J Clin Pathol 1984;37:734-737

Production of human chorionic gonadotrophin by a

hepatoblastoma resulting in precocious pubertyRICHARD BEACH, PETER BETTS, MARTIN RADFORD, HARRY MILLWARD-SADLER

From the Departments of Paediatrics and Histopathology, Southampton General Hospital,Southampton S09 4XY

SUMMARY A two year old boy presented with precocious puberty associated with hepatoblas-toma. Serum concentrations of /3 human chorionic gonadotrophin and a-fetoprotein were raised.An aggressive chemotherapeutic regimen resulted in useful palliation and interesting changes inthe ,8 human chorionic gonadotrophin and a-fetoprotein concentrations. In contrast to a previousreport, the ultrastructure of the tumour showed frequent Golgi apparatus but no other electrondense membrane bound vesicles.

Hepatoblastoma is an embryonal tumour which canbe associated with various non-metastatic syn-dromes. a-fetoprotein or, rarely, human chorionicgonadotrophin may be produced by the tumour andmay be used as a tumour marker. Ectopic gonado-trophin production from this source is a rare causeof precocious puberty in boys.

Case report

PRESENTING FEATURESA boy aged 28 months presented with a four monthhistory of rapid skeletal growth, increasing penilesize, pubic hair, and deepening of the voice. Exami-nation showed him to be on the 90th percentile forheight and weight and to have oily skin, a deepvoice, pubic hair (stage II), and genital development(stage IV).' However, both testes were small(Prader Beads 3 ml). There was a large, firm, irregu-lar hepatic mass extending down to the level of theumbilicus.

MANAGEMENTLiver imaging using both ultrasound and radionu-cleotide scanning showed a mass 8 cm in diameterwithin the right lobe of the liver. At laparotomy thetumour was found to extend across into the left lobeof the liver and was considered inoperable. Needlebiopsy samples of the tumour were taken. There wasno evidence on clinical examination, chest radio-graph, and bone scan or at laparotomy for thespread of the tumour beyond the liver.

Accepted for publication 30 March 1984

LABORATORY INVESTIGATIONSResults of laboratory investigations were as follows:haemoglobin concentration 8*8 g/dl; erythrocytesedimentation rate 38 mm in the first hour; serumbilirubin and liver transaminase values normal;plasma alkaline phosphatase >2000 IU/l; serum 8human chorionic gonadotrophin concentration 197IU/l (normal <5 WUAl); a-fetoprotein concentration404 x 103 KU/I (normal <SKU/l); plasma testos-terone 49 nmol/l (normal for adult male <30 nmol/1); plasma oestradiol 520 pmol/l (adult males <160pmol/l); basal plasma follicle stimulating hormoneconcentration 2 IU/I with no rise on luteinising hor-mone releasing hormone stimulation; basal luteinis-ing hormone concentration 41 IU/I (owing to a crossreactivity with /8 human chorionic gonadotrophin).

PATHOLOGYLight microscopy showed a vascular tumourarranged in a trabecular/sinusoidal pattern withnumerous foci of haemopoiesis in the sinusoidalchannels. The predominant tumour cell was largeand polygonal and resembled fetal hepatocytes, buta few smaller, oval to polygonal cells with less cyto-plasm resembling embryonal hepatocytes were alsopresent (Fig. la). A mesenchymal stromal compo-nent to the tumour was not identified. Electron mic-roscopy confirmed the foci of haemopoiesis. Thelarge polygonal tumour cells had complex foldedand interdigitated plasma membranes (Fig. lb).Desmosomes were not seen but large numbers ofmicrofilaments were prominent beneath the plasmamembranes. Mitochondria were numerous and usu-ally round. Abnormal circular and septal cristae

734

copyright. on N

ovember 30, 2020 by guest. P

rotected byhttp://jcp.bm

j.com/

J Clin P

athol: first published as 10.1136/jcp.37.7.734 on 1 July 1984. Dow

nloaded from

Production of human chorionic gonadotrophin by a hepatoblastoma resulting in precocious puberty_u."ItWM. ,_ _*_,4 __1E ~ -t ~a.__ ¢ ~ a-

e- b

te a

Fig. 1 (a) Tumour cells oftwo types are present. There are large cells with abundant cytoplasm, circular mitochondriawidely dispersed among vesicular smooth endoplasmic reticulum, and a small nucleus (bottom right). Other tumour cells aresmaller but have a relatively larger nucleus and greater numbers ofmitochondria within the more electron dense cytoplasm.(uranyl acetate and lead citrate x 3200)(b) There is pronounced complexity and infolding ofthe plasma membranes ofthe tumour cells. The cell top left has formeda large intracytoplasmic vacuole into which project several microvilli. (uranyl acetate and lead citrate x 8000)(c) Portions ofan infolded nucleus are seen top right and top left, a small membrane bound peroxisome 0-42 ,cm diameter ispresent centre, and several sets ofGolgi apparatus (arrows) surround the peroxisomes. There are numerous microfilamentsand microtubules also present within the cytoplasm. (uranyl acetate and lead citrate. x 26 000)

735

copyright. on N

ovember 30, 2020 by guest. P

rotected byhttp://jcp.bm

j.com/

J Clin P

athol: first published as 10.1136/jcp.37.7.734 on 1 July 1984. Dow

nloaded from

Beach, Betts, Radford, Millward-Sadlerwere often seen with them. Well develcof both rough and smooth endoplasmwere present and ribosomes were alsothe cytosol. The Golgi apparatus waprominent feature and also multiple ir(Fig. Ic). Peroxisomes were also preseniory granules were not identified. Theoval with a small nucleolus and a fineeuchromatin pattern.

TREATMENT AND PROGRESSA chemotherapeutic protocol wasincluding vincristine, adriamycin, cyclopand 5 fluorouracil in six week cycles. Tinitial rapid fall in serum a-fetoprochange in serum human chorionic goconcentration and no change in the clirvirilisation. Subsequently, despite treserum a-fetoprotein concentration roSerial ultrasound scans showed noreduction in tumour size to correspoearly fall in serum a-fetoprotein concei

Treatment was well tolerated anremained active and in good health fofrom diagnosis. Subsequently, there wasdence of local tumour growth Mhepatomegaly and jaundice. Chemolwithdrawn and the child died 13 montlsentation.

106,

C

dokg 1Q040

uLido

E

E23t-10ap

0 0-- 0

' N D J F M A M J+ L 1981-

Chemotherapy started Time (monthFig. 2 Differential response ofserum tumouchemotherapy in a case ofhepatoblastoma.

)ped profilesic reticulum

r *,, .

Discussion

tree within Precocious puberty due to a virilising hepatoblas-is usually a toma is a rare but well documented occurrence.2-l many cells Cases have been confined to boys, generally belowt, but secret- three years of age, who have usually presented withnucleus was accelerated skeletal growth and virilisation. Hepaticly dispersed enlargement at presentation has been invariable.

Most authors report little or no increase in testicularsize; biopsy samples, when taken, have usuallyshown interstitial cell hyperplasia but no sper-

undertaken matogenesis, which suggests testicular stimulation)hosphamide by a gonadotrophin with only interstitial cell'here was an stimulating activity. The circulating gonadotrophintein but no which was originally detected by bioassay in earlyonadotrophin reports has subsequently been identified as humannical signs of chorionic gonadotrophin using a radioimmunoassayatment, the specific for the ,3 chain.48 Human chorionicxse (Fig. 2). gonadotrophin has also been isolated from tumourappreciable cells cultured in vitro.4 Human chorionic gonado-nd with the trophin stimulates the testicular interstitial cellsntration. leading to androgen production and subsequentd the child virilisation. Follicle stimulating hormone concentra-pr 10 months tions are unaltered-hence there is little increase ins clinical evi- testicular size. The high circulating luteinising hor-vith further mone concentrations are caused by cross reaction oftherapy was human chorionic gonadotrophin in the luteinisinghs after pre- hormone assay.

The raised plasma oestradiol concentration in thiscase and in previous reports3 68 was probably due toperipheral conversion of circulating androgens. Clin-ical evidence of feminisation has been restricted togynaecomastia in one case.2

Raised concentrations of circulating a-fetoproteinare not diagnostic of hepatoblastoma and are also

AFP (KU/I) found in hepatocellular carcinoma and some* teratomas showing extra embryonal differentation.

Circulating a-fetoprotein concentrations offer a use-ful means of assessing response to treatment in sometumours. The differential response of humanchorionic gonadotrophin and a-fetoprotein tochemotherapy in this case, together with a previoussimilar report,3 suggests either synthesis by separatecell lines or differential sensitivity to chemotherapyof metabolic pathways in the same cell.Long term survival is dependent on removal of

the tumour; without surgical resection the prognosisBHCG (lu/i) is measured in months, although occasionalX o responses to irradiation9 or vincristine'° have been'o- recorded. Our aggressive use of chemotherapyI I- I apparently controlled the growth of this inoperableJ A S 0 tumour for about nine months. A biochemical

"response" to chemotherapy was noted with serum)s) a-fetoprotein concentration rapidly falling at their markers to start of treatment. Circulating a-fetoprotein con-

centrations may therefore provide an index of

736

copyright. on N

ovember 30, 2020 by guest. P

rotected byhttp://jcp.bm

j.com/

J Clin P

athol: first published as 10.1136/jcp.37.7.734 on 1 July 1984. Dow

nloaded from

Production ofhuman chorionic gonadotrophin by a hepatoblastoma resulting in precocious puberty 737

response to treatment in these tumours but must beinterpreted cautiously since no similar fall in serum,8 human chorionic gonadotrophin concentrationoccurred in our patient. None the less, as treatmentwas well tolerated and maintained the child in excel-lent general health, the chemotherapeutic regimenappears to have produced useful palliation in a sur-gically inoperable case.

In the only published report on the ultrastructuralappearances of a virilising hepatoblastoma secretorygranules were found within the tumour cell cyto-plasm.7 This is in contrast to our findings; tumourcells from our patient showed prominent and oftenmultiple Golgi apparatus and, although peroxisomesand lysosomes were also present, there were noother membrane bound electron dense granules. Ashuman chorionic gonadotrophin is a glycoproteinthe presence of Golgi apparatus would be expectedbecause this is required for addition of the carbohy-drate side chains to the polypeptide. Conversely,secretory granules necessary for the storage ofintermittently released cellular proteins would notbe essential and, indeed, in our study were notpresent.

References

Tanner JM. Growth and endocrinology in the adolescent. In:

Gardner L, ed. Endocrine and genetic diseases of cbildhood.Philadelphia: Saunders, 1969.

2 Reeves RL, Tesluk H, Harrison CE. Precocious puberty associ-ated with hepatoma. J Clin Endocrinol 1959;19: 1651-9.

3Hung W, Blizzard RM, Migeon CJ, Camacho AM, Nyhan WL.Precocious puberty in a boy with hepatoma and circulatinggonadotrophin. J Pediatr 1963;63:895-903.

Braunstein GD, Bridson WE, Glass A, Hull EW, Mclntire KR.In vivo and in vitro production of human chorionic gonado-trophin and alpha-fetoprotein by a virilizing hepatoblastoma.J Clin Endocrinol Metab 1972;35:857-62.

Van Vaerenbergh P, Thijs L, Delbeke MJ, Craen M. A case ofmalignant hepatoma with precocious puberty. Acta Paed Belg1972;26:78-87.

6 McArthur JW, Toll GD, Russfield AB, Beiss AM, Quinby WC,Baker WH. Sexual precocity attributable to ectopic gonado-trophin secretion by hepatoblastoma. Am J Med1973;54:390-403.

Kumar EV, Kumar L, Pathak IC, Dash RCJ, Joshi VV. Clinical,hormonal and untrastructural studies of a virilizing hepatoblas-toma. Acta Paed Scand 1978;67:389-92.

Flores F, Solando A, Reveil R, et al. Isosexual precocious pub-erty in a male infant with hepatoblastoma. Rev Invest Clin1979;31:251-5.

Cohn R. Right hepatic lobectomy in children. Am J Surg1969; 118:512-76.

'° Lascari AD. Vincristine therapy in an infant with probablehepatoblastoma. Pediatrics 1970; 54:109-2.

Requests for reprints to: Dr R Beach, Department ofPaediatrics, Level G, East Wing, Southampton GeneralHospital, Southampton S09 4XY, England.

copyright. on N

ovember 30, 2020 by guest. P

rotected byhttp://jcp.bm

j.com/

J Clin P

athol: first published as 10.1136/jcp.37.7.734 on 1 July 1984. Dow

nloaded from