Reactive Splenomegaly and Variation of Lymphoid-Plasma Cell Population Associated with a Mouse Pituitary Thyrotropic Tumor*

EDITH E. SPROULANDRAUL GRINBERG (Rosiceli Park Memorial Institute and New York Slate Department of Health, Buffalo, New York)

SUMMARY A transplantable thyrotropic pituitary tumor, subline L24a, which grew after 13 months of dormancy in an intact mouse was associated in its early passage with a variety of lymphoid tumors. On subsequent passage, slow growth over a 6- to 12- month period was regularly accompanied by striking splenomegaly without lymphoid or thymic neoplasia. The enlargement was due to a great increase in cells of the lymphoid series in the red pulp without loss of splenic architecture. In thyroidectomized mice plasma cells with many Russell bodies were especially numerous, and these cells were found hi hypertrophied lymphoid follicles within other organs. It is suggested that the splenomegaly and, hi earlier passage the lymphoid tumors, may represent an exaggerated antibody response to a tumor's having unusual or abnormal hormonal activity. The transplanted pituitary tumors, in turn, showed severe hemorrhagic degeneration with peripheral small lymphocyte stasis in the lymphatics.

Initial observations concerning pleomorphic reticulum through the courtesy of Dr. Jacob Furth, was studied cell- and lymphosarcomas or lymphoid hyperplasias through repeated passage for purposes of comparison. regularly accompanying a thyrotropic mouse pituitary This tumor has maintained uniform behavior with rapid neoplasm, subline L24a, have been reported (22). The autonomous growth, active secretion of TSH, and a sex original L24 pituitary tumor was developed by Dr. Jacob dependence which was lacking in the L24 line. A mam- Furth by I131thyroid ablation. At the outset of these motropic tumor, 38, from Dr. Furth's collection was experiments this tumor was an autonomous growth but carried in similar manner to provide further comparison highly responsive to suppression by thyroid hormone; of the effects on mouse lymphoid tissues of a nonthy- implants into intact mice failed to progress or remained rotropic pituitary tumor. This neoplasm grew slowly and dormant for approximately 13 months (27). Growth of irregularly during the period of this study but maintained one tumor, designated L24a, having a latent period of its hormonal effect on the mammary gland. over a year, in a thyroid-intact mouse was marked by Technical procedure.â€”Allexperiments were conducted pronounced lymphomogenesis or hyperplasia of cells of on (C57L X A)Fi hybrid female and male mice (hereafter the lymphoid group in all its subsequent passages. The called LAFi), obtained from the Jackson Memorial present report concerns the behavior of this tumor during Laboratory, Bar Harbor, Maine. The technical details continued passage, with detailed study of the cell types of thyroid ablation, tumor transfer, autopsy procedure, affected under altered hormonal conditions. tissue section preparation, and multiple stains were es sentially as previously described (22), with some vari MATERIALS AND METHODS ations. Tumors were implanted either intramuscularly Tumors.â€”The association gains interest with the find into the thigh or into the dorsal subcutaneous tissue. The ings in the third transfer of subirne L24a. In accord with fixative for all organs contained 85 per cent ethyl alcohol, the behavior of many animal tumors having spÃ©cule 5 per cent acetic acid, and 40 per cent formaldehyde, a function, continued passage has yielded a more autono modification by Lillie of Carnoy's solution which was mous growth having reduced or altered specific activity especially successful in maintaining nuclear fine structure (7). With the use of an older tumor as donor tissue it (17). Cytoplasmic RNA is best preserved if the tissues was possible to follow the effects of a less active growth remain in Lillie's fixative for not more than 2 hours and for a period of 12 months after implantation. are then transferred to 80 per cent alcohol. A second thyrotropic neoplasm, 17, also obtained Wright-Giemsa differential stain was applied to im * Supported in part by N.I.P.H. Grant CA-06855. prints of the splenic cut surface. Imprints were necessary Received for publication May 18, 1964. for more accurate identification of cell types but required 1644

correlation with sections to locate the various changes. nature. A few mice of each group died spontaneously In later studies more uniform smears of spleen cells have and were discarded. The remainder were permitted to been prepared with a fine camel's hair brush and dextran. live until moribund and were bled from the right heart or Methyl green pyronine stain1 was used to facilitate the vena cava under ether anesthesia prior to the autopsy. identification of plasma cells in imprints and in sections. All organs were weighed and sectioned. Less variegation and greater intensity of cytoplasmic The spleen weights of control mice in Group C, examined staining follows the substitution of thionine for pyronine mainly 9-12 months after the beginning of the experi in combination with methyl green.2 This preparation ment, were close to 100 nig., with the exception of one was applied to tissue sections and smears in the later instance of spontaneous myeloid leukemia (Chart 1). studies. Most of the tumor grafts grew to lethal size earlier in in Protocol of major experiment.â€”The subline L24a thy- tact mice (Group B), with another peak in tumor growth rotropic tumor had been carried through two passages as in the later months. Thyroidectomized mice (Group A), reported (22). The mice in the third passage were or examined largely in the 6- to 8-month period after tumor ganized into three groups: implantation, developed the largest spleensâ€”several Group A: 30 mice radiothyroidectomized with 50 nc. above 2,000 mg. I131and given injections intramuscularly of tumor. Histologie and cytologie character of the splenopathy.â€”- Group B: 30 intact mice also receiving tumor. Group A: Radiothyroidectomized, tumor-bearing mice Group C : 30 control mice kept through the year of this maintained the usual splenic architecture even in the experiment. most enlarged organs (Fig. 3). The lymphoid follicles Equal numbers of male and female mice comprised were large and poorly demarcated, owing to an increase in each group. All were about 8 weeks of age and were reticulum cells, large lymphocytes, and especially plasma maintained on Rockland Farm rat diet and tap water cells in the perifollicular zone. These cells were also except prior to thyroidectomy, when Remington low prominently increased throughout the red pulp, account iodine diet3 and distilled water were substituted. ing in good part for the splenic enlargement. Mast cells were also increased 3-4 times over the number in control RESULTS4 spleens. The L24a tumor grew more slowly than previously with Plasma cells appeared in several stages of maturity, a latent period of 4-8 months, appearing first in intact recognized by their large or small, coarse, round eccentric male mice. "Reverse responsiveness" to the target organ nucleus and abundant pyrininophilic cytoplasm. The hormone has been previously noted (14). Eventually, spleens of mice bearing tumors of long duration frequently all but nine of the GOtumor grafts progressed, but those persisting 6-10 months after implantation were often mgi hemorrhagic and in good part necrotic. There were 2100 Z500 Z800 tumor cells which appeared viable in histologie sections, 00Â« o 1900 but the amount of active tumor in the large hemorrhagic O masses could not be evaluated. From the general pattern of behavior it was clear that 1700 the L24a thyrotropic tumor was autonomous but still influenced by thyroid and ovarian hormone secretion. 1500. LEUKEMIA TSH secretion was greatly reduced. Nevertheless, the grafted tumor was regularly accompanied by splenomegaly O of 10-30 times the normal size, with a disproportionate 52 1300 o Â«o o moderate response in lymph nodes and lymphoid nodules 0Â° Â° of organs (Figs. 1, 2). Splenic enlargement occurred in 1100. all mice bearing tumors, with or without the thyroid gland, and failed to develop in the few mice given inocu 900. BL lations in which tumor did not grow. There was no cor CO relation with size of the tumor, since, in a few instances, 700. tumor nodules were found only after careful sectioning of the host's thigh muscle. Comparable observations are 500. made in regard to human endocrine tumors; minute occult

nodules may have striking systemic effect of lasting 300. 1The most successful methyl green pyronine was obtained from Chroma-Gesellschaft Schmid Co., distributed by Roboz Surgical 100. CC C0â€ž Instrument Co., Washington, D. C. 2Contributed by personal communication from Dr. A. RoquÃ©, -n 5 6 7 8 9 IO te Roswell Park Memorial Institute, Buffalo, New York. C CONTROL 3Obtained from the Nutritional Biochemicals Corp., Cleveland â€¢ INTACT MONTHS AFTER INOCULATION 28, Ohio. O SO JIC 1131 * Presented in part at Annual Scientific Session of American Association for Cancer Research, Toronto, Canada, May, 1963 CHART 1.â€”Spleen weights of LAFi mice with L24a thyrotropic (21). tumor.

Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1964 American Association for Cancer Research. 1646 Cancer Research Vol. 24, October 1964 were populated by plasma cells with large protoplasmic nodes in older mice of many strains. Their presence in masses which were pyronine-positive and stained mod greater numbers in Group A mice was not related to age erately with periodic acid-Schiff reagent, indicating their and contrasted with the appearance of lymph nodes in glycoprotein nature. Similar masses were also found the control group. extracellularly and were recognized as Russell bodies, The thymus was not significantly altered in size or which have been variously interpreted as the result of histologie character in tumor-bearing mice (Fig. 6). The secretion or degeneration of plasma cell cytoplasm (26) bone marrow, when examined, and the blood channels of (Fig. 3). organs failed to show recognizable increase in lymphoid Group B: The follicular and vascular architecture also cell content. persisted in the enlarged spleens of intact tumor-bearing Lymphoid nodules in organs such as lung, liver, and mice, but the cell population was more uniform and kidneys (Figs. 7-9) were moderately hyperplastic in mice differed from that in Group A. Plasma cells were less with enlarged spleens, but diffuse infiltration, as observed numerous, and small lymphocytes predominated in the in leukemia, was found only in the two cases of malignant red pulp cords (Fig. 4). About four to eight mitotic disease developing in the 90 mice of this experiment. figures occurred per high-power field. The lymphoid fol In addition to enlargement of renal lymphoid nodules, licles were enlarged and poorly defined. Germinal centers the kidneys of radiothyroidectomized mice with a pre were not distinct, but areas of lymphoblastic or reticulum- ponderance of plasma cells sometimes showed Schiff cell proliferation appeared in some follicles. One reticu- positive "hyaline droplets" in the cytoplasm of convoluted lum-cell sarcoma developed in a mouse in the older age tubules and casts in distal tubules. These organs did group. This was believed to have been a spontaneous not, however, present the picture of "myeloma kidney" occurrence. which accompanies plasmacytoma in the mouse as in Group C: No abnormalities in the pattern or cell man (5). distribution were found in the spleens of control mice of Effect of 50 nc. /'3I alone.â€”Fourmice surviving 1 year comparable age, with the exception of the one instance of after thyroid ablation have been autopsied. All had myeloid leukemia. Erythropoiesis was usually at a large, hemorrhagic pituitary tumors. The thymus and normal level of activity, but in experimental as well as in spleen were atrophie, indicating that the isotope alone control animals individual mice had an increase in nu had not stimulated hyperplasia of lymphoid cells. cleated red cells in the splenic red pulp. It was not Endocrine organs.â€”The pituitary glands in Group A possible to correlate the degree of hematopoiesis with the mice regularly showed a threefold enlargement in both severity of hemorrhage in tumors or with hormonal state sexes following ablation of thyroid tissue. The ap of the mice in this study. Myelopoiesis proceeded at the pearance of "thyrotrophs" (Fig. 10) attested to the lack usual rate in control mice but was relatively inconspicuous of regulating thyroid hormone, and sections of the thyroid in the enlarged spleens of tumor-bearing animals. area failed to reveal follicular tissue, although the para Table 1 shows the relative number of plasma cells thyroid glands were often recognized in collapsed stroma counted in the red pulp of the spleens. Although there of the thyroid gland. The pituitary glands of intact mice was great individual variation, both tumor-bearing groups were small, 2 mg. or less, and contained uniform basophilic showed an increased accumulation over that in the normal cells. They have not been studied with differential stains. spleens. The preponderance of the plasma cell in radio- The average weights of ovaries were 19.0 Â± 3.4 and thyroidectomized mice was highly significant. 18 db 2.1 mg. in the experimental groups, compared with a Other hematopoietic organs.â€”Thelymph nodes generally mean of 13.1 Â±2.3 mg. in control mice. Histologically, were only moderately increased in size, except in the two tumor-bearing mice showed a moderate increase in follicu obvious instances of malignant lymphoma. Their his lar and luteinizing activity, as previously described. The tologie structure was well maintained, and the cell popula testes were not significantly altered in weight or appear tion followed, in good part, the cell distribution in the ance. No variation in average adrenal gland weight or spleen. When plasma cells and Russell bodies were structure was found when tumor-bearing mice were com abundant in the spleen they were also more numerous in pared with controls of the same sex. The adrenals of the medullary cords of lymph nodes (Fig. 5). Plasma females of all groups were larger than those of the male. cells with Russell bodies are a normal inhabitant of lymph The thyroid glands of intact tumor-bearing mice failed to develop a significant increase in mean weight, as com pared with the glands of untreated mice. The histologie TABLE 1 appearance of the glands suggested a proliferative hyper- THE PEE CENT OF PLASMACELLSIN THERED PULP OF SPLEEN- activity, since the lining cells of the follicles were cuboidal rather than flat and colloid storage was reduced (Fig. 11). A, C, thyroidect., B, intact, DO The glands, however, were not as congested as those PercellsAbove cent of plasma tumor (No. intact, tumor tumor (No. mice)135220Group(No.mice)071825Groupmice)002929 associated with highly active thyrotropic tumors. When animals were sacrificed at widely spaced times, 5015-50Below the opportunity to pool the blood of individual mice of each group for TSH determination was forfeited. Bio- 15Total assays by the McKenzie method (13) were performed at intervals. The paucity of control mice for each assay, no. mice:Group necessitated by the small quantity of blood serum from

Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1964 American Association for Cancer Research. SPROULAND GRINBERGâ€”Splenomegalyand Thyrotropic Tumor 1647 single mice, precludes acceptance of the results as signifi great hyperplasia by Tumor 17, is associated with little cant; nor does averaging the figures in each group appear hyperthyroidism may be found in the prominent lutein to be a legitimate procedure, since the tests were per and follicular hyperplasia of the ovaries and the severe formed at intervals of months. The only further indica involution of the thymus possibly attributable to ovarian tion of possible thyrotropic stimulation of the thyroid hyperactivity. Both gonadal enhancement and thymic gland can be observed in the liver, which showed moderate atrophy are opposed by normal thyroid hyperactivity, hepatic cell hypertrophy and hyperplasia with less lymph which is assumed to be minimal hi these experimental oid hyperplasia in the intact tumor-bearing mice (Fig. 12). animals. The tumor does not grow in intact male mice. The appearance of the liver cell may reflect a continued The spleens of mice bearing Tumor 17 are enlarged mild stimulus to the thyroid gland (4). Thyroidectomized only 3-5 times, with cellular increase as well as congestion mice had smaller hepatocytes but greater lymphoid and erythropoiesis. Congestion in all organs indicates a hyperplasia in portal areas (Fig. 8), which canceled out hypervolemic basis, at least in part. The cause of eryth- any significant difference in total organ weight in the ropoietic activity in these mice is not understood. two groups. Lymphocytes and plasma cells are moderately increased The histologie appearance of the pituitary tumor has in the red pulp, and no instance of the striking spleno remained as described previously except for excessive megaly accompanying L24a tumor has appeared. How hemorrhage and necrosis. There was variable lympho- ever, the short course of Tumor 17 is an inevitable result cytic and plasma-cell response at the periphery of the of rapid tumor growth, which may be facilitated by the tumor. Stasis of small, deeply stained lymphocytes lesser degree of lymphoid reaction. without visible cytoplasm, in lymphatic channels, was Mammotropic tumor 38, studied briefly in this labora observed here as well as in some thymus gland, spleen, tory, has presented exaggerated myelopoiesis throughout and lymph node sections. the red pulp, with moderate erythropoiesis and lymph Subsequent behavior of L24& tumor.â€”The growth vigor follicle enlargement. This is essentially the response to of this tumor on continued passage has diminished to the the presence of a variety of transplanted tumors and point of impracticability for comparative or hormonal probably has a complex origin not specifically related to studies. In this laboratory mouse-to-mouse continuity the behavior of one tumor cell type. An exaggerated was lost. The excess tumor from that providing the reversible myelo-leukemoid reaction to a transplanted grafts for this study was frozen in liquid nitrogen for a squamous-cell carcinoma has been described in detail (10). year. On subcutaneous inoculation into 4-day-old mice, only two tumors have grown after 8 months in those given DISCUSSION subcutaneous hydrocortisone through the suckling period The lymphoid response to the presence of thyrotropic and for 3-day periods at monthly intervals thereafter. tumor L24a has been designated as hyperplasia rather These two mice had only moderately enlarged spleens of than neoplasia, since architectural derangement of en about 500 mg., and the increase could be accounted for larged spleens and organ infiltration were minimal. in part by congestion and erythropoiesis. Lymphoid Pleomorphic cell types and variation in plasma-cell differ follicles in the spleen were reduced to half size and were entiation also suggested a uonmalignant state. It has widely separated by congested red pulp with both erytho- not been possible to obtain progressive growth by the poiesis and increased lymphocytes and reticulum cells. transfer of lymph nodes or spleen to adult or suckling It is not possible to conclude that hydrocortisone was homologous mice. The former were followed for a year. responsible for suppression of the pronounced lymphoid The mice given injections of enlarged spleen in the neonatal and plasma cell hyperplasia with two animals alone. The period were sacrificed at 10 months. Only one tumor, remaining mice are being observed for further develop an unusual reticulum-cell sarcoma, with many large ments. On continued passage, the autonomous L24a multinucleated cells of histiocytic appearance, was found tumor recovered from the above hydrocortisone-treated in the mesentery. This may be regarded as fortuitous suckling mouse grows more rapidly, with commensurate or as an indication that the spleen implanted was pre- moderation of splenic cellular response. The tumor is malignant. However, the distinction between prominent now being developed for physiologic studies. hyperplasia and the neoplastic state, classified as either Splenomegaly with thyrotropic tumor 17.â€”Conclusions lymphosarcoma or leukemia, is not a clear one. A period cannot be drawn from comparison of the effects of tumors of hyperplasia with normal organ pattern precedes and having widely different hormonal activity. However, merges imperceptibly with the more diffuse spread of the behavior of another pituitary TSH-secreting tumor, spontaneous lymphoma (18). Plasma-cell granulomas described in detail elsewhere,6 may contribute some sup and plasmacytomas develop under related but varied port for considerations expressed in the discussion. Thyrotropic tumor 17 is an autonomous "reversely conditions, and it is presumed that the former eventually responsive" growth with a short incubation period, and it may lead to the neoplastic growth (19). It is possible that growth of the pituitary tumor has is fatal within about 2-A months. There is evidence of augmented a low genetic tendency to develop lymphoma. active TSH secretion in an enlarged, congested thyroid The LAFi hybrid is a vigorous strain of uniform genetic gland histologically very hyperplastic and vascular; yet state. These mice have been utilized in radiation longev the tumor does not grow in thyroidectomized mice. ity and disease incidence studies because of their long life Further evidence that the thyroid gland, stimulated to and large healthy litters. The incidence of spontaneous 1Data of one of the authors (E. S.) to be published. lymphomas is approximately 13 per cent in females and

6 per cent in males living beyond 18 months (25). A L24a tumor-bearing mice represented response to a pro higher incidence was reported by Nowell et al. in long-term longed antigenic stimulus. It should be recalled that experiments with LAFi mice (16). These authors found this tumor emerged after 13 months of dormant state in an over-all incidence of 22 per cent nonthymic lymphatic an intact mouse, presumably suppressed by thyroxine leukemia in 601 males and females kept through life. antagonism. This autonomous, long-dormant growth Pulmonary adenomas appeared in 24 per cent and ovarian may have a cell population derived from a minority pi tumors in 11 per cent of the females. During the 12 tuitary cell type of distinct specific activity, ordinarily months of our experiment (mice up to 13.5 months of age) repressed. Other transplanted pituitary tumors with adenoma of the lung appeared in two mice, and no ovarian more physiologic secretion and, hence, less antigenicity tumors were seen. Only one leukemia, presenting a and shorter course, may call forth relatively less cellular contrasting picture of diffuse organ infiltration and gen response. A milder plasma cell or lymphoid response in eralized lymph node enlargement, was noted in the 30 regional lymph nodes and spleen has been described by control mice. The leukemia of strain A mice, the male Baruah and others during the progressive growth of a parent of LAFi hybrids, does not characteristically in- variety of transplanted tumors (3, 20). involve the thymus and lymph nodes (7). Metcalf has called attention to an increased incidence It is also possible that activity of a latent virus may of reticular tumors in C3H mice subjected to prolonged have been facilitated in some manner by the presence of antigenic stimulation and suggested that random this pituitary tumor. We have not been able to support neoplastic mutations from increased mitotic activity or such a concept by transfer of the spleen, perhaps because activation of a latent tumor virus may have been the the growth was in a preneoplastic state. If virus is mechanism of origin of the tumors (15). Malignant eventually recovered from the spleen, the initial stimulus lymphoid tumors appeared with the original growth of will still not be established. Virus has been isolated L24a tumor in our studies (22). These lymphomas may from radiation-induced lymphomas in mice (11) and have represented the ultimate effect of such a prolonged contributed to lymphomogenesis with chemical car antigenic stimulus. The hemorrhagic necrotic state of cinogens (8). the pituitary tumors with stasis of small dark lymphocytes The present experiments do not support the hypothesis, at the periphery is further evidence in favor of intense previously presented, that high thyrotropin stimulus alone, antibody activity. or in combination with somatotropin or radiation, was The explanation for greater numbers of plasma cells responsible for associated lymphoid growth (22). The with Russell bodies in response to tumors in thyroidec- present tumor has low thyrotropic hormonal activity, tomized mice, as compared with intact mice, is not clear. as evidenced by the appearance of the thyroid gland. Two possibilities suggest themselves: Unopposed TSH However, a long period of mild thyrotropin hyperactivity may have had a direct effect on the lymphocyte, effecting may have played a role. In addition, a thyrotropin transformation to the plasma cell. Alternately, radiation analog or another form of thyroid-stimulating hormone in the form of 50 nc. I131may have augmented the tendency may be a product of the pituitary tumor. An entity in this direction. distinct from thyrotropin has been recognized in the The association in man of lymphoid hyperplasia and plasma of patients with Graves' disease (1). The sub lymphoma with hyperthyroidism, especially Graves' stance manifests its presence in a delayed peak of I131 disease, has been discussed by Ultmann and associates release from the thyroid in mouse bioassay. Antiserum (24). Concurrent hyperthyroidism and an unusual against bovine or human TSH does not neutralize long- lymphomatous disease associated with intracytoplasmic acting thyroid stimulator present in serum of a thyrotoxic crystals in lymphoplasmacytoid cells has also been re patient (2). Long-acting thyroid stimulator is believed corded by Goldberg, who regarded the cells as akin to to have a site of origin other than the normal pituitary those seen in some cases of WaldenstrÃ¶ms macroglobu- gland (6, 13) but could conceivably be present in pituitary linemia (9). Thomson reports acute leukemia developing tumor cells. Evidence for the existence of such a delayed in a patient treated with I131for hyperthyroidism but thyrotropic effect was reported in our bioassay of the exonerates the isotope, since chromosomal aberrations blood of mice developing lymphomas while bearing the were not found (23). L24A tumor in its earlier passages (22). REFERENCES The concept of an abnormal or unusual hormone se creted by pituitary tumor cells of the mouse leads, on 1. ADAMS,D. D. The Presence of an Abnormal Thyroid-Stimu lating Hormone in the Serum of some Thyrotoxic Patients. J. theoretical grounds, to the possibility that lymphoid and Clin. Endocrinol. 18:699-712, 1958. plasma-cell hyperplasia with numerous Russell bodies in 2. ADAMS,D. D.; KENNEDY, T. H.; PURVES, H. D.; AND SIRETT,

FIG. 1.â€”Splenomegaly in mouse bearing thyrotropic tumor L24a. FIG. 2.â€”Comparative size of spleens from tumor-bearing mouse and control mouse. FIG. 3.â€”Increased lymphocytes and plasma cells in red pulp of spleen of Group A thyroidectomized mouse bearing L24a tumor. Many intra- and extracellular Russell bodies are noted. X 400. FIG. 4.â€”Increased lymphocytes in red pulp of spleen of Group B intact mouse bearing L24a tumor. X 400.

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Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1964 American Association for Cancer Research. FIG. 5.â€”Increased plasma cells in medulla of lymph node of CÃ¬roupAthyroidectomized mouse. There was no disturbance of architecture. X 400. FIG. 6.â€”Normal thymic pattern and cell content in L24a tumor-bearing mouse with splenomegaly. X 200. FIG. 7.â€”Perivascular lymphoid-plasma cell hyperplasia in lung of Group A thyroidectomized mouse with L24a tumor. X 400. FIG. 8.â€”Periportal lymphocyte proliferation and normal hepatocytes in (Â¡roupA thyroidectomized mouse bearing L24a tumor X 400.

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Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1964 American Association for Cancer Research. FIG. 9.â€”Perivascular lymphocyte hyperplasia in kidney in Group B intact L24a tumor-bearing mouse. X 4CO. FIG. 10.â€”"Thyrotrophs" in pituitary gland of Group A thyroidectomized mouse. X 400. FIG. 11.â€”Mildhyperplasia of thyroid gland in Group B intact mouse bearing L24a tumor (lia) as compared with normal gland of control mouse (116). X 400. FIG. 12.â€”Periportal lymphoid nodule and hyperplasia of hepatocytes in Group B intact mouse bearing L24a tumor. X 400 (compare with that of thyroidectomized mouse, Fig. 8.).

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Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1964 American Association for Cancer Research. Reactive Splenomegaly and Variation of Lymphoid-Plasma Cell Population Associated with a Mouse Pituitary Thyrotropic Tumor

Edith E. Sproul and Raul Grinberg

Cancer Res 1964;24:1644-1655.

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