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Dysgerminoma S

Dysgerminoma S

Postgrad Med J: first published as 10.1136/pgmj.43.500.400 on 1 June 1967. Downloaded from

Postgrad. med. J. (June 1967) 43, 400-405.

Dysgerminoma S. A. SELIGMAN M.D., F.R.C.S., M.R.C.O.G. Luton and Dunstable Hospital

IT IS generally accepted that the is The cytoplasm is clear except where retracted by a tumour arising from the ovarian germ cells. It fixation. There is a striking picture of uniformity is identical with its male counterpart, the semi- of the cells which are arranged in an alveolar noma, and with tumours found in other areas pattern, being separated by fibrous septa infiltrated where germ cells may be present-retroperitoneally by . In some areas a columnar and in the thymus and pineal. The origin of this arrangement may predominate. There may be areas type of tumour from the spermatogonia of of necrosis and symplastic giant cell formation. atrophic tubules has been demonstrated in dogs The clinical features of dysgerminoma have (Scully & Coffin, 1952) although these tumours, been studied in a series from the Tumour Registry whilst similar in some aspects to the classical of the Royal College of Obstetricians and Gynae- human , in others resemble the human cologists and compared with previous important spermatocytic seminoma (Scully, 1961). Histo- collections of cases (Novak & Gray, 1938; Seegar, logical relations of the dysgerminoma indicate an 1938; Sjovall, 1943; Santesson, 1947; Mueller, origin from oocytes of the normal female germinal Topkins & Lapp, 1950; Pedowitz, Felmus & lineage (Hughesdon, 1959). Grayzel, 1955; Thoeny et al., 1961; Koller & The typical histological pattern is easily recog- Gjonnaess, 1964; Pece, 1964). copyright. nizable, with large nucleii distorted from their The series, up to the end of 1965, contained basic spherical shape, with one or more nucleoli. twenty-nine cases. One of these was combined with http://pmj.bmj.com/ on September 28, 2021 by guest. Protected

FIG. 1. Dysgerminoma. Postgrad Med J: first published as 10.1136/pgmj.43.500.400 on 1 June 1967. Downloaded from

Dysgerminoma 401 a , the patient dying of leukaemia Some of the women are admitted in an emer- (Chalmers, 1950). This tumour behaved differently gency, either with abdominal pain due to accidents from the rest, the teratomatous element pre- to the tumour, or, as two of the Tumour Registry dominating, and has been excluded from this cases were, because of acute retention of urine. series. It is of interest that one of the patients with There can also be difficulty with micturition of a combined teratoma and seminoma studied by less dramatic onset. the Testicular Tumour Panel and Registry also Other less frequent symptoms were: upset bowel died of leukaemia (Collins & Pugh, 1964). habit, either constipation or diarrhoea, dysmenorr- hoea, general malaise. In two patients the tumour Clinical features was found antenatally (Bigby, 1961). Age incidence (Table 1) The tumour is principally one of young adults. TABLE 3 In about 70% of cases the age of onset is between Symptoms 10 and 30. It is rare after the menopause and in 210 cases from Twenty-six cases girls in whom it occurs before the reproductive age Symptoms literature from Tumour is often accompanied by hormonal changes. (%) Registry (%) Lump 35 58 TABLE 1 Pain 36 46 Age incidence Lump + pain - 27 Menstrual upset - 19 Twenty-eight cases Emergency 14 15 Age (years) 500 cases from from Tumour Urinary upset - 12 literature (%) Registry (%) 0-10 7 4 involved (Table 4) 10-20 37 25 The two are not involved to an equal 20-30 34 46 extent, the and left ovaries affected in right being copyright. 30-40 12 21 the ratio of 5 : 4. This is the same 40-50 5 4 as for involve- 50+ 5 0 ment of the testes with seminoma and is evidence against some of the bizarre theories advanced to explain this discrepancy in the male. It is probably Duration of symptoms (Table 2) of more relevance that in most normal female This is a rapidly growing tumour, usually bring- birds the right gonad is a rudimentary structure as ing the patient to hospital within weeks of the a result of an organ specific inhibitory substance onset of symptoms. It may, however, be asympto- in the left produced gonad (Gardner, Wood & http://pmj.bmj.com/ matic, being found on routine antenatal examina- Taber, 1964). tion or during the investigation of primary In some cases bilateral ovarian involvement is amenorrhoea. found at operation or on histological examination. TABLE 2 In only one case in the series was the apparently Duration uninvolved ovary later the seat of a dysgerminoma, of symptoms after an interval of 2 years. An ovarian biopsy Duration of Sixty-nine cases Twenty-six cases 6 months after the original operation had not symptoms from literature from Tumour revealed any evidence of involvement at that time. on September 28, 2021 by guest. Protected (%) Registry (%) Acute 15 8 TABLE 4 <3 months 54 57 Ovary affected 3-6 months 7 19 6-12 months 10 8 500 cases from Twenty-seven cases > 12 months 7 0 Side literature from Tumour Registry Asymptomatic 7 8 (%) (%) Right 50 44 Symptoms (Table 3) Left 36 37 The commonest presenting symptoms are an Bilateral 14 19 abdominal mass, abdominal pain, or both. Although the tumour is generally regarded as being Mortality (Table 5) hormonally inactive, about 20% of patients had In most patients who die from dysgerminoma, some menstrual upset. Precocious puberty or the the progress of the disease is rapid and they suc- onset of vaginal bleeding in patients with primary cumb within 1 year, after which the death rate amenorrhoea may be the presenting symptom. subsides, but even a 5-year interval of freedom Postgrad Med J: first published as 10.1136/pgmj.43.500.400 on 1 June 1967. Downloaded from

402 S. A. Seligman does not guarantee cure. One patient in the series to be involved at operation in three cases in the developed metastases and died 6 years after the series and the Fallopian tube once, indicating that original operation. In Table 5, percentages are of if conservative surgery is not contemplated the cases surviving. uterus should be removed with both tubes and ovaries. In one patient death was associated with TABLE 5 rupture of an infiltrated bladder. Post-operative survival rates The sites of metastatic spread are difficult to 237 cases from Cases from Tumour define owing to the paucity of post-mortem reports Years literature (%) Registry (%) in the literature and the position with regard to seminoma in the male is little better. Clinical 1 55-5 71 (from 23 cases) reports cannot usually give the precise origin of 5 41 59 (from 17 cases) deeply sited masses. Apart from the patient with the combined teratoma and dysgerminoma, only Survival is markedly related to the extent of the one post-mortem was performed in the series. disease at operation (Table 6). Where this is limited Common sites of appear to be along to one ovary, the outlook is good, but where the the aortic chain of lymph nodes and in the supra- tumour has spread, and this includes bilateral clavicular nodes. Any of the abdominal viscera ovarian involvement, the outlook is poor. may be involved, particularly the liver and kid- neys. Lungs, pleura and are the sites TABLE 6 of frequent metastasis, whilst the vertebrae in all Effect of extent of disease on 5-year survival rate regions of the spine seem particularly prone to 215 cases from Seventeen cases from involvement with large malignant masses and Extent of literature Tumour Registry consequent paralysis. disease (%) (%) Limited 64 90 Tumours of dysgenetic gonads Spread 23 14 Robert Meyer (1931) who first suggested the copyright. name disgerminoma (spelled dis-) found the The presence of bloody ascites at operation is of tumour to occur in twenty-seven intersex patients grave import, clear ascites not necessarily so but only twenty-one apparently normal females. (Table 7). This is overemphasized in the Tumour This ratio has not been confirmed. In the Tumour Registry series due to the small numbers involved. Registry series four patients had intersex states. One had a mixed , the chromo- TABLE 7 somal complement of patient and tumour being Effect of ascites on 5-year survival rate of the normal male type (Seligman, 1967). The http://pmj.bmj.com/ precise nature of the intersex condition in the other Thirty-one cases Six cases from three is not known, but testicular tissue was Type of from literature Tumour Registry present ascites in one and typical dysgenetic gonads with calcifi- (%) (%) cation in another. Clear 33 100 In 1953, Scully described a gonadal tumour, Bloody 12-5 0 which he named a gonadoblastoma, in part dys-

but elsewhere composed of Sertoli or on September 28, 2021 by guest. Protected The operative findings give a good indication granulosa cells and Leydig or theca cells, and of the prognosis. Those patients who at operation associated with masculinization. He refers to these are found to have growths which have spread cells as respectively of sex-cord and mesenchymal beyond one ovary, with haemorrhagic ascites, origin although the embryological derivation which adhesion or rupture of the tumour, are killed by he gives is not universally accepted (Richardson, their disease usually within weeks of operation and 1966) and the female cells morphologically corre- almost invariably within 3 years, and in this group sponding to the Leydig cells are the ovarian hilus of patients the tumours do not readily respond to cells. radiotherapy. In patients with a solitary encap- The gonadoblastoma probably always arises in sulated tumour, not adherent and with no ascites, tissues of testicular origin containing the Y there is a good prognosis, most recurrences being chromosome (Teter et al., 1964b), the gonads being extremely radiosensitive and radiocurable. Only dysgenetic, that is, unlike the agenetic or streak one such patient in the series died, following a gonads of Turner's syndrome, containing recog- recurrence at 3 years. nizable germ cells and sometimes the non-germinal Spread of the disease in the pelvis can occur in elements discussed above. Degeneration and cal- any direction by infiltration. The uterus was found cification are frequent in dysgenetic gonads and Postgrad Med J: first published as 10.1136/pgmj.43.500.400 on 1 June 1967. Downloaded from

Dysgerminoma 403 the calcification may be visible on X-ray. Calcifica- associated rarely with precocious puberty preced- tion is also found in the testes of ing virilization. They are sometimes palpable on and testicular feminization. It is never observed in clinical examination but often only revealed at dysgerminoma or seminoma in patients with laparotomy. They may be present with acute pain normal somatosexual development. due to torsion. In only about 10% of cases are In order to understand the significance of there symptoms indicating a rapidly growing tumours of dysgenetic gonads, some of the experi- tumour and in these cases histological examination mental studies on the production of gonadal shows the predominant tissue to be the dys- tumours may be given. germinomatous element. Granulosa cell tumours can be produced in the Teter (1960) has extended the classification of experimental animal either by irradiation (Furth these tumours, mainly on a histological basis. He & Butterworth, 1936), or by inactivating the calls the tumours gonocytomas and describes four oestrogen output of the ovary in the liver by trans- types. planting the gonad into the spleen (Biskind & Gonocytoma Type I. This consists of pure Biskind, 1944). Similar tumours are produced by dysgerminoma. testicular transplantation (Biskind & Biskind, 1945) Gonocytoma Type 11. This is a mixed form con- and these tumours may become malignant and sisting of dysgerminoma cells associated with metastasize (Li, 1948). Sertoli-granulosa type cells. These may present an It is thought that the experimental production of ovarian follicular type pattern with Call-Exner these gonadal tumours is due to a constant excess bodies or a testicular tubular pattern and both may secretion of gonadotrophin by a pituitary freed be present in the one tumour. Teter described this from oestrogenic or androgenic control (Burrows type as sometimes showing oestrogenic activity & Horning, 1952). Chorionic gonadotrophin will which disappears following removal of the also produce increased activity in ovarian hilus tumour, but this is unusual and oestrogenic effects cells (Sternberg, Segaloff & Gaskill, 1953). are not restricted to this group. There have been The dysgenetic gonads of the intersex patient metastases from tumours of this nature, but only copyright. may be likened to these gonads in experimental the dysgerminomatous elements have been affected animals, having the same hormonal environment. with no evidence of follicular structures. There is a tendency to hyperplasia and neoplasia Gonocytoma Type III. This contains three types in dysgenetic gonads and the early stages of this of cells: (1) germ cells, (2) Sertoli-granulosa cells, have been described as gonadoblastoma-in-situ and & (3) Leydig-thecalutein type cells. It is often (Teter, Philip Wecewicz, 1964a). The germ cells associated with virilization, although such tumours may give rise to dysgerminoma and the non- have been described with effects

oestrogenic http://pmj.bmj.com/ germinal elements may also form tumours, the (Strumpf, 1965) or precocious puberty (Borghi occurrence of Leydig cell tumours being a well- et al., 1965). Teter regards this tumour as identical recognized hazard of dysgenetic gonads (Warren with the et gonadoblastoma, but Scully makes it al., 1964). The incidence of neoplasia in dys- quite clear that the tumour may be diagnosed with- genetic gonads is high. Teter & Tarlowski (1960), out all three cell in thirteen types being demonstrable histo- personal cases, found two dys- logically, quoting reported cases which Teter , one gonadoblastoma and one hilus as into cell tumour. regards falling Types II or IV. In the retained testes of Gonocytoma Type IV. This Teter describes in on September 28, 2021 by guest. Protected the testicular feminiza- cases with of virilism tion syndrome, Morris & Mahesh (1963) found symptoms which disappear one after removal of the tumour. Histologically he only reported malignant tumour among teen- describes a and two in their homogenous form of gonocytoma with aged patients twenties, but in proliferation of the or fifty cases aged 30 or over there were eleven malig- Leydig thecalutein type cells nant either marginally or in the opposite gonad. This tumours, mainly germinomas, as well as histological picture can also be found in patients fifteen tubular adenomas and ten cysts. This figure in does not whom the virilism is preceded by precocious probably give a true incidence of neo- isosexual puberty (Giusti et al., 1962). plasia in these patients as symptoms of the One of tumours were the features. the patients in the Tumour Registry presenting series also had precocious puberty (Hain, 1949) and this case is instructive in that after the publica- Gonadoblastoma: clinical features tion further sections of the tumour showed These are benign tumours, often bilateral, and chorion-epitheliomatous elements, emphasizing in 75% of patients are discovered in the investiga- that the cellular tion of complete composition of a tumour primary amenorrhoea or other features of may not be revealed in the material taken for intersex conditions, although they have been histological examination. Postgrad Med J: first published as 10.1136/pgmj.43.500.400 on 1 June 1967. Downloaded from

404 S. A. Seligman Teter's classification does not give a complete patients had an initial radical operation but it is picture of the tumour and its hormonal effects, not known if radiotherapy was given in this case. merely the cellular elements demonstrable in the Excluding this patient, who has not had any recur- sections studied. It would seem best to give a full rence, two patients only had radiotherapy post- description of both histological and hormonal operatively and neither has a recurrence. features in tumours of dysgenetic gonads, this This leaves twelve patients treated by operation being the best generic name for the group. only. Recurrences occurred in four of these. One, the patient with the unilateral gonad, aged 47, Treatment of dysgerminoma developed metastases 3 years after operation, was The definitive treatment of dysgerminoma is given radiotherapy but died. The remaining three total hysterectomy with bilateral salpingo- developed metastases after 2 years, 2 years and 9 oophorectomy followed by intense radiotherapy to months which responded to irradiation and they the pelvis and aortic lymph nodes. were alive and well 9, 7 and 3 years later. Radical surgery will usually be performed in The outcome in these twelve patients may be those patients in whom a pre-operative diagnosis compared with that of twenty-two patients with is possible-namely, patients with intersex con- similar lesions who were given conservative radio- ditions, in patients with obvious malignant or therapy at the Radiumhemmet. Two of these bilateral disease, in post-menopausal patients and patients were dead within 5 years and another two in some patients where a frozen section is available developed metastases which responded to further at operation. Often none of these conditions will radiotherapy. This does not demonstrate any prevail and the histological diagnosis only become marked superiority in the use of prophylactic con- available after the removal of a solitary ovarian servative as against therapeutic radiotherapy tumour. In a woman who has completed child- reserved for recurrences. Although current opinion bearing a full course of radiotherapy should be favours prophylactic radiotherapy, the figures from given and this is best preceded by re-operation for the Tumour Registry do not support this view. removal of the uterus, Fallopian tubes and remain- copyright. ing ovary. A far more difficult problem is the young patient Summary whose years of childbearing lie ahead. There are A series of cases of dysgerminoma is presented three possible lines of treatment. to illustrate some of the clinical features of this Firstly, the radical treatment already described. tumour. This may be preferred by some of the patients or Related tumours having their origins from their relatives and would generally be considered dysgenetic gonads are discussed. essential in tumours where chorion-epitheliomatous Methods of treatment are considered with par- http://pmj.bmj.com/ or teratomatous elements are present, although the ticular reference to conservation of function. patient already described with chorion- epithelioma (Hain, 1949) had only conservative surgery with no radiotherapy and is alive and well Acknowledgments 17 years later. I wish to thank the Scientific Advisory Committee of the Royal College of Obstetricians and Gynaecologists for Secondly, the patient may be given conservative permission to study and publish this series and particularly radiotherapy, that is with the Dr R. Magnus Haines for his remaining ovary personal help. on September 28, 2021 by guest. Protected shielded. This method is recommended by the Radiumhemmet (Brody, 1961) where eighteen pregnancies occurred in ten patients. There were References fifteen normal babies, one terminated pregnancy, BIGBY, M.A.M. (1961) Dysergerminoma of the ovary in one but one child pregnancy. J. Obstet. Gynaec. Brit. Emp. 68, 676. abortion, was malformed, a BISKIND, M.S. & BISKIND, G.R. (1944) Development of definite risk under these circumstances. tumours in the rat ovary after transplantation in the spleen. The third possibility is observation, reserving Proc. Soc. exp. Biol. (N. Y.), 55, 176. radiotherapy for those patients in whom there is a BISKIND, M.S. & BISKIND, G.R. (1945) Tumour of the rat recurrence & testis produced by heterotransplantation of infantile testis (Malkasian Symmonds, 1964). to spleen of adult castrate. Proc. Soc. exp. Biol. (N. Y.), In the Tumour Registry series there were fifteen 59, 4. patients with an apparently solitary lesion who BORGHI, A., MONTALI, E., BIGOZZI, U. & GIUSTI, G. (1965) have been followed for 3 years or more. Of these XO/XY mosaicism in a phenotypic female with gonado- all one blastoma. Attempt of classification of the clinical picture except were treated initially by a unilateral of the XO/XY mosaics. Helv. paediat. Acta, 20, 185. operation, although this was the only gonad in one BRODY, S. (1961) Clinical aspects of dysgerminoma of the patient. In one patient the uterus, tubes and re- ovary. Acta radiol. (Stockh.), 56, 209. were excised BURROWS, H. & HORNING, E.S. (1952) Oestrogens and maining ovary later. One of the Neoplasia. Thomas, Springfield, Illinois. Postgrad Med J: first published as 10.1136/pgmj.43.500.400 on 1 June 1967. Downloaded from

Dysgerminoma 405 CHALMERS, J.A. (1950) Two cases of dysgerminoma ovarii, PEDOWITZ, P., FELMUS, L.B. & GRAYZEL, D.M. (1955) one occurring in a malignant teratoma in association with Dysgerminoma of the ovary. Prognosis and treatment. acute myelocytic leukaemia. J. Obstet. Gynaec. Brit. Emp. Amer. J. Obstet. Gynec. 70, 1284. 57, 437. RICHARDSON, G.S. (1966) Ovarian physiology. New Engl. COLLINS, D.H. & PUGH, R.C.B. (Ed.) (1964) The pathology J. Med. 274, 1008. of testicular tumors. Brit. J. Urol. 36, Suppl. SANTESSON, L. (1947) Clinical and pathological survey of FURTH, J. & BUTTERWORTH, J.S. (1936) Neoplastic diseases ovarian tumors treated at Radiumhemmet. Acta radiol. occurring among mice subjected to general irradiation with scand. 28, 644. X-rays. II. Ovarian tumors and associated lesions. Amer. SCULLY, R.E. (1953) Gonadoblastoma. A gonadal tumor J. , 28, 66. related to the dysgerminoma (seminoma) and capable of sex-hormone production. Cancer, 6, 455. GARDNER, W.A., WOOD, H.A. & TABER, E. (1964) Demon- SCULLY, R.E. (1961) Spermatocytic seminoma of the testis. stration of a nonestrogenic gonadal inhibitor produced Cancer, 14, 788. by the ovary of the brown leghorn. Gen. comp. Endocr. SCULLY, R.E. & COFFIN, D.L. (1952) Canine testicular 4, 673. tumors. Cancer, 5, 592. GIUSTI, G., BORGHI, A., BIGOZZI, U., NEGRI, L. & SEEGAR, G.E. (1938) Ovarian dysgerminoma. Arch. Surg. TOCCAFONDI, R. (1962) Ovarian dysgerminoma with 37, 697. precocious isosexual puberty followed by virilization. SELIGMAN, S.A. (1967) Dysgerminoma with atypical mixed Obstet. and Gynec. 20, 755. gonadal dysgenesis. J. Obstet. Gynaec. Brit. Cwlth, 74, HAIN, A.M. (1949) An unusual case of precocious puberty 137. associated with ovarian dysgerminoma. J. clin. Endocr. 9, SJOVALL, A. (1943) Disgerminome des ovariums. Acta 1349. obstet. gynec. scand. 23, 585. HUGHESDON, P.E. (1959) Structure, origin and histological STERNBERG. W.H., SEGALOFF, A. & GASKILL, C.J. (1953) relations of dysgerminoma. J. Obstet. Gynaec. Brit. Emp. Influence of chorionic gonadotropin on human ovarian 66, 566. hilus cells (Leydig-like cells). J. clin. Endocr. 13, 139. KOLLER, O. & GJONNAESS, H. (1964) Dysgerminoma of the STRUMPF, I.J. (1965) Gonadoblastoma in a patient with ovary. Acta obstet. gynaec. scand. 43, 268. gonadal dysgenesis. Amer. J. Obstet. Gynec. 92, 992. LI, M.H. (1948) Malignant granulosa-cell tumor in an TETER, J. (1960) A new concept of classification of gonadal intrasplenic ovarian graft in a castrated male mouse. tumors arising from germ cells (gonocytoma) and their Amer. J. Obstet. Gynec. 55, 316. histogenesis. Gynaecologia, 150, 84. MALKASIAN, G.D. & SYMMONDS, R.E. (1964) Treatment TETER, J., PHILIP, J. & WECEWICZ, G.R. (1964a) Mixed of the unilateral ovarian gonadal dysgenesis with gonadoblastoma in situ. Amer. J. encapsulated dysgerminoma. copyright. Amer. J. Obstet. Gynec. 90, 379. Obstet. Gynec. 90, 929. R. The of some ovarian TETER, J., PHILIP, J., WECEWICZ, G. & POTOCKI, J. (1964b) MEYER, (1931) pathology special A masculinizing mixed (gonocytoma III). tumours and their relation to sex characteristics. Amer. Acta endocr. (Kbh.), 46, 1. J. Obstet. Gynec. 22, 697. TETER, J. & TARLOWSKI, R. (1960) Tumors of the gonads in MORRIS, J.McL. & MAHESH, V.B. (1963) Further observa- cases of gonadal dysgenesis and male pseudohermaphro- tions on the syndrome 'testicular feminization'. Amer. J. ditism. Amer. J. Obstet. Gynec. 79, 321. Obstet. Gynec. 87, 731. THOENY, R.H., DOCKERTY, M.B., HUNT, A.B. & CHILDS, MUELLER, C.W., TOPKINS, P. & LAPP, W.A. (1950) Dys- D.S. (1961) A study of ovarian dysgerminoma with em- germinoma of the ovary. Amer. J. Obstet. Gynec. 60, 153. phasis on the role of . Surg. Gynec. NOVAK, E. & GRAY, L.A. (1938) Dysgerminoma of the ovary. Obstet. 113, 692. http://pmj.bmj.com/ Amer. J. Obstet. Gynec. 35, 925. WARREN, J.C., ERKMAN, B., CHEATUM, S. & HOLMAN, G. PECE, G. (1964) Dysgerminoma of the ovary in pregnancy. (1964) Hilus-cell adenoma in a dysgenetic gonad with Obstet. and Gynec. 24, 768. XX/XO mosaicism. Lancet, i, 141. on September 28, 2021 by guest. Protected

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