hypothalamic and pancreatic lesions with diabetes mellitus

Journal of Neurology, Neurosurgery, and Psychiatry, 1975, 38, 1003-1007

Hypothalamic and pancreatic lesions withdiabetes mellitus

SAMRUAY SHUANGSHOTI' AND PRASERT SAMRANVEJ

From the Department ofPathology, Faculty of Medicine,Chulalongkorn University, Bangkok, Thailand

SYNOPSIS A case is reported of a neoplasm of mixed mesenchymal and neuroepithelial originconsisting of plasmacytoma, lymphoma, ganglioneuroma, and astrocytoma in the same mass. Thetumour arose in the hypothalamus of a 43 year old diabetic woman who also had alpha cell hyper-plasia and beta cell hypoplasia of the islets of Langerhans. It is suggested that both hypothalamicand pancreatic lesions produced diabetes mellitus in this patient.

The manifestations of destruction of the hypo-thalamus have been frequently investigated inanimals but the opportunity to study humanlesions is rare. In this communication wedescribe a case of a hypothalamic neoplasm ofmixed mesenchymal and neuroepithelial originwith cellular abnormalities of the islets ofLangerhans. The lesions are considered to be thecause of disturbances of the carbohydratemetabolism in this instance. To our knowledge,no previous example has been recorded of com-bined hypothalamic and pancreatic lesionsassociated with diabetes mellitus.

CASE REPORT

Two years before admission to hospital, thismarried woman, aged 43 years, first experiencedhyperphagia and polyuria. The progressive symptomswere severe during the period of two months beforeadmission. One month before admission she hadintermittent diffuse headache, pitting oedema of thelower limbs, anorexia, nausea, vomiting, mental con-fusion, and transient loss of consciousness. Thesesymptoms were relieved occasionally by medicaltreatment. On the day of admission, she sufferedrespiratory difficulty and hyperpyrexia. There was nohistory of diabetes mellitus in her family. Thepatient had had 11 pregnancies, which included one

1 Address for reprints: Dr Samruay Shuangshoti, Department ofPathology, Faculty of Medicine, Chulalongkorn University, Bangkok5, Thailand.(Accepted 29 April 1975.)

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abortion, two episodes of intrauterine fetal deathone neonatal death, and seven living children.

In hospital, the range of the vital signs was re-corded as follows: body temperature, 37.5 to 39.5°C;pulse rate, 70 to 130/min; respiratory rate, 20 to40/min; and blood pressure, 60/20 to 130/70 mmHg.The obese and comatose patient responded only topainful stimulation. The pupil, which was 4 mm indiameter, was reactive to light. The eye-groundcould not be examined because of cataract. Thetendon reflexes were absent.

Routine laboratory investigations showed ahaemoglobin concentration of 90 g/l and a leuco-cyte count of 16.45 x 109/l with 64% of neutrophilsand 36% of lymphocytes. Urinalysis revealed 'oneplus' of sugar, a trace of protein, and a few granularcasts/high power microscope field. The daily volumeof urine ranged from 150 to 1 200 ml. Blood chemicalstudies showed the following values: blood ureanitrogen 8.8-11.0 nmol/l (53-66 mg/dl); creatinine36.24-53.4 tmol/l (4.1-6.6 mg/dl); fasting glucose22.5 mmol/l (405 mg/dl); sodium 150-160 mmol/l(normal, 135-145 mmol/1); chloride 114-130 mmol/l.and potassium 2.0-3.8 mmol/l. Blood pH was 7.12.The pressure of the clear and colourless cerebro-spinal fluid in a lumbar puncture was 170 mm CSF.The fluid contained 57 lymphocytes/mm3, and 1.37g/l of protein.The clinical impression was diabetic acidosis with

coma. The supportive treatment included intra-venous administration of insulin and normal salinesolution. Body temperature and blood pressurefluctuated, suggesting that the patient also hadseptic shock. Corticosteroid and antibiotics were

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_..... : ('t[> . S .. '.'FIG. 1 A. Coronal section of the brain showing tumour (arrow) occupying the hypothalamus. B. Many plasmacells and lymphocytes are clustered around a small blood vessel. H and E, x 330. C. Numerous reticulin fibresare scattered in the area ofplasma cells and lymphocytes. Wilder's stain, x 80. D. A few abnormal neurones inthe tumour are illustrated. Note nuclei with prominent nucleoli, and Nissl's bodies in the cytoplasm. Cresylviolet stain, x 330. E. An abnormal ganglion cell with eccentric nucleus having a prominent centrally locatednucleolus and abundant coarse cytoplasmic granules of the tigroid substance is further demonstrated. Cresylviolet stain, x 800.

then given. The patient died five days after admissionto hospital.

NECROPSY Tissue (A-8170) fixed in 10% formalinwas embedded in paraffin, and the section was stainedroutinely with haematoxylin and eosin (H and E).Special stains were used as needed and includedcresyl violet for Nissl's bodies, Wilder's reticulinstains, Mallory's phosphotungstic acid haematoxylin(PTAH), and Gomori's chromium haematoxylinphloxine.The congested and oedematous brain, weighing

1 150 g, showed cerebellar tonsilar herniation. Thehypothalamic region contained a rounded, grey

rubbery mass, 2.0 cm in diameter (Fig. lA). The

anterior aspect of the mass lay just behind the opticchiasm. Laterally, it was bordered by the optictracts. Its caudal part partially filled the inter-peduncular fossa. The dorsal portion of the massprotruded minimally into the bottom of the thirdventricle. Its anteroventral aspect was in continuitywith the hypophyseal stalk. The mammillary bodieswere not seen, and presumably were included withinthe mass. It was not possible to identify the precisenuclei which were involved by the lesion because theentire hypothalamus was occupied by the mass.

Microscopically, the mass was composed ofmultiple types of cells (Figs 1 and 2). Rounded cellswith abundant violet or lavender perikaryon andeccentric nuclei having radially arranged granules of

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FIG. 3 An islet ofLangerhans demonstrating many alpha cells having coarse acido-philic cytoplasmic granules. The latter are purple in Gomori's chromium haematoxylinphloxine stain. H and E, x 280.

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Samruay Shuangshoti and Prasert Samranvej

chromatin were interpreted as plasma cells (Fig. 1B).Small and rounded cells containing scant cytoplasmand hyperchromatic nuclei were considered to belymphocytes (Fig. 1B). These plasma cells andlymphocytes were often clustered perivascularly, andthere were numerous reticulin fibres among them(Fig. 1C). Some large bizarre cells with Nissl'sbodies within the cytoplasm and nuclei with promi-nent nucleoli were regarded as neurones (Fig. ID andE). There were still many large cells with angular out-lines, abundant homogeneous cytoplasm, and eccen-tric vesicular nuclei (Fig. 2). Occasional coarseprocesses extended from the angular margin(Fig. 2B). They were interpreted as astrocytes.Reticulin fibres were absent or scantily presentaround some blood vessels in the zones of neuronaland astrocytic accumulation. Many blood vessels inthe lesion had thick and hyalinized walls. Thepituitary gland was normal.The pancreas which weighed 70 g had the usual

number of islets of Langerhans, but individual isletsshowed an increase in number of cells containingnumerous cytoplasmic granules which were eosino-philic in H and E preparations (Fig. 3), and purple inGomori's chromium haematoxylin phloxine stains.These were regarded as alpha cells. Pale blue cells inGomori's chromium haematoxylin phloxine stains,considered to be beta cells, were diminished innumber.

Other postmortem findings included hepatic fattymetamorphosis, arteriolar nephrosclerosis and acutetubular necrosis, and pulmonary oedema.The hypothalamic mass was diagnosed as a neo-

plasm of mixed mesenchymal and neuroepithelialorigin (combined plasmacytoma, lymphoma, ganglio-neuroma, and astrocytoma), and the islets ofLangerhans were considered to show hyperplasia ofalpha cells and hypoplasia of beta cells.

DISCUSSION

Primary intracranial plasmacytoma, lymphoma,and ganglioneuroma or ganglioglioma werereported in the medical literature (Courville,1930; Courville and Anderson, 1941; French,1947; Russell and Rubinstein, 1962; Moossy andWilson, 1967; Jakumeit et al., 1974), and somearose in the hypothalamus (French, 1947). Inour case, a unitary diagnosis cannot be offeredbecause of diversity of the cellular constituentsof the tumour. We consider the diagnosis of aneoplasm of mixed mesenchymal and neuro-epithelial origin to be most appropriate, becausethe term covers all types of cells in the lesion.

This category of combined tumours forms 1.6%of 1 028 intracranial neoplasms of our reportedseries (Shuangshoti and Panyathanya, 1974). Wehave described previously two cases of mixedneoplasm containing lymphomas, and discussedthe mode of their occurrence (Shuangshoti andNetsky, 1971a, b).Teratoma must be differentiated from the

present hypothalamic tumour because of itslocation in the midline and multiplicity ofcellular components. No elements in the mass areforeign to the brain; hence, it is not a teratoma(Willis, 1951). We regard the plasma cells andlymphocytes to be within the line of microglia.Primary neuraxial plasmacytoma and lymphomacan be recognized as variants of microglioma.

Hypothalamic lesions may produce diversifiedsymptoms and signs such as hyperphagia,diabetes mellitus, disturbances in regulation ofthe body temperature and sleep pattern, diabetesinsipidus, episodic savage behaviour, hypo-gonadism, hypothyroidism, and hypoadrenalism.These manifestations may occur singly or in acombination. Reeves and Plum (1969) reported a20 year old woman with a hamartoma at the baseof the diencephalon which destroyed the ventro-medial hypothalamus bilaterally as well as themedian eminence. The patient had hyperphagia,obesity, and a lower threshold for aggressivebehaviour. A five year old girl described byKilleffer and Stern (1970) had severe damage ofthe anterior and middle portions of the hypo-thalamus with partial preservation of the morecaudal part after removal of a craniopharyn-gioma. The child, during a period of survival ofsix years, suffered deficiency in the regulation ofthe body fluid, episodic savage behaviour, hyper-phagia, irregular sleep pattern, and inconstantbody temperature. According to Ranson andClark (1959), bilateral lesions of the caudal partof the lateral hypothalamic region producesomnolence, and inconstant body temperaturewhich varies with the environmental temperature.A lesion of the anterior hypothalamic region, onthe other hand, may result in hyperthermia.Destruction of the supraoptic nuclei is followedby the occurrence of diabetes insipidus.We are unable to locate definitely the area of

damage in our patient because of the extensiveinvolvement of the entire hypothalamus by thetumour. However, we suggest that the lesion has

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induced hyperphagia. The hyperplasia of thealpha cells and hypoplasia of the beta cells of theislets of Langerhans, and hyperphagia producedthe diabetes mellitus. Excessive accumulation ofadipose tissue in association with hyperphagiarequires increased amounts of insulin which leadsto deficiency of this hormone and consequenthyperglycaemia (Hausberger et al., 1964). Inaddition, the alpha cells produce glucagon, thehyperglycaemic-glycogenolytic hormone whichantagonizes the effects of insulin. McGavran etal. (1966) reported a diabetic patient with alphacell carcinoma of the islets of Langerhans andhepatic metastasis. The primary cancer con-tained large amounts of glucagon. Experi-mentally, certain toxic substances such as alloxandestroy the beta cells of the islets of Langerhansand leave the alpha cells intact; diabetes mellitusdevelops in such conditions (Bailey and Bailey,1943).Although Vejjajiva et al. (1969) reported a

non-diabetic patient with chronic sustainedhypernatraemia, presumably induced by a hypo-thalamic pinealoma, we are unable to concludethat the hypernatraemia of our patient wascaused solely by the hypothalamic mixed tumour.A lengthy study of her electrolytes was lacking toindicate that the hypernatraemia was chronic.Moreover, an increased serum sodium mayresult if patients with diabetic coma are treatedmainly with insulin and saline solution (School-man et al., 1955).

We are grateful to Dr Somsak Dhechakaisaya, Professorand Head of the Department of Pathology, who gave uspermission to report this case.

REFERENCES

Bailey, C. C., and Bailey, 0. T. (1943). The production ofdiabetes mellitus in rabbits with alloxan. Journal of theAmerican Medical Association, 122, 1165-1166.

Courville, C. B. (1930). Ganglioglioma, tumor of the central

nervous system: review of the literature and report of twocases. Archives of Neurology and Psychiatry, 24, 439-491.

Courville, C. B., and Anderson, F. M. (1941). Neuro-glio-genic tumors of the central nervous system: report of twoadditional cases of ganglioglioma of the brain. Bulletin ofLos Angeles Neurological Society, 6, 154-176.

French, J. D. (1947). Plasmacytoma of the hypothalamus:clinical-pathological report of a case. Journal of Neuro-pathology and Experimental Neurology, 6, 265-270.

Hausberger, F. X., Broadhead, C. L., Jr, and Hausberger,B. C. (1964). Obesity and diabetes mellitus in a rat withhypothalamic lesions: report of a case and review of theliterature. Acta Endocrinologica, 45, 600-604.

Jakumeit, K., Zimmermann, V., and Guiot, G. (1974).Intrasellar gangliocytomas: report of four cases. Journal ofNeurosurgery, 40, 626-630.

Killeffer, F. A., and Stern, W. E. (1970). Chronic effects ofhypothalamic injury: report of a case of near total hypo-thalamic destruction resulting from removal of a cranio-pharyngioma. Archives of Neurology, 22, 419-429.

McGavran, M. H., Unger, R. H., Recant, L., Polk, C., andLevin, M. E. (1966). Glucagon secreting alpha cell car-cinoma of the pancreas. New England Journal of Medicine,274, 1408-1413.

Moossy, J., and Wilson, C. B. (1967). Solitary intracranialplasmacytoma. Archives of Neurology, 16, 212-216.

Ranson, S. W., and Clark, S. L. (1959). The Anatomy of theNervous System: Its Development and Function, 10th edn,pp. 307-311. Saunders: Philadelphia.

Reeves, A. G., and Plum, F. (1969). Hyperphagia, rage, anddementia accompanying a ventromedial hypothalamicneoplasm. Archives of Neurology, 20 616-624.

Russell, D. S., and Rubinstein, L. J. (1962). Ganglioglioma:a case with a long history and malignant evolution. Journalof Neuropathology and Experimental Neurology, 21, 185-193.

Schoolman, H. M., Dubin, M. S., and Hoffman, W. S.(1955). Clinical syndromes associated with hypernatremia.Archives of Internal Medicine, 95, 15-23.

Shuangshoti, S., and Netsky, M. G. (1971a). Neoplasms ofmixed mesenchymal and neuroepithelial origin: relation to'monstrocellular sarcoma' or 'giant-celled glioblastoma'.Journal of Neuropathology and Experimental Neutrology, 30,290-309.

Shuangshoti, S., and Netsky, M. G. (1971b). Brain tumor ofmixed mesenchymal and neuroepithelial origin: casereport. Journal of Neutrosurgery, 34, 808-813.

Shuangshoti, S., and Panyathanya, R. (1974). Neural neo-plasms in Thailand: a study of 2 897 cases. Neutrology(Minneap.), 24, 1127-1134.

Vejjajiva, A., Sitprija, V., and Shuangshoti, S. (1969).Chronic sustained hypernatremia and hypovolemia in a

hypothalamic tumor: a physiologic study. Neurology(Minneap.), 19, 161-165.

Willis, R. A. (1951). Teratomas. In Atlas of Tumor Pathology,section 3, fascicle 9, p. 9. Armed Forces Institute ofPathology: Washington, D.C.

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