Abnormal alkaline phosphatase ofhepatic type in cerebrospinalfluid ofa patient with intracranial metastasisfrom lung cancer

that liver-type ALP was produced in a patientwith meningioma, but they did not find anabnormal ALP value. In addition, we did notfind-abnormal ALP values in 100 patientswith non-neoplastic intracranial diseases.Taken together, our data suggest that theabnormal ALP found in the cerebrospinalfluid from this patient was liver-type ALPproduced by intracranial cancer cells whichhad metastasised from an alveolar lung ade-nocarcinoma.

This work was supported in part by a grant from the Ministryof Education, Science and Culture ofJapan.

1 Harris H. The human aLkaline phosphatases: what weknow and what we don't know. Clin Chim Acta 1990;186:133-50.

2 Simko V. Alkaline phosphatase in biology and medicine.Dig Dis Sci 1991;9:189-209.

3 Moss DW. The nature and origin of alkaline phosphatasein hepatobiliary disease. Z Med Lab Diagnost 1989;30:355-63.

4 Alpers DH, Eliakim R, DeSchryver-Kecskemeti K.Secretion of hepatic and intestinal alkaline phos-phatases: similarities and differences. Clin Chim Acta1990;186:211-24.

5 Komoda T, Koyama I, Nagata A, Sakagishi Y, Kurata M,Kumegawa M. A possible mechanism of induction andtranslocation into blood stream of rat alkaline phos-phatase activity by bile duct ligation. Arch BiochemBiophys 1986;251:323-35.

6 Miura M, Matsuzaki H, Bailyes EM, et al. Differencebetween human liver- and bone-type alkaline phos-phatases. Clin Chim Acta 1989;168:177-88.

7 Komoda T, Sato M, Furiya K, Sakagishi Y, Sekine T.Allelic and ectopic polymorphisms in human placentalalkaline phosphatases: sugar chain heterogeneities. ClinChim Acta 1990;186:203-10.

8 Scallon B, Fung WJ, Tsang C, Li S, Kado-Fong H,Huang KS, Kochan J. Primary structure and functionalactivity of a phosphatidylinositol-glycan specific phos-pholipase D. Science 1991;252:446-8.

9 Henderson AR, Grace DM. Liver-originating isoenzymeof alkaline phosphatase in the serum: a perioplasticmanifestation of a malignant schwannoma of the sciaticnerve. J Clin Pathol 1976;29:237-40.

10 Koyama I, Miura M, Matsuzaki H, Sakagishi Y, KomodaT. Sugar chain heterogeneity of human alkalinephosphatase: differences between normal and tumourassociated isozymes. Y Chromatogr 1987;413:65-78.

11 Murakami M, Yoshioka S, Kuratsu J, Nakamura H,Ushio Y. High serum alkaline phosphatase level ofmeningioma cell origin: case report and review of theliterature. Neurosurgery 1992;30:624-7.

J Clin Pathol 1993;46:1061-1063

Cholecystitis, cholelithiasis, andganglioneuromatosis of the gall bladder:an unusual presentation ofMEN type 2b

R Chetty, S P Clark

Department ofAnatomicalPathology, The RoyalMelbourne Hospitaland University ofMelbourne,Melbourne, AustraliaR ChettyS P ClarkCorrespondence to:Dr R Chetty,Nuffield Departnent ofPathology, University ofOxford, John RadcliffeHospital, Headington,Oxford OX3 9DUAccepted for publication1 June 1993

AbstractA 40 year old man with multipleendocrine neoplasia type 2b (MEN 2b)presented with cholecystitis caused bygall stones. Twenty four years earlier, hehad had a partial thyroidectomy for acold nodule. At his initial presentationMEN 2b with medullary carcinoma of thethyroid had not been made. This wasdiagnosed while investigating his gallbladder symptoms and he was found tohave asymptomatic residual medullarythyroid carcinoma and bilateral adrenalphaeochromocytomas. The cholecystec-tomy specimen contained several mixedcalculi and extensive ganglioneuromato-sis with large, prominent nerves contain-ing ganglion cells in the gall bladder wall.

(C Clin Pathol 1993;46:1061-1063)

Neuronal hyperplasia or ganglioneuromatosisare well recognised components of multipleendocrine neoplasia type 2b (MEN 2b)"2 andneurofibromatosis.3 Ganglioneuromatosis ofthe gastrointestinal tract often precedes theappearance of medullary thyroid carcinomaand phaeochromocytoma in MEN 2b.4Within the context of MEN 2b, presentation

related to gall bladder disease is rare. A caseof MEN 2b is presented in which the patientcomplained primarily of symptoms related togall bladder disease.

Case reportThe patient was a 40 year old man who at theage of 16 years had had a partial thyroi-dectomy for a cold nodule. This was inter-preted to be a Huirthle cell carcinoma at thetime. Twenty four years later, he complainedof right upper quadrant pain, dyspepsia, andflatulence. Examination showed him to behypertensive (although he did not complainof hypertension) and to have right upperquadrant tenderness. He was also noted tohave a lump in his residual thyroid and bilat-eral loin masses. A computed tomogramrevealed an enlarged gall bladder filled withcalculi, a tumour in the residual thyroid, andbilateral adrenal medullary tumours. Sub-sequent examination showed mucosal neuro-mas of the lips, tongue, larynx and cornea.Furthermore, the patient was noted to have amarfanoid feature. MEN 2b was diagnosedand a detailed review of the patient's historydisclosed a positive family history with thepatient's mother having bilateral phaeochro-

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Figure 1 Gall bladderwall thickened by largenerves with a plexiformpattern. The surfacemucosa is intact and thereis mild chronic cholecystitis(haematoxylin and eosin).

mocytomas. A brother has a similar appear-ance to the patient and has been treated forhypertension, presumably related to phaeo-chromocytomas. None of the patient's chil-dren had any signs or symptoms of MEN.Serum calcitonin and urinary catecholaminevalues were increased. The residual thyroidwas resected and bilateral adrenalectomy andcholecystectomy were performed. One yearlater, the patient had symptoms attributableto diverticular disease and a neurogenicbladder.

Figure 2 Associated with the neuronal hyperplasia were areas ofganglioneuromatosiswith ganglion cells and proliferating Schwann cells (haematoxylin and eosin).

MethodsAll specimens were fixed in 10% bufferedformalin and processed routinely. In additionto haematoxylin and eosin stains, immuno-histochemistry was performed using thestreptavidin-biotin complex on formalin fixed,paraffin wax embedded tissue for the follow-ing antibodies: chromogranin (BoehringerMannheim, Germany, dilution 1 in 100);synaptophysin (Biogenix Medos, Australia, 1in 200); S-100 protein (Dakopatts, USA,1 in 400); neurofilament (Dako, 1 in 50);vasoactive intestinal peptide (VIP) (BiogenixMedos, Australia, prediluted); somatostatin(Dako, 1 in 300) and glial fibrillary acidicprotein (GFAP) (Dako, 1 in 150).

Pathological findingsMacroscopically, the gall bladder measured10 x 3 cm and contained several mixed cal-culi. The wall measured 0 3 cm in thicknessand the serosal surface had a ropy, nodularappearance. The mucosa appeared to bewithin normal limits. Microscopically, thegall bladder mucosa was intact and lined bynormal columnar epithelium (fig 1). The walldeep to the muscle layer and subserosa con-tained large prominent nerve trunks, some ofwhich were dumbell-shaped, simulating aplexiform neurofibroma (fig 1). The enlargednerves were accompanied by an increase inthe number of ganglion cells embeddedwithin proliferating Schwann cells (ganglio-neuromatosis) (fig 2). Occasional "giantganglia" were also seen. These foci were scat-tered randomly throughout the gall bladderwall. A mild chronic inflammatory infiltratewith attendant fibrosis was also present.The slides from the first thyroid tumourwere reviewed and these, together with the

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Cholecystitis, cholelithiasis, and ganglioneuromatosis of the gall bladder

current tumour, were typical of medullarycarcinomas. Associated areas of C-cell hyper-plasia were present. Both adrenal tumourswere classic solitary phaeochromocytomas.The Schwann cells and nerve trunks were

strongly positive for S-i 00 protein and neuro-filament. The ganglion cells were focallypositive for neurofilament but negative for allother markers.

DiscussionGanglioneuromatosis is a consistent findingin MEN 2b.5 In fact, one of the most charac-teristic and evident alimentary tract manifes-tations of the syndrome is diffuse or nodularenlargement of the lips caused by ganglio-neuromatosis.67 Major reviews of the gastro-intestinal pathology encountered in MEN 2b,however, have only briefly alluded to gallbladder disease.46

In his initial review Carney found twopatients with gall bladder disease.4 One hadgall bladder ganglioneuromatosis and theother acalculous cholecystitis. Unfortunately,microscopical examination findings were notavailable in the latter case. Symptoms relatedto gall bladder disease are not a common orwell documented mode of presentation inMEN 2b.

Ganglioneuromatosis of the gastrointes-tinal tract causes a plethora of abdominalsymptoms, including constipation, diarrhoea,colic, projectile vomiting, and, in the case ofinfants, difficulty with feeding. Despite theseprotean manifestations, the usual gastro-intestinal symptoms in MEN 2b are inter-mittent, chronic constipation and chronicdiarrhoea.6 Ganglioneuromatosis is a well

recognised cause of gastrointestinal hypo-motility and the associated diarrhoea hasbeen ascribed to high circulating serum calci-tonin concentrations produced by medullarycarcinoma of the thyroid.6 Other peptides,however, may also play a part.

In this case the ganglioneuromatosis of thegall bladder wall might have resulted in poorcontraction with a resultant stasis contribu-ting to the formation of the gall stones. Itmust be remembered, however, that chole-lithiasis is common and may be unrelated tothe presence of ganglioneuromatosis of thegall bladder.

This case illustrates a very uncommonpresentation of a patient with classic MEN 2bwho had cholelithiasis and cholecystitis withsynchronous, asymptomatic recurrent medul-lary thyroid carcinoma and bilateral adrenalphaeochromocytomas.

1 Williams ED, Pollock DJ. Multiple mucosal neuromatawith endocrine tumours: A syndrome allied to vonRecklinghausen's disease. J Pathol Bacteriol 1966;91:71-80.

2 Gorlin RJ, Sedano HO, Vickers RA, Cervenka J. Multiplemucosal neuromas, pheochromocytoma and medullarycarcinoma of thyroid. A syndrome. Cancer 1968;22:293-9.

3 Ricardi VM. Von Recldinghausen neurofibromatosis. NEnglJrMed 1981;305:1617-27.

4 Carney JA, Go VLW, Sizemore GW, Hayles AB.Alimentary tract ganglioneuromatosis: A major compo-nent of the syndrome of multiple endocrine neoplasia,type 2b. NEnglJMed 1976;295:1287-91.

5 Fuller CE, Williams GT. Gastrointestinal symptoms oftype 1 neurofibromatosis (von Recklinghausen's dis-ease). Histopathology 199 1;19: 1-11.

6 Carney JA, Hayles AB. Alimentary tract manifestations ofmultiple endocrine neoplasia, type 2b. Mayo Clin Proc1977;52:543-8.

7 Carney JA, Sizemore GW, Lovestedt SA. Mucosalganglioneuromatosis, medullary thyroid carcinoma andpheochromocytoma: multiple endocrine neoplasia, type2b. Oral Surg 1976;41:739-52.

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