Endometrial carcinoma in postmenopausal patients using hormone replacement therapy: a report on four cases

q1999 Blackwell Science Ltd Gynaecological Endoscopy 1999 8, 235–241 235

CASE REPORT

Endometrial carcinoma in postmenopausal patients usinghormone replacement therapy: a report on four cases

Hugo Maia Jr, Amelia Maltez, Luis C. Calmon, Katarina Moreira andElsimar M. CoutinhoEndoscopy Unit, CEPARH, Salvador, Bahia 4021 341, Brazil

ABSTRACT

Objective To report the occurrence of endometrial carcinoma in polyps inpostmenopausal patients using hormone replacement therapy (HRT).Setting A private hospital with facilities for carrying out hysteroscopy.Subjects Four postmenopausal patients who developed endometrialcarcinoma while using HRT.Interventions Hysteroscopy with biopsy, immunohistochemical investigationfor oestradiol, progesterone receptors and p53 overexpression.Results All four cases of carcinoma were associated with endometrialpolyps. The cancerous cells were positive for oestrogen receptors, negativefor progesterone receptors and showed p53 overexpression in all cases.Conclusions The lack of detectable progesterone receptors in endometrialcarcinomas arising in polyps in HRT patients indicates an unopposed actionof oestrogens, which may accelerate the carcinomatous changes in polypsthrough a p53 pathway.

Keywords

endometrial carcinoma, endome-trial polyp, hormone replacementtherapy (HRT), p53, postmeno-pausal bleeding, steroid receptor.

CorrespondenceH. Maia Jr, Endoscopy Unit, CEPARH, RuaCaetano Moura 35, Salvador, 40210 341Bahia, Brazil.

Accepted for publication 16 December 1998

INTRODUCTION

The use of unopposed oestrogens is associated with anincreased risk of developing endometrial carcinoma inmenopausal patients. This risk is reduced but notcompletely suppressed when progestins are added toprevent the occurrence of hyperplasia induced byoestrogens.1 However, progestins do not reverse allforms of hyperplasia including those in endometrialpolyps.2 This lack of effect is because of decreasedexpression of progesterone receptors in the glandsand stroma of endometrial polyps.3

Recently an increased incidence of endometrialpolyps was reported in menopausal patients with bleed-ing problems after using hormone replacement therapy(HRT).2,4 Polyps in these patients respond only to thegrowth-promoting effects of oestrogens which contri-bute to the persistence of different degrees of hyper-plasia inside these lesions. This unopposed action mayfavour the appearance or growth of carcinomas in

endometrial polyps in menopausal patients usingHRT.

In the present report we describe four cases of endo-metrial polyps which developed after the use of HRT.

METHODS

The diagnosis of endometrial carcinoma was made byhysteroscopy followed by biopsy using a 5-mm suctionKarman curette. This procedure was carried out using aparacervical block and CO2 was used as the distentionmedium. The diagnosis was confirmed by routinehaematoxylin–eosin stain.

The presence of oestrogen and progesterone recep-tors was determined in paraffin-embedded tissue usinga mouse monoclonal antibody to human oestrogen andprogesterone receptors (Dako, Carpinteria, California,USA). The reaction was revealed using labelledstreptavidin–biotin reagents, alkaline phosphataseand fuchsin chromogen (Dako).

236 H. MAIA e t a l .

Overexpression of p53 protein was detected by usinga monoclonal mouse antihuman p53 protein obtainedfrom Dako. The reaction was revealed as describedabove. The tumour was considered positive for p53when there was intense nuclear staining throughoutmalignant epithelium, and negative when only rarenuclei exhibited a positive stain.

CASE HISTORIES

Case 1

A 52-year-old, nulliparous patient presented with heavybleeding after using implants of oestradiol and nome-gestrol acetate for 4 years. The patient was not obeseand had no history of hypertension or diabetes.

Transvaginal sonography showed an endometrialthickness of 23 mm. Colour Doppler revealed the pre-sence of low resistance flow in the endometrium with aresistance index of 0.44. A diagnostic hysteroscopyrevealed a huge polypoid lesion, with an irregularsurface and areas of haemorrhage, occupying most ofthe uterine cavity. The adjacent endometrium lookedatrophic in areas not occupied by the base of the tumor.A suction curettage using a 6-mm Karman curette wascarried out after diagnostic hysteroscopy.

Pathological examination showed the presence of aGII endometrioid carcinoma with 20% of the tumourdisplaying solid areas. In some areas the carcinoma cellshad a papillary pattern. Immunohistochemical investi-gation for steroid receptors was negative for progester-one receptors in both carcinoma and stroma. However,there was strong positivity for oestrogen receptors inthe nuclei of cancerous cells. Overexpression for p53protein was detected by histochemical investigation incarcinoma cells but not in the stroma.

The patient underwent a total abdominal hyster-ectomy with bilateral adnectomy. The pathologicalreport was of a polypoid GII endometrioid carcinoma,occupying most of the uterine cavity with 50% invasionof the myometrium at the base of the polypoid lesion.

Case 2

A 56-year-old patient, gravida 1, para 1, with no historyof diabetes or hypertension, developed an endometrialthickness of 12 mm in 1995, after having used sequen-tial transdermal oestradiol and oral medroxyprogester-one for 1 year. A diagnostic hysteroscopy was carried outwhich revealed the presence of an endometrial polyp.The rest of the endometrium was atrophic. Following

her private physician’s advice, the patient decided tocontinue the same HRT regimen and not to have thepolyp removed.

Uterine bleeding episodes occurred regularly afterprogestin withdrawal, until 1998 when she was referredto our clinic because of persistent bleeding lasting for1 month. The endometrial thickness was then 14 mm,and there was a low resistance flow in the polypdetected by colour Doppler. A polypectomy was carriedout using a 27F resectoscope with glycine as thedistention medium.

Pathological investigation revealed the presence ofcomplex hyperplasia in the polyp with severe nuclearatypia compatible with intraepithelial neoplasia. Theglands showed a back-to-back pattern with little inter-vening stroma, which was devoid of atypical cells.Immunohistochemical examination for steroid recep-tors revealed that there was no staining for progester-one receptors in areas of atypical hyperplasia and theunderlying stroma. However, there was strong positivityfor oestrogen receptors in both areas. Overexpressionof p53 was focal and it was restricted to areas with themost severe atypias. There was no p53 overexpression inthe tumour stroma.

The patient underwent a total abdominal hyster-ectomy with bilateral adnectomy. Pathological exam-ination revealed only the presence of atrophicendometrium and adenomyosis in the uterus (Fig. 1).

Case 3

A 61-year-old, gravida 4, para 4, non-obese patient had ahistory of abnormal uterine bleeding for 2 months afterhaving used continuous conjugated oestrogens andmedroxyprogesterone for 3 years. The endometrialthickness was 23 mm and there was an irregularendometrial–myometrial junction. She underwent adiagnostic hysteroscopy that revealed the presence ofa polypoid tumour occupying most of the uterine cavitywith areas of haemorrhagia. The adjacent endo-metrium looked atrophic. A suction curettage wascarried out after hysteroscopy.

Pathological investigation revealed a high gradeendometrial adenocarcinoma (GIII), with areasshowing the presence of the hobnail cells that arecharacteristic of clear cell carcinoma. The nuclearatypias were severe. The polyp’s connective stalk, withits thick-walled blood vessels, was completely infiltratedby cancer cells. The rest of the endometrium wasatrophic. Immunohistochemical testing revealed thattumour cells and stroma were negative for progesterone

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ENDOMETRIAL CARCINOMA IN POSTMENOPAUSAL PATIENTS USING HRT 237

receptors. However, in some areas of atrophic-appearing endometrium, there was a positive stainingfor progesterone receptors. Ostrogen receptors weredetected by immunohistochemistry in both carcinomaand non-malignant endometrium. There was over-expression for p53 in the carcinoma but not in theatrophic endometrium.

The patient had a total abdominal hysterectomy withbilateral adnectomy. The pathology report was of a high

grade (GIII) carcinoma in a polypoid lesion infiltratingthe upper third of the myometrium at the base of thepolyp. The remaining endometrium was atrophic with athickness of 1 mm (Fig. 2).

Case 4

An 80-year old, gravida 5, para 4, abortion 1, non-obesepatient, who was hypertensive with no history of

q1999 Blackwell Science Ltd Gynaecological Endoscopy 1999 8, 235–241

Figure 1 Immunohistochemicalfindings for steroid receptors and p53overexpression in an endometrial polypharbouring a severe atypicalhyperplasia. Upper panel: absence ofprogesterone receptors in the atypicalglands. Middle panel: positivity foroestrogen receptors. Lower panel: p53overexpression in the atypicalepithelium.


diabetes, presented with slight vaginal bleeding afterusing tibolone for 2 years for the treatment ofosteoporosis.

Transvaginal sonography revealed an endometrialthickness of 12 mm. Diagnostic hysteroscopy revealedthe presence of a friable polyp that was removed with a6-mm suction curette. The endometrium was atrophic.Pathological examination revealed the presence of aGIII endometrial carcinoma confined to the polyp.Immunohistochemical testing showed positivity foroestrogen receptors in the cell nuclei of both carci-noma and benign glands in the polyp. Progesteronereceptors, on the other hand, were negative in both. Anoverexpression of p53 protein in the nuclei ofcarcinoma cells was shown by immunohistochemistry(Fig. 3).

DISCUSSION

This paper reports the occurrence of endometrialcarcinoma in four menopausal patients using HRT. Inthree instances the patients were using an oestrogen

plus a progestin and the fourth patient was usingtibolone, which has a progestogenic-like action on theendometrium. In three cases, the origin of the carci-noma could be traced to an endometrial polyp and inthe remaining one the endometrial carcinoma devel-oped as a polypoid lesion. The endometrium wasatrophic in three of the cases.

All four carcinomas, according to immunohisto-chemical findings, were negative for progesteronereceptors and strongly positive for oestrogen receptors.The absence of progesterone receptors in these neo-plasms suggests that oestrogens were acting unopposeddespite the concomitant administration of progestin.The absence of progesterone receptors in the benignepithelium of a polyp harbouring a carcinoma indicatesthat oestrogens may have had an unopposed action onpolyps, favouring the progression from hyperplasia tocarcinoma.

The overexpression of p53 protein in these tumours,even in early lesions not yet showing stroma infiltrationby atypical cells, indicates that mutation of this suppres-sor gene may be an early event in the initiation of


Figure 2 High grade carcinoma (GIII)with areas showing hobnail cells in anendometrial polyp. Upper panel: notethe presence of the polyp’s connectivestalk with thick-walled blood vesselssurrounded by cancerous cells. Lowerpanel: there was strong P53overexpression in the nuclei ofcarcinomatous cells.


carcinogenesis in endometrial polyps in HRT patients.The absence of p53 overexpression in the stroma ofthese tumours suggests that p53 alterations are specificto the glandular epithelium. A similar pathway wasreported in a case of clear cell carcinoma arising in anendometrial polyp.5 The occurrence of serous papillaryor clear cell carcinoma confined to an endometrialpolyp has been previously reported during meno-pause.6,7 Mutations of the tumour suppressor p53

gene are also involved in the initial steps of carcino-genesis of these tumours and they are associated with aworse prognosis.8,9

The lack of progesterone receptors in endometrialpolyps makes the latter responsive only to the prolifer-ating effects of oestrogens.3,10 This explains the persis-tence of hyperplasia in these lesions in patients usingHRT, while the adjacent endometrium is atrophicbecause of the suppressive effect of progestins.2 This


Figure 3 Presence of a high gradeendometrial carcinoma (GIII) in anendometrial polyp. Upper panel: notethe presence of malignant cells in thepolyp’s connective stalk. Middle panel:the tumour was positive for oestrogenreceptors. Lower panel: strong p53overexpression in the nuclei ofcancerous cells was shown.


unopposed oestrogenic action on polyps may favourthe progression from simple to complex hyperplasiawith atypia, and finally to invasive carcinoma, especiallyin the presence of mutation of the p53 tumour sup-pressor gene. This was observed in one patient usingtransdermal oestradiol and oral medroxyprogesterone.Two polyp biopsies taken 3 years apart showed aprogression from simple hyperplasia to a complexhyperplasia with severe nuclear atypias. The immuno-histochemical detection of p53 overexpression in thenuclei of these atypical cells indicates that mutations inthis suppressor gene occurred early in the carcino-genetic process, and this may be a characteristic oftumours that arise in polyps.

Focal expression of p53 protein has been observed inbenign endometrial polyps removed from menopausalpatients using HRT.10 The accumulation of p53 muta-tions may favour an abrupt transition from hyperplasiato carcinoma in polyps, without the slow process thatoccurs in the endometrium stimulated by oestrogens.In colonic polyps, p53 overexpression can antedate theappearance of carcinoma.11 This overexpression mayresult either from the accumulation of the mutant p53protein in cell nuclei or from an increase in p53 wild-type because of the typical genomic instability of thepolyp.

Various cytogenetic abnormalities in the mesen-chymal component of endometrial polyps have beendescribed.12 It is noteworthy that all four cases ofcarcinoma reported in this paper were progesteronereceptor-negative and oestrogen receptor-positive withoverexpression for p53. This supports the hypothesisthat these cancers had their origin in an endometrialpolyp.10 The presence of a connective stalk with thick-walled blood vessels surrounded by cancerous cells,while the rest of the endometrium was atrophic, isfurther evidence of a polyp origin for these neoplasms.The absence of progesterone receptors and the pre-sence of oestrogen receptors in all four cancersindicates that oestrogens stimulated the growth of thesetumours without being antagonized by progestins.Alterations in the p53 tumour suppressor may havecontributed to the appearance of several oncogenesin these cells, which gave them further proliferativeadvantages.

The lack of an effect of progestin on glandularhyperplasia present in polyps may pose a significantrisk for endometrial cancer development, in a patientusing HRT and having such lesions in the uterinecavity.2 Recent reports have indicated that papillaryserous carcinoma is found confined to endometrial

polyps with a significantly greater frequency.6,13 In acase–control study of curettage specimens, patientswho were subsequently found to have endometrialcarcinoma had a higher incidence of polyps comparedwith age-matched controls.14 In one study, polyps werefound adjacent to endometrial carcinomas in 34% ofthe cases.15 These findings suggest that there is at least astatistical, if not causal, relationship between the pre-sence of endometrial polyps and the development orappearance of some forms of endometrial carcinomas.This may be especially true in menopausal patients whodeveloped endometrial polyps after using HRT, becauseof the lack of effect of progestins on these lesions.However, case–control prospective studies are neededin order to determine the actual incidence of carci-noma in endometrial polyps in menopausal patientstaking HRT. Such data cannot be obtained from casereport studies such as this one.

REFERENCES

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2 Maia H Jr, Barbosa IC, Marques D, et al. Hysteroscopyand transvaginal sonography in menopausal womenreceiving hormone replacement therapy. Journal of theAmerican Association of Gynecologic Laparoscopists 1996; 4:13–18.

3 Mittal K, Schwartz L, Goswami S, Demopoulos R.Estrogen and progesterone receptor expression inendometrial polyps. International Journal of GynecologicPathology 1996; 15: 345–8.

4 Ginsburg J, Prelevic GM. Cause of vaginal bleeding inpostmenopausal patients taking tibolone. Maturitas 1996;24: 107–10.

5 Maltez A, Maia H Jr, Oliveira MC, Marques D, CoutinhoEM. Clear cell carcinoma arising in endometrial polyp.Gynaecological Endoscopy 1996; 7: 51–3.

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7 Kanbour-Shakir A, Tobon H. Primary clear cellcarcinoma of the endometrium. Clinicopathologic studyof 20 cases. International Journal of Gynecologic Pathology1991; 10: 67–78.

8 Moll UM, Chalas E, August M, Meaney D, Chumas J.Uterine papillary serous carcinoma evolves via p53driven pathway. Human Pathology 1996; 12: 1295–300.

9 Soong R, Knowles S, Williams KE, Hammond IG,Wysocki SJ, Iacopetta BJ. Overexpression of p53 proteinis independent prognostic indicator in humanendometrial carcinoma. British Journal of Cancer 1996; 74:562–7.

10 Maia H Jr, Maltez A, Calmon LC, Marques D, Coutinho



EM. Histopathology, steroid receptors and p53 inendometrial polyps of postmenopausal women underhormone replacement therapy. In: Cooper JM, Loffer FD,eds. World Congress on Hysteroscopy and Related Technologiesin the Management of Abnormal Uterine Bleeding. Santa FeSprings, CA: The American Association of GynecologicLaparoscopists, 1998: 29.

11 Boccuzi A, Terzolo M, Leonardo E, et al. High frequencyof p53 expression in colo-rectal adenomatous polyps.Anticancer Research 1995; 15: 1407–10.

12 Fletcher JA, Pinkus JL, Lage JM, Morton CC, Pinkus GS.Clonal 6p21 rearrangement is restricted to the

mesenchymal component of an endometrial polyp.Genes, Chromosomes and Cancer 1992; 5: 260–3.

13 Lee K, Belinson J. Recurrence in noninvasiveendometrial carcinoma. Relationship to uterine papillarycarcinoma. American Journal of Surgery and Pathology 1991;15: 965–73.

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Endometrial carcinoma in postmenopausal patients using hormone replacement therapy: a report on four cases