplying additional unmodified specific effector cells

16.6. Therapies supplying genetically modified effector cytotoxic cells

16.7. Managing the treatment

16.8. Potentially fatal side effects

16.9. Summary of translational issues in immunotherapies of tumors

Chapter 17. Gene therapies not related to immunological therapies

17.1. Techniques and strategies

17.2. Management of treatment in the individual patient

17.3. Summary of translational issues

Chapter 18. Less common and controversial therapies

18.1. Therapies using microbiological agents

18.2. Stem cell therapies

18.3. Epigenetic therapies

18.4. Complementary and alternative regimens

Chapter 19. Care after primary therapy

19.1. Definitions

19.2. Needs of the patient and care after primary therapy

19.3. Problems of particular cancers

19.4. Advance Care Planning

Chapter 20. Costs, ethics, and malpractice litigation

20.1. General

20.2. Paying for the costs

20.3. Ethical issues in medical treatment

20.4. Ethical issues in oncological research

20.5. Ethical issues in resource allocations at national and international levels

20.6. Litigation, malpractice, and avoidance of errors

Appendix 1. Principles of normal embryology, histology, and related cell biology

Appendix 2. Aspects of the normal genome

Appendix 3. Fixed genomic events and possible mechanisms of their causation by etiological agents

Appendix 4. Genomic instabilities: kind, effects, and roles in the immortality of tumor cell populations

Appendix 5. Methods in histologic and molecular assessments of tumors

Appendix 6. Biomarkers in molecular pathology and oncology

Appendix 7. Sublethal injuries and deaths of cells and tissues

Appendix 8. Pretarget, target, and recovery capacity defenses of cells against carcinogens and cytotoxic agents

Appendix 9. Developing and testing new therapies: clinical trials

Index

Copyright

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Preface to the second edition

The aim of this book is to provide clear explanations of the main principles, terminologies, and concepts relating to all aspects in the study of tumors. The ways in which the basic science discoveries relate to each other and underpin clinical practice—the translational aspects —are featured. The term translational issue is introduced, especially to indicate clinical and experimental phenomena in tumors for which no definite basic science explanation is available.

This edition expands and advances the accounts of all subjects discussed in the first edition. Some topics which were dealt with in single sections are now described in full chapters. The order of the chapters has been changed to a more convenient sequence. In particular, the chapters on epidemiology and prevention now follow immediately on the chapters dealing with basic science topics.

In addition, as part of this major restructure, the more directly clinically relevant material in the former Chapter 1 has incorporated into new, enlarged chapters on pathology and clinical aspects. Much basic science material has been taken from various former chapters and consolidated in appendices. Thus, the former Chapter 5 together with related sections in other former chapters forms the new Appendices 3 and 4. The former Chapter 10 has become the new Appendix 7.

Throughout this edition, almost all sections have been updated with references to the latest available literature.

Leon P. Bignold Senior Consultant Histopathologist, SA Pathology, Adelaide, and Clinical Senior Lecturer, Discipline of Pathology, University of Adelaide, Australia, September 2018

Leon Bignold died unexpectedly on November 4, 2018, the day after he finished the manuscript for this book. What remained to be done was checking the references and figures. I had lived with both the first edition and the research and writing for the second edition of Principles of Tumors and did not wish to see the work of the past years not come to fruition. As a medical librarian, I had the skills for these tasks, and with the encouragement of James Bignold and Monica Bignold, and the permission of the publisher, I undertook to do the final work to bring this book to completion.

Leon Bignold recorded his thanks for his employer, SA Pathology, and to Peter Dent in the Photography Department. I also acknowledge Peter Dent for his unswerving help with the illustrations and my colleagues in the South Australia Department of Health and Wellbeing and to Professor John Nicholls, Department of Pathology, University of Hong Kong, for their encouragement and support. Thanks also are due to Rafael Teixeira, Rebeka Henry, Samantha Allard, and Punitha Govindaradjane of Elsevier for their guidance. The proofreading team of Dr Doug Handley, Sandy Handley, James Bignold, Neil Cowey, Wendy Cowey and Sarah Houben was outstanding.

Mary Peterson Knowledge Manager South Australia Department of Health and Wellbeing, August 2019

Chapter 1

Introduction

Abstract

This chapter deals with the features of tumors as distinct from other swellings. It includes description of scientific developments contributing to study of the nature of tumors and treatments for them. The terminology used to describe tumors is explained and the study of tumors is placed in its historical context as an overall introduction to the following chapters.

Keywords

Adenoma; Carcinoma; History of medicine; Malignancy; Terminology of tumors

1.1 General

1.1.1 Features distinguishing tumors from other swellings

1.1.2 Basic classifications and terminology of the tumor types

1.2 Translational aspects and issues in the study of tumors

1.2.1 Range of sciences contributing to the understanding and treatment of tumors

1.2.2 Definitions of translational medicine and translational issues

References

Tumors are the most complex group of human diseases. Currently, they cause the death of up to a quarter of populations worldwide. They occur in extraordinarily diverse types. Their clinical, pathological, and basic science features vary not only between types but also between cases of the same tumor type. Tumors also vary in their treatability and ultimate outcomes, again both between the types and between cases of the same type of tumor. There are no certain ways to avoid most tumor types because their causes are largely unknown.

Collectively, tumors are much more variable than other diseases of unknown cause, such as the many cardiovascular, infective, inflammatory, hereditary, and nonhereditary congenital, as well as the degenerative disorders. These groups comprise fewer types, with less diversity in manifestations, together with more predictable courses, treatment responses, and outcomes than tumors.

This chapter deals with the features of tumors as distinct from other swellings. Mention is made of the range of sciences contributing to study of the nature of tumors and treatments for them. Translational concepts in the study of tumors, as well as related issues which are relevant at the present time, are described.

1.1. General

1.1.1. Features distinguishing tumors from other swellings

It is important to remember that not all swellings are tumors in the sense used in oncology. Historically, accurate distinctions between the different kinds of swelling only began in the 1830s, when improvements in techniques in microscopy allowed cells and nuclei to be seen [1]. Cell Theory and Cellular Pathology (late 1830–1850s) followed, but the methods were still not adequate for visualizing smaller normal intracellular structures, such as chromosomes.

In the late 1870 to 1880s, new improvements were made in all aspects of microscopic technology, including better stains, apochromatic lenses, and substage condensers for the beam from the light source. These inventions brought light microscopy almost to its current standards [2]. The different kinds of cells could be distinguished from each other as were the phenomena of cell division. By the mid-1890s, accumulated clinico-microscopic pathological studies had established the distinctions between the different kinds of swelling so that diagnoses could be made with reasonable reliability. It was on this basis that hospitals throughout the world began to develop departments of histopathology to examine surgical and autopsy specimens and make accurate diagnoses.

The nontumorous swellings in the body were then identified as mainly:

(i) All physiological swellings, for example, of the uterus, breasts, and thyroid gland during pregnancy.

(ii) Accumulations of fluid in tissues, as in edema.

(iii) Cysts not associated with any abnormal accumulation of cells, for example, cysts formed by the obstructions of ducts of secretory glands, as in sebaceous cysts of the skin. As another example, hematomas which had become surrounded by fibrosis, as encysted blood clots, could be distinguished from hemorrhagic tumors.

(iv) Swellings associated with inflammations. The cells of inflammatory swellings are almost always morphologically normal or show changes of degeneration or necrosis (see in Appendix A7). Inflammatory lesions have a characteristic clinical tendency to resolve or heal, which is unlike virtually all cases of true tumor.

(v) Swellings associated with repairs to tissues, for example, the callus of bone fracture sites. These, like inflammatory lesions, disappear when the broken bone ends are reunited and fully healed with new bone.

(vi) Hyperplasias and hypertrophies. Strictly, these terms refer to responses of tissues to abnormal degrees of stimulation. According to this strict definition, they regress when the stimuli to their formation are removed. An example is hyperplasia of the epidermis in lichen simplex chronicus, which is caused by chronic scratching. It disappears when the scratching stops.

    However, hyperplasia and hypertrophy are also applied to enlargement of organs where no stimulus is known. An example is the enlargement of the prostate due solely to dilatation of glands and proliferation of epithelium. This condition is called benign hyperplasia of the prostate, although no cause is known. For this reason, disorders in this category are sometimes classified as tumorlike lesions (see in Chapter 10).

(vii) Congenital lesions of organs characterized by abnormal tissue composition.

    In a strict sense, hamartomas are developmental (i.e., congenital) malformations which comprise normal tissues of the organ in abnormal proportions and spatial relationships. They grow at the same rate as normal parts of the body in early life and childhood and cease growing in adulthood in coordination with normal tissues. An example is the congenital birth mark/port-wine stain. However, the original [3,4] and many subsequent authors including Willis [5] have used hamartoma for lesions having this kind of composition but which appear only in childhood or adult life, and grow slowly and continuously. These lesions are not developmental abnormalities. They are essentially very benign mixed true tumors.

    The term choristoma is used for lesions which have the characteristics of hamartomas in the strict sense, except that they comprise tissues which are not normal to the organ. Lesions with these features are more commonly referred to as ectopias.

(viii) Other enlarging tumorlike lesions not included in the above categories.

1.1.2. Basic classifications and terminology of the tumor types

Before considering true tumors in all their details, it is essential to understand that they comprise a thousand or so different types, and that the terminology of tumors is effectively shorthand for three criteria in their classifications.

The first criterion is the organ of origin as listed in Appendix A1.1.3.

The second criterion for classification is the exact kind of parent cell within the organ system from which the tumor arose. The parent kinds of cells may be the parenchymal or the supportive cells (see in Appendix A1.2.1).

The third criterion is according to whether the tumor is benign or malignant (Fig. 1.1). Benign types of tumors grow slowly and bulge or displace, but do not invade, local vessels or adjacent organs. They may compress adjacent structures, but otherwise do little anatomical damage. No metastases occur. 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 and frequently invade and destroy adjacent structures including blood vessels and lymphatic vessels. Via the lumina of these vessels and occasionally other paths, tumor cells often then spread to distant sites, initially as micro-metastases. After unpredictable periods of time, they may grow and cause clinical features according to their locations.

These criteria of classification are the basis of the general terminology of tumors. By convention in relation to the solid tumor types (i.e., excluding hematolymphoid tumors), 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-), and

(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-), and

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

Such a tumor thus is named a gastric adenocarcinoma.

Of the hematopoietic tumors, 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 [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 in Section 3.4 and Refs. [6–8]).

Figure 1.1 Main differences between benign and malignant tumors.

Tumors of cells of the nervous system and melanocytes have complex terminologies and classifications, which can be found in relevant special texts [9].

The morphological and molecular differences between the tumor types are described in multivolume works, especially the Armed Forces Institute of Pathology's Atlas of Tumor Pathology [10], and the World Health Organization Classification of Tumours [11] (see also Section 10.1). The details of the clinical behaviors and responses to therapies of the tumor types are described in key texts of clinical oncology.

1.2. Translational aspects and issues in the study of tumors

1.2.1. Range of sciences contributing to the understanding and treatment of tumors

Up until the end of the 19th century, the study of tumors was largely in the hands of physicians, surgeons, and pathologists. From the beginning of the 20th century—almost as soon as appropriate technical advances were made—numerous other sciences have made more and more contributions to the understanding and treatments of these diseases.

At present, clinical observation of tumors has become an almost mature field of research. Nevertheless, while the manifestations of tumors themselves are largely established, novel clinical manifestations of the side effects of therapies remain to be documented and studied. An example is cytokine storm in the immunological treatment of cancers (Section 16.8.3).

Pathological anatomy and histology too seem to be relatively mature sciences, but pathologists must remain alert for new diagnostic aids and the possibilities of pathological manifestations of new therapies.

Contributions of nonclinicopathological sciences to the study of tumors include the following:

Areas of physics provide the bases of the body imaging techniques and radiation therapies. Chemistry and physiology are mainstays of pharmacology. The biochemistry of the normal cellular signaling systems is the basis of investigations of cell growth, and hence also identifies targets of many new anticancer drugs.

Bacteriology, virology, and parasitology continue to provide bases for investigation of etiology of a variety of tumors.

Classical genetics is central to the study of hereditary tumor predispositions to tumors. The methods of molecular genetics are important to the assessment of cases of some tumor types, especially carcinomas of the large bowel (colon and rectum) and breast.

Statistics have long been used in epidemiological, prevention-related, and clinical studies. More recently, computational bioinformatics has become used to analyze data derived from new technologies for sequencing nucleotides in DNA.

Cell biological studies provide insights into the mechanisms of invasion and metastasis by malignant tumors.

The technology of immunology underpins most diagnostic methods used in diagnosing tumor types. Immune responses, especially cytotoxic actions, have become prominent in tumor therapy (Chapter 16).

Epidemiological concepts remain the mainstay of attempts to identify factors associated with high incidences of particular tumors in different populations.

Psychological factors, especially the alleviation of anxiety, are important to many cancer patients in the courses of their illnesses.

For several decades, economic considerations are being taken into account in the costs and distributions of resources in cancer detection and treatment.

1.2.2. Definitions of translational medicine and translational issues

The findings of basic science investigations of tumors are not always immediately applicable in the clinical setting. A need has been perceived for basic science studies to be more oriented toward—essentially meaning more easily translated for the purposed of—diagnosis and treatment of cancer patients, and perhaps less oriented toward the biological and other phenomena of cancer for their own sake.

The journal Science Translational Medicine describes translational medicine as follows:

Often described as an effort to carry scientific knowledge from bench to bedside, translational medicine builds on basic research advances—studies of biological processes using cell cultures, for example, or animal models—and uses them to develop new therapies or medical procedures.

Translational medicine is becoming ever-more interdisciplinary. For example, researchers need new computational approaches to deal with the large amounts of data pouring in from genomics and other fields, and as new advances in physics and materials science offer new approaches to study or diagnose medical conditions.

http://www.sciencemag.org/site/marketing/stm/definition.xhtml

Translational medicine is defined by the European Society for Translational Medicine as:

… an interdisciplinary branch of the biomedical field supported by three main pillars: bench-side, bedside and community.

Cohrs RJ, Martin, T, Ghahramani, P et al. Translational Medicine definition by the European Society for Translational Medicine. New Horizons in Translational Medicine 2 (2015) 86–88

The whole topic has been summarized in a plan of the American Society for Clinical Pharmacology and Therapeutics (https://www.ascpt.org/Resources/Knowledge-Center/What-is-Translational-Medicine)

Implementation of the ASCPT Strategic Plan will be guided by a broad and inclusive description of translational medicine to reflect the diversity of scientific disciplines involved in translational research within our Society. For the purpose of this document, translational research, translational science and translational medicine will be used interchangeably with a unifying principle that the ultimate purpose is to improve human health via a bench to bedside approach. There are many definitions of translational medicine as well as translational science and translational research, which provide context for ASCPT's efforts. John Hutton ¹ defines translational research as Research [that] transforms scientific discoveries arising from laboratory, clinical or population studies into new clinical tools and applications that improve human health by reducing disease incidence, morbidity and mortality. Another perspective ² is Translational research fosters the multidirectional integration of basic research, patient-oriented research, and population-based research, with the long-term aim of improving the health of the public.

Generally, these descriptions amount to suggestions that researchers do more clinically directed basic science or collaborate more in interdisciplinary projects. Nevertheless, there are many issues in tumors for which interdisciplinary thinking seems not to have occurred, perhaps having been assigned to too-hard baskets. Translational ideas in some areas have been published, but ignored. Occasionally, results from different basic science are not conceptually compatible with each other. These also are perhaps too-hard basket matters and tend to be little discussed.

It is reasonable then to use the term translational issue for these interdisciplinary matters. They probably arise in one or more of the following ways:

(i) Researchers in particular disciplines have studied a disease strictly according to historical conventions of their discipline and have not fully appreciated the concepts deriving from other research fields.

(ii) An interdisciplinary area in the study of a disease phenomenon has not been studied at all, for lack of identification of the problem.

(iii) Theories of a disease process which have been derived from the results of one kind of research study are rendered unlikely by results from other kind of research study.

(iv) Terminology introduced in one discipline becomes confusing when the same term is adopted in another discipline with a different meaning.

Instances of these situations are mentioned where appropriate in this book.

References

[1] Bignold L.P, Coghlan B.L, Jersmann H.P. David Paul von Hansemann: contributions to oncology: context, comments and translations.  Birkhäuser Basel . 2007:41–45.

[2] Carpenter W.B.  The microscope and its revelations  enl. and rev. 7th ed. Philadelphia, PA: WH Dallinger. Blakiston; 1891. .

[3] Albrecht E. Ueber hamartome./on the hamartoma.  Verh. dtsche pathol Ges . 1904;7:153–157.

[4] Ober W.B. Selected items from the history of pathology: Eugen Albrecht, MD (1872–1908): hamartoma and choristoma.  Am. J. Pathol.  1978;91(3):606.

[5] Willis R.A.  The borderland of embryology and pathology . 2nd ed. London: Butterworths; 1962:351.

[6] Pileri S.A, Agostinelli C, Sabattini E. Lymphoma classification: the quiet after the storm.  Semin. Diagn. Pathol.  2011;28(2):113–123.

[7] Taylor C.R, Hartsock R.J. Classifications of lymphoma; reflections of time and technology.  Virchows Arch.  2011;458(6):637–648.

[8] Swerdlow S.H, Campo E, Harris N.L. WHO classification of tumours of haematopoietic and lymphoid tissues. In: Swerdlow S.H, Campo E, Harris N.L, eds.  WHO classification of tumours of haematopoietic and lymphoid tissues . Lyon: IARC; 2008.

[9] Burger P.C, Scheithauer B.W. Tumors of the central nervous system [1].  AFIP Atlas ser 4 . 2007 Fascicle 7.

[10] (Various authors). Atlas of tumor pathology, Series 1–4. Washington, DC: Armed Forces Institute of Pathology; 1950s [to present].

[11] (Various authors). World health organization classification of tumours. Several series. Lyon: International Agency for Research on Cancer; 1960s [to present].

---

¹  Wang X. A new vision of definition, commentary, and understanding in clinical and translational medicine. Clinical and Translational Medicine 2012; 1:5.

²  Rubio DM et al. Defining translational research: Implications for training. Acad Med. 2010; 85:470–5.

Chapter 2

Theories and definitions of tumors

Abstract

This chapter summarizes the development of the main theories of tumors supplemented by references to definitions put forward at various times. These theories are important because some of the words associated with them—such as plasia—remain in medical terminology and also because they may persist unrecognized in medical thinking today. The theories of tumors from ancient to modern times are analyzed, and such terms as persist are identified. The bases of major definitions of tumors, such as those developed by Johannes Müller, Rudolph Virchow, David Paul von Hansemann, James Ewing, Judah Folkman, and many others, are analyzed. The development of understanding of tumors is reflected in the various theories, from theories of causation by trauma or inflammation, infection to genomic instability. Current definitions of tumors from major textbooks and bodies such as the World Health Organization and the National Cancer Institute are described.

Keywords

History of medicine; History of tumors; Mutator phenotype; Pathology; Plasia; Tumor theory

2.1 Historical influences in concepts of tumors

2.1.1 Humors, lymph, degenerations, diatheses, and temperaments

2.1.2 Pathology is only abnormal physiology

2.1.3 Unity of nature—unity of cancer

2.1.4 Plasias

2.2 Deviations in normal biological or nontumorous pathological processes

2.2.1 Embryonic reversion

2.2.2 Altered development/maturation/differentiation of local specialization

2.2.3 Abnormal directions of specialization

2.2.4 Abnormalities deriving from inflammatory responses

2.2.5 Early infection theories

2.3 Definitions offered by 19th and early 20th century authors

2.3.1 1850–1920

2.3.2 R.A. Willis' definition

2.4 Early genomic theories, viral carcinogenesis, and definitions

2.4.1 Hansemann's theory of abnormalities in chromosomes as the basis of tumor formation

2.4.2 Work of Theodor Boveri

2.4.3 K.H. Bauer on somatic mutation as the basis of tumors

2.4.4 J.P. Lockhart-Mummery suggests somatic genomic instability in tumors

2.4.5 R.A. Willis' morphological arguments against the somatic mutation theory

2.4.6 Transformation of cells in vitro; viral causation; monoclonality of tumors

2.4.7 Uni- or oligo-nucleotide error genomic models analogous to sickle cell anemia assume monoclonality

2.4.8 Later 20th century definitions

2.5 Theories of limited polyclonalities in tumor cell populations

2.5.1 Discovery of polyclonality/heterogeneity in tumors

2.5.2 Theories of the origins of polyclonality

2.5.3 Additional points concerning clones in tumor cell populations

2.5.4 The theory of heterogeneously heterogenizing tumor cell populations, including mutator phenotype (see also Appendix A4)

2.6 Other theories and concepts of tumors

2.6.1 Blasts in tumor terminology

2.6.2 Histogenesis applied to tumors

2.6.3 Stem cells and transit-amplifying cells in the origins of tumors

2.6.4 Theories involving telomeres and the immortality of tumor cell populations

2.6.5 Theories involving plasma membrane and cytoskeleton

2.6.6 Epigenetic DNA modification and tumor formation; similarity to adduct models of carcinogenesis

2.6.7 Theories involving immunity

2.6.8 Field theory

2.6.9 Biochemical theories

2.6.10 Later chromosomal observations

2.6.11 Excessive angiogenesis

2.6.12 Discussion of the one process fits all theories

2.7 Current definitions

2.7.1 Definitions in textbooks

2.7.2 Hanahan and Weinberg's hallmarks of cancer

2.7.3 Definitions currently provided by major health agencies

2.7.4 Author's definition

References

The nature of tumors has been discussed ever since the Ancient Greeks recognized them as one of a variety of kinds of localized anatomical swelling (see in Section 2.1). Because of the complexities in all the types of tumors (see in Chapter 6), a correspondingly large number of theories have been put forward. By the 19th century, when true tumors began to be reliably distinguished from other swellings, the need was apparent for a definition which would adequately reflect their distinctive qualities vis à vis all the other localized swellings in tissues (see in Chapter 1).

This chapter summarizes the development of the main theories of tumors supplemented by references to definitions put forward at various times.

2.1. Historical influences in concepts of tumors

These concepts are noted because some of the words associated with them remain in medical terminology, and also perhaps because they may persist unrecognized in medical thinking today.

2.1.1. Humors, lymph, degenerations, diatheses, and temperaments

Hippocratic medicine held that for maintenance of health of a tissue, the four elemental fluids of the body: blood, yellow bile, black bile, and phlegm, had to be present in balanced proportions [1]. Tumors were most often considered excessive local accumulations of a black bile. This was probably because ulcerated tumors bleed, and blood blackens with time as it dries on the surface of the body [2]. Belief in imbalanced humors began to weaken with Harvey's discovery of the blood circulation (1628) which meant that localized imbalances of humors would be impossible if the locale was continuously flushed with one of the humors (blood itself).

Discovery of lacteals (Aselli in 1622) and the whole lymphatic system (Bartholin and Rudbeck independently in the 1650s) led to a new wave of speculation. Lymph—an entirely new kind of fluid—showed no sign of being balanced with anything else [3]. Furthermore, autopsy studies—which became increasingly common in the 17th century—showed that tumors are almost always white on the inside, not black. Attention of pathologists then turned toward lymph, and the term came to mean essentially any translucent fluid in the tissues which could be shown to contain dissolved material [4]. In the 18th century, the commonest theory was that tumors developed from deposits of some particular kind of material from lymph in tissues [5]. How it originated remained a mystery.

Degeneration in reference to deterioration in a lesion is mentioned in the Hippocratic works [6] but was not applied to disease generally (humors did not degenerate, they caused disease by quantitative imbalances). Lymph, however, was not a pure substance, contained coagulable material and so theoretically could degenerate. Le Dran in 1768 [7] may have been the first to suggest that tumors formed when the lymph at the site was degenerate in some way. In 1802, Bichat described the parts of the adult body in terms of individually identifiable textures (Fr tissu), hence in English tissue (see Appendix A1.1.3). He suggested that tumors are due to degeneration in these individual tissues [8]. In the next 100   years, various authors such as Rindfleish [9] suggested that tumors are degenerate cellular growths, and the term malignant degeneration, particularly of benign tumors (see Section 6.4), still has a place in medical terminology.

Diathesis was another Hippocratic term resurrected in the 18th century and persisting into the 20th century. In Hippocratic writings, the word is used frequently, but with different meanings [10]. Generally, it meant a generalized/systematic causative factor, possibly due to heredity, or acquired over long periods of time by lifestyle habits such as alcohol consumption or luxurious living [11,12].

A specific proposal for generalized causation of tumors was made by Bernard Peyrhile (1735–1804) who thought that cancers were due to viruses, transmitted from animals [13]. The reason for a tumor arising in a particular site was conceived to be a local precipitating condition or event, such as trauma. As late as the mid-20th century, trauma was held to be a factor in tumor causation [14].

Another Ancient suggestion for a generalized cause of disease was temperament. Hippocratic/Aristotelian teachings linked specific kinds of diseases to congenital personality traits. For example, choleric personalities were thought to be predisposed to fevers. Temperament was considered a possible contributory factor in disease as late as the 1870s [15].

2.1.2. Pathology is only abnormal physiology

The Hippocratic theory of humors implied that normal physiology is determined by balances of humors, and diseases are due to imbalanced humors—i.e., disturbed physiology. Hippocratic teaching also precluded disease-causation by exogenous factors, especially invisible living things. As physiology developed in the 19th century, the Ancient philosophical principle persisted—in the face of all facts to the contrary—that diseases are only disturbances of physiological processes.

Johannes Müller (1801–58) in 1838 described some of the cells in different types of tumors (Fig. 2.1) [16], and Cell Theory was enunciated by his student Theodor Schwann (1810–82) jointly with Mattias Schleiden (1804–81) [17]. As pathological histology developed, however, the most influential author on the topic of tumors was Herman Lebert (1813–78). Lebert emphasized the idea of pathology as only abnormal physiology by the title of his first text "Physiologie Pathologique" (1845) [18] This work included microscopical observations of cancers and described a kind of cell which he thought was specific for, and invariably present in, all macroscopic forms of cancers. Johannes Müller seems to have believed that disease is only altered physiology and inculcated it into his famous pupil Rudolph Virchow (Fig. 2.2) [19]. Virchow entitled his most famous work Cellular Pathology as Based upon Physiological and Pathological Histology, and in it wrote:

Ever since we recognized that diseases are neither self-sustaining, circumscribed, autonomous organisms, nor entities which have forced their way into the body, nor parasites which have rooted themselves on it [i.e., not due to fungi such as Schönlein had described, see above] but that they represent only the course of physiological phenomena under altered conditions: - ever since this time, the goal of therapy has had to be the maintenance or the re-establishment of normal physiological conditions.

Cited in Bignold LP, Coghlan BL, Jersmann HP. Virchow's Cellular Pathology 150   years later. Semin Diagn Pathol. 2008; 25 (3):140–6.

The idea of disease as only deranged physiology was supported also by the famous biomedical experimentalist, Claude Bernard (1813–78).

Physiological and pathological states are ruled by the same forces; they differ only because of the special conditions under which the vital laws manifest themselves [20].

Figure 2.1 Johannes Müller's drawings of cytological abnormalities in the cells of cancers of the breast. (A) "Fig. 1. Meshes formed by the bundles of fibres of carcinoma reticulare of the breast as they appear after the globules are removed. (B) Fig. 2. Globules from the reticulum of carcinoma reticulare. Within the globules are germinal cells with their nuclei, and on either side of the figure is a granular opaque corpuscle. (C) Fig. 9. Very irregular caudate bodies from a soft fungus of the female breast, the precise nature of which was never accurately ascertained. (D) Fig. 18." Bundles of fibres from a fibrous tumor of the mamma, in Professor Pockel’s museum. Note the absence of detail in cytoplasm and nuclei of cells. Other figures in the book depicted a variety of tumors, including in stomach, soft tissue, brain and bone. 

Source: Images taken from Drawings sheet 2 in the original work (1838) [16].

Figure 2.2 Title page of Cellular Pathology by Rudolf Virchow.

This opinion held by these leaders of their respective disciplines—and especially Virchow's opposition to the microbial theory of disease—retarded pathology for several decades. And further, the idea that tumors represent a derangement of a normal cellular process persisted into the late 20th century (see Section 2.2).

2.1.3. Unity of nature—unity of cancer

Aristotle—among many Greek thinkers—had believed that natural things are unified [21]. This derived mainly from the cosmological idea of one creation by one Being, for which the similarities of things within each of the broad Kingdoms of Nature: Animal, Vegetable, and Mineral were taken as support [22].

According to Wolff, Peyrilhe in 1773 was the first to recognize the unitary nature of all cancers [23]. What is clear is that Lebert explicitly credited the idea of unity. In his second major work "Traite practique des Maladies cancereuses (1851), Lebert devoted a whole chapter to the unity of cancer" (Fig. 2.3) [24]. His argument was that macroscopic appearances—scirrhous, encephaloide, fibroplastique, medullary, hemorrhagic, etc.—are all seen focally to greater or lesser extents, in cancers of all organs.

Figure 2.3 Title page of Lebert's book (1851).

Subsequent authors, for example, Julius Vogel (1814–80), Rudolf Virchow (1821–1902), and many others, discovered numerous differences in microscopic appearances of tumor cells. However, they appear not to have considered that differences between tumor types have any theoretical significance.

In the 20th century, James Ewing (1866–1943) in his book Neoplastic Diseases [25] and R.A. Willis in his Pathology of Tumors [26] continued with the idea of unity based on the observation that cancers share a small number of important properties—growth, invasion, and metastasis—ignoring the details. Foulds (1969, 1976) considered neoplasia as one process, which developed to one of five phases: A, B1, B2, C1, C2 in different tumor types [27].

The facts that in more subtle ways, tumors differ significantly from one another and potentially have different mechanisms of induction have rarely been considered in theories of cancer.

This historical failure to fully incorporate detailed pathological observations of tumors into theories of these diseases has had the effect of distracting cancer researchers from attempting to explain the many and varied differences in detail between the types of cancer. The concept of unity rather than the plurality of malignant tumors remains dominant. It has been reinforced by government agencies throughout the 20th century. Names such as Imperial Cancer Research Fund, National Cancer Institute, War on Cancer, and Cancer Moon Shot are used without variation. Had the true biology of malignant tumors been recognized, their names would have been Imperial Fund for Research on the Cancers/Cancerous Diseases, National Institute for the Cancers/Cancerous Diseases, etc.

2.1.4. Plasias

The other idea originating from the Ancients was that changes in forms of things are driven by hypothetical forces. The idea was sketched by Plato (4th century BC) in his Timaeus and adapted slightly by subsequent philosophers [28]. It was still accepted in the early 19th century, being used particularly by Jean Frederic Lobstein (the Younger, 1777–1835) [29]. This surgeon and pathologist noted that similar sorts of pathological tissues could be seen in different organs and assumed that the pathological tissue types were the effects of different forces on lymph in the particular places. He named the distinct pathological tissue types plasias. He called normal growth euplastic; excessively growing normal tissue hyperplastic; mildly abnormal excessively growing tissues homeoplastic; mildly abnormal growing tissues heteroplastic; and markedly excessively abnormal growing tissues cacoplastic. The suffix -plasia entered medical terminology in this way.

The term neoplasia was used by Virchow in 1854 to indicate the idea that true tumors occur through a hypothetical new kind of tissue-forming influence [19]. This process was considered unrelated to any normal biological or pathological tissue-forming process. Initially, the term was not popular, but was later taken up, for example, by Lancereaux in (1888) [30] and has been widely used since the early 20th century, especially by James Ewing [31–33].

Metaplasia was introduced by Virchow in 1885 [34]. In 1890, anaplasia was introduced by David Paul Hansemann (1858–1920) as a hypothetical common process in all malignant tumors. The term has been used ever since—although not according to its original meaning—to describe highly malignant tumors [35] (see also Section 2.4.1 and Ref. [28]).

Dysplasia was introduced by Klebs in 1890 in his "Allgemeine Pathologie" for growth disorders of bone, and from the 1920s, it was applied to some forms of leukemias [36].

From the late 1940s onward, it has been used for abnormalities in the squamous cells of the uterine cervix (see Ref. [37]).

2.2. Deviations in normal biological or nontumorous pathological processes

By the 1840s, anatomists and pathologists were studying tissues and cells in normal biological processes (for example, embryonic development), as well as in all recognized pathological processes. When studying tumors, the historical philosophical background (see Section 2.1) led them to look for a single (unified) normal or pathological biological process which is degenerated in tumors.

The candidate normal biological phenomena considered were any preadult, including embryological, phase in the life of the parent or other kind of cell, as well as any reactive cellular phenomena and effects of infections.

2.2.1. Embryonic reversion

Possibly the first to put forward this kind of theory was Royer-Collard in 1828 [38]. The basic observation for the idea was that tumors are made up of cells which, like embryonic cells, grow more rapidly and have less cytoplasm than adult cells. Later in the 19th century, microscopic studies showed that tumor cells and embryonic cells also occasionally invade adjacent tissues and metastasize (see in Sections 6.9 and 6.10 and Appendix A1.5). Various versions of the idea were developed by Cohnheim in 1867 [39], Boll in 1876 [40], and endorsed by Ewing [32]. An example of embryonic reversion was thought to be myxomas, because of their resemblance to embryonic connective tissue and in particular the myxoid kind known as Wharton's jelly [41].

In the 20th century, the idea of embryonic reversion as the basis of some types of tumors arising in adults persisted, being expressed in the terminology -blastomas (see in Section 6.5.2). More recently, some molecular pathological and cell biological findings have been interpreted as supporting the idea:

(i) Embryonic proteins may be found in small number of tumor types arising in adults [42]. Examples are alpha-feto protein in hepatocellular carcinomas, and carcinoembryonic antigen in colonic carcinomas [43].

(ii) Some growth factors in tumors are active in embryonic and fetal life, for example, nerve growth factor [44] and insulin-like growth factor [45] (see in Chapter 4).

(iii) Genes for embryonic development, for example, the HOX family of genes, may be altered in certain kinds of tumors [46]. The general issue of whether any particular alteration in a gene has any role in the origin of the tumor, or is an epiphenomenon of genomic instabilities is discussed in Appendix A4.

(iv) Commonly, carcinoma cells in culture, and also occasionally in human tumors, change to spindled, sarcoma-like cells. This is interpreted by some investigators as a version of the epithelial-mesenchymal transition which occurs in the early embryonic plate [47–51] (see in Appendix A1.1.2; Fig. 2.4).

2.2.2. Altered development/maturation/differentiation of local specialization

Tissues which turn over (labile kinds of cells, see Appendix A1.3.3) comprise (1) local tissue stem cells, (2) cells in the process of maturing (reaching terminal differentiation), and (3) mature cells which are in the process of dying of their own accord (see discussion of apoptosis in Appendix A7.5).

Hansemann invented the term dedifferentiation (see Section 2.4.1) and other authors adopted it with the meaning that tumor cells have lost the ability to mature fully (see in Ref. [28]). The idea of failed cytodifferentiation as an essential step in neoplastic development was advocated by Bullough [52] and others in the 1960s (see in Ref. [53]).

In recent decades, the phenomena of maturation have been revisited, with the proposal that tumor cells accumulate because they have lost the ability to die of their own accord on maturation. In this scenario, all the cells produced by cell division remain in variably mature states in the mass. The suggestion has been termed failed terminal differentiation, failed senescence, failed physiological cell death, and failed apoptosis (see Appendix A7.5). Possible mechanisms of this are loss of the genes for physiological cell death, or possibly abnormal epigenetic regulation of these genes [54] (and see in Appendix A2.7).

Figure 2.4 The major theories of tumors involving biological processes.

Prolonged life spans could easily coexist with excessive rates of proliferation at the level of the local tissue stem cells, as is most commonly thought to be the primary abnormality of tumors (see also Sections 2.6.3 and 2.6.4; and Appendix A1.3.2).

2.2.3. Abnormal directions of specialization

These theories involve altered specialization pathways, as can occur as a nontumorous pathological process. Thus, in the late 19th century, it was thought that a malignant tumor might develop because its parent cell begins to express the features of other kinds of cells, especially leukocytes (see below and in Sections 6.6–6.8). Late in his life, Virchow suggested the idea in terms of metaplasia [55], as is discussed in Ref. [28]. The öogenic aspect of Hansemann's early thinking (see Section 2.4.1) was another theory based on abnormal direction of specialization. Currently, the overall concept is often described in terms of reprogramming of cells via different gene activations [56].

2.2.4. Abnormalities deriving from inflammatory responses

The idea that inflammation precedes cancer was proposed by Boerhaave in 1742 [57] and adopted by many subsequent authors, including Broussais in 1832 [58] and Virchow in his early work (in Ref. [19]). The notion became less popular when histopathology developed so that inflammatory lesions could be reliably distinguished from true tumors, but has been supported in the 20th century by Nicholson [59] and Haddow [60]. Many contemporary authors are exploring further aspects of this possible cause of tumors [61–68]. The fundamental mechanisms usually involve excessive and/or deviant inflammatory, reactive, or regenerative responses to chronic irritation, with the possible concurrent involvement of other factors.

2.2.5. Early infection theories

At this point, it may be noted that shortly after Pasteur discovered the microbiological origin of many inflammatory diseases, theories of infection and/or parasitism became the most popular concept of the origin of tumors [71]. The evidence was mainly the finding of microorganism-like structures in tumor cells. One discovery in this era is worth noting. In 1913, J. Fibiger (1867–1928) discovered that a parasite in cockroaches can cause stomach cancer in mice. Fibiger was awarded a Nobel Prize for Medicine on the basis of this discovery, but more recently, his explanations of the phenomenon have been derided [28 (pp. 313–314), 69]. Nevertheless, the phenomenon is an example of how a particular hereditary predisposition may require a particular carcinogenic agent for the tumor to occur (see also Sections 3.1.7 and 5.10).

2.3. Definitions offered by 19th and early 20th century authors

2.3.1. 1850–1920

The definitions put forward in this period are of little relevance today. A useful summary of them was given by James Ewing (1866–1943) [32]. He noted that eight authorities at the time all used increased growth as a sine qua non of a tumor, with variably other abnormalities. Ewing concluded:

I believe with Prudden∗ that beyond the autonomy of tumor growth, it is difficult to add any element to our definition which may apply to all blastomas∗∗.

Ewing went on to say that more descriptive definitions were easily applied, but that with more study, some of the described qualities might become less significant (as criteria of definition).

Since Ewing, almost all authorities have agreed that the only common feature of tumors is inappropriate and unceasing, autonomous accumulation of cells [31,32,70,71]. In addition to tumorous swellings, the definition also applies to most cases of in situ tumors (in Sections 3.4 and 8.2.9). In these latter lesions, the whole tissue may not be markedly increased in volume, but tumor cells may fill normally cell-free spaces such as the lumina of ducts.

2.3.2. R.A. Willis' definition

Rupert A. Willis (1898–1980) was a pathologist in Melbourne, Australia, and later at Leeds, UK. He wrote three insightful books on tumors and their relationships to normal biological phenomena [72–74].

His definition in Pathology of Tumors (1948) [72] has probably been the most popular over the last half century.

A tumor is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues, and persists in the same excessive manner after cessation of the stimuli which evoked the change.

The definition was conventional, except for the inclusion of growth persisting after cessation of the causative stimulus. This distinguishes tumors from hyperplasias (see in Section 1.1.1). Although Willis did not explain why he included the phrase in his definition, the notion clearly reflected the established experimental observations (which Willis referred to elsewhere in his book) that carcinogens applied for short intervals to a tissue such as skin cause cancerlike morphological changes which regress on cessation of application of the carcinogen. Only when the carcinogen is repeatedly applied for long periods does the true tumor appear. This, as is essential for the definition, does not regress with cessation of application of carcinogen, but continues to grow, invade, and eventually metastasize.

Willis did not indicate any pathogenetic mechanism for either the tumorlike morphological abnormalities or the tumorous change. Nor did he include the most fundamental characteristic of tumors: - that they occur in many different types. His definition is consistent with the idea that the change in the normal cell is a genomic event. However, Willis discounted this mechanism (see Section 2.4.5) and declared in relation to the issue of pathogenesis of tumors "Ignoramus—We do not know" [72 (p. 207)].

2.4. Early genomic theories, viral carcinogenesis, and definitions

2.4.1. Hansemann's theory of abnormalities in chromosomes as the basis of tumor formation

The first genetic theories of tumors emerged in the 1880s. Edwin Klebs (1834–1913) in 1889 suggested that tumor cells might be hybrids, resulting from fusion of nuclei of different kinds of cells, for example, an epithelial cell nucleus with a leukocyte nucleus [28 (p. 69)]. The first proposal that tumors depend on a disturbance of the intrinsic hereditary material of the cell was made by David Paul Hansemann (1858–1920; Fig. 2.5; see Ref. [28]). In his first paper on the topic, Hansemann (1890) suggested that the primary disturbance in tumor cells is in the balance of their chromosomal numbers. He suggested ways in which these abnormalities could possibly be induced by carcinogens and might be related to the nuclear changes, altered specialization, and lineage fidelities of tumor cells. Hansemann initially supposed that the chromosomal abnormalities arose through activation of a deviant, öogenesis-like process in a normal cell. Hansemann called the process anaplasia, which he defined as a process resulting in the phenotypic effects (although that term was not used at the time) of

Figure 2.5 David Paul Hansemann (1856–20). (A) Portrait (courtesy of Herr Wolfgang von Hansemann, grandson). (B-D) Photomicrographs of abnormal mitotic figures in tumor cells published by Hansemann in 1893. Hansemann's main contributions to oncology were: – the idea that tumors may occur through endogenous changes in the hereditary material of normal cells – the suggestion that these changes might come about through abnormalities of chromosomes (whole or in parts) – the words ‘de-differentiation’ and ‘anaplasia’, which he used to denote the morphological and behavioral abnormalities in tumor cells brought about by the chromosomal lesions. The words have become almost universally used in medicine for these abnormalities, but without reference to chromosomal abnormalities – descriptions of many other general aspects of tumors.

(i) Dedifferentiation (meaning loss specialization from öocyte to ovum) together with

(ii) An increased capacity for independent existence (meaning metastatic potential)

Within 10   years, Hansemann abandoned the activated oogenesis aspect of his theory and in 1904 suggested that tumors form from two, possibly particular, reassortments or damage events in chromosomes in parent cells (see pp. 287–289 in Ref. [28]).

Regardless of the öogenic and chromosomal aspects of this theory, Hansemann's concept of degrees of anaplasia was useful to histopathologists. This was because previous classifications of tumors had used two discrete categories based on Lobstein's ideas [28]. In the main, this meant dividing tumors into homeoplastic and heteroplastic. This classification offered no way of indicating degrees of abnormalities. Hansemann's terms anaplasia and (de)differentiation became universal because they could be used for phenomena which are continuously variable (as discussed in Section 6.2).

2.4.2. Work of Theodor Boveri

In 1914, Theodor Boveri (1862–1915) described a theory of tumors based on observations of chromosomes in cells of doubly fertilized (i.e., triploid) sea urchin eggs [75]. No other cell biological abnormalities in tumors were considered [76,77]. The idea was essentially a modification of Hansemann's ideas of imbalances in chromosomal numbers causing tumor formation. There was little discussion of issues such as specialization in cells, which Hansemann's theory addressed.

2.4.3. K.H. Bauer on somatic mutation as the basis of tumors

Although a few authors, e.g., Tyzzer in 1916 [78] and Whitman in 1919 [79], had hinted at somatic mutation as the basis of tumor formation, the first extensive discussion was provided by K.H. Bauer (1890–1978). In 1923, he published a hypothesis of tumor formation through mutations in normal body cells [80]. However, subsequently he read H. J. Muller's article Artificial transmutation of the gene [81]. Bauer then wrote his book (1928) [82] in which he reviewed mutation theory in general, mutation in germ cells, mutations in body cells before discussing tumor-conditioning mutations in humans—i.e., hereditary predispositions. The remainder of the book consists of a review of the pathology and other characteristics of tumors, and then known etiological factors.

The relationship between heredity and exogenous carcinogens was discussed, and the perceptive comment made (Ref. [82] p 60, translated B. Coghlan):

… the biological question presents itself as inheriting tissue-imperfections which, with additional external factors, favour substantially the emergence of tumour

Original emphasis

Bauer concluded by stating that all properties of tumor cells could be accounted for by the "gene-biological" mode of thought applied as mutations as the cause of tumors [82 (p. 71)].

2.4.4. J.P. Lockhart-Mummery suggests somatic genomic instability in tumors

In addition to Hansemann and Boveri, Winge in 1930 wrote on the chaotic nature of tumor cell populations due to chromosomal aberrations [83]. However, it was J.P. Lockhart-Mummery (1875–57) in 1934 who gave the first detailed account of the theory that tumors are abnormal populations deriving from genomic events in normal cells [84]. He argued that, by analogy with species—which must undergo mutations in their precursor gametogenic cells to produce abnormal descendants—tumors deriving from somatic cells must be caused by mutations in the genomes of those precursor somatic cells.

Lockhart-Mummery discussed the roles of inheritance and exogenous carcinogens (chemicals and radiations) in the etiology of tumors. However, the work is most notable for discussing genomic instability in tumor formation. He observed the differences in susceptibility to radiation-induced mutations in Drosophila versus the European wasp, and the fact that within a century or so, the human species had produced many new germ-line mutant diseases, such as von Recklinghausen's disease (inherited predisposition to nerve tumors). From that, he argued that a similar propensity in humans to somatic mutation would account for the greater incidence of tumors in them both with age, and in comparison with other species. He attributed the tendency of tumors to develop in nontumerous lesions with high rates of cell production to mutations originating in mitosis of those cells. He further suggested that additional mutations are the basis of tumor progression.

The innocent tumor is due to a gene mutation for excessive growth of certain cells of the epithelium, and the malignant tumor which superimposes itself on the adenoma is due to another gene mutation in certain cells of that tumor.

Ref. [84 p. 118].

Lockhart-Mummery did not, however, discuss the individual abnormalities in tumor cells, or how possibly an individual mutation might be required for each abnormality.

2.4.5. R.A. Willis' morphological arguments against the somatic mutation theory

Willis in his Pathology of Tumors [72] (see Section 2.3.2) reviewed the abnormal morphologies and behaviors of tumor cell populations in the various common types of tumors. He then rejected any role for Mendelian genetics [85]—as the subject was understood at the time—in tumor formation.

In the 1940s, it was known that Mendel had based his laws on observations of only a limited number of traits in one test organism (the sweet pea, Fig. 2.6). His experimental results had the following features:

(i) The phenotypic changes were all-or-nothing, i.e., not showing variability.

(ii) The phenotypic changes were always fully expressed in one generation (for dominant traits) or two (for recessive traits—in the F2 generation).

(iii) These effects do not change further in subsequent generations without another genomic event.

As his first law (1868) Mendel had concluded from his results that:

• Characters/traits are determined by parentally derived paired factors/alleles; one from each parent.

• Each allele, regardless of from which parent, is either dominant or recessive (except in sex-linked disorders). Two dominant alleles have the same effect on the trait as one dominant allele. Only two recessive alleles change the trait.

Mendel also proposed (as his second law) that the factors are distributed independently during production of gametes. In the 1900s, however—after the discovery of equal