MALIGNANT LYMPHOMAS IN ANIMALS

Transcription

1 THE AMERICAN JOURNAL OP CLINICAL PATHOLOGY Vol. 38, No. 1, pp July, 1962 Copyright 1962 by The Williams & Wilkins Co. Printed in U.S.A. MALIGNANT LYMPHOMAS IN ANIMALS A SURVEY OF PRESENT KNOWLEDGE HILTON A. SMITH, D.V.M., M.S., PH.D. Armed Forces Institute of Pathology, Washington 25, D. C, and Baylor University College of Medicine, Waco, Texas At approximately the same time that lymphoid neoplasia and leukemia were coming to be understood as a single clearcut entity in human medicine, the corresponding disorders were recognized and reported in the domestic animal. Although exact references are not readily available, Leisering 25 is usually credited with the first recognition of "leukemia" in a horse in 1858 and in swine and cattle a few years later. Siedamgrotzky 44 saw it in a dog in Greatly enlarged spleens first attracted attention in most of these cases. At the present time, as part of the worldwide attack on the etiologic mysteries of neoplasia, malignant lymphomas and leukemias of animals are receiving considerable attention, and they constitute a promising field for research pertinent to all species. This article is an attempt to summarize what has been presented on the subject from various sources. Before going further it is probably best to attempt to clarify the rather varied terminology relating to the disease (or diseases) we are discussing. The hematologist views the disorder as leukemia; the morphologic pathologist sees the anatomic enlargements and calls the disease malignant lymphoma. Certain other terms which are or have been in common use are essentially synonymous with malignant lymphoma or some of its subtypes. These include lymphosarcoma, 10 ' 12. w. ' " 61 lymphoblastoma, 8, 24 ' 41,46 and lymphocytoma. 17 ' 22,26 ' 28 30,31,42, 52 Nothing would be gained by entering into the controversy of which term is preferable; all have their advocates. As to Received, February 15, 1962; accepted for publication April 6. Dr. Smith is Fellow, AFIP, and Research Associate, Baylor University College of Medicine. Supported by Grant AT (40-l)-2784, U. S. Atomic Energy Commission. lymphomas, all are malignant and the adjective might seem unnecessary. Customarily, however, the whole term "malignant lymphoma" is used. By (lymphogenous) leukemia we understand the presence in the circulating blood of immature or anaplastic cells recognizable as precursors of lymphocytes, monocytes, or granulocytes, usually in huge numbers, so that the total white cell count is far beyond normal limits. Ordinarily leukemia, 1, 4, 11, 13, 18, 20, 36, 43-47, ag j u g t de. 75 fined, occurs as an accompaniment of malignant lymphoma, although only a minority of malignant lymphomas in animals are so accompanied and, conversely, an occasional example of leukemia is encountered, in connection with which the lymphoma can not be demonstrated grossly. The fact that the 2 conditions occur together, as well as other considerations, has convinced most authorities that they are 2 manifestations of the same disease, and we shall view them in this light. Hence, when we refer to malignant lymphoma it will be with the understanding that the abnormal blood picture of leukemia may well be a part of the syndrome and possibly the only disorder clinically recognizable. We believe that the name of leukemia for a more or less recognizable clinical syndrome without either lymphoma or a definitely leukemic blood picture (aleukemic leukemia) is more a matter of clinical convenience than of fundamental concept. Malignant lymphoma, as used here, will mean any tangible neoplastic proliferation of lymphoid tissues, which may or may not be detectable by clinical examination. Most frequently the proliferation involves marked enlargement of several or many lymph nodes of the body. The involvement of only a single node, however, is not precluded. In roughly half of the cases con-

2 76 SMITH Vol. 38 spicuous proliferation of anaplastic tissue results in distinct enlargement of the spleen, as well as of lymph nodes. Quite uncommonly the thymus is the principal and apparently the primary seat of lymphoid proliferation. In company with tumorous enlargement of the strictly lymphoid organs there may or may not be infiltrations or discrete neoplastic masses in various other organs. Most authorities regard these as the result of metastasis from a primary lesion in some lymphoid organ. There are, however, a not inconsequential number of cases in which lymphoid masses form in nonlymphoid tissues without any apparent primary in any lymphoid organ (node, spleen, tonsil, Peyer's patches, or thymus). We shall not attempt to explain these, but in the present state of knowledge must include them within the bounds of our definition. Likewise included are tumors of anaplastic lymphoid-appearing cells in the skin and subcutis, although these neoplasms possibly include special types more or less related to the mast-cell tumors and transmissible "venereal" tumors, found chiefly in the dog. 7 ' In addition to the preceding, it is necessary to mention the term "leucosis," 2 ' 3 > 16 ' 16 ' 19 ' 36,88 > 66 which is widely used by North European veterinarians as a designation presumably synonymous with both leukemia and malignant lymphoma as above defined. In the United States "leukosis" is usually restricted to a transmissible disease of birds characterized by lymphoid proliferations or leukemic changes. As yet it has not been demonstrated to have too much in common with lymphoma or leukemia in mammals. In the present paper this, as well as the extensively studied leukemias of laboratory animals, will be ignored. European investigators recognize a cutaneous "leucosis" in cattle but admit it may be unrelated to the usually accepted form. It is seldom recognized in the United States. Reactive hyperplasias would apparently need to be carefully excluded from this diagnosis. With these explanations in mind, we may proceed to summarize what is known about malignant lymphoma and leukemia in animals. Some of the statements made will be based upon studies still in progress; hence, they will have to remain for the present as generalities believed to be well founded but subject to detailed and precise interpretation later. OCCURRENCE IN VARIOUS SPECIES Malignant lymphoma is known to occur in all domestic and some wild mammals (elephants, giraffes, hyenas, seals, polecats, opossums), although there are good indications that it is considerably more frequent in some species than in others. These indications come chiefly from (1) the not-tooprecise experiences of clinical practice; (2) the records of certain large veterinary hospitals and diagnostic laboratories, usually teaching institutions; and (3) the records of the U. S. Meat Inspection Division (Agricultural Research Service, U. S. Department of Agriculture). Complete data on the incidence of malignant lymphoma in proportion to the total animal population are not available, but some idea of the frequency or rarity of the disease in the various domestic species can be obtained from the proportions among autopsies and laboratory diagnoses, such as those listed in Table 1, which come from the Texas School of Veterinary Medicine (Texas Agricultural and Mechanical College, College Station, Texas) over a period of 11 years. TABLE l LIMITED SAMPLING OF INCIDENCE OF MALIGNANT LYMPHOMA DIAGNOSED IN DOMESTIC SPECIES DURING AN 11-YEAR PERIOD* Species Equine Bovine Ovine Caprine Porcine Canine Feline Number of Cases Diagnosed Number Diagnosed as Lymphoma Per cent of total diagnoses Number per 100, * Source Texas School of Veterinary Medicine.

3 July 1962 MALIGNANT LYMPHOMAS IN ANIMALS 77 It is perhaps worthwhile to mention certain studies that have been reported in dogs, although they deal with the proportion of lymphomas to total illnesses, not to total deaths nor to total population. Wirth 67 in 1931 found malignant lymphoma in 0.36 per cent of 2763 dogs brought to a clinic in Vienna. Bloom and Meyer 6 in 1945 reported 0.2 per cent of 10,000 dogs brought to a single hospital in New York City as having this disease. Meier 29 in 1957 found that of all dogs presented at a particular hospital in Boston over a period of 10 years, 0.1 per cent were suffering from malignant lymphoma. Cohen and co-workers 9 have initiated a very thorough study of all dogs in the State of New Jersey but have not yet arrived at figures on total incidence. In Table 2 we have listed data from the U. S. Meat Inspection Division on the number of animals coming to slaughter that, upon postmortem inspection, proved to be afflicted with malignant lymphoma, their meat being condemned. The figures are from the Summary of Activities, Meat Inspection Division, 1960, except in the case of horses and goats. Owing to the small, statistically insignificant number of lymphomas in these 2 species, the figures represent one-tenth of the total for 10 years instead of 1 year, These data are believed to portray with a fair degree of accuracy the relative susceptibility of the various domestic species. The percentage for the porcine species may well be somewhat lower than it would be if as high a proportion of breeding animals was Equine Bovine (more than 1 yr. old) Calves (less than 1 yr. old) Ovine Caprine Porcine allowed to reach mature or old age as is the case with the other farm species, inasmuch as the incidence admittedly increases with age in any species. There is no way to make an accurate comparison of the incidence in dogs and cats with that in the farm animals. It is only in the 2 former species that the natural life span and the diseases that go with advanced age are not curtailed by slaughter of a majority of animals. In cattle it may be estimated that x %o of the males and far more than half of the females go to market at an early age. Thus, less than one-fourth of all cattle reach the middle of a natural life span, the time when the majority of these neoplasms develop (age incidence, Table 3). Allowing for the fact that a minority do occur before middle life, it still seems safe to estimate that if the lives of all cattle were terminated only by other than man-made events, there would be at least 3 times as many malignant lymphomas as are revealed by the data of the Meat Inspection Division. A more or less similar line of reasoning applies to the other meat-producing species. In the case of horses 39 it is probable that the incidence found at meat inspection is unnaturally high, inasmuch as usually only the infirm and economically useless horses are killed for meat. Although the figures compiled from the Texas Veterinary Medical School are of limited statistical significance because of the smallness of the numbers, they do tend to confirm this view. In Table 1 it will be seen that the incidence in horses is 3^5 that in cattle; in Table 2 the corre- TABLE 2 INCIDENCE OF MALIGNANT LYMPHOMA IN SLAUGHTERED ANIMALS* Total Slaughtered 199, ,454, ,975, ,447, , ,494,437.0 Number Lymphomas Per cent Per 100, * Source Summary of Activities, U. S. Meat Inspection Division (Agricultural Research Service, U. S. Department of Agriculture).

4 78 SMITH Vol. 88 TABLE 3 INCIDENCE OF MALIGNANT LYMPHOMA, BY AGE Age (Inclusive Period) Species Less than 4 mo. 4-7 mo mo. 1-2 yr. 3-5 yr. 6-8 yr. 9 yr. or more Bovine Feline Canine Canine Texas A. & M. School of Veterinary Medicine sponding fraction is 241- The high incidence in cats is based upon very small numbers and may well be misleading (although it is interesting to note similar findings at Angell Memorial Animal Hospital, in Boston). The extremely low numbers in goats and sheep are in accord with the well known resistance of those species to neoplasia in general. In summary, it seems that if the proportional incidence of malignant lymphoma in goats is taken as 1, the other species would manifest approximately the following incidence: sheep, 2; horses, 4; swine, 5; dogs (and cats), 22; calves (under 1 year of age), 8; other cattle, 56. INCIDENCE Incidence at different ages. As to the part played by the patient's age, decisive figures are not as yet available. In the bovine species it can be stated with certainty that malignant lymphoma does not wait for the "cancer age" of middle life before making its attack, for calves only a few weeks old have been found among its victims. Still, the neoplasm is unquestionably more frequent among the old. This has led to the suspicion among some European investigators that there may be 2 forms of "leucosis," one in the young and another in older cattle. If such is the case, however, no differential criteria other than age itself have been discovered. In species other than the bovine, available data do not suggest that the disease is of importance in young animals, a conclusion subject to possible revision when more complete studies are Riser Animal Hospital 0.0 I I 100 I 9.41 I 85 I 6.26 I available. For the present, precise data are limited to the small numbers available from the Texas School of Veterinary Medicine and the Riser Animal Hospital, Chicago, Illinois, as summarized in Table 3. Incidence in different sexes. Sex apparently is of no importance in the incidence of this disease. Geographic incidence. Geographic distribution may be a feature fully deserving the attention it is currently receiving. In the United States the indications, up to the present, that malignant lymphoma may have a regional distribution have come principally from a study of the records of condemnation of slaughtered bovine carcasses made available by the U. S. Meat Inspection Division. The geographic variations were first brought to light by Lt. Colonel C. M. Barnes, USAF, Veterinary Corps, of the Atomic Energy Commission, who reported (without publication) upon the condemnations encountered in the year The corresponding figures for the fiscal year 1960 have since been made available by the Meat Inspection Service. Possibly one conclusion that can be drawn unequivocally from these data is that throughout the arid Rocky Mountain and Pacific regions the incidence of bovine malignant lymphoma is uniformly and remarkably low, ranging from 0 to 7, with a mean of 3, per 100,000, as compared with 18 for the national average. Among the areas of high incidence are the following: (1) a zone which may be called the Southern Plains, reaching from southeastern Kansas

5 July 1962 MALIGNANT LYMPHOMAS IN ANIMALS 79 FIG. 2 (left). Nodular form of invasion in heart of 4-year-old dog. There was tricuspid insufficiency with extreme edema of the limbs and belly wall. PIG. 3. (right). Infiltrative form of malignant lymphoma in bovine myocardium. The white streaks among the muscle bands are the result of infiltrating lymphocytes. PIG. 1. Lymphomatous enlargement of parotid gland, and parapharyngeal, precapsular, coxal, prefemoral, popliteal, and supramammary lymph nodes. This cow was aleukemic; she lived several months.

6 80 SMITH Vol. 38 through Oklahoma and the eastern (but not the western) half of Texas to the Gulf (inspection stations of Arkansas City, Kansas; Oklahoma City, Oklahoma; Fort Worth, San Antonio, and Houston, Texas). Incidence here varies from 29 to 91 per 100,000, with an average of 60. (2) Minnesota and the western Great Lakes region (stations at Detroit, Michigan; Chicago, Illinois; Milwaukee, Madison, and Green Bay, Wisconsin; South St. Paul and Austin, Minnesota). The incidence in this area varies from 12 to 91, averaging 42.5 per 100,000. (3) Western Kentucky and Tennessee (Nashville and Memphis, Tennessee; Louisville, Kentucky; and Memphis, Mississippi). The incidence here varies from 26 to 68, with an average of 46 per 100,000. Incidence varies greatly over the other parts of the United States, but averages are low. As officials of the Meat Inspection Division have themselves pointed out, to rely upon these data as conclusive evidence of important geographic trends is premature until further investigations have proved that the differences have, indeed, a geographic basis and are not incidental to marketing practices or other aspects of the meat production industry. Such investigations are in progress, as well as certain other geographic compilations. At the same time, it is interesting to note that the Minnesota region, with its high bovine incidence, is reported to have the highest human incidence of any part of the United States. Regarding parts of the world other than the United States, we have very few details. Reports of the disease come from every civilized area, and there is no doubt that malignant lymphoma in the domestic animals is of world-wide distribution. In Europe a majority of leading scientific papers on the subject come from the Scandinavian and Germanic countries, but we are not able to state whether it is the disease itself or, rather, the research being done on it that is the more extensive in those countries. We can state that the incidence in Denmark is so high that malignant lymphoma of bo vines is being handled as an epizootic disease, with quarantines and attempts at eradication. 3 This is in contrast to the situation in the United States, where the animal disease is at present of small economic concern and research is aimed principally toward assistance in conquering the ailment in man. In Sweden, we are told, 83 the principal incidence is in just 1 part of the country where vaccination against a form of piroplasmosis is practiced; this introduces complications that will not be discussed here. Chronologic features. There is a widespread feeling that malignant lymphoma and leukemia are on the increase in the human race, although there are investigations also that point in an opposite direction. As with other aspects of the disease in animals, the only definite figures so far compiled on large numbers of animals are from the U. S. Meat Inspection Division. In slaughtered cattle, condemnations for malignant lymphoma were 9.3 per 100,000 (based on 13,000,000) in The annual reports depicted a gradual climb until in 1959 there were 18.2 cases per 100,000 (based on 17,000,000). In 1960 there was the first decline in the series, the incidence being 16.9 per 100,000. Here again certain questions of practical interpretation are under study (by this writer and veterinarians of the Meat Inspection and Animal Disease Eradication Divisions) and must be answered before these data can be accepted unequivocally as pointing to a general increase in the frequency of malignant lymphoma and leukemia. The cattle involved, although numbering many millions, were animals in an apparent state of health slaughtered for food. Compilations on animals that have died of the disease are in the process of being made from data obtained at veterinary hospitals and colleges. SYMPTOMS AND LESIONS The symptomatology manifested in a given individual obviously varies in accordance with the organs and parts of the body invaded. Many cases are not detected until loss of weight, strength, and usually appetite call attention to a state of general malaise, the disease being already well advanced. The most common specific manifestation is the pronounced enlargement of a number of lymph nodes (Fig. 1).

7 July 1962 MALIGNANT LYMPHOMAS I N ANIMALS '">" " ' '"/'.>-."' 81 Illliltlfcfe i0. FIG. 4 (upper). Organs from a cow with widespread involvement; complete cross section of uterine cornu near its tip, and a segment where the circular section is larger (2 nodules of lymphoma). Section of wall of stomach (abomasum) with 1 gastric fold of normal height. All parts are tremendously thickened with invading lymphomatous tissue. FIG. 5 (lower). Nodular form of invasion, kidney of a cat. This is a presenting symptom in more than half of the clinical cases. At postmortem examination, lymph nodes are found to be invaded in approximately 95 per cent, but a few cases occur in which visceral organs are the seat of lesions without any detectable involvement of lymph nodes. The nodes are firm but painless and movable. The degree of enlarge- ment often reaches several times normal size; if it is only minimal, the differential diagnosis must include consideration of tuberculosis and similar granulomas. In a considerable portion of cases the lymph nodes of the thoracic inlet are enlarged to the extent that there is interference with respiration and even with the return venous flow. This seems to be most ^J1'I":;C'*"

8 82 SMITH Vol. 38 frequent in cattle and represents the only location where mechanical obstruction of vital function is common. Lymph nodes in the thoracic cavity often are greatly enlarged, but only rarely have they caused impairment of circulatory function. Although pulmonary osteoarthropathy sometimes accompanies severe compression of pulmonary air space in the dog, we know of no instance in any species where this has been a result of lymphomatous tumors. Abdominal and pelvic lymph nodes rather regularly reach huge dimensions, but noticeable interference with function usually depends on invasion of particular organs. Enlarged inguinal nodes have been known to interfere with elimination of feces and urine, but this is not usual. The author has seen bovine ureters whose total outside diameter was increased from a normal 3 mm. to 10 times that figure, the lumen itself and its mucosal lining remaining normal and the flow of urine unimpeded. The usual softness of the neoplastic tissue doubtless accounts for this relatively benign situation. Involvement of the various lymph nodes of the head occurs with frequency but usually not to the point of producing prominent symptoms. A rather startling and not highly infrequent lesion in the bovine is accumulation of tumorous tissue in the retrobulbar region of the orbit so that the eyeball protrudes far from its natural position and may ultimately be completely displaced. The condition may be unilateral or bilateral. 5 Invasion of the eyeball itself is not unknown. Among specific organs, the heart 42 is frequently invaded, in the bovine species perhaps to the extent of 60 per cent of cases. Sometimes separable nodules of soft, homogeneous, white tissue are formed (Fig. 2); sometimes narrow pale streaks are the visible signs of infiltration between muscle bundles (Fig. 3). It is always the base of the heart and walls of the atria that are involved, occasionally with later extension to the ventricles. In spite of this often extensive invasion, death from cardiac arrest does not easily occur. The lungs are spared in the great majority of cases, a fact that may be kept in mind in the gross distinction of the rather frequently encountered metastases of carcinomas. Speaking again of the bovine, invasion of the wall of the stomach (abomasum 14 ) is common (Fig. 4); involvement of the intestine is less so. When any part of the digestive tube is invaded, the process seems to spread into the wall from the serosal side, the mucosa being reached last, and in most cases found at death to be without ulceration. The latter is not unknown, however, and death from a perforating gastric ulcer is reported in 1 case by Theilen. 49 Intestinal stasis may constitute the terminal symptomatic picture, even without any premonitory signs, in those instances in which the gastrointestinal tract is extensively tumorous. The bovine nonglandular stomachs (rumen, reticulum, omasum) often bear subserous lumps of lymphomatous tissue protruding from their serosal surfaces, and occasionally this tissue invades the wall in the same manner as in the other digestive viscera. The liver in most instances escapes invasion, although there are exceptions. When invasion does occur it usually proceeds from the islands of Glisson (portal areas), ultimately producing rounded white nodules of small or large size. Involvement of the pancreas seems to be extremely rare. The kidneys are invaded more frequently than the liver. Invasion most often consists of an insidious infiltration among the renal tubules, which may not be detectable at gross inspection. This statement is especially true in the bovine, perhaps because bovine animals die in an earlier stage of the disease than do some more resistant species. In the dog and cat (Fig. 5), and also in the pig (Fig. 6), discrete tumor nodules in the kidneys are not rare. The uterine wall is invaded in a considerable number of bovine cases (Fig. 4). Usually a number of rounded and irregularly distributed nodules appear beneath the serosal surface, spreading inward toward the mucosa only later, much as in the gastrointestinal tract. Massive involvement of the cervix has been noted. The perivaginal and perirectal tissues have been the seat of extensive growths, and dystocia has been

9 July 1962 MALIGNANT LYMPHOMAS IN ANIMALS 83 reported as the result of them, although this is exceptional. Invasion of the ovaries must be rare, although the writer has seen extensive invasion of a rabbit's ovaries. He has encountered 1 bovine ovary in which the corpus luteum was extensively infiltrated, all other parts of the ovary being spared. A tumor in the mammary gland is practically certain to be something other than malignant lymphoma, although invasion of the bovine mammary gland has been reported once8 and has been observed once by the writer, the supramammary lymph nodes sharing in the process but revealing no direct extension from one to the other. Entrance of this tumor into the cranial cavity must be extremely rare, but invasion into the spinal canal is not (Fig. 7). Theilen49 found it in 3 cases out of 22. The usual result is a not too slowly developing FIG. 6 (upper). Kidney of a pig infiltrated by malignant lymphoma. (The black specks represent petechiae, an incidental occurrence.) FIG. 7 (lower). Malignant lymphoma filling peridural spaces of spinal canal, surrounding lumbar nerve roots and cauda equina. Cow given euthanasia after being unable to rise for 19 days.

10 84 SMITH Vol. 38 posterior paralysis, with total recumbency often being the first disorder noticed (in the bovine). Although as a tumor of the spinal canal the meningioma probably would be first to come to mind, malignant lymphoma would have a much greater probability, at least in some of our domestic species. The tumor usually surrounds the nerve trunks and fills the canal at a given level; actual invasion of nervous tissue seldom, if ever, occurs. Saving the best (or the worst) for the last, the spleen is an organ of much importance in the study of malignant lymphoma, although this relation is not well understood. In perhaps 75 per cent of cases in the bovine, canine, and probably all domestic species the spleen is enlarged, sometimes to tremendous dimensions. In these cases the splenic pulp is largely replaced by anaplastic lymphoid cells, the malpighian corpuscles being, at least, obscured. There is another type of splenic involvement in which the organ is moderately increased in size. Its cut surface manifests greatly enlarged corpuscles as prominent white bodies evenly scattered through the dark splenic pulp. Considerable difficulty is experienced in determining whether these enlarged corpuscles are truly neoplastic or merely hyperplastic. The morphology of the large lymphoid cells within the corpuscles is of little assistance, being characteristic merely of what is usually called a lymphoblast. More enlightenment is to be derived from the estimation of the cell types, neoplastic or otherwise, in the surrounding splenic pulp and the other recognized signs of malignancy. It is, on the other hand, entirely possible to have typical lymphomatous involvement of other organs and lymph nodes while the spleen remains in an apparently normal state, grossly and microscopically. In the canine and some other species there are also spleens in which malignant lymphoma appears as discrete masses of neoplastic tissue bulging from an otherwise normal organ. It may well be that these different types of splenic involvement have some importance in diagnosis and classification, but what this is we have yet to learn. Of thymic lymphomas, or thymomas, it may be said that they occur in the bovine and other species, sometimes attaining large size without involving any other part of the body. They are quite rare, however, in contrast to what is true in some laboratory species. Most lymphoid tumors at the thoracic inlet appear anatomically in bovines to have arisen in the lymph nodes of the region, and they occur most frequently at an age when the thymus has long ceased to be demonstrable. In some animals the bone marrow has been demonstrated to contain a high proportion of diffusely distributed neoplastic cells. In others certain areas of marrow are replaced by the lymphoid neoplasm. In many, no change in the bone marrow is apparent. The number of animals in which detailed studies of the bone marrow have been made is limited, and nothing definite can be said as to proportions of the different groups in any of our domestic species. Histopathology. Microscopic classification of malignant lymphomas in animals is incomplete, 23 ' 32 and nothing of importance can be offered at this time. Hematology. Some animals afflicted with malignant lymphoma have the exceedingly high white blood cell counts and the predominance of lymphocytes that we have designated as indicative of leukemia. 66 Many of the lymphoid cells are recognizably immature or anaplastic in their morphologic detail. In other patients, the lymphoma is entirely aleukemic, the white cell counts remaining within normal limits. Although counts covering large numbers of animals are not available, it would seem that the leukemic cases are in a minority. Whether it is possible for the leukemic stage to shift to an aleukemic one, or vice versa, as is said to happen in man, it is impossible to say. Certain investigators have developed "keys" by which they classify all the cattle in a herd in 1 of 3 groups, "leukotic," suspicious, or normal. As an example, the key used by Rosenberger 88 places in the "leukotic" group all cattle having total leukocyte counts of more than 18,000 per cu. mm., coupled with proportions of lymphoid cells at or above 75 per cent of the total white cells. Less than 10,000 total

11 July 1962 MALIGNANT LYMPHOMAS IN ANIMALS 85 leukocytes (12,000 in animals younger than 2 years of age), with not above 60 per cent lymphocytes, is regarded as normal, and counts and percentages in the intermediate range place the animal in a "suspicious" group. In numerous herds the cattle classified by those investigators as "leukotic" constitute a large proportion. These cattle are in good clinical health and usually remain so; hence, the presence of "leukosis" is by no means synonymous with malignant lymphoma. Nevertheless, it is in herds in which there have recently been 1 or more cases of malignant lymphoma that the "leukotic" animals appear. These investigators, we understand, visualize the "leukotic" animals as being in a "prestage," which may develop into malignant lymphoma (lymphosarcoma) or may subside. If these beliefs are confirmed, some new concepts of the pathogenesis of lymphoid neoplasia may be in order. ETIOLOGY There is nothing certain on this subject; hence, little need be said. Based upon the frequency in certain herds, there is evidence pointing toward hereditary susceptibility, but at present this evidence is highly fragmentary. The same herds of high occurrence are also used to suggest a contagious cause, a virus. There are those, indeed, who believe that the presence of a virus has been demonstrated. 37 The various lines of evidence pointing toward irradiation as at least a causative factor are well known. Resolution of this will await further investigation. TREATMENT A few researchers 9 27 are systematically using irradiation, nitrogen mustards, and newer drugs in the treatment of dogs. The results seem to be what would be expected on the basis of experience in human medicine. In the farm animals, for obvious reasons, no treatment has been attempted. SUMMARY The current knowledge and beliefs regarding malignant lymphoma and lymphogenous leukemia in animals are surveyed. Peculiarities of incidence are presented with respect to species, age, and geographic distribution. Symptomatology, gross pathologic features, and hematology in the domesticated animal are described. Current theories on etiology, as well as therapeutic practices, are mentioned. SUMMARIO IN INTERLINGUA Nostre currente cognoscentias (e opiniones) in re maligne lymphoma e leucemia lymphogene in animates es revistate. Peculiaritates del incidentia con respecto a specie, etate, e distribution geographic es presentate. Esdescribitele symptomatologia, le characteristicas macro-pathologic, e le hematologia in le domesticate animal. Le currente theorias es mentionate con respecto al etiologia. Etiam le practicas therapeutic es discutite. Acknowledgments. The author wishes to express his gratitude to Dr. R. C. Reisinger and others of the U. S. Animal Disease Eradication Division and the U. S. Meat Inspection Division for their active cooperation in gathering data pertaining to slaughtered animals; to Dr. R. J. Lukes and others of the Armed Forces Institute of Pathology for their consultations and assistance in difficult interpretations; to the U. S. Atomic Energy Commission for financing this study; and to the Baylor University College of Medicine for the time allowed for work at the AFIP. REFERENCES 1. AHBBBG, B.: Biochemical studies in Sweden on bovine leukemia, Report 22. In Conference on Comparative Studies in Leukaemias. Philadelphia: World Health Organization, BENDIXBN, H. J.: Untersuchungen iiber die Rinderleukose in Danemark. Deutsche tierarztl. Wchnschr., 67: 4-7; 57-63; ; , BENDIXBN, H. J.: Investigations on bovine leukosis in Denmark, Reports 12, 13, 14. In Conference on Comparative Studies in Leukaemias. Philadelphia: World Health Organization, BIESTEE, H. E., AND MCNXJTT, S. H.: A case of lymphoid leukemia in the pig. J. Am. Vet. Assn., 69: , BLOOM, F.: Unilateral exophthalmos associated with leukemia in a cat. Vet. Med., 32: 1, BLOOM, F., AND MEYEB, L. M.: Malignant lymphoma (so-called leukemia) in dogs. Am. J. Path., 21: , BLOOM, F., PAFF, G. H., AND NOBACK, C. R.:

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