Classification of Neoplasms: A Critical Appraisal Robert W. Huntington, Robert W. Huntington III, Samuel Stearns Perspectives in Biology and Medicine, Volume 20, Number 2, Winter 1977, pp. 215-222 (Article) Published by Johns Hopkins University Press DOI: https://doi.org/10.1353/pbm.1977.0076

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CLASSIFICATION OF NEOPLASMS: A CRITICAL APPRAISAL ROBERT W. HUNTINGTON* and ROBERT W. HUNTINGTON IHf

In scientific or practical study, schemes of classification and nomencla-

ture have to be recognized as at once indispensable and fallible. They are devices of human students, hence subject to all human fallibilities. A scheme improvised for opening a new field of study will be based on conjecture, and one used for some time in a field under continued

exploration cannot be expected to incorporate the newest data and insights. Yet in medicine, as in other scientific and practical endeavors, workers must communicate through a mutually understandable ter-

minology. While it is no longer hoped that dreaded things can be made harmless by proper placatory pronunciation of their names [1], the attempt to cope scientifically with diseases demands an effort to give them

right names, indicative of causes and results, and to group them properly in order to facilitate comparison and contrast, which are indispensable to the accumulation of knowledge. Thus, while traditional classifications are not to be taken too seriously, taxonomy is not to be

regarded as a hopelessly frivolous operation. The proper attitude to-

ward schemes of classification is one of critical scrutiny in the hope of improvement. Ceteris paribus, schemes based on discernment of alternatives, or of clusters and gaps, will be more satisfactory than those imposed on even and continuous distributions. Thus humans, and even fishes [2, 3], can

usually be classed as male or female, and human blood groups can be listed as O, A, B, or AB despite such variants as A2, Ax, or Bombay. However, in tabulations of human weight, height, or age, groups must be demarcated arbitrarily. Dialectically speaking, classification into groups presupposes discontinuity, and application of classificatory grouping to a continuous series is like applying a polygon to a circle. Just *Director of medical services and consulting pathologist emeritus, Kern Medical Center, Bakersfield, California. Address reprint requests to 470 Wellington, Cambria, California 93428.

!Assistant professor of pathology, University of Wisconsin Medical Center, Madison,

Wisconsin 53706.

Perspectives in Biology and Medicine ¦ Winter 1977 | 215

as a polygon approaches a circle by acquiring an infinite number of sides, a descriptive nosology of a continuously variable set would require

infinite variations for a complete fit. All too often the classifier sets up more categories than he or his colleagues can use, with the fit still far short of perfection. Problems Involved

A philosopher glancing at tumor biology might anticipate that classification of neoplasms would be difficult under any conceivable

scheme, and might recall Cassirer's comment [1] that human capacity to make language is closely related to capacity to make myths. Morphologic study over the past century has demonstrated a huge and bewildering array of patterns, and more recent biochemical study has revealed another large range of discouragingly independent variables. As Foulds [4] has suggested, each individual neoplasm may be unique, and grouping, however necessary for study and management, inevitably arbitrary. Uncertainty in application of the traditional scheme of classification is vividly recorded in the assembled monthly minutes [5] of the regional study groups of the California Tumor Tissue Registry. Unanimity is unusual, while near-tie votes are not. Split is inter- rather than intragroup, with some groups all for alternative A, others for B, and intragroup consensus clearly representing persuadability rather than firm individual judgment. Yet the participants are outstanding both in concern with tumor pathology and in opportunity for self-education. Further indication of the unsatisfactory state of tumor classification is

afforded by the vigor of attempts to improve it. In the endeavor to get tumor pathologists to "speak the same language," there have been elaborate definitions of categories from scholarly international committees.

"Tumor slide conferences" are regular features of meetings of pathology societies. A moderator selected for expertise in the tumor group in question tries to teach colleagues to see the sections as he sees them and

call them as he calls them. A rebel might suggest that at times the process comes perilously close to brainwashing. Yet the divergencies of interpretation remain. Current etiquette demands that when a patient with a neoplasm is transferred to another clinic the record must include not

only the histopathologic diagnosis but also the complete report and the sections from which the diagnosis was made. It is not anticipated that the pathologist of the second (transferred) clinic should be satisfied to accept his colleague's diagnosis: Rather he has the right (and duty) to make his own.

Since features amenable to objective and quantitative analysis are seldom mentioned, one suspects that the major weakness of the operation may be a radically qualitative and subjective character [6]. Other weak216 J Robert W. Huntington and Robert W. Huntington III · Classification of Neoplasms

nesses center about incongruity with current insight into the nature of neoplasia.

If after examination of a lesion the pathologist decides that it is neoplastic, he is expected to call it benign or malignant and to specify not only the site of origin but the specific cell type (anläge) at that site which was transformed into neoplasm [7, 8]. In many, perhaps in the majority of instances, identification of anläge is expected to provide adequate characterization of the pattern of the tumor. The concept of tumor classification by identification of anläge was developed at a time of rebound from the blastema concept of Rokitansky, when students were entranced with the recognition that

neoplasms did have points of resemblance to normal structures and were ultimately derived from them. The concept would have been favored by belief that the etiology of neoplasia was not only unknown but very likely unknowable. A process whose cause had eluded so many earnest students "ought not" to be extensive apart from factors related to growth restraint. Although guardedly expressed, the favored notion seems to have been that of idiopathic somatic mutation with maturation arrest. The earlier arrest, it was thought, the greater the aggressiveness of the neoplasm. Comparison of neoplastic cells with incompletely differentiated cells sometimes amounted to assumption of identity, as in the Bailey-C ushing classification of "Gliomas" [9, p. 93; 10]. In retrospect it could be argued that, with a process capable of thwart-

ing the commitment of a normal clone toward differentiation, modifications of cellular structure and function might be expected to be extensive and drastic. Although many neoplasms have an inertial tendency to retain salient features of sites or origin, evidence specifying a single progenitor cell type is seldom unequivocal. Faith in monoclonal or, at the widest, monotypal sites of transformation, if based on reluctance to postulate multiple sites of idiopathic somatic mutation, is less plausible since displacement of the idiopathic mutation notion by demonstration of variegated causes of transformation. Even in the first flush of enthusiasm for classifying tumors by trying to name their parental cells, it was recognized that a tumor may look unlike

any normal cell group identifiable at its site of origin. In the hope of resolving such difficulties, the concept of metaplasia was developed. Metaplasia, defined as acquired modification of the character of dif-

ferentiated cells, is to be distinguished from heterotopia, developmental primary displacement [H]. Nonneoplastic metaplasia [4] is usually reversible, while neoplastic metaplasia is characteristically transmitted from early generations of neoplastic cells to their ultimate descendants. Thus keratin formation in a bronchial carcinoma will usually be recognizable in its metastases. Even if one were to assume that the metaplasia preceded neoplastic transformation and was entirely separate from it, Perspectives in Biology and Medicine · Winter 1977 | 217

and to call the metaplastic epithelium the anläge, he would agree that in this instance cytogenetic characterization of the neoplasm would not be synonymous with identification of its normal cell parentage.

Many neoplasms, some of bronchial origin, display a medley of squamous and glandular patterns. Perhaps even more confusing are neoplasms which look at once spindly and somewhat epithelial. The

attempt to pigeonhole such tumors by ascribing some to epithelium, others to stroma, calls for sympathy but not total confidence.

We have barely mentioned the benign-malignant phase of classification, despite its great practical importance. Here, too, one is faced with a lot of betwixt-and-betweens. The actuality is not of an antithetical either-or character, but one with all graduations between the

entirely benign at one end of the scale and the luridly malignant at the other. Correlation between histologic and clinicobiologic criteria is imperfect, and adequate discussion of terminologie inconsistencies would have to be lengthy. It would take even more time to review recent studies which express total confidence in the traditional classification. We shall touch briefly on

a few of these studies—on topics of lesions of infancy and childhood, of electron microscopic comparison of tumors with suggested anlagen, of inheritable tumor syndromes, and of suggested neurosecretory origin of several hormonally active tumors.

Traditional Classification Studies Pediatric pathologists [12, 13] are interested in a group of kidney lesions which they separate from Wilms tumors on the basis of morphol-

ogy, occurrence in early infancy, and favorable prognosis. The neutral term "lesion" is used in order to avoid unprofitable debate as to whether they are to be called tumors or hamartomas. Their recognition is of practical importance since they can be managed without radiation and consequent damage to centers of ossification. We are not entirely persuaded that differences between these lesions and Wilms tumors are

vastly greater than between the testicular tumors of infancy and other

"endodermal sinus tumors" [14]. If the suggestion should prove valid

that the infantile kidney lesions owe their properties to derivation from secondary nephrogenic mesenchyme while Wilms tumors owe theirs to origin in primary mesenchyme, it would still be dangerous to generalize

from these kidney processes and to presume that degree of undifferen-

tiatedness of precursors was often the only or the crucial factor in determining the aggressiveness of a tumor.

Comprehensive and detailed analysis of tumor cell organelle patterns with the electron microscope is appropriate and fascinating, and thejournals are full of such studies. In comparing patterns in tumor cells with 218 I Robert W. Huntington and Robert W. Huntington III · Classification of Neoplasms

those in suggested anlagen, objectivity is desirable, along with evaluation of statistically adequate numbers of cells. Since on light microscopy tumor cells often look less like their precursors than like other cells, it would be prudent to anticipate similar possibilities with electron microscopy.

The suggestion that multiple tumors of inherited syndromes are derived from closely related anlagen, while "economical," is short on direct evidence and hardly applies, for example, to Gardner's syndrome [H]. The suggestion of neural crest (neurosecretory) anlagen for several

tumors with endocrine activity [15, 16] is fascinating and plausible since neutral crest derivatives are everywhere; thus, for example, if one has difficulty in referring the endocrine function of modullary thyroid carcinoma to thyroid anläge, the suggestion of neurosecretory anlange is handy. But, though it is fashionable to refer pancreatic islets and isletish tumors to neural elements, the results of a recent study hardly favor this

hypothesis [17]. We may note that the prolonged dispute over neural versus epidermal origin of pigmented naevi and melanomas is still unresolved [18, p. 1003]. Meanwhile evidence continues to accumulate which suggests that

identification of anlagen is often precarious and irrelevant. In a classic study of viral transformation by Temin [19], while the eventual morphology of the transformed cells was influenced by selection of the cell clone for transformation, it was influenced quite as decisively by selection among variant strains of transforming virus. It is well to emphasize that only in controlled studies such as this can one be certain that only a

single cell clone or type is undergoing transformation. Classifiers who ordinarily belittle the gap between pretransformation and posttransformation cells have shown a paradoxical eagerness to attribute "mixed" or composite tumor patterns to divergence following transformation of

a monotypal precursor. We can readily entertain this hypothesis. The converse looks quite as plausible, namely, derivation of a uniform tumor pattern from convergent transformation of varied precursors. Except in experiments such as Temin's attempt to discern anlagal identity is a

projection into the irretrievable past, with all the uncertainty of such projections [6].

As Foulds [4] has emphasized, while normally differentiating cells in switching on one set of information systems switch off others, neoplasms

often exhibit mixtures of active information systems without parallel in normal structures. Such a medley may represent repression of information active in the precursor and derepression of information repressed in the precursor. Examples have already been given, and it is easy to cite others. Thus thyroid tumors frequently show little resemblance to normal thyroid follicular pattern, and those which come close to it may be

lacking in all or part of specific activity. On the other hand, there is Perspectives in Biology and Medicine · Winter 1977 | 219

increasing awareness of endocrine activity of tumors or nonendocrine sites [20, 21].

A Look into the Future

Continued availability of repressed information should occasion no surprise. Any limitations upon it must be largely nonchromosomal, since

differentiating cell lines other than erythrocytes, platelets, and postmeiotic germ cells continue to replicate the chromosome pattern of the zygote, and there is direct evidence for totipotency of nuclei for differentiated cells [22]. Transformation by "retroviruses" involves

modification of host cell genomes by introduction of proviral DNA. With this go possibilities of recombination and transduction [23]. Neoplastic cells often differ from all normal clones in chromosome number and

pattern, antigenicity, and cell products.

Continued uncritical acceptance of a system of classification based on depreciation of the extent of change associated with neoplastic transformation looks imprudent, and failure to take note of observations and

interpretations not in accord with that scheme may delay the advance of knowledge. We sympathize with colleagues reluctant to acknowledge large flaws in the scheme, since our own reluctance was overcome only

after much hard thinking. We are aware that critics of accepted schemes will be challenged to put up or shut up, to keep quiet unless ready to submit a new scheme or at least a detailed list of revisions rather than the few

suggestions we feel able to offer. We hope to amplify our list after further cognition.

After indicating the site of the structure found to contain neoplasm, an opinion would be given as to whether the neoplasm was primarily at that site or metastatic to it. If the tumor is deemed metastatic, some

suggestion as to the primary site may be expected, along with an indication as to whether that suggestion is a reasonable certainty, a guess, or somewhere in between. If the tumor is primary, as in a mastectomy specimen, it would then be classified in accordance with presence or

absence of evident regional metastasis. If the case has been adequately studied, clinically or at autopsy, the tumor would then be categorized

according to presence or absence of evidence of distant metastasis. If

there is no substantial evidence of metastasis, appraisal of aggressive potential is called for. We would place the benign-malignant division with a code for anticipation of aggressiveness, 0-1, minimal to slight; 1-2, slight to moderate; 2-3, moderate to high; and 3-4, high to very high. Further classification would be in broad morphologic categories, reflecting the actual patterns rather than inferences about cellular parentage. Subdivisions would be based on characteristics practically

important in the management of the patient, such as hormone produc220 I Robert W. Huntington and Robert W. Huntington HI ¦ Classification of Neoplasms

tion or elaboration of CEA [4]. Thus we are not convinced of the importance of resorting to electron microscopy in order to differentiate "small

cell carcinomas" from "oat cell carcinomas" [24]. Indeed, we would not

be unwilling to lump patterns now called embryonal rhabdomyosarcoma, sympathicoblastoma, Ewing's tumor, aggressive lymphosarcoma, and oat-cell and small-cell carcinoma under the heading of "The Very

Bad Cancer with the Small Cells" and to divide in accordance with sites

and clinical features. In a tumor predominantly small cell, a few cells of myoid pattern would suggest myoid parentage, but only to the extent that the presence of keratin would suggest squamous epithelial parentage.

We do not look for easy and satisfactory classification in the foreseeable future, for we regard neoplasms in the aggregate as a multidimensional continuum in which group demarcations will be arbitrary. Continuing long-range study will be needed to keep the imperfections of classification within the limits of tolerability. We anticipate that effort toward prevention may require etiologic classification but hesitate to predict its usefulness for those who deal with unprevented neoplasms. We think that microscopic pattern will continue to be the basis of clinicopathologic classification. The ultimate role of electron microscopy

remains to be determined. We would hope for increasing discernment of relevant factors which could be appraised objectively and quantitatively. Chemical and immunologic markers might serve, and accurate

estimation of such familiar features as nuclear pycnosis and nucleocytoplasmic ratios might prove useful.

While hoping for more objectivity, we anticipate that a large subjective element will remain. The indispensability of such an element in cultural anthropology has been ably suggested [25], and the situation in other branches of biology may not be totally dissimilar. In anthropology it is hoped that the subjective can be kept within bounds if complete objective records of crucial events are preserved for interpretation by students with diverse viewpoints. By analogy, it might be useful to have collections of sections of neoplasms preserved for repeated review by several observers in the light of continuing clinical records and eventual autopsy findings. REFERENCES

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SELF-RIDICULE

I have no great excess of wit; it is not quite my manner. My somber thoughts do not permit the use of comic grammar,

but dismal themes of tragic tone are more to my persuasion, nor do I readily condone an effort at dissuasion, for I am bad, and I am sad,

I pleasure in my sorrow. If I grew happy and were glad,

what would I do tomorrow?

Samuel Stearns

222 I Robert W. Huntington and Robert W. Huntington III ¦ Classification of Neoplasms