A c t a Path. Jap. 28(6): 995-1002, 1978.
MALIGNANT PITUITARY CHROMOPHOBE ADENOMA I N AN INFANT ACCOMPANYING DIABETES INSIPIDUS Chao Hui FANG(HAYASHI),Michiyasu AWAI, Hisasi NAKATUKA, Satimaru SENO, Yasuko YAMATOGI*, Hideo INOUE,and Syunsuke OHTAHARA* Department of Pathology and, *Pediatrics, Okayama University Medical School, Okayama (Received on April 1, 1978)
This report deals with a 1.5-year-old male infant terminating in viral pneumonia and “diabetes insipidus”. The autopsy revealed malignant pituitary chromophobe adenoma, invading the wall of the third ventricle, extending to the periventricular-, dorsomedial- and ventromedial area, skipping to the lateral area adjacent to the optic nerve, and permeating into the subarachnoid space of the cerebrum. At the onset of disease polydypsia and polyuria were marked followed by interstitial pneumonia with high fever, and later generalized tonic convulsion terminated in death. This case is peculiar in at least t w o respects. Firstly, this is the youngest reported case of malignant chromophobe adenoma. Secondly, the manifestation of diabetes insipidus is rare in chromophobe adenoma. The malignant adenoma probably occurred from the primitive gland rest of chromophobe cells in the posterior lobe becoming malignant during the course of growth development and destroyed the cells of the posterior lobe, resulting in diabetes insipidus. ACTA PATH. JAP. 2 8 : 995-1002, 1978.
Introduction Benign pituitary adenomas composed about 12 percent of 5,000 intracranimal tumors studied by KERNOHAN and SAYRE’. In their 600 cases of pituitary adenoma, 565 were so-called chromophobe adenomas and the remainder were eosinophilic adenomas. cOSTELL03 examined semi-serial sections of 1,000 “normal” pituitary glands and found “adenomas” in 225 cases. These adenomas were classified into the following cell types: 140 (52.8 percent) chromophobic; 20 (7.5 percent) eosinophilic; 72 (27.2 percent) basophilic; and 33 (12.5 percent) contained two or even three types of cells. Chromophobe adenoma commonly occurred between 30 to 60 years of age7. The youngest age reported were: 2 years3, 7 years’, and 18 years of agel4. The oldest was 85 years of age3. The average age of chromophobe adenoma incidence was 41.4 years in each sex, and the ratio of males-to-females was slightly higher in males7. The pituitary adenomas was usually accompanied with Gushing’s syndrome or a ~ r o m e g a l i a ~ , Malig~. nancy may arise in the anterior lobe occasionally, in the preexisting benign adenomas; however, this was very rare6. Furthermore, only one in 165 cases of pituitary adenoma indicated chromophobe adenoma associated diabetes insipidus2. ~
# S@,%#
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996
MALIONANT CHROMOPHOBE ADENOMA
Acta Path. Jap.
Case Repmt Clinical Data
A 1.5-year-old Japanese male infant was first admitted to Okayama University Hospital on September 25, 1968, with the mother’s complaint of pollakisuria and polydypsia for two weeks durations. Word observation indicated that the “pollakisuria” was in fact polyuria. The mother also reported abnormal behavior, such as head banging and impulsiveness. The family history was not remarkable and was negative for both neurological and psychiatric diseases. The patient was the first-born and had a fullterm normal delivery. Physical examinations : The patient was a normally developed, well-nourished infant with a healthy appearence. The head was normal in size and shape; the neck was symmetrical without abnormal swelling. There was no sign of goiter or enlargement of the cervical lymph nodes. Laboratory exumination : Hematologic data showed hemoglobin, 11.4 gm ; red cell count, 55 x lo4; and white cell count, 13900/cmm with 32.8% neutrophils, 63.5% lymphocytes, 0.5% eosinophils, and 3.2% monocytes. Red cell and whte cell morphology on smear specimens was normal. Chemical analysis of serum revealed urea nitrogen, 9 mg/100 ml; potassium, 4.7 mEg/liter, sodium, 138.5 mEg/liter; and fasting glucose, 90 mg/100 ml. The glucose tolerance test was within normal limits. Water-uptake was 3,200 to 3,800 ml/day, and the total volume of urinary output was 2,200 to 3,200 ml/day. Urinalysis values indicated specific gravity, 1,002 to 1,003; no glucose; no protein; and the sediments showed no red cells nor white blood cells, and no casts. After 8-hour water deprivation, the urinary specific gravity rose t o 1,013 to 1,017. Pitressin test revealed a decrease urinary volume, while the specific gravity increased by 1,013, and the urinary sediments revealed no abnormality. An intravenous pyelographic study demonstrated that the kidneys were normal in shape and function. A lumbar puncture yielded a clear and colorless spinal fluid. The opening pressure was 350 mm/Hg, and after 4 ml of clear colorless fluid was removed, the closing pressure was 200 mm/Hg while crying. Examination of the spinal fluid showed no cells and was negative for the Nonne and Pandy tests. The ocular fundus was normal and the visual field could not be measured due to technical difficulties. On X-ray films of skull, the sella turcica was almost normal in shape and size, EEG showed low voltage dysrhythmia, however, no focal sign of abnormality was evident. Diabetes insipidus was suspected from the clinical impression, but this could not be verified from the data just described. Therefore, treatment included only sedatives for the nervousness, and the patient ws released from the hospital on October 25, 1968. Thereafter, he was under the care of the local doctor near his home. The second admission began on February 2, 1969, as an emergency patient in coma
28(6): 1978
(:.[I.
P . \ N I : el at
997
with clonic convulsions. Several days beforc the second admission our patient was exposed to a n incitlental with influenza. and from the evening of February 1, fever (39 C), cough and nasal dischargz mere reported. He was afebrile the next morning, hit interniitteiit tonic convulsions limited to the arms were noticed and he entered coma. On admission, the ntermittent convulsions changed to generalized clonic convulsion, that containued for 10 seconds to several minutes. The patient was in a comatose state with cyanotic lips, had dry, pale and cold skin, a feeble pulses and gasping inspiration, as in Cheyne-Stoke’s breathng. On opening the eyelids, the pupils deviated upward and showed a slow niiotic reaction to light, and anisocoria was rioted with the left pupil being larger. Xeurological ezamination : Abdoniinal wall reflex (-) ; cremasteric reflex
(-) ;
biceps reflex- rt. f , It. 4 4 ; triceps reflemt. ?J, It. TJ; P.T.R. -rt. f f . It. TJ, A.T.R. - rt. 4 , It. f , Kernig’s sign (-), and no nuchal rigidity. Spastic convulsions, mainly limited to the upper extremites continued for one to several minutes and recurred with 0.5 second intermittence, a t 6 p.m. on February 2 . Thereafter, the convulsions progressed to generalized clonic convulsion in all extremities. The patient died a t 7.30 a.m., February 4, 1969. Laboratory Jindings : Hematologic data hematocrit, 12.3%; red blood cell count,
575x 104/cmm; white blood cell count, 10,10O/cmm; urea nitrogen, 15.0 mg/100 ml; potasium 5.8 mEq/liter ; sodium 125.0 mEq/liter, and bolld sugar, 220 nig/dl after glucose injection. Lumbar puncture - cell number, 22/3 in high power field; Nonne (-); and Pandy (-). Examinations for vision and ocular fundus could not be performed for technical reasons. An electrocardiogram revealed a sinus irregular rhythm. EEG examination revealed a nonspecific abnormal wave in the hypothalamus; however, a specific recruiting rythym of 14c/s observed during tonic seizure status and niarked low voltage-waves were intermittingly seen. A special finding was that many anticonvulsants, such as Diazepari commonly effective in non-specific, prolonged seizure activities had no remarkable effect. Postmortem
Emmination
Mucroscopic Jiiadings : The pituitary gland was slightly enlarged and soft, somewhat like a cyst, and contained small amount of mucinous yellowish substance. The capsule was thin and not adhesive. No destruction was seen on the sella turcica. The sella turcica was not enlarged a t necropsy or in an earlier roentgenograph of the skull. Cerebrum and cerehelluin mere markedly edematous and congested, especially the cerebrum. Macroscopically, the basilar area mas somewhat cloudy but foci of carcinomatous invasion or metastasis were not obvious. Patent foramen ovale was seen in the heart. No evidence of thymus hypertrophy. Both lungs were markedly congested, with a pneumonia-like appearance. The spleen was strongly congested and revealed follicular atrophy. The other organs revealed no remarkable findings, except for congestion and edema.
Microscopic jindings : Hematoxylin-eosin stained tunlor sections revealed almost
MALIOKANT CHROMOPHOBE ADENOMA
Ackc Path. Jap.
28(6): 1978
C.H. FANG d
939
d
all areas of the pituitary gland being extensively invaded or compressed by cancer cells with papillary or sinusoidal arrangement (Figs. 1, 2). Tumor cells, however, did not infiltrate the sella turcica. The tumor cells were pleomorphic, mainly cuboidal, or polyhedral shaped, with some mitotic figures, and the cells with giant nuclei or multinucleated giant cells were occasionally detected (Fig. 2). The neoplastic cells were determined to be chromophobic cells in Trichrome stained sections (Fig. 3). I n some areas a small number of normal eosinophilic cells intermingled with the neoplastic cells. The chromophobic cells projected from the infundibular recess through the stalk, invaded the third ventricle, extending to the periventricular-, dorsomedial- and ventromedial areas, and also skipping to the lateral area around the bilateral optic nerves. In addition to these massive extensions, multiple vascular permeations were observed in the Virchow-Robin’s spaces of cerebrum and cerebellum (Fig. a), and the chromophobic cells were found disseminating the subarachnoid space; however, most cells seemed only attached to the surface of the pia mata without infiltration. This indicates that the cancer cells circulated in the intracranial spaces and circulating system. The invasion was massive and extensive, but morphologically no significant degeneration or destruction of nuclei was seen adjacent to the infiltrating foci. It appeared that the infiltrating foci were not sufficiently large to produce damage to adjacent nerve cells. The infiltrating foci are schematically represented in Fig. 5. Hematoxylin-eosin stained sections of the lungs revealed interstitial pneumonia. No particular changes were seen in the thyroid gland, thymus, pancreas, kidneys, adrenal glands, or other organs. The patient showed diabetes insipidus. The microscopic examination after necropsy revealed widely extended carcinomata originating from the pituitary gland, and proliferating cells were clearly chromophobic cells in trichrome stained tissue sections (Fig. 3). The tumor in the pituitary gland was made up mostly of chromophobic cells with a few eosinophilic cells, but basophilic cells were not evident. These eosinophilic cells were probably residue of normal component, because no eosinophilic cells were found in the infiltrating foci of either cerebrum or cerebellum. The criteria of malignancy is difficult to establish in chromophobe adenomas. BAILEY~ reported that the extension and invasion of neighboring structures are not indicative of malignancy and that “perhaps frequency of mitosis is the only reliable criterion”. KERNOHAN and SAYRE’agreed that the tumor size was not a good histologic indication of malignancy. JEFFERSON~ used the term “malignant adenoma” to ~
~~
~~
~
~~
~
~
~-
Fig. 1. Low magnification of malignant pituitary adenoma. The tumor is forming a sinusoidal or papillary arrangement with massive infiltration. There is some stroma but only few blood vessels are evident. H-E Stain x 100. Fig. 2. High magnification of malignant pituitary adenoma. The tumor cells are pleomorphic with nongranular cytoplasm, forming a sinusoidal arrangement. Arrow shows a multinucleated giant cell. H-E Stain x 400. Fig. 3. Invasive pattern in third ventricle. The tumor is composed of chromophobic cells, forming a sinusoidal or papillary arrangement and massively spreading into the periventricular area and compressing brain tissue. Trichrome Stain x 200. Fig. 4. Invasion into the Virchow-Robin’s space (W) and pevio-optic area (P). H-E Stain x 100.
1000
MALIQNANT OHROMOPHQBE ADENOMA
Acta Path. Jap.
Fig. 5. Infiltration of malignant pituitary adenoma. Dor. ; Dorsal area, DM; Dorsomedial nuclear region, I n t Cap; Internal capsule, Opt tr.; Optic tract, Para; Para ventricular nuclei, Perivent; Periventricular nuclei, Lat; Lateral area, VM; Ventromedial nuclei.
indicate a tumor that had burst through its capsule and widely expanded. However, et a1.12 he did not use the term malignancy with a histologic orientation. SCHNITKER encountered three malignant chromophobe adenomas in a series of 84 adenoma cases. These authors preferred the term “malignant adenoma” to “carcinoma of the pituitary gland”, however, others have used the term invasive adenoma as being more correct than the designation “carcinoma of the pituitaryll”. In our case, the cyto-histological characteristic of the tumor warrant a malignant diagnosis: pleomorphism, cells with giant and multinuclei, active mitosis, and tumor extending to neighboring tissues, multifocally permeating into Virchow-Robin’s spaces, disseminating to the subarachnoid space. A rare case of subarachnoid matastasis was also reported by MAUONICKet al.*. The onset symptoms included polydypsia and polyuria, and no Cushing’s syndrome or acromgalia. The polydypsia and polyuria were reacrive in the Pitressin test. Microscopically, the carcinomata massively invaded the pituitary gland with a few
28(6): 1978
C.H. BAND d d
1001
eosinophilic cells. And the tumor of the pituitary gland projected from the infundibular recess through the stalk and invaded into the hypothalamic periventricular-, dorsomedial areas and also into a part of the ventromedial area. This evidence suggests that symptoms of diabetes insipidus were produced by selective damage to the posterior lobe of the pituitary gland with a small normally functioning anterior lobe, and/or the hypothalamico-neurohypophysealtract. No infiltrations were found in the hunger and satiety centers. The implusive behavior, head banging, and EEG findings of recruiting rhythm (prolonged seizure activity) may have been induced by hypothalamic injury. No particular changes were found in the kidneys, pancreas, and adrenal glands. NATELSON~ reported a rare case of pituitary eosinophilic tumor associated with acromegaly, diabetes mellitus and diabetes insipidus. I n our case hyperglycemia (220 mg/dl) was found after glucose injection, but the glucose fasting test could not be conducted. The age incidence of the youngest patients with invasive chromophobe adenoma of the pituitary gland was two years3, seven years’, and 18 years14 of age. Our 1.5 year old patient is unusual in manifesting malignancy a t such an early age, and is the youngest reported case with this syndrome. S U S M A found N ~ ~ two case of primitive gland rest in the pars posterior in 71 cases of embryonic pituitary out of 230 autopsied cases. This evidence strongly suggests that the tumor probably occurred from the primitive glandular rest of chromophobe cells in the posterior lobe transforming to malignant cells during the course of growth development. References 1. BAILEY,O.T. and CUTLER,E.C.: Malignant carcinomas of the chromophobe cells of the pituitary body. Arch. Pathol. 29: 368-399, 1940. 2. BRONSON, S.R. and PATTERSON, H. JR. : Surgical experience with chromophobe adenomas of the pituitary gland. J. Neurosurg. 34: 726-729, 1971. R.T.: Subclinical adenoma of the pituitary gland. Am. J. Pathol. 12: 205-216, 3. COSTELLO, 1963. 4. CUSHING,H. : “Dyspituitarism” : Twenty years later, with special consideration of the pituitary adenomas. Arch. Interm. Med. 51 : 487-557, 1933. 5. CUSHINQ,H. and DAVIDOFF,L.M.: The Pathological Findings in Four Autopsied Cases of Acromegaly with a Discussion of Their Significance. Monograph 22. Rockefeller Institute for Medical Research, 1927. G.: Extracellar extensions of pituitary adenomas. Proc. Roy. SOC.Med. 33: 6. JEFFERSON, 433458, 1940. J.S. and SAYRE,G.P.: in Armed Forces Institute of Pathology. Atlas of Tumor7. KERNOHAN, pathology, Section X, Fascile 36: Tumor of the pituitary gland and infundibulum, 81, National Research Council, Washington, D.C., 1956. M.J., RUBINSTEIN, L.J., DACSO,M.R., and RIBNER,H. : Chromophobe adenoma 8. MADONICK, of pituitary gland with subarachnoid metastases. Neurology. 13 : 836-840, 1963. R.P. : Coexistance acromegaly, diabetes mellitus and diabetes inspidus, Ann. 9. NATELSON, Int. Med. 40: 788, 1954. 10. ROBBINS,S.L.: Pathology Basis of Disease, W.B. Saunders, Philadelphia, 1974, p. 1363. 11. ROBINSTEIN,L.J.: in Armed Forces Institute of Pathology. Atlas of tumor pathology, Fascicle 6: Tumor of the central nervous system, 314, National Research Council, Washington, D.C., 1972.
1002
MALIGNANT OHROMOPHOBE ADENOMA
Acta Path. Jup.
12. SOHNITKER, M.T.,CUTLER, E.C., BAILEY,O.T., and VAUQHAN,W.W.: The chromophobe adenomas of the pituitary. Pathologic features and response to irradiation based on a study of 81 verified caaes. Am. J. Roentgenol. 40: 645-659, 1938. 13. SUSMAN, W.: Embryonic epithelial rests in the pituitary. Brit. J. Surg. 19: 571-576, 1932. W.W.: The place of irradiation in acromegaly. Am. J. Roentgenol. 40: 660-668, 14. VAUQHAN, 1938.
MALIGNANT PITUITARY CHROMOPHOBE ADENOMA I N AN INFANT ACCOMPANYING DIABETES INSIPIDUS Chao Hui FANG(HAYASHI),Michiyasu AWAI, Hisasi NAKATUKA, Satimaru SENO, Yasuko YAMATOGI*, Hideo INOUE,and Syunsuke OHTAHARA* Department of Pathology and, *Pediatrics, Okayama University Medical School, Okayama (Received on April 1, 1978)
This report deals with a 1.5-year-old male infant terminating in viral pneumonia and “diabetes insipidus”. The autopsy revealed malignant pituitary chromophobe adenoma, invading the wall of the third ventricle, extending to the periventricular-, dorsomedial- and ventromedial area, skipping to the lateral area adjacent to the optic nerve, and permeating into the subarachnoid space of the cerebrum. At the onset of disease polydypsia and polyuria were marked followed by interstitial pneumonia with high fever, and later generalized tonic convulsion terminated in death. This case is peculiar in at least t w o respects. Firstly, this is the youngest reported case of malignant chromophobe adenoma. Secondly, the manifestation of diabetes insipidus is rare in chromophobe adenoma. The malignant adenoma probably occurred from the primitive gland rest of chromophobe cells in the posterior lobe becoming malignant during the course of growth development and destroyed the cells of the posterior lobe, resulting in diabetes insipidus. ACTA PATH. JAP. 2 8 : 995-1002, 1978.
Introduction Benign pituitary adenomas composed about 12 percent of 5,000 intracranimal tumors studied by KERNOHAN and SAYRE’. In their 600 cases of pituitary adenoma, 565 were so-called chromophobe adenomas and the remainder were eosinophilic adenomas. cOSTELL03 examined semi-serial sections of 1,000 “normal” pituitary glands and found “adenomas” in 225 cases. These adenomas were classified into the following cell types: 140 (52.8 percent) chromophobic; 20 (7.5 percent) eosinophilic; 72 (27.2 percent) basophilic; and 33 (12.5 percent) contained two or even three types of cells. Chromophobe adenoma commonly occurred between 30 to 60 years of age7. The youngest age reported were: 2 years3, 7 years’, and 18 years of agel4. The oldest was 85 years of age3. The average age of chromophobe adenoma incidence was 41.4 years in each sex, and the ratio of males-to-females was slightly higher in males7. The pituitary adenomas was usually accompanied with Gushing’s syndrome or a ~ r o m e g a l i a ~ , Malig~. nancy may arise in the anterior lobe occasionally, in the preexisting benign adenomas; however, this was very rare6. Furthermore, only one in 165 cases of pituitary adenoma indicated chromophobe adenoma associated diabetes insipidus2. ~
# S@,%#
a%, +%
A,
%B E%A, l4E 995
%T, #k
m%AHB
R%
996
MALIONANT CHROMOPHOBE ADENOMA
Acta Path. Jap.
Case Repmt Clinical Data
A 1.5-year-old Japanese male infant was first admitted to Okayama University Hospital on September 25, 1968, with the mother’s complaint of pollakisuria and polydypsia for two weeks durations. Word observation indicated that the “pollakisuria” was in fact polyuria. The mother also reported abnormal behavior, such as head banging and impulsiveness. The family history was not remarkable and was negative for both neurological and psychiatric diseases. The patient was the first-born and had a fullterm normal delivery. Physical examinations : The patient was a normally developed, well-nourished infant with a healthy appearence. The head was normal in size and shape; the neck was symmetrical without abnormal swelling. There was no sign of goiter or enlargement of the cervical lymph nodes. Laboratory exumination : Hematologic data showed hemoglobin, 11.4 gm ; red cell count, 55 x lo4; and white cell count, 13900/cmm with 32.8% neutrophils, 63.5% lymphocytes, 0.5% eosinophils, and 3.2% monocytes. Red cell and whte cell morphology on smear specimens was normal. Chemical analysis of serum revealed urea nitrogen, 9 mg/100 ml; potassium, 4.7 mEg/liter, sodium, 138.5 mEg/liter; and fasting glucose, 90 mg/100 ml. The glucose tolerance test was within normal limits. Water-uptake was 3,200 to 3,800 ml/day, and the total volume of urinary output was 2,200 to 3,200 ml/day. Urinalysis values indicated specific gravity, 1,002 to 1,003; no glucose; no protein; and the sediments showed no red cells nor white blood cells, and no casts. After 8-hour water deprivation, the urinary specific gravity rose t o 1,013 to 1,017. Pitressin test revealed a decrease urinary volume, while the specific gravity increased by 1,013, and the urinary sediments revealed no abnormality. An intravenous pyelographic study demonstrated that the kidneys were normal in shape and function. A lumbar puncture yielded a clear and colorless spinal fluid. The opening pressure was 350 mm/Hg, and after 4 ml of clear colorless fluid was removed, the closing pressure was 200 mm/Hg while crying. Examination of the spinal fluid showed no cells and was negative for the Nonne and Pandy tests. The ocular fundus was normal and the visual field could not be measured due to technical difficulties. On X-ray films of skull, the sella turcica was almost normal in shape and size, EEG showed low voltage dysrhythmia, however, no focal sign of abnormality was evident. Diabetes insipidus was suspected from the clinical impression, but this could not be verified from the data just described. Therefore, treatment included only sedatives for the nervousness, and the patient ws released from the hospital on October 25, 1968. Thereafter, he was under the care of the local doctor near his home. The second admission began on February 2, 1969, as an emergency patient in coma
28(6): 1978
(:.[I.
P . \ N I : el at
997
with clonic convulsions. Several days beforc the second admission our patient was exposed to a n incitlental with influenza. and from the evening of February 1, fever (39 C), cough and nasal dischargz mere reported. He was afebrile the next morning, hit interniitteiit tonic convulsions limited to the arms were noticed and he entered coma. On admission, the ntermittent convulsions changed to generalized clonic convulsion, that containued for 10 seconds to several minutes. The patient was in a comatose state with cyanotic lips, had dry, pale and cold skin, a feeble pulses and gasping inspiration, as in Cheyne-Stoke’s breathng. On opening the eyelids, the pupils deviated upward and showed a slow niiotic reaction to light, and anisocoria was rioted with the left pupil being larger. Xeurological ezamination : Abdoniinal wall reflex (-) ; cremasteric reflex
(-) ;
biceps reflex- rt. f , It. 4 4 ; triceps reflemt. ?J, It. TJ; P.T.R. -rt. f f . It. TJ, A.T.R. - rt. 4 , It. f , Kernig’s sign (-), and no nuchal rigidity. Spastic convulsions, mainly limited to the upper extremites continued for one to several minutes and recurred with 0.5 second intermittence, a t 6 p.m. on February 2 . Thereafter, the convulsions progressed to generalized clonic convulsion in all extremities. The patient died a t 7.30 a.m., February 4, 1969. Laboratory Jindings : Hematologic data hematocrit, 12.3%; red blood cell count,
575x 104/cmm; white blood cell count, 10,10O/cmm; urea nitrogen, 15.0 mg/100 ml; potasium 5.8 mEq/liter ; sodium 125.0 mEq/liter, and bolld sugar, 220 nig/dl after glucose injection. Lumbar puncture - cell number, 22/3 in high power field; Nonne (-); and Pandy (-). Examinations for vision and ocular fundus could not be performed for technical reasons. An electrocardiogram revealed a sinus irregular rhythm. EEG examination revealed a nonspecific abnormal wave in the hypothalamus; however, a specific recruiting rythym of 14c/s observed during tonic seizure status and niarked low voltage-waves were intermittingly seen. A special finding was that many anticonvulsants, such as Diazepari commonly effective in non-specific, prolonged seizure activities had no remarkable effect. Postmortem
Emmination
Mucroscopic Jiiadings : The pituitary gland was slightly enlarged and soft, somewhat like a cyst, and contained small amount of mucinous yellowish substance. The capsule was thin and not adhesive. No destruction was seen on the sella turcica. The sella turcica was not enlarged a t necropsy or in an earlier roentgenograph of the skull. Cerebrum and cerehelluin mere markedly edematous and congested, especially the cerebrum. Macroscopically, the basilar area mas somewhat cloudy but foci of carcinomatous invasion or metastasis were not obvious. Patent foramen ovale was seen in the heart. No evidence of thymus hypertrophy. Both lungs were markedly congested, with a pneumonia-like appearance. The spleen was strongly congested and revealed follicular atrophy. The other organs revealed no remarkable findings, except for congestion and edema.
Microscopic jindings : Hematoxylin-eosin stained tunlor sections revealed almost
MALIOKANT CHROMOPHOBE ADENOMA
Ackc Path. Jap.
28(6): 1978
C.H. FANG d
939
d
all areas of the pituitary gland being extensively invaded or compressed by cancer cells with papillary or sinusoidal arrangement (Figs. 1, 2). Tumor cells, however, did not infiltrate the sella turcica. The tumor cells were pleomorphic, mainly cuboidal, or polyhedral shaped, with some mitotic figures, and the cells with giant nuclei or multinucleated giant cells were occasionally detected (Fig. 2). The neoplastic cells were determined to be chromophobic cells in Trichrome stained sections (Fig. 3). I n some areas a small number of normal eosinophilic cells intermingled with the neoplastic cells. The chromophobic cells projected from the infundibular recess through the stalk, invaded the third ventricle, extending to the periventricular-, dorsomedial- and ventromedial areas, and also skipping to the lateral area around the bilateral optic nerves. In addition to these massive extensions, multiple vascular permeations were observed in the Virchow-Robin’s spaces of cerebrum and cerebellum (Fig. a), and the chromophobic cells were found disseminating the subarachnoid space; however, most cells seemed only attached to the surface of the pia mata without infiltration. This indicates that the cancer cells circulated in the intracranial spaces and circulating system. The invasion was massive and extensive, but morphologically no significant degeneration or destruction of nuclei was seen adjacent to the infiltrating foci. It appeared that the infiltrating foci were not sufficiently large to produce damage to adjacent nerve cells. The infiltrating foci are schematically represented in Fig. 5. Hematoxylin-eosin stained sections of the lungs revealed interstitial pneumonia. No particular changes were seen in the thyroid gland, thymus, pancreas, kidneys, adrenal glands, or other organs. The patient showed diabetes insipidus. The microscopic examination after necropsy revealed widely extended carcinomata originating from the pituitary gland, and proliferating cells were clearly chromophobic cells in trichrome stained tissue sections (Fig. 3). The tumor in the pituitary gland was made up mostly of chromophobic cells with a few eosinophilic cells, but basophilic cells were not evident. These eosinophilic cells were probably residue of normal component, because no eosinophilic cells were found in the infiltrating foci of either cerebrum or cerebellum. The criteria of malignancy is difficult to establish in chromophobe adenomas. BAILEY~ reported that the extension and invasion of neighboring structures are not indicative of malignancy and that “perhaps frequency of mitosis is the only reliable criterion”. KERNOHAN and SAYRE’agreed that the tumor size was not a good histologic indication of malignancy. JEFFERSON~ used the term “malignant adenoma” to ~
~~
~~
~
~~
~
~
~-
Fig. 1. Low magnification of malignant pituitary adenoma. The tumor is forming a sinusoidal or papillary arrangement with massive infiltration. There is some stroma but only few blood vessels are evident. H-E Stain x 100. Fig. 2. High magnification of malignant pituitary adenoma. The tumor cells are pleomorphic with nongranular cytoplasm, forming a sinusoidal arrangement. Arrow shows a multinucleated giant cell. H-E Stain x 400. Fig. 3. Invasive pattern in third ventricle. The tumor is composed of chromophobic cells, forming a sinusoidal or papillary arrangement and massively spreading into the periventricular area and compressing brain tissue. Trichrome Stain x 200. Fig. 4. Invasion into the Virchow-Robin’s space (W) and pevio-optic area (P). H-E Stain x 100.
1000
MALIQNANT OHROMOPHQBE ADENOMA
Acta Path. Jap.
Fig. 5. Infiltration of malignant pituitary adenoma. Dor. ; Dorsal area, DM; Dorsomedial nuclear region, I n t Cap; Internal capsule, Opt tr.; Optic tract, Para; Para ventricular nuclei, Perivent; Periventricular nuclei, Lat; Lateral area, VM; Ventromedial nuclei.
indicate a tumor that had burst through its capsule and widely expanded. However, et a1.12 he did not use the term malignancy with a histologic orientation. SCHNITKER encountered three malignant chromophobe adenomas in a series of 84 adenoma cases. These authors preferred the term “malignant adenoma” to “carcinoma of the pituitary gland”, however, others have used the term invasive adenoma as being more correct than the designation “carcinoma of the pituitaryll”. In our case, the cyto-histological characteristic of the tumor warrant a malignant diagnosis: pleomorphism, cells with giant and multinuclei, active mitosis, and tumor extending to neighboring tissues, multifocally permeating into Virchow-Robin’s spaces, disseminating to the subarachnoid space. A rare case of subarachnoid matastasis was also reported by MAUONICKet al.*. The onset symptoms included polydypsia and polyuria, and no Cushing’s syndrome or acromgalia. The polydypsia and polyuria were reacrive in the Pitressin test. Microscopically, the carcinomata massively invaded the pituitary gland with a few
28(6): 1978
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eosinophilic cells. And the tumor of the pituitary gland projected from the infundibular recess through the stalk and invaded into the hypothalamic periventricular-, dorsomedial areas and also into a part of the ventromedial area. This evidence suggests that symptoms of diabetes insipidus were produced by selective damage to the posterior lobe of the pituitary gland with a small normally functioning anterior lobe, and/or the hypothalamico-neurohypophysealtract. No infiltrations were found in the hunger and satiety centers. The implusive behavior, head banging, and EEG findings of recruiting rhythm (prolonged seizure activity) may have been induced by hypothalamic injury. No particular changes were found in the kidneys, pancreas, and adrenal glands. NATELSON~ reported a rare case of pituitary eosinophilic tumor associated with acromegaly, diabetes mellitus and diabetes insipidus. I n our case hyperglycemia (220 mg/dl) was found after glucose injection, but the glucose fasting test could not be conducted. The age incidence of the youngest patients with invasive chromophobe adenoma of the pituitary gland was two years3, seven years’, and 18 years14 of age. Our 1.5 year old patient is unusual in manifesting malignancy a t such an early age, and is the youngest reported case with this syndrome. S U S M A found N ~ ~ two case of primitive gland rest in the pars posterior in 71 cases of embryonic pituitary out of 230 autopsied cases. This evidence strongly suggests that the tumor probably occurred from the primitive glandular rest of chromophobe cells in the posterior lobe transforming to malignant cells during the course of growth development. References 1. BAILEY,O.T. and CUTLER,E.C.: Malignant carcinomas of the chromophobe cells of the pituitary body. Arch. Pathol. 29: 368-399, 1940. 2. BRONSON, S.R. and PATTERSON, H. JR. : Surgical experience with chromophobe adenomas of the pituitary gland. J. Neurosurg. 34: 726-729, 1971. R.T.: Subclinical adenoma of the pituitary gland. Am. J. Pathol. 12: 205-216, 3. COSTELLO, 1963. 4. CUSHING,H. : “Dyspituitarism” : Twenty years later, with special consideration of the pituitary adenomas. Arch. Interm. Med. 51 : 487-557, 1933. 5. CUSHINQ,H. and DAVIDOFF,L.M.: The Pathological Findings in Four Autopsied Cases of Acromegaly with a Discussion of Their Significance. Monograph 22. Rockefeller Institute for Medical Research, 1927. G.: Extracellar extensions of pituitary adenomas. Proc. Roy. SOC.Med. 33: 6. JEFFERSON, 433458, 1940. J.S. and SAYRE,G.P.: in Armed Forces Institute of Pathology. Atlas of Tumor7. KERNOHAN, pathology, Section X, Fascile 36: Tumor of the pituitary gland and infundibulum, 81, National Research Council, Washington, D.C., 1956. M.J., RUBINSTEIN, L.J., DACSO,M.R., and RIBNER,H. : Chromophobe adenoma 8. MADONICK, of pituitary gland with subarachnoid metastases. Neurology. 13 : 836-840, 1963. R.P. : Coexistance acromegaly, diabetes mellitus and diabetes inspidus, Ann. 9. NATELSON, Int. Med. 40: 788, 1954. 10. ROBBINS,S.L.: Pathology Basis of Disease, W.B. Saunders, Philadelphia, 1974, p. 1363. 11. ROBINSTEIN,L.J.: in Armed Forces Institute of Pathology. Atlas of tumor pathology, Fascicle 6: Tumor of the central nervous system, 314, National Research Council, Washington, D.C., 1972.
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12. SOHNITKER, M.T.,CUTLER, E.C., BAILEY,O.T., and VAUQHAN,W.W.: The chromophobe adenomas of the pituitary. Pathologic features and response to irradiation based on a study of 81 verified caaes. Am. J. Roentgenol. 40: 645-659, 1938. 13. SUSMAN, W.: Embryonic epithelial rests in the pituitary. Brit. J. Surg. 19: 571-576, 1932. W.W.: The place of irradiation in acromegaly. Am. J. Roentgenol. 40: 660-668, 14. VAUQHAN, 1938.
