Pediatric Tumors

Immunological and Molecular Markers

John T. Kemshead

• Publisher: CRC Press
• Year: 2020
• ISBN:
  9781000141924
• Edition: 1
• Topic: Medicine
• Subtopic: Medical Theory, Practice & Reference

This monograph explains the considerable impact that monoclonal antibodies and molecular probes have had on the diagnosis of tumor types and sub-types. It explains how radiolabelled monoclonal antibodies have also been used as imaging agents to try to improve the oncologist's ability to define residual tumor deposits after combination chemo/radiotherapy. Finally, the childhood malignancies that still have a poor prognosis are presented, and new novel ways of therapy are explained.

Chapter 1

PATHOLOGY AND EPIDEMIOLOGY

John R. Pincott

TABLE OF CONTENTS

I. Introduction

II. Collaborative Investigations and Classifications

III. Light Microscopic Methods of Diagnosis

IV. Ultrastructural Examination

V. Immunohistology

VI. Histochemistry and Cytochemistry

VII. In Vitro Culture

VIII. Cytogenetics

IX. Epidemiology

References

I. INTRODUCTION

The management of many adult and childhood tumors has been transformed in recent years. Part of this change has derived from improved accuracy of diagnosis which has allowed the more appropriate tailoring of therapeutic regimens. Consequently, the effectiveness of radiotherapy and combinations of potent chemotherapeutic agents has been enhanced while their concomitant toxicity has been minimized. As a result, the prognosis of many tumors has been improved and the quality of life of the patients bearing them enhanced.

An integral part of this diagnostic improvement has been a change in the approach to the histopathological assessment of the tumors. Refinements of classification with recognition of new tumor types and subtypes and the employment of more sensitive methods of diagnosis have all contributed to improved diagnostic precision, on which more effective treatment can be based.

Some of the methodological advances introduced in recent years have been the result of direct study of childhood tumors. Others, however, have stemmed from related fields such as adult oncology, from which techniques have been adapted, often with great effect.

One of the more subtle changes in the area of childhood tumor assessment which has, however, contributed significantly to these improvements is the pooling of knowledge and resources for a concerted effort to examine specific aspects of particular oncological problems. It has been recognized that for most pathologists, a childhood tumor is an uncommon occurrence, so that even a lifetime of experience will be an insufficient database to make a significant impact on clinical management. In addition, limitations on manpower and financial constraints have also encouraged a collaborative approach to this numerically relatively small, but clinically very important area. Hence, scientific and financial considerations have, exceptionally, tended to work towards the same logical end.

This pooling of knowledge and experience has particularly manifested itself in the creation of specialist centers for the treatment of tumors of childhood, and the establishment of multicenter collaborative studies between these groups, each designed to address a particular oncological issue or gather data on a specific tumor. An early consequence of this approach has been the classification of some of the more common tumors histopathologically in a manner which has proved to have demonstrably more clinical relevance. A particular advantage of this approach has been the recognition of classes of tumor which bear a particularly poor prognosis, and for which an especially intensive therapeutic regimen can therefore be justified. Just as important as these are the tumors which, despite past opinions to the contrary, systematic study has demonstrated to have an especially good prognosis. In these cases therapy can be minimized, thus improving the trauma to the child and reducing the risk of early and late sequelae of treatment.

Occurring independently of developments in approaches and organization of scientific investigation have been improvements and exciting innovations in the scientific techniques themselves. Many of these are based on existing methods, well proven over many years of use, but which utilize the techniques in a different way, or with added refinements to tailor them to specific diagnostic needs. In this regard, for example, the increasing use of fine needle aspiration cytology has, from the patient’s viewpoint, made some histological diagnoses considerably less troublesome than an open biopsy, while for the physician it has provided a far speedier tissue diagnosis.

The method is, however, largely based on many years’ experience in the established techniques of morphological assessment in the field of exfoliative cytology. Elsewhere, investigative techniques such as electron microscopy, long valued for the insight they have provided into the subcellular basis of pathological appearances, have developed through the stage of supporting diagnoses made primarily by traditional histological methods to a vital component of the pathologist’s armamentarium in the laboratory investigation of tumors, requiring great skill, experience, and patience.

Within the science of histochemistry, progress has been made in recent years beyond the level of the use of “special stains” to characterize cells merely by cataloguing their staining characteristics. More advanced techniques are now utilized to identify individual cytoplasmic components and contents, such as enzymes, which permit not only observations on the functions of the cells, but also some deduction as to the histogenesis of the tumor.

Among the many techniques available for the investigation of tumors, immunohistology has probably made the greatest impact. Methods have been developed to identify both surface and cytoplasmic antigens which have considerably enhanced the identification and elucidation of histogenesis of tumor cells. In addition, the use of particular forms of fixation and proteolytic enzymes to “unmask” cytoplasmic antigens has allowed the application of some of these techniques to paraffin wax-embedded tissues. In turn, this has permitted immunohistology to be applied in diagnostic pathology laboratories with minimal disturbance of routine, and has also released much archive material for more detailed assessment. Unfortunately, surface antigens are, on the whole, less amenable to demonstration under these conditions, and tissues under investigation require to be processed separately, usually by frozen section or cytology from impressions of fresh tumor. Monoclonal antibodies to surface antigens are most effectively applied in this manner. They are highly specific, which makes them a very useful tool in the differential diagnosis of morphologically similar tumors. However, as antigen expression can vary considerably between tumors of the same type, and even between individual cells in the same tumor, it is a necessary precaution to employ monoclonal antibodies in panels, rather than individually for diagnostic purposes.

Other less widely used techniques may also be appropriate in the investigation of individual cases, and in some instances have been developed or differently applied in recent times to considerable effect. For example, observation of the differentiation and behavior of tumor cells in tissue culture can be time consuming and resource intensive, but in combination with other techniques (such as catecholamine fluorescence for the diagnosis of neuroblastoma or monoclonal antibodies for the differential diagnosis of small round cell tumors of childhood) can be very effective and specific. Cytogenetic examination can be of interest in particular areas, such as specific types of Wilms’ tumors or retinoblastomas, though more for etiological and clinical genetic purposes than diagnostic. In the related areas of oncogene expression and amplification, however, there has been a recent upsurge in interest, though the diagnostic application and specificity of such techniques remain to be validated.

In conclusion, it should be said that a broad spectrum of histopathological methods is available for the diagnosis and classification of childhood tumors. Many of these are relatively recent innovations, and new developments are continually being applied to this field of study. For convenience, this variety of investigative techniques is presented as a sequence of separate fields of study, though in practice matters work out very differently.

It is usual in the process of diagnosis of a specific tumor for the techniques considered most appropriate to that case to be selected from each of the groups of investigations and applied in the order dictated by clinical circumstances, likely diagnosis and its differential diagnosis, as well as the availability of manpower and other resources. It is clear that for intelligent planning of these various studies and the setting of priorities, there must be close liaison between physician and pathologist.

It is also worth recording that many of the techniques described require preparation and planning to perform. Many investigations, particularly histochemical and immunohistological, can only be carried out on fresh, snap-frozen material, which require the advance preparation of a freezing mixture. Cytology on tumor imprints cannot be carried out if the specimen is plunged directly into formalin directly after resection or biopsy, and this act also considerably increases the difficulty of rapid diagnostic or specialist frozen section work. Good ultrastructural examination is best done on fresh, refrigerated glutaraldehyde which clearly requires to be prepared in advance.

Further, few laboratories have the resources to carry out all the investigations listed. In addition to the establishment of specialist centers for particular investigations, the need for close collaboration between physician and pathologist is also valuable in permitting advance arrangements to be made for transfer of the material in question to the laboratory where the required investigations will be undertaken.

The same considerations apply to the establishment of a central diagnostic registry where material may be sent for review, collation, or comparison. Collaboration between specialist centers of pediatric oncology in this manner considerably benefits the individual patient while speeding the accumulation of knowledge of particular tumors, especially those which occur infrequently.

II. COLLABORATIVE INVESTIGATIONS AND CLASSIFICATIONS

Despite the establishment of specialist centers dedicated to the diagnosis and treatment of childhood malignancies, the number of tumors of any particular type seen in an individual center is still small. This has been one of the main stimuli to the setting up of collaborative investigations between specialist centers and others, on a national and international basis.

On...