J Clin Pathol 1981;34:785-789

Placental involvement in congenital neuroblastomaCHARLES R SMITH,* HELEN SL CHAN,t DJ DESAtFrom the *Department of Pathology and the tDivision of Hematology, The Hospital for Sick Children,Toronto and the tDepartment ofPathology, McMaster University, Hamilton, Ontario, Canada

SUMMARY We describe two cases of congenital neuroblastoma involving the placenta and reviewpreviously reported cases. The placentae in congenital neuroblastoma have a bulky, hydropicappearance, and contain tumour cells which are confined to the fetal circulation. The tumour emboliare not macroscopically identifiable. Pathophysiological mechanisms of placental involvement byfetal and maternal malignancies are considered. The rarity of this lesion may be artefactual, and mayresult from failure to examine grossly enlarged placentae in cases of stillbirth and hydrops fetalis.Congenital malignancy must be considered in the differential diagnosis of an abnormally largeplacenta.

Neuroblastoma is the commonest solid malignanttumour of childhood, arising from primitiveneuroectodermal cells originating in the adrenalmedulla or ganglia of the sympathetic nervoussystem. On rare occasions, it may present in thenewborn period and these patients may haveevidence of widespread metastatic disease. Con-genital neuroblastoma associated with placentalinvolvement is an even rarer occurrence and onlysix cases have been reported.'-5 We present twofurther cases of congenital neuroblastoma occurringin liveborn infants where there was extensiveplacental involvement.

Case reports

Case I (Hospital for Sick Children, Toronto)This female infant was born by vaginal delivery at40 wk gestation to a gravida 1, para 0 mother. Thepregnancy was complicated by pre-eclampsia in thethird trimester. The infant's birth weight was 3800 g.She had mild respiratory distress and markedabdominal distention with dilated veins on theoedematous abdominal wall. The umbilicus waseverted. The abdominal organs could not bepalpated because of ascites. Radiography andultrasonography showed gross hepatomegaly, butno evidence of calcification within the enlarged liver.There was a large mass in the left suprarenal regionwhich extended across the midline and displaced theleft kidney inferiorly. Liver scan demonstrated patchyuptake of radionuclide, suggestive of diffuse tumour

Accepted for publication 26 November 1980

infiltration. Haemoglobin was 12 g/dl; the urinaryvanillylmandelic acid (VMA) excretion was in-creased to 226 ,umol/24 h (44-8 mg) (normal < 5Lmol/24 h (0-1 mg)); the urinary homovanillicacid (HVA) was 200 ,tmol/mmol (322 mg/g)creatinine (normal < 22 umol/mmol (1I2-35 mg/g));and the carcinoembryonic antigen (CEA) was4.5 ,ug/l (normal < 2 Htg/l). The serum uric acid andserum aspartate aminotransferase concentrationswere increased and the serum albumin was 2-5 g/dl.The baby was diagnosed as having congenitalneuroblastoma of the left adrenal with hepaticmetastases. She received a single course of totalabdominal radiation (400 rads) and chemotherapy(vincristine and cyclophosphamide), but died on the97th day of life. The mother's 24 h-urinary VMA,total catecholamine and HVA were normal.The placenta weighed 1150 g and its pale brown,

bulky appearance was reminiscent of changes oferythroblastosis fetalis. Neuroblastoma cells werefound within the fetal vascular channels of thechorionic villi, either singly or in clumps androsettes (Fig. 1). At no point did the tumour cellsextend through the vessel wall into the villous stroma,nor were they found in the intervillous space. Lessthan 5% of the villi contained tumour cells andscattered groups of villi were affected. The villi hadan immature appearance, similar to that seen inmaterno-fetal rhesus incompatibility. The abundantstromal cells resulted in a hyperplastic appearanceand cytotrophoblastic cells were prominent (Fig. 2).The individual neuroblastoma cells had dark,rounded nuclei with small amounts of poorly-demarcated cytoplasm. Electron microscopy demon-

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Fig. 1 Clump ofneuroblastoma cells(arrow) within a fetalvascular channel.Haematoxylin and eosinx 4800.

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strated membrane-bound secretory granules withinthe cytoplasm of the cells.At necropsy the neuroblastoma was found to

originate from the left adrenal and had spread to theright adrenal gland. Massive liver involvement wasassociated with gross ascites.

Case 2 (McMaster University Medical Centre,Hamilton)This female infant was born to a gravida 1, para 0mother at 38 wk gestation. The birth weight was2770 g. The infant was hydropic with massiveabdominal distention and extreme hepatomegaly.The other abdominal organs were obscured byascitic fluid, and could not be palpated. The infantshaemoglobin was 10 g/dl and the serum albumin was2-5 g/dl. She received an exchange transfusion withwhole blood which resulted in transient improvementin her haemoglobin and albumin concentrations,but she remained anuric. Ultrasonograms revealedthe presence of kidneys bilaterally. A bone marrowbiopsy showed the presence of diffuse clusters ofneuroblastoma cells within the marrow spaces. Theplacenta weighed 680 g and showed focally hydropicvilli. Within the vessels of the villi numerous clustersof neuroblastoma cells were present. There was somestromal hypercellularity, but it was not as marked asin case 1.

The infant died aged 21 days. Necropsy showed amassively enlarged left adrenal gland with completereplacement by neuroblastoma cells. Massivedeposits of tumours were seen in the oppositeadrenal gland, liver, kidney, bone marrow, spleen,myocardium, lung, pancreas, pancreatic lymphnodes, ovaries, dorsal root ganglia, celiac ganglion,small and large bowel, pituitary, thyroid, and middleear.

Discussion

In addition to materno-fetal blood group incom-patibilities, maternal disease (for example, diabetesmellitus, anaemia, cardiac disease), intrauterineinfections, prolonged gestational periods and fetalanomalies (for example, anencephaly, trisomy 21and other genetic disorders), congenital malignanciesmay cause placental enlargement. Six previous casesof congenital neuroblastoma are recorded.1-5 As inour present cases, the placentae had a hydropicappearance with recorded weights of up to 1100 g.Two of the infants were stillborn and in the otherfour, the longest period of survival was 17 days.Fetal vascular channels within the placentae con-tained tumour deposits, but invasion of the stromaof chorionic villi was not found. There were noreports of spread into the maternal circulation

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Placental involvement in congenital neuroblastoma

Fig. 2 Immature chorionic villishowing separation offetalvascular channelsfrom thetrophoblast layer by abundantvillous stroma. Haematoxylin andeosin x 800.

(intervillous space) nor evidence of metastases inthe mother. As pointed out by Willis,6 tumour embolithat do not multiply and invade adjacent tissues arenot metastases in the true sense of the word, and thepreviously reported cases of placental involvement incongenital neuroblastomal-5 describe tumour em-bolism rather than the metastatic spread.

It is not clear why placental hydrops shoulddevelop in association with congenital neuroblas-toma. Strauss and Driscoll (1964),' when reportingthe first cases, suggested an immune reaction to thetumour cells as the cause of the placental enlarge-ment with increased numbers of Hofbauer cells andnuclear debris being present; however, an associatedlymphocytic infiltrate was not described, nor was it afeature of our cases. Plugging of the placental vesselsby tumour cells may be a factor, but placentalenlargement may not necessarily reflect the extent ofvascular involvement,3 and this mechanism can beinvoked only if detailed morphometric studiesassessing the extent of vascular deposits have beenmade. A case of congenital neuroblastoma withplacental enlargement but without tumour embolihas been described.7 This would suggest that theplacental changes are not merely the result of thepresence of neuroblastoma cells. Increased placental

growth may be a response to compensate for fetalanaemia,5 as the four liveborn infants and ourpresent cases were anaemic. Obstruction of theplacental venous return is another possibility, as hasbeen postulated to occur in bilateral congenitalnephroblastoma8 and congenital cystic adenomatoidmalformations of the lung,9 both of which may pre-sent with placental enlargement. Placental enlarge-ment may be found in diseases where changes inhaemodynamics do not occur(forexample, congenitalsyphilis and toxoplasmosis), and the pathogenesis ofthe placental changes seen in infants with congenitalneuroblastoma remains uncertain. Both of our in-fants had evidence of massive liver involvement, andthere was marked hypoalbuminaemia, and some ofthe placental hydropic change may have resultedfrom alterations in plasma proteins.

Other congenital lesions have involved theplacenta. An enlarged placenta containing lym-phoblastic cells was thought to have been due to acongenital leukaemia,'0 although the stillborn fetuswas not examined. A definite example of fetalleukaemic cells within chorionic villi was illustratedby Fox."Two cases of placental involvement by congenital

giant pigmented nevi have been reported.'2 13 One

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author "hypothesised" the filtration of nevus cellsfrom the fetal circulation by the placenta.12 Analternate theory,'3 based on the relative proximityof the developing umbilical stalk to the neural tube inthe embryo, is that of aberrant migration of neuralcrest cells to the placenta. Interestingly, in both casesonly the interstitial tissue of placental villi containedthe pigmented nevus cells and they were not presentwithin fetal vascular channels. When this is con-sidered in the light of the apparent inability ofcongenital neuroblastoma cells to penetrate into thevillous stroma in the placenta, abnormal migrationrather than haematogenous spread becomes a moreplausible hypothesis.Though rare, placental metastases from a maternal

neoplasm have been reported on more occasions thanmetastases from fetal neoplasms. Beside reports ofleukaemia or lymphoma, at least 36 maternal neo-plasms have involved the feto-placental unit." 14-18Villous invasion has been documented in only aminority of the patients and the deposits of thematernal neoplasm have been located in the inter-villous space in the majority of cases. In eight of the18 instances of malignant melanoma, spread to thefetus occurred. As with fetal neoplasms, the inabilityof most maternal neoplasms to penetrate thechorionic villi is not understood. It may be dueto the mechanical stability of the trophoblastic celllayer, or the possible control of tumour invasion by afetal immunological mechanism. While the absenceof lymphoid cells in the villi adjacent to the inter-villous tumour deposits lends no morphologicalsupport to this latter hypothesis, the regression ofmetastatic malignant melanoma in two of the eightaffected infants17 18 would suggest that the fetus doeshave some protective immunological mechanisms.In those instances in which invasion of chorionicvilli by maternal tumour could not be demonstrated,but fetal involvement occurred, infarction ofchorionic villi may have led to a breakdown of theplacental barrier.

Just as the maternal immune system can destroyfetal erythrocytes which cross the placental barrier,it may have a similar protective function in the eventof transplacental spread of congenital malignancies.Cells from a congenital neuroblastoma that gainaccess to the maternal circulation may, therefore, besequestered and destroyed by the mother's immuno-logical defences. It is likely that the patterns ofplacental involvement in cases of maternal and fetalneoplasms, reflect the complex, and poorly under-stood, immunological balance that exists in a normalpregnancy. Thus, as a general rule, maternalneoplasms are confined to the intervillous space,while fetal neoplasms are restricted to the chorionicvilli. That this is an oversimplification is suggested by

the relative rarity of choriocarcinomata invading thefetus, as opposed to metastatic spread in themother;19 however, this exception does emphasisethe importance of the trophoblastic layer in feto-maternal immunological balance.

In view of the important role of the placenta in thefetal circulation, it is uncertain whether the re-ported low incidence of placental involvement bycongenital malignancies is real or artefactual. Theplacenta may not be available for examination inmany infants, and when available, may not beexamined histologically. The tumour emboli are notvisible on gross inspection and are easily overlooked.The newborn infant may not manifest a congenitalmalignancy at the time of delivery and retrieval ofthe placenta may not be possible. The unevendistribution of tumour cells within placental villi maygive rise to sampling errors; and the similarity tofetal leucocytes and nucleated erythrocytes allowsmisinterpretation.3 We emphasise the importance ofplacental examination, including detailed histologicalstudy, in all cases of hydrops fetalis or placentalenlargement or both.

References

Strauss L, Driscoll SG. Congenital neuroblastoma involvingthe placenta. Pediatrics 1964;34:23-3 1.

2 Anders D, Frick R, Kindermann G. Metastasierendesneuroblastonma des feten mit aussaat in die plazenta.Geblhrtshilfe Fraiuen1heilkd 1970;30:969-75.

3 Anders D, Kindermann G, Pfeifer U. Metastasizing fetalneuroblastoma with involvement of the placentasimulating fetal erythroblastosis. J Pediatr 1973 ;82:50-3.

Jurkovic 1, Fric 1, Boor A. Placenta pri neuroblastome. CsPediat 1973 ;28 :443-5.

5Johnson AT, Halbert D. Congenital neuroblastomapresenting as hydrops fetalis. NC Med J 1974;35:289-91.

6 Willis RA. The spread of tutinours in the human bodei. 3rd edl.London: Butterworths, 1973 :47.

Birner WF. Neuroblastoma as a cause of antenatal death.Am J Obstet GYnecol 1961;82:1388-91.

" Hustin J, Chef R. Nephroblastomatose diffuse bilaterale.J GYnecol Obstet Biol Reprod (Paris) 1972;1 :373-84.

! Gottschalk W, Abramson D. Placental edema and fetalhydrops: A case of congenital cystic and adenomatoidmalformation of the lung. Obstet GY'necol 1957;10:626-31.

10Benirschke K, Driscoll SG. The pathology of the hunianplacenta. Berlin: Springer-Verlag, 1967.

Fox H. Pathology of the Placenta. Philadelphia: WBSaunders, 1978:362.

12 Holaday WJ, Castrow FF. Placental metastasis from afetal giant pigmented nevus. Arch Dermatol 1968;98:486-8.

' Demian SDE, Donnelly WH, Frias JL, Monif GRG.Placental lesions in congenital giant pigmented nevi. AmJ Clin Pathol 1974;61:438-42.

" Potter JF, Schoeneman M. Metastasis of maternal cancelto the placenta and fetus. Cancer 1970;25:380-8.

1 Russel P, Laverty CR. Malignant melanoma metastases inthe placenta: A case report. Pathology 1977;9:251-5.

16 Weber FP, Schwartz E, Hellenschmeid R. SpontaneouLs

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inoculation of melanotic sarcoma from mother tofoetus. Br MedJ 1930;i:537.

17 Aronsson S. A case of transplacental tumor metastasis.Acta Paediatr Scand 1963 ;52:123-4.

18 Cavell B. Transplacental metastasis ofmalignant melanoma.Acta Paediatr Scand (Suppi) 1963 ;146:37-40.

19 Kruseman ACN, VanLent M, Blom AH, Lauw GP.Choriocarcinoma in mother and child, identified by

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immunoenzyme histochemistry. Am J Clin Pathol 1977;67:279-83.

Requests for reprints to: Dr DJ deSa, Department ofPathology, McMaster University, 1200 Main Street West,Hamilton, Ontario, Canada L8S 4J9.

The June 1981 issueTHE JUNE 1981 ISSUE CONTAINS THE FOLLOWING PAPERS

Review articleCytochemistry in the bioassay of hormones JCHAYEN, LUCILLE BITENSKY

Costs of a clinical chemistry laboratory JA STILWELL

Changes in thrombin-stimulated platelet malondial-dehyde production during the menstrual cycle HTINDALL, M ZUZEL, RC PATON, GP MCNICOL

Relation between postoperative antithrombin IIIconcentrations and site of operation SP GRAY,JA BILLINGS, VALERIE NEWTON, AUDREY OLIVE

Adriamycin cardiotoxicity: report of an unusualcase with features resembling endomyocardialfibrosis W FITTER, DJ DESA, KRM PAI

Malakoplakia of the adrenal gland E BENJAMIN,H FOX

Morphometric differences between urothelial cellsin voided urine of patients with grade I and grade IIbladder tumours MATHILDE E BOON, PHJ KURVER,JPA BAAK, ECM OOMS

Interstitial nephritis AJ DIXON, CG WINEARLS, MSDUNN1LL

Method for measuring fibrinolytic activity in a singlelayer of cells AT RAFTERY

Forms of vitamin B12 in radioisotope dilution assaysJA BEGLEY, CA HALL

Data handling and reporting for microbiologyspecimens with a small laboratory computer systemRA LANDOWNE

Rapid detection and presumptive identification ofClostridium difficile by p-cresol production on aselective medium KD PHILLIPS, PA ROGERS

Relation between concentrations of metronidazoleand Bacteroides spp in faeces of patients withCrohn's disease and healthy individuals A KROOK,B LINDSTROM, J KJELLANDER, G JARNEROT, L BODIN

Impaired bacteriological responses in babies aftermaternal iron dextran infusion MH WEBSTER,SHEENA A WAITKINS, A STOTT

Hepatitis and other infections in clinical laboratorystaff, 1979 NR GRIST

Screening for toxoplasmosis in pregnancy EJBROADBENT, R ROSS, ROSALINDE HURLEY

Enzyme-linked immunosorbent assay for measure-ment of antibody against cytomegalovirus andrubella virus in a single serum dilution AM VANLOON, JTHM VAN DER LOGT, J VAN DER VEEN

Trypsinised human 0 erythrocytes in the detectionof rubella-specific IgM by sera fractionation onsucrose density gradient and absorption with staphy-lococcal protein A W AL-NAKIB

Occurrence of IgM antibodies to BK and JCpolyomaviruses during pregnancy PATRICIA EGIBSON, ANNE M FIELD, SYLVIA D GARDNER, DULCIE VCOLEMAN

Human rotavirus antigen detection by enzyme-immunoassay with antisera against Nebraska calfdiarrhoea virus HK SARKKINEN

Technical methodA simple method of concentrating small samples ofcerebrospinal fluid for electrophoresis ARWFORREST

Letters to the Editor

Book reviews

Notices

Copies are still available and may be obtained from the PUBLISHING MANAGER,BRITISH MEDICAL ASSOCIATION, TAVISTOCK SQUARE, LONDON WCIH 9JR, price £3'00, including postage

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