Gonadotrophin-Releasing Hormone (GnRH) Analogues in the Treatment of Mixed Mullerian Tumours of the Uterus: Two Case Reports and Review

Subjects/Discussion. Two cases of clinical and radiological response of recurrent mixed Mullerian tumours following treatment with either nasal (Buserilin) or intramuscular (Goserilin) GnRH analogues are reported and a short review of the evidence to support this treatment option presented.


Introduction
M ixed M ullerian tumours, derived from the m esenchym al rem nants of the urogenital ridge and epithelium originating from the coelom ic cavity, are rare but usually rapidly fatal uterine tumours of post-reproductive w om en. Recurrence after surgery is com m on even in app arently early disease and survival despite subsequent radiotherapy or chemotherapy extrem ely poor.
The in vitro ® nding of G nRH receptors on som e tum our lines led us to try treatment w ith nasal G nRH analogues in two patients with som e signi® cant, albeit temporary, success.

C ase 1
A 70 year-old m other of eight children, presented in April 1993 with a short history of post m enopausalbleeding. She had passed through the m enopause aged 38 and had never taken horm one replacem ent therapy. Her past m edical history included recently diagnosed non-insulin dependent diabetes m ellitus w ith nothing else of relevance.
There was no evidence of uterine enlargem ent on exam ination, but Vabra curettage suggested a heterologous m alignant m ixed M ullerian tumour (Carcinosarcom a) and she subsequently underwent a total abdom inal hysterectomy with bilateral salp-ingo-oophorectomy and om entectomy. T here was no evidence of extra-uterine spread at laparotom y and histology con® rm ed a poorly differentiated carcinosarcom a with no m yometrial invasio n (Stage 1a).
D espite the early stage at presentation, within a year (M arch 1994) she developed pelvic pain asso ciated w ith a palpable vaginal m ass. A CT scan con® rm ed a soft tissue mass 4 3 5 cm above the vaginal vault causing partial right ureteric obstruc-F ig. 1. C T scan (pelvis) of patient (C ase 1) before treatm ent with a G nR H analogue dem onstrating a right-sided m ass of recurrent tum our (arrowed) causing ureteric obstructio n. 1996. From February 1996 there w as rapid local growth in the pelvis and she died from obstructive renal failure in April 1996.

Case 2
A 49 year-old m other of two was referred from a m enopause clinic w ith a short history of irregular vaginal bleeding on com bined horm one replacement therapy, w hich she had taken for ® ve years. She had a com plex past m edical history featuring several operations for adenocarcinom a of the bow el (complicating polyposis coli), culm inating in a panproctocolectom y with ileostom y form ation in 1986. A further operation for bowel obstruction had taken place in 1989, with no evidence of tumour recurrence. Vabra curettings obtained on 5 July 1993 demonstrated app arently poorly differentiated adenocarcinom a of endom etrial origin, but im m unocytochemistry of the subsequent hysterectomy specimen con® rm ed a heterologous m alignant mixed m esoderm al tumour. Tum our volum e was small and in® ltration con® ned to the super® cial m yom etrium only (Stage 1b).
After som e initial com plications arising from her previous extensive pelvic surgery, she rem ained well until D ecem ber 1994, when she developed pelvic pain and haem aturia associated with a pelvic m ass.
M RI scanning con® rm ed a 5 3 5 cm vault m ass extending to S3, w ith no pelvic lym phadenopathy. Subsequent cystoscopy excluded invasive tum our in the bladder.
She was comm enced on G oserelin acetate 3.6 m g/28 days in February 1994. There w as rapid clinical regression, and both a C T scan and M RI perform ed in June 1994 show ed no evidence of tum our progression.
After com pleting six cycles of G oserilin she rem ained in rem ission until N ovem ber 1994, when increasing pelvic and low back pain was found to be associated with radiological recurrence. She was com m enced on salvage radiotherapy (Mid plain dose of 40 Gy in 20 daily fractions); despite som e initial success in sym ptom reduction, she developed recurrent sm all bow el obstruction associated with progressive left iliac lym phadenopathy. T he form er was thought more likely to be due to surgical adhesions rather than tumour, and w ith careful dietary adjustm ent and pain control she rem ained reasonably well until April 1996.
Increasing back pain w as asso ciated with tum our re-growth and was treated with three cycles of C yclophosph am ide (Farm italia, UK ) and Cisplatin (Farm italia, U K) in early 1996; clinically there was a partial response, but radiological con® rm ation was dif® cult because of her previous surgery. Incontrovertible evidence of tumour progression was, however, shown on PET scanning in M arch 1997, and she is currently m anaged on M ST 300 m g bd,

F ig. 3. M R I scan (pelvis) of patient (Case 1) three m onths after completing treatm ent with a G nR H analogue. Post-treatment evidence of enla rgem ent is now present (arrowed) but areas of central necrosis persist and there is com pression rather than invasion of local structur es.
tion and right-sided pelvic lym phadenopathy extending to the para caval region (Fig. 1). In view of her pain and the rapid return of disease she w as com menced on G oserelin acetate 3.6 mg/28 days (Zoladex, ICI, UK ) w ith rapid resolution of sym ptom s. Pelvic exam ination w as norm al in June 1994 and m agnetic resonance im aging (M RI) perform ed the sam e m onth showed no signi® cant increase in tum our size or progression of the pelvic lymphadenopathy (Fig. 2).
She rem ained in both radiological and clinical rem ission and com pleted the six-m onth course of treatment. F urther M RI assessm ent in D ecember 1994 showed evidence of central necrosis in the tum our m ass and no lym phadenopathy (Fig. 3).
In March 1995 a further episode of vaginal bleeding heralded the return of progressive tum our. An offensive polypoid tumour arising from the vaginal vault was excised and com bined radiotherapy and nasal Buserelin acetate 150 m g TD S (Suprecur, H oeschst, U K) suppressed her disease until early Am itriptyline 10 m g nocte and O romorph 40 m g as required.

D iscussion
M ixed M ullerian tumours are traditionally divided into two groups depending on whether the m esenchym al and epithelial elements are uterine (`hom ologous' , e.g. sm ooth m uscle, endom etrial strom a) or non-uterine (`heterologous' e.g. striated m uscle, cartilage, bone) in origin (Table 1). Carcinosarcom as, containing m alignant com ponents from both cell lines, are com m oner than the pure uterine sarcom as but still com prise less than 2% of uterine tum ours. 1,2 They are rare during reproductive life, with a m edian incidence at age 65. 3 Risk factors overlap w ith endom etrial cancer (nam ely hypertension, diabetes and nulliparity) but to a lesser degree. 2 The m ost reliable risk factor is previous pelvic irradiation, although the true incidence (between 5 and 35% at ten years) is disputed. 4 Staged in the sam e m anner as endom etrial tum ours, treatm ent of early disease is by total abdom inal hvsterectomy and bilateral salpingooophorectomy w ith peritoneal cytological sam pling. 5 T he role of lym phadenectom y rem ains unclear. Prognostic indicators such as the degree of m itotic activity, cellular atypia and cervical involvem ent are less useful than in endom etrial tumours, 6 although vascular involvem ent and positive cytology are of sinister portent. 7 W hether to treat with adjuvant radiotherapy or chem otherapy (and indeed the optim um timing and/ or agent used) is still uncertain, with distant recurrence a perpetual problem. 2 Advanced (stage III and IV) or recurrent disease has an app alling prognosis regardless of treatm ent. 8 Speci® c GnRH receptors have been dem onstrated in normal m yom etrium , leiyom yom ata, 9 epithelial ovarian and endom etrial cancer cells, 10± 12 and a num ber of hum an cancer cell lines (M CF-7, M D A-M B-231, LN CaP ). 13 In vitro inhibition of growth by G nRH analogues has been clearly demonstrated in ovarian tum ours 14 and there has been som e early (and limited) success in treating advanced endom etrial and ovarian cancer with Goserelin. 15,16 In the above cases the clinical situation was judged to warrant intervention w ith as few sideeffects as possible. Both women were in® rm and reluctant to undergo radiotherapy or aggressive chem otherapy; adverse effects of G nRH treatm ent were thought to be unlikely and treatment comm enced on the ® rst H ippocratic principle.
There was con® rm ed clinical rem ission in both cases lasting over a year w ith no signi® cant sideeffects. W e suggest that further research in elucidating the role of GnRH analogues in the treatment of these rare tumours is indicated at both a cellular and therapeutic level.