Endometrial Carcinoma Can Develop in Patients on Tamoxifen ...
Endometrial Carcinoma Can Develop in Patients on Tamoxifen ...
Endometrial Carcinoma Can Develop in Patients on Tamoxifen ...
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SHORT COMMUNICATIONS<br />
<str<strong>on</strong>g>Endometrial</str<strong>on</strong>g> <str<strong>on</strong>g>Carc<str<strong>on</strong>g>in</str<strong>on</strong>g>oma</str<strong>on</strong>g> <str<strong>on</strong>g>Can</str<strong>on</strong>g> <str<strong>on</strong>g>Develop</str<strong>on</strong>g> <str<strong>on</strong>g>in</str<strong>on</strong>g><br />
<str<strong>on</strong>g>Patients</str<strong>on</strong>g> <strong>on</strong> <strong>Tamoxifen</strong> Therapy<br />
S Z Omar, M Med (0 &G), V Sivanesaratnam, FRCOG, Department of Obstetric & Gynaecology<br />
University Malaya, 50603 Kuala Lumpur<br />
Introducti<strong>on</strong><br />
Breast cancer c<strong>on</strong>stitutes 54.8 percent of deaths from<br />
malignancies <str<strong>on</strong>g>in</str<strong>on</strong>g> female genital tract <str<strong>on</strong>g>in</str<strong>on</strong>g> Malaysia, 1995 1 •<br />
It is also the sec<strong>on</strong>d most comm<strong>on</strong> death (19.4%) from<br />
malignancies <str<strong>on</strong>g>in</str<strong>on</strong>g> females <str<strong>on</strong>g>in</str<strong>on</strong>g> Malaysia. The use of adjuvant<br />
tamoxifen therapy c<strong>on</strong>t<str<strong>on</strong>g>in</str<strong>on</strong>g>uously for five or more years<br />
has c<strong>on</strong>tributed to l<strong>on</strong>ger survivals <str<strong>on</strong>g>in</str<strong>on</strong>g> these patients.<br />
Several recent reports of possible associati<strong>on</strong> between<br />
tamoxifen treatment and endometrial pathologies, such<br />
as endometrial hyperplasia, endometrial polyps,<br />
adenomyosis, endometrial carc<str<strong>on</strong>g>in</str<strong>on</strong>g>oma and endometrial<br />
sarcoma are of c<strong>on</strong>cern to the cl<str<strong>on</strong>g>in</str<strong>on</strong>g>icians. We present here<br />
2 cases of advanced endometrial carc<str<strong>on</strong>g>in</str<strong>on</strong>g>oma after<br />
tamoxifen therapy.<br />
Case History 1<br />
HA was a 70 years old lady, para 5, seen <str<strong>on</strong>g>in</str<strong>on</strong>g> the<br />
gynaecology cl<str<strong>on</strong>g>in</str<strong>on</strong>g>ic with a <strong>on</strong>e-year history of occasi<strong>on</strong>al<br />
per vag<str<strong>on</strong>g>in</str<strong>on</strong>g>al bleed<str<strong>on</strong>g>in</str<strong>on</strong>g>g. She atta<str<strong>on</strong>g>in</str<strong>on</strong>g>ed menarche at the age<br />
of 12 and menopause about thirty years ago. In 1991,<br />
she was diagnosed to have carc<str<strong>on</strong>g>in</str<strong>on</strong>g>oma of right breast. A<br />
right mastectomy and axillary nodes clearance were<br />
performed. Follow<str<strong>on</strong>g>in</str<strong>on</strong>g>g surgery, she was commenced <strong>on</strong><br />
tamoxifen 20 milligram daily for a period of five years.<br />
There was no significant medical history of<br />
hypertensi<strong>on</strong>, diabetes mellitus or family history of<br />
breast cancer.<br />
On exam<str<strong>on</strong>g>in</str<strong>on</strong>g>ati<strong>on</strong>, there was mild pallor noted. A healed<br />
right mastectomy scar with no local recurrence was seen.<br />
The abdomen was soft with a mass just palpable <str<strong>on</strong>g>in</str<strong>on</strong>g> the<br />
suprapubic regi<strong>on</strong>. Vag<str<strong>on</strong>g>in</str<strong>on</strong>g>al exam<str<strong>on</strong>g>in</str<strong>on</strong>g>ati<strong>on</strong> revealed a ten<br />
weeks size uterus palpable bimanually. No other masses<br />
noted <str<strong>on</strong>g>in</str<strong>on</strong>g> the adnexal regi<strong>on</strong>. Histopathological<br />
exam<str<strong>on</strong>g>in</str<strong>on</strong>g>ati<strong>on</strong> of the endometrial tissue was reported as<br />
"adenocarc<str<strong>on</strong>g>in</str<strong>on</strong>g>oma of the endometrium". CT scan of the<br />
abdomen and pelvis showed the uterus to be enlarged<br />
measur<str<strong>on</strong>g>in</str<strong>on</strong>g>g 8.5 x 7 x 6.5cm with hydrometra, there was<br />
an omental cake, ascites and enlarged paracaval and<br />
paraaortic nodes. No focal lesi<strong>on</strong>s were noted <str<strong>on</strong>g>in</str<strong>on</strong>g> the liver<br />
or spleen.<br />
Patient and family were counselled and a total<br />
abdom<str<strong>on</strong>g>in</str<strong>on</strong>g>al hysterectomy, bilateral salp<str<strong>on</strong>g>in</str<strong>on</strong>g>gooophorectomy,<br />
supracolic omentectomy and<br />
appendicectomy were undertaken. Operative f<str<strong>on</strong>g>in</str<strong>on</strong>g>d<str<strong>on</strong>g>in</str<strong>on</strong>g>gs<br />
were that of about 700mls straw coloured ascitic fluid,<br />
omental cake adherent to the anterior abdom<str<strong>on</strong>g>in</str<strong>on</strong>g>al wall<br />
and <str<strong>on</strong>g>in</str<strong>on</strong>g>ferior edge of the liver. The uterus was about 10<br />
weeks size, with tumour nodules over its surface;<br />
tumour <str<strong>on</strong>g>in</str<strong>on</strong>g>filtrati<strong>on</strong> was extensive to the parametrium,<br />
the rectal serosa and ·the pelvic and bladder perit<strong>on</strong>eum.<br />
Both ovaries were normal, an enlarged para-aortic node<br />
close to the renal artery was palpable. The rest of the<br />
abdom<str<strong>on</strong>g>in</str<strong>on</strong>g>al c<strong>on</strong>tents were normal. The estimated<br />
<str<strong>on</strong>g>in</str<strong>on</strong>g>tra-operative total blood loss was 300mls.<br />
Post-operative recovery was uneventful and the<br />
histology c<strong>on</strong>firmed the f<str<strong>on</strong>g>in</str<strong>on</strong>g>d<str<strong>on</strong>g>in</str<strong>on</strong>g>gs of an endometrial<br />
adenocarc<str<strong>on</strong>g>in</str<strong>on</strong>g>oma, the presence of an endometrial polyp<br />
and adenomyosis of the myometrium. The right ovary,<br />
omentum and appendix showed evidence of metastasis.<br />
Surgico-pathologically she had <str<strong>on</strong>g>Carc<str<strong>on</strong>g>in</str<strong>on</strong>g>oma</str<strong>on</strong>g> of the<br />
Endometrium Stage 3C Grade 3. She was then<br />
commenced <strong>on</strong> adjuvant chemotherapy, Carboplat<str<strong>on</strong>g>in</str<strong>on</strong>g>um<br />
300mg/m2. Follow<str<strong>on</strong>g>in</str<strong>on</strong>g>g the third course of chemotherapy,<br />
she was noted to have recurrence of the tumour. She was<br />
managed symptomatically and succumbed so<strong>on</strong> after.<br />
280<br />
Med J Malaysia Vol 54 No 2 June 1999
ENDOMETRIAL CARCINOMA CAN DEVELOP IN PATIENTS<br />
Case History 2<br />
Miss FM was a 53 years old s<str<strong>on</strong>g>in</str<strong>on</strong>g>gle nulliparous<br />
postmenopausal lady who presented with an episode of<br />
pervag<str<strong>on</strong>g>in</str<strong>on</strong>g>al bleed<str<strong>on</strong>g>in</str<strong>on</strong>g>g with clots. Four years ago she had a<br />
simple right mastectomy and axillary node sampl<str<strong>on</strong>g>in</str<strong>on</strong>g>g for<br />
a Manchester stage 3 <str<strong>on</strong>g>in</str<strong>on</strong>g>filtrat<str<strong>on</strong>g>in</str<strong>on</strong>g>g ductal carc<str<strong>on</strong>g>in</str<strong>on</strong>g>oma of<br />
breast. Post-operatively she had DXT to loco-regi<strong>on</strong>al<br />
nodes and was prescribed tamoxifen 20 milligram daily.<br />
On exam<str<strong>on</strong>g>in</str<strong>on</strong>g>ati<strong>on</strong>, a healed right mastectomy scar was<br />
seen with no local recurrence. No abnormalities were<br />
detected <strong>on</strong> abdom<str<strong>on</strong>g>in</str<strong>on</strong>g>al palpati<strong>on</strong>. Vag<str<strong>on</strong>g>in</str<strong>on</strong>g>al exam<str<strong>on</strong>g>in</str<strong>on</strong>g>ati<strong>on</strong><br />
revealed a mobile uterus of about 8 weeks size. No<br />
adnexal masses were noted. She was then counselled for<br />
a fracti<strong>on</strong>al dilatati<strong>on</strong> and curettage and the<br />
histopathological exam<str<strong>on</strong>g>in</str<strong>on</strong>g>ati<strong>on</strong> of the endometrial<br />
curett<str<strong>on</strong>g>in</str<strong>on</strong>g>g was reported as a "well differentiated<br />
adenocarc<str<strong>on</strong>g>in</str<strong>on</strong>g>oma". She subsequently underwent an<br />
extrafascial hysterectomy and bilateral salp<str<strong>on</strong>g>in</str<strong>on</strong>g>gooophorectomy.<br />
Postoperatively she recovered<br />
uneventfully and the histology of the specimen showed<br />
no residual endometrial malignancy but the presence of<br />
a metastatic adenocarc<str<strong>on</strong>g>in</str<strong>on</strong>g>oma <str<strong>on</strong>g>in</str<strong>on</strong>g> the left ovary. In view of<br />
the surgicopathological stage 3 grade 1, she<br />
subsequently received DXT to the pelvis and has had no<br />
evidence of tumour recurrence at eight years follow-up.<br />
Discussi<strong>on</strong><br />
<strong>Tamoxifen</strong> is widely used as adjuvant therapy for breast<br />
cancer patients. It has m<str<strong>on</strong>g>in</str<strong>on</strong>g>imal side effects and is judged<br />
to be safe. Adjuvant tamoxifen treatment significantly<br />
improves both the recurrence-free <str<strong>on</strong>g>in</str<strong>on</strong>g>terval and the<br />
overall survival rate'. In the uterus, tamoxifen has the<br />
capacity to occupy the oestradiol receptor <str<strong>on</strong>g>in</str<strong>on</strong>g> the<br />
endometrial cells. Nevertheless, <str<strong>on</strong>g>in</str<strong>on</strong>g> the low oestradiol<br />
(E2) envir<strong>on</strong>ment of menopause/premenopause women,<br />
tamoxifen can also functi<strong>on</strong> as an oestrogen ag<strong>on</strong>ist <strong>on</strong><br />
these receptors. Such an effect <strong>on</strong> the human<br />
endometrium <str<strong>on</strong>g>in</str<strong>on</strong>g> vivo had already been dem<strong>on</strong>strated by<br />
Gorodeski et all. These f<str<strong>on</strong>g>in</str<strong>on</strong>g>d<str<strong>on</strong>g>in</str<strong>on</strong>g>gs <str<strong>on</strong>g>in</str<strong>on</strong>g>dicate that the<br />
postmenopausal endometrium is sensitive to tamoxifen.<br />
Recent studies have shown an <str<strong>on</strong>g>in</str<strong>on</strong>g>creased <str<strong>on</strong>g>in</str<strong>on</strong>g>cidence of<br />
endometrial proliferati<strong>on</strong>, hyperplasia and polyposis <str<strong>on</strong>g>in</str<strong>on</strong>g><br />
women tak<str<strong>on</strong>g>in</str<strong>on</strong>g>g tamoxifen 4 Ag<strong>on</strong>ist acti<strong>on</strong>s of tamoxifen<br />
could expla<str<strong>on</strong>g>in</str<strong>on</strong>g> these effects, but these acti<strong>on</strong>s are thought<br />
to be early, transient and quickly replaced by an<br />
overwhelm<str<strong>on</strong>g>in</str<strong>on</strong>g>g oestrogen antag<strong>on</strong>ism. Endometriosis has<br />
been reported <str<strong>on</strong>g>in</str<strong>on</strong>g> several women who were treated with<br />
tamoxifen, <str<strong>on</strong>g>in</str<strong>on</strong>g>clud<str<strong>on</strong>g>in</str<strong>on</strong>g>g <strong>on</strong>e who was diagnosed after 15<br />
years of menopause'.<br />
Vary<str<strong>on</strong>g>in</str<strong>on</strong>g>g endometrial pathologies, <str<strong>on</strong>g>in</str<strong>on</strong>g>clud<str<strong>on</strong>g>in</str<strong>on</strong>g>g endometrial<br />
carc<str<strong>on</strong>g>in</str<strong>on</strong>g>oma has been reported <str<strong>on</strong>g>in</str<strong>on</strong>g> 18 - 35.5% of patients<br />
who have been <strong>on</strong> tamoxifen therapy. This fact is<br />
important and should not be overlooked. Majority of<br />
these patients will be asymptomatic and could have<br />
escaped detecti<strong>on</strong> if they were not under proper medical<br />
supervisi<strong>on</strong>; <str<strong>on</strong>g>in</str<strong>on</strong>g>clud<str<strong>on</strong>g>in</str<strong>on</strong>g>g vag<str<strong>on</strong>g>in</str<strong>on</strong>g>al scan to assess the<br />
endometrial cavity and if necessary endometrial<br />
sampl<str<strong>on</strong>g>in</str<strong>on</strong>g>g at regular <str<strong>on</strong>g>in</str<strong>on</strong>g>tervals. Women receiv<str<strong>on</strong>g>in</str<strong>on</strong>g>g<br />
tamoxifen as treatment for breast cancer who<br />
subsequently develop uter<str<strong>on</strong>g>in</str<strong>on</strong>g>e carc<str<strong>on</strong>g>in</str<strong>on</strong>g>oma are at risk for<br />
high grade endometrial carc<str<strong>on</strong>g>in</str<strong>on</strong>g>oma with a poor<br />
prognosis' as illustrated <str<strong>on</strong>g>in</str<strong>on</strong>g> Case 1.<br />
It has been claimed that endometrial and breast cancers<br />
may share certa<str<strong>on</strong>g>in</str<strong>on</strong>g> comm<strong>on</strong> risk factors, which<br />
predispose those w~th primary breast cancer to develop<br />
sec<strong>on</strong>d primary cancer of the endometrium, irrespective<br />
of tamoxifen treatment. It has been suggested that<br />
progestogen treatment may be c<strong>on</strong>sidered for protecti<strong>on</strong><br />
from and reducti<strong>on</strong> of the risk of endometrial cancer <str<strong>on</strong>g>in</str<strong>on</strong>g><br />
tamoxifen-treated patients. However, various studies<br />
have also shown the negative effect of such therapy <str<strong>on</strong>g>in</str<strong>on</strong>g><br />
<str<strong>on</strong>g>in</str<strong>on</strong>g>creas<str<strong>on</strong>g>in</str<strong>on</strong>g>g the risk of breast cancer 4 •<br />
It is thus, important to closely m<strong>on</strong>itor the effects of<br />
tamoxifen therapy <strong>on</strong> the genital tract <str<strong>on</strong>g>in</str<strong>on</strong>g> breast cancer<br />
patients, so as to give a positive overall effect <strong>on</strong> the<br />
women's life expectancy.<br />
Med J Malaysia Vol 54 No 2 June 1999<br />
281
SHORT COMMUNICATIONS<br />
1. Vital Health Statistic: M<str<strong>on</strong>g>in</str<strong>on</strong>g>istry of Health Malaysia 1995.<br />
2. Rea D, Poole C, Gray R. Adjuvant tamoxifen: how l<strong>on</strong>g<br />
before we know how l<strong>on</strong>g? BM] 1998; 316 :1518-19.<br />
3. Gorodeski GI, Beery, Luuenfeld B, et al. <strong>Tamoxifen</strong><br />
<str<strong>on</strong>g>in</str<strong>on</strong>g>creases plasma oestrogen-b<str<strong>on</strong>g>in</str<strong>on</strong>g>d<str<strong>on</strong>g>in</str<strong>on</strong>g>g equivalents and has<br />
an estradiol ag<strong>on</strong>istic effect <strong>on</strong> histologically normal<br />
premenopausal and postmenopausal endometrium. Fertil<br />
Steril 1992; 57: 320.<br />
4. Ismail SM Pathology of endometrium treated with<br />
tamoxifen.] Cl<str<strong>on</strong>g>in</str<strong>on</strong>g> Pathol1994;47: 827-33.<br />
5. Cohen I, Altaras MM, Shapira], Tepper R, Beyth Y, Post<br />
menopausal tamoxifen treatment and endometrial<br />
pathology. Obs & Gynae Survey 1994; 47: 823-29.<br />
282<br />
Med J Malaysia Vol 54 No 2 June 1999