Endometrial carcinoma with choriocarcinomatous differentiation: A case report and review of the literature

Gynecologic Oncology 113 (2009) 291–294

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Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y g y n o

Case Report

Endometrial carcinoma with choriocarcinomatous differentiation: A case report and review of the literature Takashi Yamada a,⁎, Hiroshi Mori b, Masanori Kanemura c, Masahide Ohmichi c, Yuro Shibayama a a b c

Department of Pathology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan Department of Clinical Pathology, Minoh City Hospital, 5-7-1 Kayano, Minoh, Osaka 562-8562, Japan Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan

a r t i c l e

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Article history: Received 30 October 2008 Available online 20 February 2009 Keywords: Endometrial cancer Adenocarcinoma Choriocarcinoma Trophoblastic tumor Choriocarcinomatous differentiation hCG

a b s t r a c t Background. Choriocarcinomas unrelated to pregnancy, teratomas, or germ cell tumors have been found in the stomach, lungs, colon, esophagus, bladder, breast, renal pelvis and other sites. Case. We present a case of a 58-year-old woman with endometrial carcinoma with choriocarcinomatous differentiation. She received surgery and chemotherapy for endometrial adenocarcinoma. However, a metastatic tumor of choriocarcinomatous element appeared at the vaginal cuff 9 months after surgery. Additional chemotherapy for choriocarcinoma resulted in a decrease in the serum hCG and the tumor regressed. Fifty months following surgery, she is alive without disease. Conclusion. Treatment and follow-up must be performed not only for the adenocarcinoma element but also for the choriocarcinoma element in patients presenting with endometrial carcinoma with choriocarcinomatous differentiation. © 2009 Elsevier Inc. All rights reserved.

Introduction Choriocarcinomas unrelated to pregnancy, teratomas, or germ cell tumors have been found in the stomach [1], lung [2], colon [3], esophagus [4], bladder [5], breast [6], renal pelvis [7] and other sites. They are believed to arise from poorly differentiated carcinoma or develop as carcinoma with choriocarcinomatous differentiation. They invariably contain and produce human chorionic gonadotropin (hCG) peptide hormone. We report a case of endometrial carcinoma with choriocarcinomatous differentiation, and reviewed the literature with regard to malignant uterine tumor with choriocarcinomatous differentiation. Case report A 58-year-old gravida 1, para 1 with menopausal status for 6 years presented with postmenopausal bleeding. She had uneventful surgical and gynecological histories with no history of hormonal replacement therapy. Her height was 143 cm and her weight was 45 kg. The gynecological examination revealed a painless enlargement of the uterus with thick endometrium. Magnetic resonance imaging showed that a bulky mass, measuring about 5 cm in diameter, existed in the uterine cavity involving the anterior wall of the uterine body. The tumor in the endometrial biopsy specimen was diagnosed as poorly differentiated endometrioid adenocarcinoma with bizarre giant cells. ⁎ Corresponding author. Fax: +81 72 684 6513. E-mail address: [email protected] (T. Yamada). 0090-8258/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2009.01.005

Chest X-ray and abdominal computed tomography showed no signs of metastatic lesion. Under the diagnosis of endometrial cancer, an abdominal hysterectomy with bilateral salpingo-oophorectomy and pelvic lymphadenectomy were performed. The hysterectomy specimen, measuring 95 × 75 mm, showed a partially necrotic and hemorrhagic polypoid mass of approximately 45 × 45 mm in the endometrial cavity. Tumor grew with infiltration, as well as lymphovascular and blood vessel involvements, into the inner third region of the myometrium. The resected vaginal cuff as well as both adnexa and the resected lymph nodes were free of tumor (FIGO stage 1b). The pathological examination revealed 2 distinct tumor types. Approximately half of the tumor showed a well differentiated endometrioid adenocarcinoma, without psammoma bodies (Fig. 1a). The remaining parts of the tumor showed a biphasic morphology, containing mononuclear cells and syncytial-like giant cells resembling choriocarcinoma (Fig. 1c). There was a close transition from the endometrioid to the choriocarcinomatous areas on several slides (Fig. 1b). Immunohistochemical analysis for CA125 (Dako, clone OC125) and vimentin (Dako, clone V9) were positive in the adenocarcinomatous part, and human chorionic gonadotropin (Dako, polyclonal) was positive in the choriocarcinomatous part, especially in the syncytiallike cells. Keratin (Dako, clone AE1, AE3) was positive in both elements. Syncytial-like cells in the lymphovascular involvement were stained intensely with hCG. The preoperative serum β-hCG value was not measured because choriocarcinoma was not suspected before surgery. The

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Fig. 1. The tumor showed a well differentiated endometrioid adenocarcinoma without psammoma bodies (a), a biphasic morphology, containing mononuclear cells and syncytiallike giant cells (c) and a close transition from the endometrioid to the choriocarcinomatous areas (b). (H&E, bar = 100 μm).

postoperative serum β-hCG values, 19 mIU/mL (post operative day (PO) 15), 28 mIU/mL (PO 18), and 38 mIU/mL (PO 20), were increased as compared to before the start of the chemotherapy. As the lymphovascular and blood vessel involvements, the increasing serum β-hCG values and the histology (endometrioid adenocarcinoma with choriocarcinomatous differentiation), 5 courses of the CTP (carboplatin, CBDCA; therarubicin, THP; cyclophosphamide, CPA) regimen were selected as the chemotherapy for this uterine endometrial adenocarcinoma case. After the start of chemotherapy, the levels of serum β-hCG decreased to 2.3 mIU/mL (PO 53) and b0.1 mIU/mL (PO 83). However, 9 months after the surgery, a tumor appeared at the vaginal wall near the vaginal cuff and the serum β-hCG value increased again to 1.7 mIU/mL. Histology of the metastatic tumor at the vagina showed mostly mononuclear cells and syncytial-like giant cells, as choriocarcinoma without any adenocarcinoma component. Thus, chemotherapy was switched to the EMACO (etoposide, VP-16; methotrexate, MTX; actinomycin D, ACD; cyclophosphamide, CPA; vincristine, VCR) regimen, leading to a subsequent decline of the βhCG values and complete resolution of vaginal metastatic disease after 6 courses. Since then, the patient has maintained a disease-free status and the serum β-hCG values were within normal range for 3 years after the 2nd chemotherapy course. Fifty months have passed since surgery. Discussion More rarely, true choriocarcinomatous differentiation is seen histologically in nontrophoblastic tumors, including stomach [1], lung [2], colon [3], esophagus [4], bladder [5], breast [6], and renal pelvis [7], as well as gynecologic cancers. Both syncytiotrophoblast and cytotrophoblast elements, or either one alone, may be present.

When choriocarcinomatous differentiation is seen, hCG can generally be demonstrated immunohistochemically in the syncytiotrophoblastlike cells of these tumors, and these patients tend to have high serum or urine levels of hCG. Fifteen cases in the literature have reported histological choriocarcinomatous differentiation in malignant uterine tumors. Thirteen of these involved uterine body tumors (11 endometrial cancers [8–15] and 2 carcinosarcomas [16,17]) and 2 involved cervical cancers [18,19], as shown in Table 1. All 15 cases, including the present one, complained of abnormal genital bleeding. In all cases of choriocarcinomatous element, hCG was demonstrated immunohistochemically and all, except for not measured cases, had high levels of serum or urine hCG. In the 11 endometrial cancer cases, the mean age was 68.9 years (48–88 years), and 9 of the 11 patients were multigravida. As for the histology of the co-existing tumors, 9 of 11 were endometrioid adenocarcinomas and 2 of these were serous adenocarcinomas. The primary tumors included areas of choriocarcinomatous differentiation, but in 5 cases of metastatic or recurrent tumors, 2 were choriocarcinoma, 1 was serous adenocarcinoma, 1 was endometrioid adenocarcinoma without co-existing histology, and 1 was described as the same as primary tumor. Prognosis is not good because only 2 of 11 cases had no evidence of disease. In the 2 carcinosarcoma cases, both of them were nulligravida and the carcinomatous elements were endometrioid adenocarcinoma. One of these patients died of the disease 7 months after initial diagnosis. In the 2 cervical cancer cases, histology of both cases showed mucinous adenocarcinoma of endocervical type, and 1 of these patients died of disease 4 months after surgery. The pathogenesis of trophoblastic differentiation in nongestational and non-germ cell tumors is not well understood. It is more difficult to understand mixed tumors that are categorically different. Two

Table 1 Cases of malignant uterine tumor with choriocarcinomatous differentiation Author

Year

Case Age (y) Gravidity no. and parity

Endometrial carcinoma Civantos and 1972 1 Rywlin [8] 1987 2 Savage et al. [9] Pesce et al. [10]

Present case

Nguyen et al. [17]

1/1

Well AD

3

78

ND/0

Poor AD

4

48

5/ND

Poor AD

5

63

Multi/multi AD

1995

6

83

0/0

Mod AD

1998

7

88

ND/1

Clear cell AD

1998

8

68

4/4

1998

9

54

6/6

Poor AD, clear AD, SPC Mod AD

2006

10

61

3/3

SPC

2008

11

58

1/1

Well AD

71

0/0

34

0/0

39

5/4

Mucinous AD

65

0/0

Mucinous AD, hepatoid carcinoma

Cervical carcinoma Collins 1989 1 et al. [18] Shintaku 2000 2 et al. [19]

–

+

ND

Chorio

TAH, BSO

ND

–

Medroxyprogesterone, + 5FU, DXR, megestrol acetate CDDP, BLM, VCR –

ND

TAH

Same as primary ND

Positive Serum β-hCG:19,500 mIU/mL Positive Serum β-hCG:3050 mIU/mL Positive Urinary hCG:10,000 IU/24 h Positive Serum hCG:100,000 mIU/mL Positive Serum hCG: 851 IU/L

70

2000 2

–

ND

SPC

Carcinosarcoma Khuu 2000 1 et al. [16]

Follow-up Status time (mo) at last follow-up

ND

ND

ND

+

DOD

–

14 Lungs, brain, peritoneum, liver, kidneys Pelvic lymph nodes 1.5

DOD

–

ND

Lungs

ND

ND

TAH, BSO

MTX, VP-16, BLM, CDDP –

–

ND

14

DOD

TAH, BSO

CDDP, VP-16

–

ND

Peritoneum, lungs, liver Lungs

1

AWD

–

TAH, BSO

–

+

–

None

16

DOD

SPC

TAH, BSO, OMT, LD Megestrol acetate, PTX, CBDCA TAH, BSO MTX, CPA, ACD,VP-16, folinik acid TAH, BSO, LD MTX, EMACO(VP-16, MTX,ACD, CPA, VCR)

–

–

Pelvic lymph nodes 16

NED

–

–

24

DOD

–

–

Retroperitoneal mass Lungs

3

DOD

Chorio

TAH, BSO, LD

CBDCA, THP, CPA, EMACO(VP-16, MTX, ACD, CPA, VCR)

–

–

Vaginal cuff

36

NED

– Carcinosarcoma Positive Serum hCG: 283 mIU/mL postoperation Carcinosarcoma Positive Serum Chorio β-hCG:32,000 mIU/mL

TAH, BSO, LD

–

–

Alive

None

8

NED

TAH, BSO, OMT, LD BLM, VP-16, CDDP, EMACO (VP-16, MTX, ACD, CPA, VCR), CDDP, PTX

+

–

Lungs, brain, para-aortic lymph node

7

DOD

Positive Serum β-hCG:95 mIU/mL Positive Serum β-hCG:5514 mIU/mL Positive Serum hCG:225,000 IU/L postoperation Positive Serum β-hCG:38 ng/mL postoperation

Positive Serum β-hCG:30 mIU/mL Positive Serum β-hCG:113 ng/mL postoperation

AD ND

–

TAH, BSO, LD

–

+

Alive

–

28

NED

ND

TAH, BSO

CDDP, PTX

ND

–

Lungs

4

DOD

T. Yamada et al. / Gynecologic Oncology 113 (2009) 291–294

Kalir et al. [11] Black et al. [12] Bradley et al. [13] Tunc et al. [14] Horn et al. [15]

Irradiation Autopsy Metastasis and invasion

Positive Urinary hCG:1000 IU/24 h Positive –

3/2

1991

Chemotherapy

hCG stain

87

hCG level

Surgery Histology at metastasis or recurrence

Coexisting tumor

ND: not described. SPC: serous papillary carcinoma. AD: adenocarcinoma. well: well differentiated. mod: moderately differentiated. poor: poorly differentiated. hCG: human chorionic gonadotropin. chorio: choriocarcinoma. TAH: total abdominal hysterectomy. BSO: bilateral salpingo-oophorectomy. OMT: omentectomy. LD: lymphadenectomy. 5-FU: 5-fluorouracil. DXR: doxorubicin. CDDP: cisplatin. BLM: bleomycin. VP-16: etoposide. PTX: paclitaxel. CBDCA: carboplatin. MTX: methotrexate. CPA: cyclophosphamide. ACD: actinomycin D. VCR: vincristine. THP: therarubicin. DOD: dead of the disease. AWD: alive with the disease. NED: no evidence of the disease.

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popular hypotheses regarding the origin of extragenital or nongestational choriocarcinoma are both based on the “embryonic rest” theory [17]. The first theory suggests that a group of germ cells, coming to rest in the region of the urogenital ridge, fails to complete their migration to the gonadal tissue, and subsequently undergo malignant transformation. The second theory suggests that nests of totipotent germ cells are left in ectopic sites outside the urogenital ridge during early embryonal development, fail to undergo apoptosis, and then subsequently transform into choriocarcinoma. This would explain choriocarcinomas originating from organs remote from the urogenital tract. A third theory, supported by recent molecular analyses of the tumors [1,7], suggests that a tumor consisting of adult tissue elements may undergo retrodifferentiation or dedifferentiation, resulting in cells with different morphological features, for example, trophoblastic and nontrophoblastic differentiations. We thought that adenocarcinoma was basic histology and chose the regimen for endometrioid adenocarcinoma in this case. Actually the serum β-hCG decreased to the normal range once. Although the recurrent tumor appeared after that, the regimen for choriocarcinoma lead to a complete resolution, since the histology was only choriocarcinoma. The prognosis depends on the sensitivity of the chemotherapy. As the histology of the recurrent tumor is both adenocarcinoma and choriocarcinoma in previous reports, it would be necessary to use the regimen which is sensitive to both of them. Urine and serum hCG levels are not routinely used as tumor markers in preoperative testing for malignant uterine tumors. When choriocarcinoma was suspected in a biopsy or cytology of endometrium, hCG should be measured. For uterine adenocarcinoma with choriocarcinomatous differentiation, treatment and follow-up must be done not only for adenocarcinoma but also for the choriocarcinoma element. Conflict of interest statement The authors declare that there are no conflicts of interest.

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