WHO. World Health Organization. International Histological Classification of Tumours – serie

Knowledge of tumours of the thyroid gland has advanced consider- ably in the 22 years that have elapsed since work was started on the first edition of Histological Typing of Thyroid Tumours. In the intro- duction to that volume it was recognized that the definitions and clas- sifications put forward would need revision in time, and the present text differs substantially from the first edition. As far as is possible, however, the framework of the classification proposed remains the same, as the original classification was widely accepted and proved useful in many studies. The link between the morphological type of thyroid tumour and its epidemiology, natural history, function, prognosis and response to therapy has been further strengthened since the first edition. In par- ticular, the decision taken to separate papillary and follicular carcino- mas and exclude a mixed papillary follicular type has been well justi- fied.One of the major changes has been the recognition that many tu- mours regarded 20 years ago as small cell carcinoma were really ma- lignant lymphoma, and this development has been incorporated into this edition, with increased importance given to primary malignant lymphoma of the thyroid. Much work has also been done on medul- lary carcinoma of the thyroid, its link with mUltiple endocrine neo- plasia syndromes, and its association in its inherited form with C-cell hyperplasia; this too is recognized by an expanded section on this tu- mour.

This classification is based primarily on the microscopic characteris- tics of tumours and therefore is concerned with morphologically identifiable cell types and histological patterns as seen with conven- tional light microscopy. The term tumour is used synonymously with neoplasm. The phrase tumour-like is applied to lesions that clinically or morpholog- ically resemble neoplasms but do not behave biologically in a neo- plastic manner. They are included in this publication because they give rise to problems in differential diagnosis and because of the un- clear distinction between neoplasms and certain non-neoplastic le- sions. Synonyms are listed only if they have been widely used or are considered helpful for the understanding of the lesion. In such cases, the preferred term is given first and followed by the synonym. The current revision includes the recognition of a preinvasive le- sion, prostatic intraepithelial neoplasia, which is commonly associat- ed with carcinoma. It also recognises the paracrine-endocrine ele- ments in prostate carcinoma and other subtypes of adenocarcinoma.Although the emphasis of the classification is on histological typ- ing, consideration should also be given to the degree of differentia- tion and nuclear anaplasia, extent of local spread, vascular and lym- phatic invasion, and the occurrence of metastasis. The revision in- cludes grading (p. 14), staging (p. 32), and handling and reporting of the different types of specimens (p. 1).

This classification is based primarily on the microscopic characteris­ tics of tumours. It is therefore concerned with the identification of cell types and histological patterns as seen by conventional light micro­ scopy. In general, time-honoured terms have been retained. Syn­ onyms are listed only if they have been widely used or if they are con­ sidered to be important for understanding the disease process. In such cases, the preferred term is given first, followed by the synonym in parentheses. The individuality of a tumour manifests itself principally in its histological appearance and the extent of spread at the time of diag­ nosis. This volume is concerned only with the histological classific­ ation of tumours. Anatomical extent or staging is covered in the TNM Classification.! The histological classification of a tumour de­ pends on two main parameters, typing and grading, and a number of additional parameters which may apply to selected examples. Histological Typing This divides tumours of a given organ into different types according to their direction of differentiation. Although this may frequently in­ dicate the underlying histogenesis of the tumour, it may be difficult or impossible to identify the cell of origin. Note is taken of the structure and function of cell types, as well as the overall growth pattern of the tumour, with the aim of matching these features to those of a normal tissue found in the same organ.

This classic WHO reference has been updated in a new edition; it provides a standardized set of terms and definitions which facilitate national and international comparisons of data.

One of a series sponsored by the World Health Organisation, this new edition updates part of the recognized international classification of tumors.

Tumours and tumour-like lesions occurring in the Upper Respiratory Tract and Ear are classified and defined using internationally accepted terminology and diagnostic criteria. The second edition of this WHO publication has been substantially revised and expanded in collaboration with pathologists in 8 countries.

Knowledge of tumours of the salivary glands has advanced consider­ ably in the two decades that have elapsed since work was started on the first edition of Histological Typing of Salivary Gland Tumours. A great deal of information has been collected about newly de­ scribed tumour entities and the behaviour and prognosis of the pre­ viously classified tumours. Immunohistochemistry, cytophotometry, hybridization techniques, tissue culture and chromosomal analysis have increased our understanding of many tumours. Histological Typing Histological typing divides tumours of a given organ into different types according to their direction of differentiation. Although this may frequently indicate the underlying histogenesis of the tumour, it may be difficult or impossible to identify the cell of origin. Note is taken of the structure and function of cell types, as well as the overall growth pattern of the tumour, with the aim of matching these fea­ tures to those of a normal tissue found in the same organ. The principles of the second edition of the WHO Histological Typing of Salivary Gland Tumours are based on the following axioms: - The classification is orientated to the routine work of the surgical pathologist. The inclusion of rare but clearly defined tumour en­ tities should be helpful to surgical pathologists consulting with clinicians.

Inter-relationships of the Dental Tissues The tooth germ has three main components -the enamel organ, the dental papilla and the dental follicle (Fig. 1). The enamel organ is an epithelial structure derived from the ectoderm that lines much of the oral cavity. The dental papilla and the dental follicle are ectomesen­ chymal (mesectodermal), being partly derived from cells that mi­ grated from the neural crest early in embryogenesis. Both the gross morphology of the tooth germ and the differentiation of its cells de­ pend upon a complex pattern of inductive interactions between the epithelium and the ectomesenchyme. The sites in which the teeth will form appear to be determined before the commencement of epithelial downgrowth from the oral epithelium to form the odontogenic epithelium. This epithelial downgrowth (the dental lamina ), the development of the enamel or­ gans of the individual teeth, and the morphology of each enamel organ, are controlled by the ectomesenchyme. The enamel organ is responsible for the formation of enamel and comprises four layers: outer dental epithelium, stellate reticulum, stratum intermedium and inner dental epithelium (Figs. 1 and 2a).

During the two decades since the publication of the first edition of Histological Typing of Bone Tumours, new methods of diagnosis, es- pecially radiological imaging techniques (computed tomography and magnetic resonance imaging), associated with advances in the new cytomorphological methods including immunohistochemistry, DNA ploidy analysis, cytogenetic chromosomal investigation, etc., have greatly improved our diagnostic tools and treatment results. These advances are reflected by the publication of new editions of various important textbooks in recent years. In these publications classifica- tion criteria differed. In contrast, the WHO classification has been relatively unaltered, and has introduced a limited number of new entities and subdivided others because of distinct histological features and biological be- haviour. In general the framework and the concept of the original classifi- cation, as it has been widely accepted, remains essentially unchanged. The classification is based on the line of histological differentiation, in many instances reflecting the type of intercellular matrix material produced.This approach is justified because it avoids theoretical his- togenetic controversies.

The first edition of Histological Typing of Soft Tissue Tumours, pub- lished in 1969, represented a major step in the standardization of nomen- clature in this specialty area. Accompanied by a glass slide set of more than a hundred common and exotic tumours, this book resulted in the rapid assimilation of a universal set of guidelines and diagnostic defini- tions by pathologists in many countries. In the intervening two decades numerous changes have occurred, and our committee has been chal- lenged by the desire to incorporate new and exciting findings from the areas of immunohistochemistry and molecular biology into the classifi- cation with the need to develop a simple reproducible classification for practising pathologists. The current system, while based principally on standard microscopic observations, acknowledges and cites the use of di- agnostically valuable ancillary techniques. Changes in the Classification Although the original classification utilized the concept of "histogene- sis" or tissue of origin in defining tumours, we have departed from that point of view, acknowledging the impossibility of determining histogen- esis by morphologic means alone.This classification is based on the "line of differentiation", or stated simply, by comparing tumours to the nor- mal cell they most closely resemble without necessarily implying origin therefrom. As in the old classification we have interpreted the term "tu- mours" in the broadest sense of the word and have, therefore, included neoplastic and non-neoplastic conditions.

Although more than 12 years have passed since publication of the first WHO histological classification of central nervous system (CNS) tumours, the changes in this revised edition are not radical. Only one formerly recognized entity has been deleted: the monstrocellular sarcoma, because there is immuno- cytochemical evidence of its astrocytic nature. Several new tumour types have been added: the pleomorphic xanthoastro- cytoma has been generally acknowledged for almost a decade; the neurocytoma has gradually evolved as a clinical-pathological entity; and two new entries, the dysembryoplastic neuroepi- thelial tumour and the desmoplastic infantile ganglioglioma, have only been characterized morphologically during the past few years. We regard the classification as an international standard to facilitate communication and have tried to avoid current con- ceptual controversies. The majority of partiCipants supported inclusion of the term "primitive neuroectodermal tumour" (pNET).However, because of our limited knowledge of the biol- ogy of embryonal CNS tumours, preference was given to use PNET selectively, rather than applying it to all small cell embryo- nal childhood tumours, irrespective of their histological pheno- type. Ependymomas and meningiomas now have new histological SUbtypes. Most of these are not associated with biological behaviour different from the parent tumour type, but their description will aid the practising pathologist to identify and classify these lesions. 2 Introduction Histological Typing Following the philosophy of this WHO series, classification is based primarily on histological assessment of cell types and tis- sue patterns recognized by conventional light microscopy.

The task of updating the classification was given to theClassification and Nomenclature Committee of theInternational Society of Gynecological Pathologists and itsfour subcommittees. This classification reflects the presentstate of knowledge and modifications are almost certain tobe needed as experience accumulates. Since many of thetumours and tumour-like conditions in the classificationoccur in several sites in the female genital tract,cross-referencing from one site to another has been done inillustrating these lesions.

This is a classification of tumours and tumour-like lesions of the liver. It is based primarily on the microscopic characteristics of the tumours, and is therefore concerned with morphologically identi- fiable cell types and histological patterns. The haematoxylin- and eosin-stained section remains the mainstay of morphological diag- nosis, but special histochemical stains are often helpful and have been referred to in the explanatory notes. Readers interested in specific special stains mentioned in the text should consult Labora- tory Methods in Histotechnology of the Armed Forces Institute of *Pathology, Washington, D. c., USA. 1 The results of immunohisto- chemical methods for identifying various tumour "markers" have also been noted whenever indicated. The present classification incorporates all the previously classi- fied tumours, but also includes several new lesions, viz. biliary papil- lomatosis, the fibrolamellar variant of hepatocellular carcinoma and epithelioid haemangioendothelioma. Several subtypes of hepato- blastoma are mentioned. A serous type of bile duct cystadenoma is described.The section on tumour-like lesions has been expanded to include focal fatty change and inflammatory pseudotumour. The section on adenomatous hyperplasia, including macroregenerative nodules, has been amplified. The number of photomicrographs has been increased from the original 56 to 150. Unlike the first edition, the photomicrographs in the second edition are mostly black and white. All are new and were taken of representative cases on file at the Armed Forces Institute of Pathology.

The second edition of this book is devoted entirely to the exocrine pancreatic tumours. It is the result of a collaborative effort of pathologists from 7 countries and is more extensive and detailed than the previous edition, which was published 17 years ago.

Although this second edition retains the concise format of the first edition, the number of tumours described has increased considerably, especially in the melanocytic, adnexal, fibrous tissue and lymphoid neoplasms. Care has been taken to avoid needless subclassification, so as to limit the expansion of categories to those fulfilling demonstrable histological criteria. The commentaries remain succint whilst including the major diagnostic points, with reference to relevant immunohistochemical features. All the illustrations have been changed since the first edition. Of particular importance is the fact that close collaboration with the authors of the AFIP Atlas of Tumor Pathology on Melanocytic and Non-melanocytic Tumors of the Skin ensures a consistent approach to the classification.

There are two major differences in concept between this volume and others in the International Histological Classification of Tu­ mours series. The first of these is the inclusion of more clinical aspects than has usually been the case and the second is a con­ centration on a more limited range of conditions. There are sev­ eral reasons for adopting this approach. With regard to both cancer and pre cancer of the oral mucosa, we believe it is impor­ tant that general pathologists, in whose interests this volume has primarily been written, should be informed of the significance of the clinical features of the various lesions under discussion as they may on the whole be unfamiliar with them. Also, we con­ sider it necessary to draw attention to those conditions particu­ lar to the oral tissues that may give rise to appearances which are important in differential diagnosis but can be misleading to the pathologist who does not have detailed knowledge of these tissues. On the other hand, many of the benign and malignant tumours that affect the oral tissues have been dealt with in other volumes in the series and we believe that little or no advantage would be gained by repeating them here.

This classification is based primarily on the microscopic charac- teristics of tumours and, therefore, is concerned with morpho- logically identifiable cell types and histological patterns, as seen with conventional light microscopy. The term tumours is used synonymously with neoplasm. The phrase tumour-like is applied to lesions which resemble neo- plasms, clinically or morphologically, but do not behave biologi- cally in a neoplastic manner. They are included in this classifica- tion because they give rise to problems in differential diagnosis and because of the unclear borderline between neoplasms and certain non-neoplastic lesions. Synonyms are listed only if they have been used widely, or if they are considered to be helpful to the understanding of the lesion. In such cases, the preferred term is given first, followed by the synonym. Although the emphasis of this classification is on histological typing, in the examination of kidney tumours, consideration should be given to the degree of cellular anaplasia, the extent of local spread, vascular and lymphatic invasion, and the occur- rence of metastasis.The scheme of histological grading suggested here is as fol- lows: Grade I applies to the tumours that have the least degree of cellular anaplasia compatible with a diagnosis of malignancy; . grade II! applies to tumours with the most severe degrees of cel- lular anaplasia; and grade I! applies to those tumours in be- tween. This scheme is applicable to the carcinomas of the renal parenchyma and pelvis.

This classification is based primarily on the presence of morpho- logically identifiable cell types and growth patterns that can be correlated with the clinical behaviour of the tumour and, in some cases, with tumour markers in the serum. Although some of the histological terms and definitions have histogenetic impli- cations, this classification is not meant to be histogenetic. The terminology adopted for individual tumours is based on their general acceptance and world-wide usage. Synonyms are includ- ed only if they have been widely used in the literature or if they are considered helpful in understanding the lesions. Controver- sial histogenetic terms have been avoided whenever possible. The term tumour is used synonymously with neoplasm. The term tumour-like is applied to non-neoplastic lesions which clin- ically or morphologically resemble neoplasms; they are included in this classification because of their importance in differential diagnosis. Because of the many similarities between testis tumours and those of the ovary, an attempt has been made to follow the WHO histological typing of ovarian tumours. Histological Classification of Testis Tumours 1 Germ Cell Tumours 1.1Precursor lesions - intra tubular malignant germ cells 1.2 Tumours of one histological type (pure forms) 1 1.2.1 Seminoma ...906113 1.2.1.1 Variant - Seminoma with syncytiotrophob- stic cells 1.2.2 Spermatocytic seminoma ...9063/3 1.2.2.1 Variant - Spermatocytic seminoma with sarcoma 1.2.3 Embryonal carcinoma ...9070/3 1.2.4 Yolk sac tumour ...907113 Polyembryoma ...

Although the histological typing of ovarian tumours is the focus of this volume, other aspects of investigation of a specimen of ovarian tumour are also important. Some of these aspects are mentioned in the text or illustrated. They include tumour grading, which is impor- tantprognostically and therapeutically for certain types ofovarian tu- mour, quantification ofcomponents in mixed tumours and evaluation of the stroma of certain tumours that are associated with endocrine function. Grading methodologies have varied from one tumour type to another and from one group of investigators to another for the same type of tumour. Because a standard internationally recognized grading methodology has not been established, no specific guidance is presented in this volume. Nevertheless, grading by any generally acceptable method should be incorporated in the diagnosis whenever appropriate. The clinical and pathological classification of the extent of tu- mour growth (staging) should be taken into account for the purposes of treatment and prognosis. The TNlV1/FIGO system is therefore in- cluded (p. 45). Histological Classification of Ovarian Tumours 1 Surface Epithelial-Stromal Tumours 1.1 Serous tumours 1. 1. 1 Benign 1 1. 1. 1. 1 Cystadenoma 8441/0 Papillary cystadenoma 8460/0 1. 1. 1. 2 Surface papilloma ...8461/0 1. 1. 1. 3 Adenofibroma; cystadenofibroma ...9014/0 1. 1. 2 Of borderline malignancy (of low malignant potential) 2 1. 1. 2. 1 Cystic tumour 8442/1 Papillary cystic tumour ...846211 Surface papillary tumour...8463/1 1. 1. 2. 2 1. 1. 2. 3 Adenofibroma; cystadenofibroma 9014/1 1. 1.

The 1973 WHO classification of bladder tumours anticipated a probable need for eventual revision of the criteria for diagnosing papillary and flat bladder neoplasia. A workshop sponsored by the WHO consisting of pathologists, urologists, cytologists, oncologists and basic scientists interested in bladder tumours addressed this subject, and after a follow- -up meeting sponsored by the International Society of Urological Pathology, the classification and terminology used in this text were agreed upon. A major change is in the introduction of a new category: papillary urothelial neoplasm of low malignant potential. Many of the tumours previously designated as papillary transitional cell carcinoma, grade I now fall into that category. Another major change is in the designation of flat lesions, and this includes a definition of carcinoma in situ. Furthermore, a number of variant forms of urothelials carcinomas are included as well as new entities not recognized when the 1st edition was issued.

This second edition is the result of a collaborative effort of ophthalmic pathologists from 11 countries and is more extensive and detailed than its predecessor published in 1980. Several new tumour entities have been added, while the list of histological variants has been expanded and examples of immunoreactivity included. The publication of the revised eye and adnexal tumour classification is accompanied by 112 photomicrographs.

Lung cancer is currently the most frequently diagnosed major cancer in the world and the most common cause of cancer mortality world- wide. This is largely due to the carcinogenic effects of cigarette smoke. Over the coming decades, changes in smoking habits will greatly influ- ence lung cancer incidence and mortality throughout the world. These changes may also impact upon the histological types of lung cancer. Tumour classification is important for consistency in patient treat- ment, and because it provides a basis for epidemiologic and biologi- cal studies. The previous WHO classification was published in 1981 and since then considerable progress has been made in our understanding of cer- tain lung tumours 1. The concept of neuroendocrine tumours of the lung has been refined with recognition of large cell neuroendocrine carci- noma and modification of criteria for atypical carcinoid. Atypical ade- nomatous hyperplasia is now recognized as a potential precursor to adenocarcinoma. Studies have documented the histological hetero- geneity of lung carcinomas, particularly among adenocarcinomas and poorly differentiated carcinomas.Molecular studies have also shown that hamartomas and sclerosing hemangiomas are true neoplasms rather than tumour-like lesions. This classification is based on histological characteristics of tumours seen in surgical or needle biopsy and autopsy material. Though a large percentage of lung carcinomas are now diagnosed on cytology specimens, the classification does not address cytology.

This classification represents a project aimed at bringing together the variety of ways thymic epithelial neoplasms have been classified. It focuses on their growth characteristics, and cytoarchitectural features . The classification, though restricted to the thymic region rather than the mediastinum in general, also covers neuroendocrine, germ cell, lymphoid, and stromal tumours, as well as tumour-like lesions and the neck tumours of thymic or related branchial pouch derivation.