Ectopic pinealoma: an unusual clinical presentation and ... · the ectopic pinealoma, a...

Journal of Neurology, Neurosurgery, and Psychiatry, 1973, 36, 864-873

Ectopic pinealoma: an unusual clinical presentationand a histochemical comparison with a

seminoma of the testisJ. M. BEELEY, J. J. DALY, W. R. TIMPERLEY, AND J. WARNER

From the Departments of Medicine and Neuropathology, The United Sheffield Hospitals, Sheffield

SUMMARY A patient with ectopic pinealoma first presented with apparent anorexia nervosa andhypernatraemic coma. A history of diabetes insipidus two months previously was not known onadmission to hospital. The diabetes insipidus was unmasked by the administration of steroids.Neuroendocrinal and neuropathological aspects of the case are discussed with reference to themarch of symptoms due to the growth of the tumour. Histochemical evidence is presented supportingthe similarity between ectopic pinealoma and seminoma which suggests that they may more properlybe referred to as atypical teratomas.

The first case of ectopic pinealoma was describedby Stark in 1928; the patient exhibited diabetesinsipidus, visual disturbance, and anteriorpituitary insufficiency, which have since becomerecognized as a typical neuroendocrine triadassociated with such a tumour. The initialsymptom is usually diabetes insipidus and of thecases reviewed by Rubin and Kramer (1965) andin subsequent case reports (Beaufils, Chapman,and Nedey, 1968; Ghatak, Hirano, and Zimmer-man, 1969; Vejjajiva and Sitprija, 1969; Schrub,Dubnisson, Hellemand, and Leroy, 1970;Kageyama, 1971; Sohn and Pittman, 1971)overt diabetes insipidus was present in 37 of the41 patients described. Vejjajiva and Sitprija(1969) were the first to describe ectopic pineal-oma with hypernatraemia in the absence ofdiabetes insipidus. Other uncommon featuresdescribed as a result of hypothalamic involve-ment are disturbance of temperature regulation,hyperphagia, and anorexia.

This paper describes a patient with a diagnosisof anorexia nervosa who presented in hyper-natraemic coma and in whom diabetes insipiduswas unmasked by administration of steroids. Atnecropsy she was shown to have an ectopicpinealoma.The derivation of such tumours has aroused

considerable interest. They have been thought by

various authors to be closely related to theseminoma of the testis and to dysgerminoma ofthe ovary. Hence, they have been called ger-minomas and atypical teratomas. In view of thefact that a fresh specimen of tumour becameavailable from a second case, it was felt that, bycomparing a variety of histochemical stains onthe ectopic pinealoma, a seminoma of the testis,and the normal pineal gland, some evidencemight be found to support either a pineal orgerminomatous origin for this tumour.

CASE REPORT

In September 1971 a 22 year old single girl, whoworked as a children's nanny, was admitted tohospital semi-comatose. The history available onadmission was that in her early teens when 168 cm(5 ft 6 in.) tall and only 50 4 kg (8 st) in weight, sheconsidered herself overweight and went on a strictdiet. Menarche occurred normally at 14 years of agebut menses ceased in August 1970. In September1971 she became severely anorectic with resultingweight loss after she learned that her father had aninoperable carcinoma of the bronchus (Fig. 1). Adiagnosis of anorexia nervosa was made at psychi-atric consultation and treatment with tranquillizersand cyproheptadine resulted in improved appetiteand slight weight gain. For one week before admis-sion she complained of headaches and dizziness, andprogressively became drowsy.

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Ectopic piliealoina

FIG. 2. Radiograph of the chest showing soft patchyopacities at the apex of the right lung.

i ^^;Z g FIG. 1. Photograph of the patientshowing the severe state ofanorexia.

....^....

EXAMINATION On admission she was semiconscious,emaciated, dehydrated, and pyrexial (380 C). Thepulse rate was 100/minute and the blood pressure95/60 mmHg. Her skin was pale and waxy; pubicand axillary hair was scanty. There was slight neckstiffness but no localizing neurological signs.

INVESTIGATIONS Preliminary investigations revealedanaemia, hypernatraemic dehydration, an apparentlymphocytosis in the cerebrospinal fluid (CSF) andsoft patchy opacities at the apex of the right lung onthe radiograph of the chest (Fig. 2).

PRELIMINARY LABORATORY RESULTS Initial investiga-tion showed: haemoglobin, 72% (iron deficient onfilm); leucocyte count, 10,000/cmm (normal differen-tial); platelets 70,000/cmm; ESR 90 mm/hr (Wester-gren); serum sodium 185 mEq/l.; serum potassium3-1 mEq/l.; serum bicarbonate 27 mEq/l.; bloodurea 66 mg/100 ml., and blood sugar 65 mg/100 ml

Examination of a mid-stream specimen of urineshowed a specific gravity of 1-010, a trace of albu-min, no sugar, a positive test for ketones and noorganisms. At lumbar puncture the cerebrospinal

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J. M. Beeley, J. J. Daly, W. R. Timperley, and J. Warner

*.k-HYDRCORTISONE .

IKTRESSINTHYROXINE M

FIG. 3. Variation of serum

sodium in relationship totreatment given.

7 8 9DAYS AFTER ADMISSION

380

360

E 340

E 3200

E

' 300

280

* * HYDROCORTISONE .| PITRESSIN 1

THYROXINE

0 1 2 3 4 5 6 7 8 9 101 20DAYS AFTER ADMISSION

fluid showed a pressure of 150 mm water, white cellcount 38/cmm (9500 lymphocytes, 50 polymorphs),red cell count 7/cmm, protein 70 mg/100 ml., sugar55 mg/100 ml., and a negative Lange curve. Stainsfor bacteria including acid-fast bacilli were negative.

In view of the hypernatraemia, an intravenousinfusion of 500 dextrose was immediately started andintravenous hydrocortisone was given as supportivetherapy. Opacities in a radiograph of chest and thecells in the CSF suggested a diagnosis of tubercu-losis and, therefore, streptomycin, isoniazid, andrifampicin were administered whilst further investiga-.tions were in progress. On this therapy, includingcontinued hydrocortisone 100 mg daily, there was

FIG. 4. Variation in serum

osmolality in relationiship totreatment giveni.

only a marginal improvement in the electrolyte andclinical state. Though the volume of intravenousfluid was progressively increased to 6 1./day, theurine output persistently outstripped input.

It now became clear that she had developeddiabetes insipidus and her clinical and biochemicalstate began to improve only when subcutaneouspitressin was administered.

Further investigations revealed reduced gonado-trophin production and thyroid hypofunction.Radiographs of the skull showed a normal pituitaryfossa; echogram showed a central 8 mm thirdventricle; electroencephalography (EEG) showedwidespread generalized slow wave activity and a

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Ectopic pinealoma

HYDROCORTISNE ..v._-v--....

FIG. 5. Variation in urineoutput in relationship totreatment giveni.

DAYS AFTER ADMISSION

.HYDROCORTISONE*.:r .::*.*.-..*O| PITRESSIN

THYROXINE1

0123 4 5 6 7 8 9 ~~~~~10/1-2

FIG. 6. Variation in urineosmolalit.y in relationship totreatment given.

DAYS AFTER ADMISSION

gammascan showed a high suprasellar uptake ofisotope.

Other investigations at this stage showed a bloodcholesterol of 125 mg/100 ml.; protein-bound iodine2 7 ,ug/100 ml.; and the T3 resin uptake test 21.4%.Examination of the urine showed an excretion of11 -8 mg of total oestrogens per 24 hours (l7-7 mg=100%); 2-0 i.u. of follicular stimulating hormone per24 hours and less than 10 i.u. of luteinizing hormoneper 24 hours.

Within one week of admission the chest radio-graph became clear and therefore antituberculous*therapy was withdrawn. By this time she was fully-conscious and able to give a history of one month's

transient polydypsia and of polyuria two monthsbefore admission.

Steroids were now withdrawn and a short synac-then test revealed a low resting cortisol level with anormal response. The resting cortisol level at 9.00a.m. was 53 ,ug/100 ml. After 1 mg synacthen sub-cutaneously the cortisol level was 20 ,ug/100 ml.after 45 minutes and 23-2 ,ug/100 ml. after 60minutes.

Steroids were then reintroduced and pitressin waswithdrawn for a trial period during which time shedeveloped a high urinary output with resultinghypernatraemia and dehydration. Despite highserum osmolalities she did not become thirsty at any

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J. M. Beeley, J. J. Daly, W. R. Timperley, and J. Wariner

FIG. 7. Sagittal section of brain showing the tutmour in the hypothalamus.

FIG. 8. Section of tumour showing two main cell types. Haematoxylin andeosin stain. x 535.

stage. Pitressin was therefore recommenced andfluid balance was restored.

Subsequently, steroids were again withdrawn andshe became oliguric (700 ml. urine/day) with a highurinary osmolality 80 (mosm/l.) and low serumosmolality (257 mosm/l.).

Figures 3 to 6 show the variations in serum sodium

and osmolality and urine output and osmolalityrespectively in relationship to the treatment given.At this stage a diagnosis of hypothalamic tumour

was assumed and full replacement therapy withsteroids, pitressin, and thyroxin was commenced.For a short period her general condition remainedsatisfactory with reasonable control of fluid and

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electrolyte balance, though she was persistentlyhypothermic and her optic discs appeared pro-gressively paler.

Before any definitive treatment could be con-

sidered, she lapsed into coma without disturbance offluid balance and developed extensor spasms of thearms and flexor spasms of the legs. She died withoutregaining consciousness.

POST MORTEM EXAMINATION The body was that ofan emaciated girl aged 22 years. The relevant grossfindings were confined to the brain where there wasa partially cystic greyish mass of tumour in thehypothalamus extending from the mamillarybodies posteriorly to the optic chiasma anteriorly. Itinvolved the lamina terminalis and the anterior andmedial thalamus (Fig. 7). The lungs showed broncho-pneumonia.

Histologically, the tumour was composed of twocell types, one cell being small and round and verysimilar to a lymphocyte; the other type was con-siderably larger, with round nuclei and prominantnucleoli (Fig. 8). Mitotic figures were easily found.The cysts noted macroscopically were full of paleeosinophilic colloid. No other tissue componentswere seen in sections taken at multiple levels. Thetumour 'appeared to be actively infiltrating thecerebral tissues at its edges and there was a mildgliotic reaction around it. The picture was that of an'ectopic pinealoma' (germinoma or atypical tera-toma).

CASE 2

A fresh sample of tumour was provided from anecropsy on a woman aged 19 years with an ectopicpinealoma by Dr. P. G. Lynch, Department ofNeuropathology, Manchester University. Histo-logically the tumour showed features similar to theprevious case.

METHODS

A sample of fresh testicular seminoma was obtainedfrom a surgical specimen. Three normal adult pinealglands were obtained from necropsies performedwithin 12 hours of death. Blocks from all threetissues were frozen onto chucks with liquid nitrogenand cryostat sections were cut at 10 [L. The followinghistochemical staining reactions were performed:

DEHYDROGENASES The technique was that of Pearse(1960) using the following substrates: sodium L-

glutamate, sodium DL-/3-hydroxybutyrate, glucose-6-phosphate disodium salt, 6-phosphogluconic acidbarium salt, sodium DL-ce-glycerophosphate, sodiumDL-isocitrate, sodium lactate, sodium succinate, and

sodium malate. A fresh solution of 01 M triphos-phopyridine nucleotide was used for the pentose-shunt enzymes, no coenzyme was used for succinicdehydrogenase, and 0 1M diphosphopyridinenucleotide was used for the rest. Sodium cyanide(0IM) was used as a respiratory inhibitor for allenzymes except the pentose-shunt enzymes where01 M sodium azide was used instead.

Sections were incubated for 45 minutes at 370 C.

DIAPHORASES Sections were incubated in a mediumcontaining 0dIM reduced diphosphopyridinenucleotide (DPNH) or reduced triphosphopyridinenucleotide (TPNH) and nitroblue-tetrazolium at pH7 4 for 45 minutes.

CYTOCHROME OXIDASE The method of Burstone(1960) using p-aminodiphenylamine and 3-amino-9-ethylcarbazole was used. Sections were incubatedfor one hour before chelation in cobaltous acetate.

ALKALINE PHOSPHATASE A naphthol AS-TR phos-phate method was used (Burstone, 1958). The pH ofthe incubating medium was 8 9 and Red Violet L-Bsalt was used as coupling agent.

ACID PHOSPHATASE A similar method to that usedfor alkaline phosphatase was used except that the pHof the incubating medium was 5 2.

NON-SPECIFIC ESTERASE The method was based onGomori's modification of the technique of Nachlasand Seligman (1949) using a-naphthyl acetate as sub-strate, and Fast Blue BB salt as coupling agent.

TABLEENZYMES FOUND IN DIFFERENT TISSUES EXAMINED

Enzyme Pinealomna Seminomna Pineal gland

Large Small Large Small Pineo- Gliacells cells cells cells cytes

Dehydrogenases6-phospho-gluconic acid + + + + + +G-6-Phosphate + + + + + +a-glycerophosphate + + + + + +Lactic acid + + + + + +Isocitric acid + + + + + +Succinic acid + + + + + +Malic acid + + + + + +Glutamic acid + + + + + +,3-Hydroxy-butyric acid + + + + + +

DPNH diaphorase + + + + + +TPNH diaphorase + + + + + +Cytochrome oxidase + + + + + +Acid phosphatase + + + + + +Esterase + + + + + +Leucine amino-peptidase 0 0 0 0 0 0Alkaline phosphatase + - + - - -

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870 J. M. Beeley, J. J. Daly, W. R. Timperley, and J. Warner

FIG. 9. Non-specific esterase stain on pinealoma showing strong activity in large cellsand weak activity in small lymphocyte-like cells. x 540.

FIG. 10. Non-specific esterase stain on seminoma showing strong staining of largecells and weak staining of lymphocytes. x 540.

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Ectopic pinealoma

FIG. 11. Alkaline phosphatase stain on pinealoma showing strong staining of largecells and negative reaction in small cells. x 800.

lo.?v .r .-'i;. ,v x.t> 9tr JR*

If'

FIG. 12. Alkaline phosphatase stain on seminoma showing strong reaction in largecells and negative reaction in lymphocytes. x 540.

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J. M. Beeley, J. J. Daly, W. R. Timperley, and J. Warner

LEUCINE AMINOPEPTIDASE The method was that ofBurstone and Folk (1956) using L-leucyl-/-naph-thylamide as substrate. Sections were incubated forone hour at pH 7-1.

RESULTS

The Table shows the enzymes found in thevarious cell types. All enzymes investigated, withthe exception of leucine aminopeptidase andalkaline phosphatase, were present in all celltypes. The large cells of both the pinealoma andseminoma and the pineocytes showed strongeractivity than the small round cells and glia(Figs 9 and 10). No cells showed leucine amino-peptidase activity.The most striking and significant feature was

the presence of strong alkaline phosphataseactivity in the large cells of both the pinealomaand the seminoma (Figs 11 and 12). No activitywas seen in pineocytes.

DISCUSSION

There has been a considerable amount of contro-versy as to the nature of the 'ectopic pinealoma'.They have been thought by some (Russell, 1954,L0ken, 1957, Simson, Lampe, and Abell, 1968)to be closely related to the germinomas of thepineal gland, the seminoma of the testis, and thedysgerminoma of the ovary.

In an electron microscopical study Ramsey(1965) stated that this type of tumour shows nostriking resemblance to epithelial cells, ependy-mal cells, or parenchymal cells of the pinealgland. Brihaye and Parmentier (1955) also feltthat the lack of affinity for silver of the large cellswas against their being derived from pinealparenchymal cells. We are unaware of any pre-vious histochemical comparison between thistype of tumour and a seminoma of the testis.The histochemical finding of a virtually

identical pattern in the ectopic pinealoma andthe seminoma provides some further evidencethat these two tumours are, in fact, closelyrelated and that the term atypical teratoma isprobably more appropriate than ectopic pineal-oma. The most striking feature was the presenceof strong alkaline phosphatase activity in thelarge cells of both tumour types. This enzymewas not seem in pineocytes of the normal pinealgland. The similarities between the otherenzymes studied could occur by chance as they

are nearly all possessed to a certain degree bymost cell types. Large cells would probably beexpected to show a higher activity in view of thegreater amount of cytoplasm. Alkaline phospha-tase, however, is an uncommon enzyme and isrelated in most cases to specific function, usuallyto the transport of substances across membranes-that is, in capillaries, choroid plexus, arachnoidgranulations, biliary epithelium, small intestinalepithelium, and the proximal renal convolutedtubule. It is unlikely that the finding of itsactivity in two histologically similar cells wouldbe found by chance alone, certainly in view ofthe fact that no similar cell is seen in the normalpineal gland.On the clinical side the first case showed

several features of additional interest. It pre-sented with a symptom complex which wasconfidently diagnosed and successfully treatedas anorexia nervosa. The patient was a youngfemale with a higher than average IQ who hadbecome involved in the pursuit of thinness(Bruch, 1965; British Medical Journal, 1969).While Lewin, Mattingly, and Millis (1972) havedescribed a case of anorexia nervosa due to awell differentiated astrocytoma, they were unableto explain the anorexia on anatomical grounds,as the tumour, unlike our case of ectopic pineal-oma, was not involving the lateral hypothalamuswhere animal experiments have located thefeeding centre (Anand and Brobeck, 1951).The subsequent hospital presentation of our

case in hypernatraemic coma raised variouspossibilities; these included hyperosmolar dia-betic coma, diabetes insipidus, nephrogenicdiabetes insipidus, intracranial disease, saltpoisoning, or gastrointestinal fluid loss. Theabsence of any recent polyuria or polydypsiaseemed to exclude a diagnosis of diabetesinsipidus and other possibilities were not sub-stantiated. It would seem likely that the hyper-natraemic dehydration was explained by thedevelopment of hypodypsia due to destructionof the thirst centre in the anterior hypothalamus.This is a rare occurrence that has previouslybeen described as occurring after subarachnoidhaemorrhage (Jenkins, 1972).The supportive administration of steroids

when our patient was comatose resulted in grosspolyuria due to unmasking of diabetes insipidus.It is known that cortisol is necessary for the

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excretion of a water load and that integrity ofadenophyseal function is necessary for thepolyuria of diabetes insipidus. In our case, theanterior pituitary gland was shown to be histo-logically normal and we believe that its functionwas impaired as a result of destruction of themedian eminence of the hypothalamus wherereleasing hormones, including corticotrophinreleasing factor, are produced. As the posteriorpituitary gland was also intact, the diabetesinsipidus was presumably due to damage occur-ring at some level up to, or including, the supra-optic nucleus. It is not unusual to encountertransient symptoms of diabetes insipidus, as inour patient, when posterior pituitary function isfirst lost and cortisol production is subsequentlyimpaired. Furthermore, corticosteroid adminis-tration in this situation will unmask diabetesinsipidus (Kageyama, 1971).

There are a few reports of successful treatmentof ectopic pinealoma by radiotherapy (Horraxand Wyatt, 1947; Troland and Brown, 1948;Rubin and Kramer, 1965; Kageyama, 1971). Itis important, therefore, to recognize the possi-bility of ectopic pinealoma presenting in themanner of our patient.

We would like to thank the Departmentof Medical Illustration at the United SheffieldHospitals for preparing the graphs and Mr. K.Horton, chief technician in the Department ofNeuropathology for his technical help.

REFERENCES

Anand, B. K., and Brobeck, J. R. (1951). Localization of'feeding center' in hypothalamus of rat. Proceedings of theSociety for Experimental Biology and Medicine, 77, 323-324.

Beaufils, F., Chapman, A., and Nedey, R. (1968). Un cas depinealome ectopique. Anesthesie, Analgesie, Reanimation,25, 429-439.

Brihaye, J., and Parmentier, R. (1955). Pinealome ectopiquedans la region chiasmatique. Semaine des Hopitaux,Archives d'Anatomie Pathologique, 31, A.170-A. 174.

Bruch, H. (1965). Anorexia nervosa and its differentialdiagnosis. Journal of Nervous and Mental Disease, 141,555-566.

Burstone, M. S. (1958). Histochemical comparison ofnaphthol AS-phosphates for the demonstration ofphosphatases. Jouirnal of the National Cancer Institute, 20,601-615.

Burstone, M. S. (1960). Histochemical demonstration ofcytochrome oxidase with new amine reagents. Journal ofHistochemistrv and Cytochemistry, 8, 63-70.

Burstone, M. S., and Folk, J. E. (1956). Histochemicaldemonstration of aminopeptidase. Journal of Histo-chemistry and Cytochemistry, 4, 217-226.

Ghatak, N. R., Hirano, A., and Zimmerman, H. M. (1969).Intrasellar germinomas: A form of ectopic pinealoma.Journal of Neurosurgery, 31, 670-675.

Horrax, G., and Wyatt, J. P. (1947). Ectopic pinealomas inthe chiasmal region: report of three cases. Journal ofNeurosurgery, 4, 309-326.

Jenkins, J. S. (1972). The hypothalamus. British MedicalJournal, 2, 99-102.

Kageyama, N. (1971). Ectopic pinealoma in the region of theoptic chiasm. Report of five cases. Journal ofNeurosuirgery,35, 755-759.

British Medical Jouirnal (1969). Anorexia nervosa (leadingarticle). British Medical Jouirnal, 1, 529-530.

Lewin, K., Mattingly, D., and Millis, R. R. (1972). Anorexianervosa associated with hypothalamic tumour. BritishMedical Journal, 2, 629-630.

Loken, A. C. (1957). On the relation of atypical pinealomasto teratoid tumours. Acta Pathologica et MicrobiologicaScandinavica, 40, 417-424.

Nachlas, M. M., and Seligman, A. M. (1949). The histo-chemical demonstration of esterase. Journial of the NationalCancer Institute, 9, 415-425.

Pearse, A. G. E. (1960). Histochemistry: Theoretical andApplied. 2nd edn. Churchill: London.

Ramsey, H. J. (1965). Ultrastructure of a pineal tumour.Cancer, 18, 1014-1025.

Rubin, P., and Kramer, S. (1965). Ectopic pinealoma: aradiocurable neuroendocrinologic entity. Radiology, 85,512-523.

Russell, D. S. (1954). 'Ectopic pinealoma': its kinship toatypical teratoma of the pineal gland. Report of case.Journal ofPathology and Bacteriology, 68, 125-129.

Schrub, J.-CI., Dubnisson, M., Hellemand, B., and Leroy,J.-C1. (1970). L'hypernatremie neurogene. Semaine desHdpitautx de Paris, 46, 2084-2089.

Simson, L. R., Lampe, I., and Abell, M. R. (1968). Supra-sellar germinomas. Cancer, 22, 533-544.

Sohn, A. P., and Pittman, J. G. (1971). Multiple hypo-thalamic disorders produced by a suprasellar germinoma.Rocky Mountain Medical Journal, 68, 23-27.

Stark, H. (1928). Tumor der glandula pinealis und desHypophysisgebietes. Zentralblau fifr die gesamte Neuro-logie und Psychiatrie, 48, 72-73.

Troland, C. E., and Brown, C. A. (1948). Precocious pubertyof intracranial origin. Journal of Neurosurgery, 5, 541-555.

Vejjajiva, A., and Sitprija, V. (1969). Chronic sustainedhypernatremia and hypovolemia in hypothalamic tumour.A physiologic study. Neurology (Minneap.), 19, 161-166.

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