17 Müllerian Adenosarcoma of the Uterus with Sarcomatous Overgrowth Following Tamoxifen Treatment for Breast Cancer

JANUARY-FEBRUARY REV. HOSP. CLÍN. FAC. MED. S. PAULO 55(1):17-20, 2000

MÜLLERIAN ADENOSARCOMA OF THE UTERUS WITH SARCOMATOUS OVERGROWTH FOLLOWING TAMOXIFEN TREATMENT FOR BREAST CANCER

Filomena Marino Carvalho, Jesus Paula Carvalho, Eduardo Vieira da Motta and Jorge Souen

RHCFAP/2998 CARVALHO FM et al. - Müllerian adenosarcoma of the uterus with sarcomatous overgrowth following tamoxifen treatment for breast cancer. Rev. Hosp. Clín. Fac. Med. S. Paulo 55 (1):17-20, 2000.

SUMMARY: Müllerian adenosarcoma with sarcomatous overgrowth presented by a 52-year-old female patient after adjuvant tamoxifen treatment for breast carcinoma is described. The diagnosis was made on histological basis after curettage and complementary total hysterectomy with bilateral salpingo-oophorectomy. The immunohistochemical study showed high expression of estrogen receptors in the epithelial component of the lesion and irregularly positive findings in the stroma. The proliferative activity evaluated by Ki-67 immunoexpression was higher in the stroma than the epithelium. Some of the stromal cells showed rhabdomyoblastic differentiation. The association of tamoxifen use and development of mesenchymal neoplasms is discussed.

DESCRIPTORS: Uterine adenosarcoma. Breast cancer. Tamoxifen. Uterine sarcoma.

Adenosarcomas are characterized nancy, and 1had a diagnosis of Stein- CASE REPORT as tumors containing benign or atypi- Leventhal syndrome5. Two patients of cal epithelial and malignant stromal this series had carcinoma of the breast A 52–year-old multiparous woman components. They present as polypoid that was treated 5 and 2.5 years ear- underwent left mastectomy and right masses arising from the endometrium lier5. Recently, Mourits et al. (1998) quadrantectomy for bilateral breast and can invade the subjacent myo- described a case of a 71-year-old pa- cancer, clinical stage II. Both tumors metrium. Most adenosarcomas are tu- tient who developed a uterine adenosa- were invasive ductal carcinoma. The mors of low malignant potential. Re- rcoma after two years of adjuvant pathological stages were pT2, pN2 and currence occurs in approximately 24% tamoxifen treatment for breast cancer13. pT2, pN1biii, respectively at left and of cases and is related to deep myome- We discuss the role of tamoxifen on right. The surgical treatment was fol- trial invasion5. A variant from the usual the benign and malignant stromal pro- lowed by 6 cycles of taxol and pattern with a sarcomatous overgrowth liferation of the endometrium and adriamycin and regional radiotherapy has been described by Clement6. This present a case of adenosarcoma with at both breasts. Five months after the variant is an overgrowth of the ade- sarcomatous overgrowth in a woman surgery she began tamoxifen therapy nosarcoma by a pure sarcoma with receiving antiestrogen therapy for with 20 mg daily. After 6 months of consequent higher recurrence rate, me- breast cancer with tamoxifen. tamoxifen therapy, endometrial thick- tastases, and fatal outcome6. ness was determined by ultrasound to Of the 100 cases described by be 5.8 mm. Five months later the en- Clement and Scully, 5 had a history of dometrial thickness was 11 mm, and 1 estrogen use; 1 had a history of mater- From the Department of Gynecology, Hospital year later it was 27 mm. The diagno- nal usage of a hormone of unknown das Clínicas, Faculty of Medicine, University sis was done by curettage under gen- of São Paulo. type during the first trimester of preg- eral anesthesia, and the patient under-

17 REV. HOSP. CLÍN. FAC. MED. S. PAULO 55(1):17-20, 2000 JANUARY-FEBRUARY

Figure 1 - Product of total hysterectomy with Figure 2 - Histological aspect of the endometrial lesion, showing the epithelial and stromal component. polypoid lesion in the endometrium. Note the hypercellular area near the gland (hematoxylin-eosin; 100X). went total abdominal hysterectomy with bilateral salpingo-ooforectomy.

PATHOLOGICAL STUDY

The uterus was enlarged, weighed 230 g and measured 9.5 X 6.1 X 5.2 cm. The uterine cavity measured 8.5 cm in length and had an endometrial polypoid lesion measuring 4.0 cm that was partially necrotic with signs of superficial myometrial invasion. (Fig. 1). The microscopic examination showed a biphasic neoplasm with glands of endometrioid pattern and a cellular stromal component that tended to coa- lesce into more densely hypercellular cuffs around the epithelial component

(Fig. 2). The stromal cells were Figure 3 - Area of neoplastic stroma with pleomorphic and rhabdoid cells (hematoxylin-eosin; 400X). spindle-shaped or pleomorphic and had rhabdoid areas (Fig. 3). The mitotic count was 6 per 10 high power field The immunohistochemical study positive for estrogen receptors, and (HPF). Areas of prominent stromal was carried out to identify estrogen re- stromal cells were irregularly positive component accounted for 40% of the ceptor (ER), proliferative activity, and for estrogen receptors. Twenty percent tumor. There were foci of stromal fi- rhabdomyoblastic differentiation with of stromal cells and 5% of epithelial brosis and hemorrhage without necro- the monoclonal antibodies 1D5 cells were positive for MIB1, indica- sis. Vascular invasion was not seen. (Dako), MIB-1 (Immunotech) and ting that the proliferative activity was There were areas of superficial myo- desmin DE-R-11 (Dako), respectively. higher in the stroma. The more pleo- metrial invasion. Eighty percent of epithelial cells were morphic areas were positive for

18 JANUARY-FEBRUARY REV. HOSP. CLÍN. FAC. MED. S. PAULO 55(1):17-20, 2000 desmin, indicating muscular differen- The occurrence of polyps is increased mesenchymal neoplasm is higher than tiation. in tamoxifen-treated postmenopausal expected. women compared with untreated pa- The proliferative effect of DISCUSSION tients, but this alteration is not ob- tamoxifen in endometrium seems to be served in premenopausal tamoxifen- related to an effect primarily on stro- Breast cancer treatment with treated12. On the other hand, some mal cells and perhaps on vascular tamoxifen has been associated with the workers have found lower levels of es- structures. The polyps, so frequently development of hyperplasia and carci- trogen and progesterone receptors in associated with tamoxifen use, are pro- nomas of the endometrium17. However, endometrium of postmenopausal liferation with an important stromal- the most common finding has been tamoxifen-treated patients than in con- vascular component. Zhao et al.20 have uterine polyps8,10,18,19. Fotiu et al.11 have trol groups composed of healthy shown that endometria of women re- studied the histopathologic features of women with and without estrogen receiving tamoxifen express 50 curettage specimens from patients placement therapy7. In our study, posi- adrenomedullin, a growth factor for under tamoxifen treatment and experi- tivity for ER was lower in the stromal endotelial cells, postulating that induc- encing abnormal bleeding; 44% had component of the lesion compared tion of this angiogenic factor is part of cervical and endometrial polyps. A with the epithelium and inversely pro- the mechanism by which tamoxifen re- clinical study of 245 cases has found portional to the proliferative activity. sults in endometrial hyperplasia. an association of endometrial polyps This finding was the same as that no- Bhargava et al.3, using in vitro model, and tamoxifen in 8% of patients with ticed by others 13 and can be explained have found an increase in the prolifera- breast cancer.15 Exacoustos et al.10 have by a loss of expression of steroid re- tive activity due to tamoxifen in the observed thicker endometrium in pa- ceptors due to neoplastic transforma- endometrial stromal cells over the con- tients receiving tamoxifen compared to tion. Considering that the epithelial trols. Decensi et al.9 compared en- controls. In that study, 23 cases of component is not neoplastic yet, it ex- dometria of tamoxifen-treated breast pathological endometrium out of 38 presses high levels of receptor. This cancer patients and controls and have cases were observed: 19 polyps and 4 finding can explain the development of observed an antiproliferative effect of hyperplasia10. hyperplastic lesions and carcinomas in tamoxifen on the epithelium and a Tesoro et al.19 found 24 cases of some endometria. Some groups have growth-promoting effect on the stroma, abnormal endometrium in a group of found carcinoma arising within suggesting that the endometrial prolif- 80 postmenopausal women treated tamoxifen-associated endometrial pol- eration is mediated by the stromal with tamoxifen for breast cancer: 13 yps14. component. polyps, 5 hyperplasia, 3 tubal metapla- There are many reports of sarcomas In conclusion, the exact mechanism sia, 2 carcinomas, and 1 breast carci- in patients under tamoxifen use1,2,4,18. regarding the role of tamoxifen in the noma metastatic to endometrium.19 Clement et al.4 described 6 cases of development of epithelial and mesen- Polypoid structures, morphologically uterine adenosarcomas associated with chymal neoplasms remains unclear, but similar to endometrial polyps, were tamoxifen therapy. Considering the rar- there is no doubt that all cases of en- observed even in endometriotic foci in ity of these tumors, it seems that the dometrial thickening must be investi- patient under tamoxifen treatment16. association of tamoxifen therapy with gated in tamoxifen users.

RESUMO RHCFAP/2998

CARVALHO F M e col. – Ade- É descrito o caso de uma paciente foi feito em bases histológicas após nossarcoma Mülleriano com do sexo feminino, 52 anos, com curetagem uterina e histerectomia to- componente sarcomatoso predomi- adenossarcoma Mülleriano com tal complementar com anexectomia bi- nante, após tratamento adjuvante do componente sarcomatoso predomi- lateral. O estudo imuno-histoquímico câncer de mama com tamoxifeno. nante, que se apresentou após mostrou alta expressão de receptores Rev. Hosp. Clín. Fac. Med. S. tratamento adjuvante com tamoxifeno de estrogênio no componente epitelial Paulo 55 (1):17-20, 2000. para câncer de mama. O diagnóstico da lesão e positividade irregular no

19 REV. HOSP. CLÍN. FAC. MED. S. PAULO 55(1):17-20, 2000 JANUARY-FEBRUARY estroma. A atividade proliferativa mostraram diferenciação rabdomio- DESCRITORES: Adenossarcoma avaliada através da imunoexpressão do blástica. A associação entre uso de uterino. Câncer de mama. Ki-67 foi maior no estroma do que no tamoxifeno e desenvolvimento de Tamoxifen. Sarcoma uterino. epitélio. Algumas células estromais neoplasias mesenquimais é discutida.

REFERENCES

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