Endometrial Carcinoma With Trophoblastic Differentiation An Aggressive Form of Uterine Cancer

Carlo Pesce, MD,* Maria J. Merino, MD,* Joe T. Chambers, MD,f and Francisco Nogales, MDS

Three cases of poorly differentiated endometrial adenocarcinoma showing trophoblast-like differentiation are reported. The multinucleated, syncytiotrophoblast-like cells were strongly positive for &human chorionic gonadotropin (B-HCG) by immunohistochemical study. High levels of &HCG were also present in the patients’ serum, but dropped significantly after treatment. The patients had an unusually rapid and progressive clinical course with widespread dissemination and death by tumor. Cancer 68:1799-1802,1991.

ARCINOMAS in which trophoblastic components C (syncytiotrophoblast and cytotrophoblast) are pres- ent are rarely found in extragenital organs, such as stom- a ~ h , ’ - ~ large inte~tine,~ and urinary bladder.5 p-Human chorionic gonadotropin (P-HCG) production can be demonstrated immunohistochemically in such cases, and high concentrations of 0-HCG are usually present in the serum of these patients. Occasionally, tumors at different sites may show partial trophoblastic differentiation, with only syncytiotrophoblast or cytotrophoblast present.’ In the female genital tract, these neoplasms are extremely rare, with only two cases of endometrial adeno- carcinoma’.’ and one of ovarian carcinosarcoma* with trophoblastic differentiation having been described.

We studied three cases of endometrial adenocarcinoma with choriocarcinomatous differentiation. The areas of choriocarcinoma included p-HCG-positive syncytiotro- phoblast-like cells; high levels of P-HCG could be detected in the serum of the patients. The tumors followed an un- usually aggressive behavior with poor patient outcome. These cases constitute the basis of our report.

Case Reports

Case 1

A 78-year-old nulliparous woman had profuse vaginal bleed- ing. At physical examination, prominent axites was noted, as

From the *Laboratory of Pathology. National institutes of Health, Bethesda, Maryland: tYale Lniversity. New Haven, Connecticut; and the $University of Granada. Granada. Spain.

Address for reprints: Maria J. Merino. MD, Laboratory of Pathology, National Institutes of Health. Building 10, Room 2N212, Bethesda, MD 20892.

Accepted for publication February 9. 199 I .

well as a large uterine mass. Computed tomography (CT) studies revealed intestinal matting with diffuse retroperitoneal lymph- adenopathy. An endometrial biopsy was positive for a poorly differentiated adenocarcinoma in which choriocarcinomatous areas were noticed. Serum levels of 8-HCG, assessed because of the histologic findings, were found to be elevated (19,500 mIU/ ml). The patient was started on cisplatin, bleomycin, and On- covin (vincristine); levels of 8-HCG decreased to 460 mIU/ml after the first treatment, and to 49 mIU/ml after the second cycle of chemotherapy. The patient, however, continued to de- teriorate and died with extensive disease 47 days later. No au- topsy was performed.

Case 2

A 48-year-old woman, gravida 5, underwent a total abdominal hysterectomy after a cervical biopsy positive for poorly differ- entiated carcinoma. The serum levels of p-HCG were 3050 mIU/ ml, but dropped after surgical resection and two cycles of meth- otrexate to 17 mIU/ml. Two months later, the patient has de- veloped pulmonary metastases with elevation of serum 0-HCG levels and is being treated with multiple chemotherapy (etopo- side, bleomycin, and cisplatin).

Case 3

A multiparous 63-year-old woman had metrorrhagia. After an endometrial biopsy proved to be positive for carcinoma, the patient underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy. The patient did well until a year later, when she developed massive abdominal recurrence and distant metastases to the lungs and liver. Biopsy was performed on one of the abdominal nodules and showed a tumor consistent with her uterine primary. Urinary 8-HCG levels were persistently elevated (100,OOO IU/24 hours) until death. which occurred 2 months after recurrence.

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1800 CANCER October 15 199 1 Vol. 68

FIG. I . Poorly differentiated en- dometrial cancer (Patient 1). The tumor was predominantly composed of solid sheets of epithelial cells, but larger pleomorphic and occasionally multinucleated tumor cells were present (H & E, X 150).

Histopathologic Results cytoplasm, large nuclei, and irregular distribution of the chromatin. Admixed with the neoplastic epithelia1 cells, there were large, multinucleated cells with dense eosino- philic cytoplasm (Fig. 3) that resembled syncytiotropho- blast. Prominent vascular invasion was identified in all cases. In Patient 3, the material obtained from the peri- toneal implant was identical to that of the primary tumor.

Immunoperoxidase for P-HCG (Dako, Santa Barbara,

The tumors in the three patients, which showed similar histologic features, are discussed together. The neoplasms were composed of solid sheets of cells (Fig. 1 ) with prom- inent areas of hemorrhage and necrosis. Focal glandular formation (Fig. 2) was seen in the better differentiated areas. The tumor cells were large with abundant clear

FIG. 2. Focal glandular formation was noted (Patient 3). Notice the presence of markedly abnormal cells (H & E, X200).

No. 8 ENDOMETRIAL CA WITH DIFFERENTIATION * Pesce et d. 1801

of the urinary bladder; positive HCG staining both in these components and in the transitional carcinoma cells sug- gested that the trophoblastic cells were differentiating functionally and morphologically from a transitional car- cinoma cell precursor. The previous data of Rodenburg et al.,” who demonstrated HCG in six of 14 transitional cell carcinomas of the bladder without a morphologically recognizable component of syncytiotrophoblast-like cells, appeared to support this interpretation. Trophoblastic dif- ferentiation also has been reported in a case of malignant mixed mesodermal tumor of the ovary, with clusters of 0-HCG-positive, trophoblast-like malignant cells recog- nized among both the epithelial and the stromal malignant components.8

This type of differentiation at extragenital sites appears to represent a spectrum of progressive changes, ranging from slight HCG production in normal epithelial and carcinoma cells to the formation of tumors entirely com- posed of syncytiotrophoblast and cytotrophoblast, which are morphologically and functionally indistinguishable from chonocarcinoma. This pattern was exhibited also by the case of endometrial adenocarcinoma with tropho- blastic component reported by Savage and co-workers7 and is similar to the current three cases. Whereas only syncytiotrophoblast-like cells were found in the primary endometrial carcinoma, trophoblastic differentiation was complete in the metastases, with both elements present.

Our three cases of endometrial adenocarcinoma showed areas of trophoblast-like cells, probably derived through metaplasia of the tumor cells. Cases of tumors exhibiting a trophoblastic component without fertilized ova as pre- cursors have been reported in other organs, and have also been related to retr~differentiation,~.’~ highly differentiated metapla~ia”~~-” of the tumor cells, or to neometaplasia probably due to tumor heterogeneity. This latter possi- FIG. 3. (Top) At higher magnification the syncytiotrophoblastic cells

showed prominent abnormal nuclei and abundant eosinophilic cytoplasm (H & E. original magnification X250). (Bottom) These cells stained strongly for b-HCG by imniunoperoxidase techniques (PAP, original magnification X250).

CA) (Fig. 3) showed strong positivity in the multinucle- ated, choriocarcinoma-like cells, and focal positivity for placental alkaline pho:sphatase (PLAP, Dako) were also focally positive. The tumor cells stained strongly for ker- atin (AE 1 + AE3, Boehringer Mannheim, Indianapolis, IN) (Fig. 4) and epithelial membrane antigen (Dako).

Discussion

P-HCG is known to be produced by normal extragon- adal tissues9 or tumors, of various sites, such as the lung, liver, breast, colon, adrenal gland, kidney, and pros-

phoblast-like components in a transitional cell carcinoma lshikawa co-workers5 found syncfliotro- FIG. 4. All tumors showed diffuse and intense staining for cytokeratins

tate. 3.4.10. I I

(PAP, original magnification x250).

1802 CANCER October 15 199 I Vol. 68

bility also explains the occurrence of another type of neo- plastic differentiation in non-germ cell tumors, primitive endodermal tissues of yolk sac type occurring in endome- trioid ovarian carcinoma, and transitional cell carcinoma of the nasopharynx. 163” Further support for this hypoth- esis is provided by the case of gastric carcinoma with both trophoblastic and yolk sac components reported by Garcia and Ghali.” This two-way differentiation, similar to that seen in embryonal carcinoma, suggests that these tumors may express phenotypically extraembryonal tissues, such as placenta and primitive endoderm. Extraembryonal dif- ferentiation may manifest itself biochemically with a-fe- toprotein or 0-HCG production and morphologically with a yolk sac or choriocarcinoma component.

Immunohistochemical demonstration of markers, such as P-HCG and human placental lactogen (HPL), in large multinucleated cells may support the identification of trophoblastic differentiation in carcinoma. Recognizing trophoblastic differentiation in endometrial adenocarci- noma is important for assessing the patient’s prognosis because this pattern was associated in the current three cases with an aggressive behavior, lack of response to che- motherapy, and early onset of metastases, which are un- usual in endometrial adenocarcinoma. The patient de- scribed by Savage and co-workers’ also had a rapid course and died 14 months after diagnosis with widespread met- astatic disease.

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