I. Spontaneous Chromophobe Pituitary Tumors* Neoplasia in the Parakeet

Neoplasia in the Parakeet I. Spontaneous Chromophobe Pituitary Tumors*

HANS G. SCHLUMBERGER

(Deparimen@ of Pathology, College of Medicine, 0kw Sioie L'niveri@i4i, Columbus 10, Ohio)

Tumors of the pituitary make up approximately Shell parakeets were first brought to Europe about 1850; 7 per cent of the intracranial neoplasms of man their ready acclimatization, frequent color mutations, and ability to learn to talk made them popular cage birds. During (61). As isolated cases they have been found in the the early 1920's parakeets became sought-after pets in this horse (41, 48), dog (29, 37), cow (1), deer (53), country, but following epidemics of psittacosis traceable to Indian buffalo (16), baboon (25), and mouse (@3, them their number declined sharply after 1929. Since World 54). Following the description by Olga Fischer of War 11 there has been renewed public interest, innumerable large hypophyseal adenomas in two old rats (15), small aviaries are now scattered throughout the country, and the parakeet population has risen enormously. several investigators have reported a high mci To obtain birds with tumors, advertisements were placed dence of these tumors in rats of advanced age (1@, in a popular pet magazine and in monthly bulletins of the two 40, 46, 47, 59, 60). Only two instances of reported national budgerigar societies. The great majority of birds pituitary tumors in animals other than mammals are received alive and are kept under observation in the laboratory aviary for days or weeks. Feeding and care of the are known to the writer. One was seen in an birds is similar to that employed by most breeders (13). A African parakeet Agapornis pullaria by Slye useful guide to the more common diseases of the parakeet (54); the second,a chromophobeadenomain an has been recently published (14). aquarium fish Lebistes reticulatus, was recently described by Stolk (55). The absence of additional reported cases in the lower vertebrates is par PHYSICAL SIGNS OF PITUITARY Nzoi'i.asi.@ ticularly striking among the birds where thousands The most striking sign of a pituitary tumor in of chickens, ducks, turkeys, and geese are autop the parakeet is uni- or bilateral ocular proptosis sied yearly by veterinary pathologists (27). (Fig. 1). This was observed in nine of the 50 cases This report is based on a study of 50 parakeets (18 per cent) and is due to invasion of the retro with pituitary tumors. . The investigation was ocular tissue by the tumor which pushes the eye undertaken after a bird brought to the writer by outward. Despite this evidence of a large rapidly Dr. Jerome Rini proved to have such a lesion and growing tumor, birds so afflicted often survive for when a cursory examination of several flocks had several weeks. In one instance (No. 29) proptosis revealed the prevalence of the tumor (50). The of the left eye was observed for 6 months prior to cases presented are unselected and represent the death; at autopsy the retro-ocular tumor was first 50 pituitary neoplasms examined in this found to be a papillary adenoma of the Harderian laboratory. gland wholly unrelated to the pituitary which, however, was enlarged to S times normal size. This MATERIALS AND METHODS is the only instance in which proptosis was not The parakeet under study is Mdop.ittacus undu1aius, a attributable to the pituitary neoplasm. memberof the parrot family (Psittacinae). It is known in this Impaired vision is the most frequently oc country by a variety of names, such as shell parakeet, grass curring symptom of a pituitary tumor in man parakeet, undulate parakeet, and budgerigar. The latter term (61) ; the same is true of the parakeet. In this series is derived from the name given the bird by the natives of Australia, where it lives on the grassy plains and in shrubbed nineteen of 50 birds (38 per cent) became totally semi-desert regions. The name â€œlovebird,â€•thoughoccasionally blind or showed evidence of serious visual dis used, should be reserved for an African bird of a different turbance. One of the earliest signs was frequent genus. blinking, suggesting increa@sedlight sensitivity, and a This investigation was supported in part by a research photophobia. Blindness was indicated by failure grant from the Ohio Department of Health; from the National of the bird to fly about the cage; instead it walked Cancer Institute, U.S.P.H.S.; and by an institutional re on the bottom or climbed up the sides. When the search grant from the American Cancer Society. observer's hand was suddenly brought close to its Received for publication November 28, 1953. head the bird did not startle or blink. To insure 237

adequate feeding it was often necessary to place dysfunction of the neurohypophysis. In the bird food and water on the floor of the cage so that the the neurohypophysis appears as the infundibular bird would literally stumble upon it. An unsteady process (43) and possesses antidiuretic as well as gait was occasionally manifested, but whether this oxytocic and pressor properties (9). The destruc should be attributed to impaired vision and/or tion or distortion of this structure by the pituitary involvement of other cerebral centers is difficult to tumor may account for the symptoms described. determine. The cerebellum was never invaded by The significance of obesity or emaciation in the the tumor nor was a marked degree of imbalance affected birds aLso poses a problem. Obesity could like that observed in parakeets with primary cere be attributed to the diminished activity often ob bellar or middle-ear lesions encountered. served in these birds, and the emaciation might The sequence of events that characterizes pro be readily explained by assuming that visual gressive involvement of the optic nerves is ex disturbances affect the birds' ability to feed. How hibited by No. 18, in which there may also have ever, several of the obese birds showed no differ been damage to the vestibular nerve. The bird ence in activity when compared to their normal hatched November 15, 1950; impaired vision was cage mates, and many of the emaciated birds had first noted early in December, 1952. By the middle no visual impairment. In normal parakeet hens of that month he was blind; proptosis became ap 2â€”4years old there is often a pronounced deposi parent on January 1, 1953. A few days later his tion of fat beneath the skin of the breast and ab gait became unsteady, and by February 1 he domen, as well as in the peritoneum, mesentery, could not raise his head which was twisted to one and liver. Such obesity is uncommon in the normal side. The bird remained in this condition for 2 male; yet of the seventeen obese birds with pitui weeks, when he lapsed into coma and died. tary tumors, seven were males. The possible Cerebral involvement is indicated by somno mechanism of obesity and emaciation in these lence and the occurrence of convulsive seizures. parakeets will be considered in the discussion. Although a terminal convulsion is often seen in Several of the physical signs observed in birds birds dying of various causes, the convulsions ob with pituitary tumors characterize similar lesions served in birds with a pituitary tumor have their in man. Jefferson (32) has listed somnolence, onset several days before death. The seizures are thirst, and polyuria among the outstanding fea accompanied by an incoordinated beating of the tures in patients with pituitary' adenomas that wings on the floor of the cage associated with have extended into the hypothalamus. clonic twitching of the legs and occasional piercing cries. The convulsion lasts for about 30 seconds GuosaMonpuoioor followed by a 2â€”3-minute period of unconscious The pituitary body of birds occupies the same ness during which the bird appears to be dead. relative position as it does in mammals, viz., the Recovery is usually abrupt, and the bird may sub pituitary fossa of the basi-sphenoid directly be sequently climb back on its perch. Five or six hind the optic chiasm. In the avian pituitary the seizures may occur before death. pars anterior or glandular hypophysis greatly ex It is difficult to assess the effect of the tumor on ceeds the posterior in bulk; there is no pars inter the bird's intellect; nevertheless, in the case of a media (44). The average weight of the pituitary of pet an evaluation is occasionally possible. Thus, a young adult parakeet is 0.65 mg., its diameter is one owner wrote that her bird (No. 7) wanted as 1.0 mm., and its shape is that of a flattened sphere. much attention from his mistress during the 2 cI?oup I: Diffuse enlargement of the pituitary weeks he was obviously ill as he did formerly. He (Table 1).â€”In twenty birds (40 per cent) the was less active than before and would fly to his pituitary was diffusely enlarged, measuring 2-5 favorite perch and sleep. He was a good talker and mm. in diameter (Fig. 2). However, the weight of exercised this ability until the day he died. these glands was up to 10 times that of the normal Diarrhea is very frequently observed in birds gland. The capsule was intact, but occasionally with pituitary tumors, but it is a common symp the surface was nodular and the gland firmer than tom of many minor ills of the parakeet and its normal. Only one of the birds (No. 38) showed cause is difficult to determine. However, in birds evidence of visual impairment; this was attribut the normally semi-solid urine is mixed with the able to compression of the optic chiasm. Diarrhea feces in the cloaca; therefore, polyuria would give and polydypsia were occasionally encountered; rise to signs simulating those of diarrhea. An asso seven of the birds were obese. In none was a diag ciated polydypsia noted in three cases suggests nosis of pituitary tumor made before death. that at least in several instances the diarrhea was Group II: Locally invasive tumors (Table @).â€”Of actually a manifestation of polyuria resulting from the 50 birds in the series, 28 (56 per cent) showed

Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1954 American Association for Cancer Research. Scnumn@iwm@â€”Pitui@ary Tumors in the Parakeet 289 extension of the neoplasm beyond the confines of nerves and passed through the optic foramen into the sella, but the lesion had not metastasized. The the retro-orbital tissue. Gross evidence of optic tumor had grown into one or both orbits in nine nerve involvement characterized by the presence cases (Fig. 3). Careful examination of the orbital of tumor nodules (Fig. 4) was only seen in five bones, however, rarely showed evidence of de- instances. In an equal number the cancellous bone struction ; the tumor had grown along the optic of the basi-sphenoid was invaded; in four of these

TABLE 1 NONINVASIVE PITUITARY TuMoRs (GRoup I)@ Auo Bird Age Large Impaired ciated no. State (yr..) Sex Obese thyroids vision tumor Remarks 2 Ohio S@ F A 2X3 mm. diffuse enlargement of gland 7 Mich. 4 M History of drinking much water 8 Texas F Compression of normal pituitary by tumor cells 20 Ohio 2 M + Subjected to artificial light 8 hours daily 21 N.Y. 1@ M + + Rapid weight gain in last 6 weeks of life 24 Texas 14 F + Fatty dystrophy of the liver 25 Texas F A 3X8.5 mm. firm gray tumor at pituitary site 26 Ohio F Diffuse involvement of entire pituitary 27 Wis. 2 F + Egg incarcerated in oviduct 29 Ohio 24 M + Papillaryadenomaof rightHarderiangland 81 Ky. F + + + Papillaryadenoca.in eachkidney,fatty liver 35 Mimi. M + + Diarrhea for several months 88 N.J. ft F + + Had young previous year; during past year laid no eggs 40 Mo. S M + Pap. adenoca.in kidney;8-4 hrs.dailyartificiallight 41 FIn. 2 F Fatty liver 42 Calif. 2 M + Pap. adenoca.in kidney two adenomasin pituitary 48 Ohio F + +. Combined weight of thyroids, 16.8 mg. 45 Texas 2 M + Pap. adenoca.in kidney, combined weight of thyroids, 5.8 mg. 48 FIn. 24 F Retained egg with yolk peritonitis 50 Fla. 24 M + Enlarged fatty liver produced abdominal swelling a The pituitary tumors in this group ranged in size from S to 8.6 mm. in diameter.

TABLE 2 LOCALLY iNVASiVE PITUITARY TuMoRs (GRoup II)

Bird AgeLargeImpairedciated(yr..)SexObeset.byroidsvisiontumor4F no. State Remarks 1 Ohio retro-ocular tumor with exophthalmos 4 Calif. mid-brain5FBilat.M+ +Left A 7-mm. tumor mass extends into 5 Texas extensionSM retro-ocular and mid-brain 6 IlL brain stem, bone, and oropharynx 9 Texas stemI F+++Invaded An 8-mm. tumor that invaded brain 10 Wis. 6-mm. nodular tumor; 4 bra.artiFiciallight daily 11 N.J. 2 M + A 5-mm. tumor, invaded bone; pap. adenoca. left kidney 12 Kan. muscleS2F M++ ++A Invaded bone, brain and extra-ocular 14 Ill. rt. orbit, bone and oropharynx 15 111. 3F F ++ Invaded left orbit, bone and oropharynx 16 Texas M + Invaded rt optic nerve; low intensity artificial light all night 17 Texas M + Small tumor invaded optic chiasm 18 Maine M Loft retro-ocular tumor with exophthalmos 19 Texas M A S-mm. pituitary tumor invading brain stem 22 Texas F + Tumor invading base of skull 23invasion46Texas M++ +Invaded Bilateral retro-ocular 28 Calif. SXS mm. tumor invaded brain to depth of 2 mm. 30 Mich. 4 F A 3-mm. tumor invading bone 32 Pa. 2 F A 3-mm. tumor invading floor of sella 38 N.Y. 21 M Massive tumor with retro-ocular and pharyngeal invasion 34 Calif. S M A 4X5-mm. tumor invading brain 36 W.Va. 2 F + A 5-mm. tumor invading bone; exposed to artificial light 37 N.C. M + A 5-mm. tumor invading brain 89 Tens. 2* F + ++ A 6-mm. tumor invading brain and bone 44 Calif. 1* F Tumor invaded left retro-ocular tissue. First became very obese, later emaciated 14 F + Tumor invaded left retro-ocular tissue and oropharynx. A fibrosarcoma in spleen; adenocarcinoma in kidney 47 La. F + ++A Deep extension of tumor into brain 49md. FIn.S 2@F F+ ++ A 3-mm. tumor invading infundibulum

the tumor protruded into the oropharynx (Fig. 6). Gilmour (24) described one in which metastases No evidence could be found for an origin of these were found in both the liver and kidneys. tumors from embryonic rests within the sphenoid bone, the so-called pharyngeal pituitary gland MICROSCOPIC Moai'nowor (85). The cellular composition of the avian pituitary Compression and/or invasion of the adjacent resembles that of the mammalian gland in that the brain tissue was apparent in eleven of these birds characteristic acidophils, basophils, and chromo (Fig. 5). In several instances the intracerebral ex phobes are present (44). Differential staining of tension of the tumor was much larger than the the bird hypophysis is often difficult (49), and even portion occupying the region of the pituitary with the technic of Severinghaus (52) the granules (Figs. 7and8). in the parakeet pituitary lack the briffiance of In keeping with the anatomical evidence of those found in the human gland. The most thor optic nerve and brain involvement in this group of oughly studied avian pituitaries are those of the 28 birds is the finding that in fourteen (50 per cent) pigeon (51) and of the chicken (42). In their study there was serious@impairment of vision often end of the pituitary in eighteen species of birds, Rahn ing in blindness. Obesity was notable in nine birds; and Painter (43) noted a regional restriction of cell only four of these had shown signs of visual dis types which they identified as the â€œavianpituitary turbance. pattern.â€• This agrees with the findings of Schooley In man invasion of retro-ocular tissue has not in the pigeon (51), in which the posterio-central been reported, although erosion of the sella with area of the pituitary shows a preponderance of penetration of the sphenoid sinus and even of the basophils, the anterior-peripheral area a majority nasopharynx are described (2, 33, 56). Most au of acidophils. A similar distribution is seen in the thors have classified such tumors as adenomas, re parakeet pituitary. Investigations of the bird serving a diagnosis of malignancy for those in pituitary are largely in agreement that the granu stances in which there was an accompanying lar acidophils and basophils develop from the non vascular invasion, e.g., of the cavernous sinus (84). granular chromophobes. Group III: Metasias&Ang tumors.â€”In only two The predominant cell type in the pituitary birds (4 per cent) was there evidence of metastasis tumors of parakeets is the chromophobe, a cell from the pituitary tumor. One of these was No. 3, which is also the chief component of most mam a male bird bred in Ohio, which had a pituitary malian pituitary neoplasms. A cytological distinc tumor that had deeply invaded the overlying tion between hyperplasia and neoplasia in the brain and produced a large retro-ocular extension. pituitaries of Group I, and between the localized On histological examination a small metastatic tumors of Group I, the invasive tumors of Group nodule was found in the kidney. The second case II, and the metastasizing carcinomas in Group III with metastasis was a bird bred in South Carolina; is difficult. Gardner (22) has noted a similar diffi here, too, the secondary tumor was associated culty in distinguishing sharply between chromo with a large pituitary neoplasm (No. 13). The phobe hyperplasias and chromophobe adenomas primary tumor had extended through both optic in the pituitary glands of rats and mice. foramina and appeared as a 5 X 5 mm. mass in The diffusely enlarged pituitary that has not each retro-ocular space. The liver was small, and invaded the surrounding structures and that is approximately two-thirds of it was replaced by only two to four times the size of the normal nodules of firm grayish-pink tumor tissue (Fig. 9). pituitary usually shows almost complete replace Both of these birds were males; the age of the ment of the granular by the chromophobe cells first was unknown, that of the second was (Fig. 10). Occasionally, small nests and interlacing years. The first bird was well nourished at the strands of acidophils are present among the chro time of death, the second was emaciated; both mophobes; less often, normal chromophobes and were blind. acidophils are compressed by the neoplastic chro Metastasis of human pituitary tumors is appar mophobe cells to form a peripheral zone about the ently very rare. Vasiliu (57) reviewed the litera tumor (Fig. 11). In these cases the adenomatous ture in 1930 and found only four cases. In two of character of the lesion is easily recognized. The these the metastases were limited to the central distinction between hyperplasia and neoplasia in nervous system; in the other two the lungs were the pituitaries of Group I cannot be made with involved. In his own case there were metastases to any certainty when based on histological or cyto several bones as well as to the dura. Dott, Bailey, logical criteria. Occasionally, careful scrutiny of and Cushing (11) reported a case in which the the slides shows that some of the cells have escaped pituitary tumor had metastasized to the liver; and from the pituitary and have invaded the pen

Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1954 American Association for Cancer Research. SCHLUMBERGERâ€”PitUitaTIJ Tunwrs in the Parakeet 241 vascular spaces of the araehnoid. In such cases a Cauious INGrunuEiwocmsrzGi.airne diagnosis of neoplasia rather than of hyperplasia No constant or significant change in the size, can be made with some assurance. weight, or histology of the parathyroids or adre The typical cell of all these tumors, whether the nals could be established in birds with pituitary latter are localized, invading, or metastasizing, has tumors. The parathyroids are easily recognized as a rather scanty pale pink or colorless cytoplasm in single yellow nodules 0.5 mm. in diameter at the which there are often a few faintly staining acido lower pole of each thyroid. The combined weight philic or basophilic granules. The spherical nucleus of the adrenaLs ranged from 6 to 9 mg. ; this is the is often dense and hyperchromatic (Fig. 12); in same as that found in normal birds. No consistent other instances the chromatin is clumped, and the histological changes could be identified, although, nuclei appear vesicular. With special fixatives and following hypophysectomy of young chicks, Nal stains the chromatin may be finely dispersed, bandov and Cord (88) found complete disappear while one or two prominent nucleoli make their ance of the adrenal cortex and degeneration of the appearance (Fig. 18). In the more malignant tu medulla. mors there is a somewhat greater variation in the The thyroids, which are bilateral in the para size and chromatin content of the nuclei than is keet and have a combined weight of 5â€”10mg., found in the benign neoplasms. were 2â€”3times normal size in nine of the 50 birds Tumor giant cells are found in all three groups. (18 per cent). Histologically, this was due more to Occasionally, the cytoplasm of these cells is rather colloid storage than to hyperplasia of the epi scant (Fig. 12), but usually it is abundant and thelium. These changes in the thyroid are of stains pink. The nuclei are single, occasionally interest in view of the thyroid hyperplasia and vesicular with prominent nucleoli (Fig. 14). Often neoplasia, respectively, reported by Fischer (15) in they are large, hyperchromatic, and irregular in two rats with spontaneous pituitary tumors. The outline (Fig. 15). thyroid plays the leading role in several of the A specific histological pattern, characteristic of methods employed to induce pituitary neoplasia these tumors, is the grouping of the cells in cords or in mice (19, 26, 86). Furth et al. (18) have shown trabeculae between parallel capillaries (Fig. 16). that normal mice bearing grafts of the autonomous Occasionally, the cells assume a columnar shape pituitary tumors have tremendously enlarged and are arranged about the capillaries in the form thyroids due to the production of thyroid-stimu of pseudorosettes (Fig. 17). These patterns, how lating hormone (TSH) by the tumor. There were ever, are not characteristic of most of the tumors no demonstrable changes in the pituitaries of six in which sheets of cells with no special relation to teen parakeets with large goiters that weighed 10- the capillaries make up the bulk of the neoplasm. 25 times more than did the normal gland. The malignant character of the locally invasive The pituitary tumors occurred with approxi tumors (Group II) is clearly indicated by their in mately equal frequency in the two sexes: 28 were filtration of adjacent structures. Although the males, 27 females. There was always a marked de. hypothalamus may be simply displaced by the chine in the sexual activity of these birds. Females expanding neoplasm, invasion by groups of tumor ceased egg laying or on rare occasions failed to cells often occurs. Most striking is the frequent care for their young. Males failed to mate. In all invasion of the optic chasm and optic nerves cases the gonads were in a state of rest, spermato (Fig. 18). Occasionally, the extraocular muscles are genesis was absent in the testes, and maturing involved (Fig. 19), and instances of penineural follicles were not seen in the ovaries. Nevertheless, infiltration have been seen (Fig. 20). The cancel fibrosis of the gonads and degeneration of the bus bone beneath the floor of the sella turcica is germ cells, as described in the fowl following often the site of direct extension from the primary hypophysectomy of young birds (88), were not tumor. present. This arrest of gonadal function in para Distant metastases (Group HI) were seen only keeLs bearing pituitary tumors suggests that the twice. In both cases the cells in the primary neo gonadotropic hormone is not elaborated by the plasm were similar to those in the metastases. In neoplastic cells. the first (No. 3) the cells of the pituitary tumor and of the renal metastasis were small with scanty AssocIATI@D Nuopiasus cytoplasm (Fig. 21). In the second (No. 13) the In seven of the 50 cases of pituitary tumor (14 cells of the primary tumor were elongate and ar per cent) there were neoplasms in other organs. In ranged in a pseudo-papillary manner; those in the one instance (Case 29) this was a papillary ade liver metastasis were similar in appearance (Fig. noma of the Harderian gland that produced a 22). proptosis of one eye suggestive of retro-ocular in

vasion by the pituitary neoplasm. However, the of fat. However, recent studies have indicated that hypophyseal tumor had produced only a diffuse the hypothalamus rather than the pituitary is enlargement of the gland without any evidence of most directly concerned with food intake and local invasion. obesity in mammals (6, 7). Electrolytic lesions in In another case (No. 46) there was a 8-mm. the ventromedial hypothalamic nuclei of the rat papillary adenocarcinoma in the left kidney and a lead to marked hyperphagia and a doubling of 1-cm. fibrosarcoma in the spleen of a bird with a body weight (30, 31). In six of seventeen obese large pituitary tumor that had invaded the retro parakeets in this series the obesity was found as ocular tissue. The remaining five cases (Nos. 11, sociated with a pituitary tumor that had invaded 31, 40, 42, 45) all bore single large papillary renal or severely compressed the adjacent hypothalamus. adenocarcinomas. In one case (No. 12) the bird, a male, was noted to Of the seven cases with associated tumors five be gaining weight while caring for the last nest of were males. The pituitary tumors in five of the young. Shortly thereafter he became blind and 6 seven were noninvasive (Group I) ; in two the weeks later died. At autopsy the pituitary was neoplasm in the pituitary showed evidence of local found to be completely replaced by a tumor that invasion (Group II). The coincidence of papillary invaded the optic nerves and hypothalamus. adenocarcinoma of the kidney in six birds with These findings in the parakeet coincide well pituitary tumors is worthy of note, for Haddow with the experimental evidence obtained with the and Horning (28) have observed the simultaneous rat. However, in eleven of the seventeen obese occurrence of pituitary adenomas and renal car birds the pituitary neoplasm was small; neither cinomas in male hamsters receiving stilbestrol. gross nor microscopic study of the adjacent struc Nevertheless, in a series of sixteen parakeets tures showed signs of pressure distortion or inva (twelve males,four females)with renaladenocar sion by the tumor. Bird No. 21, a male with a cinomas careful examination showed no changes large tumor-like accumulation of fat tissue be in the pituitary. neath the skin of the breast, may serve as an ex

TRANSPLANTATION Exrxamtssrrs ample. It had been used in a laboratory feeding test by a commercial food firm; the subcutaneous Fragments of the pituitary tumors from seven fat was first noted about 20 days after conclusion birds (Nos. 6, 9, 12, 15, 18, 24, 84) classified as of the study. At that time the bird weighed 60 Group II were inoculated into the brains of 80 gm. ; 6 days later the weight was 63.3 gin., as parakeets and 81 fowl chicks; the latter were 24â€” compared to the 85â€”40-gm.weight of other birds 86 hours old. No growth of the transplants was in the aviary that were of the same age and had observed; survival of the tissue for 1â€”2weeks was received the same feedings. However, except for obtained in both parakeets and fowl chicks (Fig. this marked degree of obesity the bird appeared to 23). Operative mortality was very low; one chick be as normal and as active as its fellows. After died of hemorrhage, and in another the cerebral several days under observation in our laboratory wound was infected. it was sacrificed, and in addition to extreme obes One of the tumors (No. 28) was also inoculated ity the only abnormality found was an enlarge into the yolk sac and allantoic membrane, respec ment of the pituitary to 8 times its normal size. tively, of 24 fowl embryos. Only three embryos Histologically, there was complete replacement of died; however, no tumor could be found in the re the normal tissue by a chromophobe adenoma but maining 21 eggs 12 days after inoculation. no evidence of invasion of surrounding tissue. Transplantation could not be carried out with material from the two cases in which the tumor The effect of hypophysectomy in birds is still had acquired a considerable degree of autonomy as not entirely clean. In adult hens Rothchild (45) evidenced by the presence of metastases. The found that hypophysectomy led to a sharp weight pituitary tumors used in the transplantation loss followed by a slow return, with stabilization of studies were probably still dependent upon subtle the body weight at about 11 per cent greater than changes in their hormonal environment in the the pro-operative weight. Using young growing manner of the conditioned neoplasms recently dis fowl 60 days old and weighing 500 gm., Nalbandov cussed by Furth (17). and Cord (88) found that increase in body weight continues after complete removal of the hypophy DISCUSSION sis and is due to the abnormal deposition of fat For many years the role of the pituitary in rather than to true growth. Carcasses of hypophy obesity has been debated, and to many investi sectomized chickens contain 5â€”7times more fat gators it appeared probable that interference with than do their controls. Whether these operative pituitary function could lead to increased storage procedures in chickens were accompanied by any

Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1954 American Association for Cancer Research. SCHLUMBEROERâ€”PitUitariJ Tunwrs in the Parakeet 248 damage to the hypothalamus is not recorded. than a year old. In addition, some of the birds are Excessive amounts of pituitary adrenocortico allowed to rear more than three clutches of young trophic hormone (ACTH) acting upon the adrenal annually. Such intensive breeding, including feed may lead to obesity. Recently, Furth et al. (20) ing and caring for the young which is carried out found that a pituitary tumor which developed in by both male and female, may lead to overstimu a mouse following ionizing irradiation was trans lation of the pituitary followed by hyperplasia and, plantable to normal untreated mice. Among the eventually, neoplasia of that organ. changes produced in the recipients were obesity No definite relationship between the thyroid and polyunia. The authors concluded on the basis and pituitary tumors in the parakeet could be of these and other findings that the tumor trans demonstrated. The condition of the thyroid in plants secreted ACTH. In the light of these find these birds has been discussed in the section on ings in mice, it seems possible that the sporadic changes in endocrine glands other than the pitui obesity found among the parakeets may be due to tary. the secretion of ACTH by some of the pituitary The effect of light on sexual activity, so-called tumors. â€œsexualphotopeniodicity,â€• has been extensively The emaciation which is more often a late mani investigated in birds (5, 8). It is of considerable festation of a pituitary tumor than is obesity may commercial importance in the poultry industry, be explained by the bird's progressive inability to where artificial light is used to prolong the day get about and feed. However, loss of appetite and light hours for egg laying (58). This custom is also emaciation have also been produced in rats by widespread among parakeet breeders. The con sharply localized electrolytic lesions in the hypo sensus is that light may stimulate the hypophysis thalamus. Its role in the parakeet cannot be de indirectly through visual perception or excitation termined from the data at hand. of deeply situated nerve centers, or directly after On the basis of the material examined it appears it has penetrated the overlying tissues (8). The re that in the parakeet pituitary there is a gradual sultant stimulation leads to an increased produc transition from hyperplasia to neoplasia. A dis tion of gonadotrophins. cussion of etiology may therefore concern itself The possibility that prolonged or more intense primarily with a consideration of factors known light may lead to hyperplasia and neoplasia of the to produce pituitary hyperplasia; the immediate pituitary is under experimental investigation. cause for the change from hyperplasia to neo Data derived from the birds received with spon plasia is unknown in the bird, as it is in other taneous tumors are inadequate to permit any con animals. clusions. Many breeders when questioned replied Adenomatous hyperplasia and neoplasia of the that the birds were exposed to varying amounts of pituitary have been produced experimentally in artificial light. Of interest is the fact that the larg several rodents, viz., mice, rats, and hamsters. est number of birds with tumors (14) were received The method employed produced a disturbance of from Texas where the intensity of solar radiation endocrine relationships involving either the pitui is well known to cause an unusually high incidence tary and the gonads (10, 21, 28, 39) or the pitui of skin cancer in man. In that state most aviaries tary and the thyroid (19, 26, 36). The problem has are outdoors. Nevertheless, there are so many been reviewed by Gardner (22). variables, e.g., a larger bird population, interested The incidence of pituitary tumors is approxi breeders willing to send their birds, etc., which mately equal among male and female parakeets. might account for such a high incidence that the This suggests that, if a pituitary-gonadal imbal significance of geographical distribution must re ance exists, it is not due to over-secretion of a main speculative. single hormone, e.g., estrogen. However, the effect No evidence that a genetic factor plays a part of stilbestrol on the pituitary of both the male and in the induction of these tumors has been oh female parakeet is being investigated. The normal life span of the parakeet is about 9 tamed. In most instances the relationship of sev years. Birds with pituitary tumors are relatively eral birds received from the same aviary was un youngâ€”the average age is 2.5 years, which repre known. The absence of records was particularly sents a period of great sexual activity. Most of the distressing when four or even six birds with pitui birds in whom an adequate history could be ob tary tumors were received from a single breeder tained were good breeders until signs of a pituitary over a period of a few months. The majority of tumor became manifest. Because of the current birds were obtained from such widely separate great demand for parakeets, rqany owners of parts of the country that kinship seems unlikely. aviaries are breeding them when the birds are less Offspring of birds that subsequently died with

pituitary tumors have been obtained in an effort 2. [email protected], 0. T., and Cumnu, E. C. Malignant Adenomas to establish inbred strains of these birds. of Chromophobe Cells of Pituitary Body. Arch. Path., 29:368â€”99,1940. 3. Bmron,, J., and O'rr, L. External and Internal Factors in SUMLMARY Sexual Activity. Effect of Irradiation with Different Spontaneous chromophobe pituitary tumors Wave Lengths on the Mechanismsof Photostimulation of are not uncommon in the parakeet, Mekpsittacus the Hypophysis and on Testicular Growth in the Immature [email protected] incidence is approximately equal Duck. Yale J. Biol. & Med., 17:27â€”46,1944. 4. Bzui@scseowsxy, F. Chronic Iodine Deficiency as Cause in the two sexes. of Neoplasia in Thyroid and Pituitary of Aged Rats. Fifty cases have been examined and the tumors Brit. J. Cancer, 7:203â€”13,1953. classified into three groups: (I) diffuse enlarge 5. Bmsoi@nimu, T. H. Sexual Photoperiodicity. Quart. Rev. ment of the pituitary (40 per cent); (II) locally Biol., 11:871â€”86,1936. invasive tumors (56 per cent); and (III) metasta 6. Baonacx, J. R. Mechanism of the Development of Obesity in Animals with Hypothalamic Lesions. Physiol. Rev., sizing tumors (4 per cent). 26:541â€”59, 1946. Signs of a pituitary neoplasm in the parakeet 7. . Physiology of Appetite. Nutrition Symposium include unilateral or bilateral exophthalmos, blind Series, 6:36â€”48,1953. ness, somnolence, polyuria, polydypsia, and obes 8. Britons, J. W. A Review of Experimental Investigations on Seasonal Reproduction in Birds. Wilson Bull., 61: ity. The parakeet has a normal life span of about 211â€”80,1949. 9 years. The average age of birds with a pituitary 9. DnLiwiau, A. M.; T@iut, L.; and Gnzwro, E. M. K. tumor was 2.5 years. The Distribution in the Chicken Hypophysis of the So The gross and microscopic morphology of the called Posterior Lobe Principle. J. Pharm. & Exper. tumors is described; it differs little from that of Ther., 51: 142â€”43,1934. 10. Dicxzx, M. M., and Woou@uv, G. W. Spontaneous Base mammalian pituitary neoplasms. philic Tumors of the Pituitary Glands in Gonadectomized In six birds (10 per cent) there was an asso Mice. Cancer Research, 9:372â€”84,1949. ciated renal adenocarcinoma. Goiter occurred in 11. Doi-r, N.; B@tnxr, P.; and Cuaax@G, H. A Consideration nine of the parakeets (18 per cent); no changes of the Hypophyseal Adenomata. Brit. J. Surg., 13:314-. 66, 1925. were observed in the adrenals. The gonads were 12. Dux, C. Recherches microscopiques sur les adenomes always in the resting state, but advanced atrophic hypophysaires du rat. Bull. Assoc. franc. Ã©tudeCancer, changes were not encountered. 35:201-16, 1948. Transplants of tumor tissue from seven different 13. FETERABEND, C. Modern Feeding of Budgerigars. Pub. birds into a total of 30 parakeets and 81 fowl All Pets Magazine, Fond du Lac, Wis., 1951. 14. . Diseases of Budgerigars. Ibid. chicks failed to grow. Most of the transplants were 15. Fiscuan, 0. Ueber Hypophysengeschwtilste der weissen intracerebral. Ratten. VirCh. Arch. f. path. Anat., 259:9-29, 1926. Factors relating to the probable etiology of 16. Fox, H. Pathologic Anatomy in the Hypophysis Cerebi in these tumors are discussed. Wild Animals. Arch. Neurol. & Psych., 17:471-80, 1927. 17. Fuurn, J. Conditioned and Autonomous Neoplasms: A Review. Cancer Research, 13:477-92, 1953. ACKNOWLEDGMENTS 18. Fun@rn, J.; Buarinrr, W. T., JR.; and GADSDEN, E. L. Grateful recognition is given the many parakeet breeders, Quantitative Relationship between Thyroid Function and dealers, and owners who contributed the birds used in this Growth of Pituitary Tumors Secreting TSH. Cancer Re investigation. search, 13:298â€”307,1953. 19. FtniTn, J.; GADSDEN, E. L.; and Bun@x@r@r,W.T., JR. REFERENCES Autonomous Transplantable Pituitary Tumors Arising in 1. ARTI0LI, D. Adenoma a cellule eosixiofile del lobo anteriore Growths Dependent on Absence of the Thyroid Gland. dell'iopfisi in un bovino. Riv. di Anat. Pat. e. di Oncol., Proc. Soc. Exper. Biol. & Med., 80:4-7, 1952. 1:298â€”302,1949. 20. Funiii, J.; G@ussnm@,E. L.; and UI@roN, A. C. ACTh

Fio. 1.â€”Bilateral exophthalmos in a blind male parakeet. to infiltration by the pituitary tumor. The bulk of the latter At autopsy large retro-ocular extensions of the primary pitui appears as an irregular flat gray mass behind the chiasm (black tary tumor were found. Bird No. 23. Mag. X1.5. arrow). See also Figure 18. Bird No 1. Mag. X3. FIG. 2.â€”Sagittal section through brain, pituitary, and Fio. 5.â€”Transverse vertical section through the brain at optic chasm. The pituitary is enlarged to 8 times normal size the level of the pituitary. The gland is completely replaced (arrow); it does not invade adjacent structures although it by a tumor (arrow) which is infiltrating the brain; the retro slightly compresses the optic chasm. See also Figure 15. ocular mass is also shown. Bird No. 1. Mag. XS. Bird No. 8. Mag. X3. FIG.6.â€”Ventralaspectof head after removal of lowerjaw Fio. 3.â€”Lateral view of head with partly exposed brain showing two adjacent hemispherical tumors. The one at showing retro-ocular extension (arrow) of pituitary tumor. mid center (arrow) is a direct extension of the pituitary neo Bird No. 1. Mag. X3. plasm through the basi.aphenoid bone into the oropharynx. Fio. 4.â€”Ventral view of brain showing retro-ocular tumor Immediately above this is a retro-ocular extension. Bird No. mass (white arrow) encircling one of the optic nerves; thicken 14. Mag. X2.5. ing and nodularity of the other nerve and of the chasm are due

Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1954 American Association for Cancer Research. FiG. 7.â€”Ventral view of head after removal of jaw showing enlarged pituitary immediately behind optic (hiasm. @4eealso Figures 8 and 17. Bird N0. 4. Mag. X3. FIG. 8.â€”Sagittal section of brain shown in Figure 7. A large darkly staining circular tumor is seen occupying the entire region of the mid-brain and infiltrating the meninges over the brain stern. The neoplastic pituitary appears as a more lightly staining ventral projection ; the cross section of the optic chiasm is indicated by an arrow. Bird No. 4. Mag. X 10. Hematoxylin and eosin stain. Fic. 9.â€”Section through liver showing pale gray tumor metastases from primary neoplasm in pituitary. For histologic structure see Figure [email protected] No. 13. FIG. 10.â€”Histological section through an entire pituitary that was grossly 3 times normal size. There is diffuse replace ment of normal tissue by chromophobe cells. infiltration of the adjacent menitiges by the (hromophohes had occurred. Bird No. @1.Mag. X20. H. and E. stain. FIG. 11.â€”Section of pituitary that was twice normal size. A chromophohe adenoma is seen compressing the adjacent normal tissue. Bird No. 45. Mag. X135. H. and F. stain.

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Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1954 American Association for Cancer Research. FIG. 1@.â€”Section from prinmry tumor that had invaded the retro-ocular tissue. Its malignant character is indicated by the variability in the size of the cell nuclei, some of which may be classified as giant forms. However, the majority of cells with their hyperchromatic nuclei and scant cytoplasm are typical of those found in both the benign and malignant chromophobe tumors. See also Figures @0and @1.Bird No. 3. Mag. X700. H. and E. stain. FIG. 13.â€”The epithelial character of the cells in a 6-mm. pituitary tumor that was invading the brain and uiiderlying bone is apparent. The nucleoli stain sharply; mO cytoplasmic granules are present. Bird No. 39. Mag. X700. Severinghaus technic. FIG. 14.â€”Giant cell in a tumor that invaded bOth orbits. See also Figure @3.Bird No. 18. Mag. X 700. H. and E. stain. FIG. 15.â€”Giant cells in a pituitary adenoma; there is some variability in size of the chromophohe cell nuclei, but no evi dence of invasionâ€”note compressioni of adjacent normal tissue. For gross appearance see Figure @.Bird No. 8. Mag. X 180. H. and E. stain. FIG. 16.â€”Trabecular pattern of cells in a pituitary tumor that had penetrated the basi-sphenoid bone. There is moderate nuclear irregularity. Bird No. 6. Mag. X550. H. and E. stain. FIG. 17.â€”Perivascular and pseudo-papillary pattern of the large intracerebral tumor shown in Figures 7 and 8. Bird No. 4. Mag. X400. H. and E. stain.

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Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1954 American Association for Cancer Research. FIG. 18.â€”Inifiltratioti of optic nerve by tumor cells. For grossappearancesee Figure4. BirdNo. 1. Mag. X105. Hand E. stain. FIn. 19.â€”Invasion of extraâ€”ocular muscle by tumor. Bird No. [email protected]. X175. H. and E. stain. FIG. @0.â€”Perineural infiltration of tumor cells. For histolog iC structure of primary see Figure 1@. Bird No. 3. Mag. X 175. II. and E. stain. FIG. 21.â€”Sectioti of kidney fronl same case as Figures 1@ aIl(l @(1,showing renal metastasis. Bird No. 3. Mag. X 175. 11. and E. stain. FIG. @2'2.â€”Metastatic tumor in liver. For gross appearance see Figure 9. Bird No. 13. Mag. X550. H. and E. stain. FIG. @23.â€”\iI1l)le tumor transplant in brain of fowl chick 15 days after inoculation of tumor from Bird No. 18. See also Figure14.Mag.X175.H. and E.stain.

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Secreting Transplantable Pituitary Tumors. Proc. Soc. 42. PAYNE, F. The Cytology of the Anterior Pituitary of the Exper. Biol. & Med., 84:253-54, 1953. Fowl. Biol. Bull., 82:79â€”111,1942. 21. G@znD@nn,W. U. The Effect of Estrogen on the Incidence 43. Ram@n,H., and PAINTER,B. T. A Comparative Histology of Mammary and Pituitary Tumors in Hybrid Mice. of the Bird Pituitary. Anat. Rec., 79:297â€”811,1941. Cancer Research, 1:345-58, 1941. 44. Roatzza, B. Innersekretorische Drilsen. II. Hypophyse in 22. . Hormonal Aspects of Experimental Tumori Handb. d. mikr. Anat. d. Menachen, Vol. 6, Part 8. genesis. In Gaz@svnz@r, 3. P., and IL&unow, A. (eds.), Berlin: Springer, 1940. Advances in Cancer Research, pp. 173â€”232.New York: 45. Romcaru, I. Notes on Survivaland Body Weight Changes Academic Press, Inc., 1953. of Adult Hens Following Hypophysectomy. Endo 23. G@m@rxa,W. U., and STRONG,L. C. An Observation of crinology, 43:298â€”805,1948. Primary Tumors of the Pituitary, Ovaries, and Mammin-ry 46. SAXTON,J. A., Ja. The Relation of Age to the Occurrence Glands in a Mouse. Am. J. Cancer, 26:541-46, 1936. of Adenoma-like Lesions in the Rat Hypophysis and Their 24. Gzi@asousn,M.D. Carcinoma of the Pituitary Gland with Growth after Transplantation. Cancer Research, 1:277- 82, 1941. Abdominal Metastases. J. Path. & Bact., 35:265-69, 1982. 47. S@txi'oN, J. A., JR., and Gaan@ss, J. B. Chromophobe 25. GOODHART,J. F. Cancer of the Pituitary Body in the Adenoma-like Lesions of Rat Hypophysis: Frequency of Anubis Baboon. Trans. Path. Soc., 36:86, 1885. Spontaneous Lesions and Characteristics of Growth of Homologous Intraocular Transplants. Cancer Research, 26. Gonss,ar@r,A. Tumorous Growth in the Pituitary and 4:168-75,1944. Trachea Following Radiotoxic Dosages of 1-131. Proc. 48. Scnxuna, H. J. Vergleichende Pathologic des Nerven Soc. Exper. Biol. & Med., 71:287â€”40,1949. systems der Saugetiere. Leipzig: Georg Theme, 1944. 27. 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Hans G. Schlumberger

Cancer Res 1954;14:237-245.

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