British HeartJournal, I974, 36, 6I3-6I6.

Carcinoid heart disease from primary carcinoidtumour of the ovaryHaemodynamic and cine coronary angiocardiographicstudy after operation

E. Stephan and J. de WitFrom the Department of Internal Medicine, Baabda State Hospital, and the Laboratory of Histology, FrenchFaculty of Medicine, Beirut, Lebanon

Eight cases of carcinoid heart disease associated with primary ovarian carcinoid tumour have been previouslyreported. A case is described in which rapid relief of all symptoms followed removal of an ovariancarcinoid argentaffin tumour. A diagnostic finding was the provocation offlushing by pressure on the ovarianmass on vaginal examination. Cardiological investigations, performed two and a half months after operation,are presented. A peculiar angiocardiographic feature was the loss of trabeculations of the right ventricle.

Examples of primary carcinoid tumour of the ovaryare being recognized with increasing frequencysince the report of the first two cases by Stewart,Willis, and De Saram (I939) and more particularlyafter the classical description of the carcinoid syn-drome in 1954 (Thorson et al.). Ghatterjee andHeather (I968) reviewed 31 cases up to I967. Inthe recent series of Haines (I97I), 6 cases out of 8were considered primary. Primary ovarian car-cinoids commonly arise from an element of abenign cystic teratoma (dermoid cyst). When noteratomatous elements are found, a diligent searchis necessary to rule' out ovarian metastasis from anextrinsic source, usually the small bowel. It is notknown why some carcinoids release endocrine pro-ducts while others do not. Chatterjee and Heather(I968) could find features of the carcinoid syndromein I4 cases out of 3I, and Haines (197I) in 4 casesout of 8 at the time of operation.

Carcinoid heart disease complicates primarycarcinoid of the ovary only in some cases and istherefore more rare. Chatterjee and Heather (I968)reported a case and reviewed three others up toI967 (Thorson et al., I958; Torvik, I960; Elis,I965). A fifth case with necropsy findings is that ofBancroft, O'Brien, and Tickner (I964). Since I967,3 new cases have been reported (Ruckes and Stall-kamp, I967; Mouchet, Guivarc'h, and Voinchet,I969; Acar et al., I970). Three patients diedwithout operation. At necropsy the typical endo-

cardial fibrosis was found with pulmonary stenosisand tricuspid valvar disease. The 6 other patientsunderwent laparotomy with oophorectomy. Rapidrelief of symptoms was obtained in all 6 patients.The ovary is a unique site for primary carcinoids

because endocrine products of the tumour aredrained directly into the systemic venous circula-tion. Thus the carcinoid syndrome is likely to appearearly and before any metastasis has occurred.Therefore, radical surgical cure is possible. Unlikecarcinoids of the ovary, carcinoids of the small in-testine have their endocrine products drained intothe liver where they are metabolized. Thus thecarcinoid syndrome does not occur unless metastaseshave been established in areas (mainly in the liver)with direct access to the systemic venous circulation.However, long-term prognosis in primary ovarian

carcinoid is uncertain. Metastases have occurred in2 cases of Haines' series (I97I) with death i and 7years after surgical removal of the primary tumour.

Case reportA 48-year-old married woman was referred in Sep-tember I972, for an intractable heart failure withorthopnoea, ascites, and lower limb oedema of about 8months' duration. She was treated with digoxin, 0o5 mgper day, and diuretics. She had suffered during theprevious 2 years from cough and short attacks of wheez-ing. At the same time there had been chronic diarrhoeawith borborygmi and weight loss from 94 to 70 kg.

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Recently, her stools had become almost liquid, with I0to 15 motions per day. There was no previous history ofrheumatic fever, chorea, leg phlebitis, kidney, or liverdisease. She was not diabetic. She had had 7 normalpregnancies and deliveries, the last one i6 years ago.Her periods ceased at the age of 44.The whole body skin was red in colour, the covered

parts pink, the face and dorsum of hands dark red andmildly cyanotic. The cheeks and nose were scaly with adirty-brown colour suggestive of pellagra. Four or fivesmall venous telangiectases were noted on the face. Shehad a history for the past 13 to 14 years of spells ofgeneralized hot flushes which increased in severity anddaily frequency from year to year. They used to lastfrom 5 to 20 minutes. They were brought on by emotion,straining at stool, strong vinegar, some cough syrups,and, instantly, by any alcoholic beverage intake. Thetongue was mildly sore and hyperaemic with a largedorsal depapillated area. The thyroid was not enlarged.The neck veins were much distended and strongly pul-sating with systole. The right lung base was dull.

Cardiac examination revealed a diffuse praecordiallift, more pronounced in the sternal and left parasternalregion, a loud parasternal pansystolic murmur whichdid not increase with inspiration with a faint diastolicrumble, and a soft systolic ejection murmur at the pul-monary area. Phonocardiograms confirmed these find-ings. The electrocardiogram showed pronounced rightaxis deviation and low voltage of QRS in all leads. Chestradiography showed a cardiothoracic ratio of 18.5/30 cm,with right atrial and ventricular enlargement. The liverwas palpable 5 fingerbreadths below the right costalmargin, and systolic pulsation was felt. There wasabdominal shifting dullness. The spleen was not palp-able.There was a massive pitting oedema involving the

whole lower limbs and the lower part of the abdominalwall. There was no hirsutes and fat distribution wasnormal. Blood pressure readings were within normallimits and did not show any remarkable variations duringflushing attacks.On vaginal examination a mass was felt in the right

pelvis. Palpation of this mass was followed by a flushingspell.

Routine blood examination, including urea, sugar,creatinine, alkaline and acid phosphatases, electrolytes,red and white blood cell count, haematocrit, haemo-globin, platelet count, and prothrombin time werenormal. The urine contained few red cells and a trace ofprotein. Determination of the 24-hour excretion of 5-hydroxyindole acetic acid (5-HIAA) in the urine wasdone three times at weekly intervals; the results werei8o, 2I0, and I94 mg, respectively.

Search for carcinoid tumours included chest tomo-graphy, gastrointestinal tract radiography with specialattention to the small intestine, and barium enema up tothe distal ileum. No abnormal findings were disclosed.Rectosigmoidoscopy up to 30 cm was normal. Radio-isotope scans of the liver with Technetium and colloidalgold did not reveal any filling defect.The pelvic mass was then again palpated on vaginal

examination and gently squeezed. A severe flushing

attack occurred. This was obtained several times againwith the same manoeuvre the following days. It did notoccur with manipulation of the pouch of Douglas, theuterus, and the left pelvis. Likewise, the liver, which wasmuch enlarged and possibly infiltrated, was compressedduring full inspiration and expiration. No flushingoccurred.A median laparotomy was performed in October

1972. About 2500 ml straw-coloured ascitic fluid wereaspirated. A tumour, the size of a big apple, was foundin the place and site of the right ovary. It was not ad-herent to the surrounding tissues and was easily re-sected. On section, it was found to be entirely solid andfirm, and as it was thought to be cancerous a totalresection of the uterus with the left ovary and tube wasperformed. The appendix and the omentum, though ofnormal appearance, were also removed. Scrutiny of thecolon, small intestine, pancreas, stomach, and externalbiliary ducts did not reveal any abnormalities. Lymphglands were not enlarged. The liver, about twice itsnormal size, was congested and pulsating strongly witheach heart beat. No induration could be felt. Two liverbiopsy specimens were taken from the right and leftlobes.

PathologyThe ovarian mass, examined after fixation for 24 hoursin formalin, was ovoid and well encapsulated. It meas-ured iix8x6cm and weighed 42og. On section, itwas firm, solid, and yellowish. Microscopical sections(Fig. a to d) were typical of carcinoid tumour; therewas a dense fibrous stroma infiltrated by mainly solidmasses and strands of closely packed cells. The capsule,though infiltrated, was not perforated. The cells haduniform shape, size, and nuclei. Confirmatory evidencewas obtained from the argentaffin reaction. Thoroughsearch for teratomatous elements was negative. Nothingcould be recognized of the ovarian structure.The right Fallopian tube, left ovary and tube, uterus,

appendix, and omentum were normal. The liver biopsyspecimens did not show any carcinoid metastasis. Thepleural fluid and the ascitic fluid did not show anymalignant cells.

ProgressThe postoperative course was smooth and there was

no more flushing, erythema, and cyanosis as from thethird day. All symptoms cleared in less than 2 weeks,including orthopnoea, lower limb oedema, and diarr-hoea. Ascites did not recur.Two and a half months after operation we performed

right and left heart catheterization with coronary arterio-graphy, and left and right ventricular angiograms. Thehaemodynamic data are indicated in the Table. A prom-inent 'v' wave in the right atrium, consistent withtricuspid regurgitation, and mild pulmonary stenosiswere evident. Cine coronary arteriography showedmoderate disease in the proximal anterior descendingartery, just at the origin of a large diagonal branch, andsome mild irregularities of the right coronary artery.

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Carcinoid heart disease from primary carcinoid tumour of the ovary 6I5

*

* ~~isi I~~~1I 4b~~

b

c d

FIG. Microscopical sections showing (a and b) a dense stroma infiltrated by carcinoid cells invarious arrangements (Haematoxylin and eosin); (c and d) cytoplasmic argentaffin re-action with a curious annular perinuclear arrangement ( Gomori stain). Magnifications are 8ofor a and c, 335 for b and d.

TABLE Haemodynamic data

Position Pressure (mmHg) 02 Saturation (%)Phasic Mean

Pulmonary artery 30/12 I8 6oRight ventricle 45/I6 60Right atrium a i6

V 24 i6 60Brachial artery I42/85 I05Ascending aorta 154/82 I05 96Left ventricle I54/15 96Left atrium to left No diastolic

ventricle pullback gradientLeft atrium I4 96

Arterial-mixed venous 02 difference, 6-i ml/ioo ml; cardiacoutput, 3-9 1./min; cardiac index, 2-2 1./min per M2; strokeindex, 23 ml; systemic resistance, 20 units (mmHg/l./min/mi2); pulmonary resistance, i unit (mmHg/l./min/m2); heartrate, 96/min.

Cine angiocardiography showed left ventricular con-tractions to be within normal limits. No mitral stenosisor regurgitation were seen. The right ventricular con-

tractions were moderately depressed with moderate in-crease in end-systolic and end-diastolic volumes. Theright ventricle appeared to be enlarged and there was lossof the right ventricular trabeculations. There was severetricuspid regurgitation seen from the first beat with an

irregular tricuspid valve. No calcification was seen. Theright atrium was large and about one and a half times thesize of the right ventricle.

In November I973, I3 months after operation, most ofthe physical signs related to the cardiac involvement hadalready disappeared. There remained a faint systolicmurmur at the left sternal border which did not increasewith respiration. Neck veins were no longer prominentand their pulsations appeared to be normal. The liver,about two finger-breadths below the costal margin, nolonger pulsated. The electrocardiogram was unchanged.The heart size radiologically had decreased. She re-mained symptom free and 5-HIAA determination at

a

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6I6 Stephan and de Wit

monthly intervals ranged between 3 and 5 mg in 24-hour urine.

CommentsIf the first spells of hot flushes are to be consideredas indicative of the tumour activity, then the age ofthe tumour must be at least 13 to I4 years. Severalgynaecological examinations had been done beforeand after menopause, the last two years ago. Noovarian mass had been felt, presumably because thetumour, though active, was too small to be palpated.

Bimanual compression of the ovarian massvaginally provoked flushing, suggesting an ovariancarcinoid, though not necessarily primary. Suchpressure on the tumour might also account for theflushing spells on straining during defaecation.As usual in carcinoid heart disease, the cardiac

findings in our patient consisted of enlargement ofthe right heart chambers with pulmonary and tri-cuspid valvar lesions. Pulmonary valve stenosis wasnot visualized in the cine angiocardiograms. Theloss of the trabeculations of the right ventricle waspresumably caused by the endocardial fibrosis,considered to be the main cardiac pathologicalfeature of carcinoid heart disease.

We are grateful to Dr. Edgar M. Gedeon, Chairman ofthe Department of Pathology of the Central PublicHealth Laboratory, for the pathological study of ourcase; to Dr. Said Sayegh, cardiologist of the BerbirMedical Centre, who performed the haemodynamic andcine coronary angiocardiographic studies; to Dr. G.Scandar who operated on the patient; and to Dr.Robert Misk, senior gynaecologist at Baabda StateHospital, for his assistance and advice.

ReferencesAcar, J., Auriol, M., Lain6e, R., Hanania, G., Grimberg, F.,

El Hachimi, and Adam, Y. (I970). Cardiopathie car-cinoide et tumeur de l'ovaire. A propos d'un cas anatomo-clinique. Annales de Midecine Interne (Paris), I2I, 329.

Bancroft, J. H. J., O'Brien, D. J., and Tickner, A. (I964).Carcinoid syndrome due to carcinoid tumour of theovary. British Medical Journal, 2, I440.

Chatterjee, K., and Heather, J. C. (I968). Carcinoid heartdisease from primary ovarian carcinoid tumors. A casereport and review of the literature. American Journal ofMedicine, 45, 643.

Ellis, J. D. (I965). Carcinoid syndrome resulting from aprimary argentaffinoma of the ovary. Proceedings of theRoyal Society of Medicine, 58, 237.

Haines, M. (I97I). Carcinoid tumours of the ovary. Journal ofObstetrics and Gynaecology of the British Commonwealth,78, I123.

Mouchet, A., Guivarc'h, M., and Voinchet, 0. (I969). Lescarcinoides primitifs de l'ovaire. J7ournal de Chirurgie,97, 9.

Ruckes, J., and Stallkamp, B. (I967). Zur Morphologie undGenese des primaren ovarialcarcinoids. FrankfurterZeitschrift far Pathologie, 76, 235.

Stewart, M. J., Willis, R. A., and De Saram, G. S. W. (1939).Argentaffine carcinoma (carcinoid tumour) arising inovarian teratomas. A report of two cases. Jrournal of Path-ology and Bacteriology, 49, 207.

Thorson, A., Biorck, G., Bjorkman, G., and Waldenstrom, J.(I954). Malignant carcinoid of the small intestine withmetastases to the liver, valvular disease of the right side ofthe heart (pulmonary stenosis and tricuspid regurgita-tion without septal defects), peripheral vasomotor symp-toms, bronchoconstriction and an unusual type of cyan-osis. American Heart_Journal, 47, 795.

Thorson, A., Hanson, A., Pemow, B., Soderstrom, N.,Waldenstr6m, J., Winblad, S., and Wulff, H. B. (1958).Carcinoid tumour within an ovarian teratoma in a patientwith the carcinoid syndrome (carcinoidosis). Acta MedicaScandinavica, I6I, 495.

Torvik, A. (I960). Carcinoid syndrome in a primary tumourof the ovary. Acta Pathologica et Microbiologica Scandi-navica, 48, 8i.

Requests for reprints to Professor E. Stephan, Depart-ment of Clinical Medicine, French Faculty of Medicine,Beirut, Lebanon.

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