Int J Clin Exp Med 2016;9(2):4858-4865www.ijcem.com /ISSN:1940-5901/IJCEM0018085

Case ReportGrowing teratoma syndrome following primary ovarian immature teratoma: two cases and review of literature

Xue-Lian Li1,2, Xian-Rong Zhou3, Hua Jiang1,2

1Department of Gynecology, OB/GYN Hospital, Shanghai Medical College, Fudan University, Shanghai, China; 2Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Shanghai, China; 3Department of Pathology, OB/GYN Hospital, Shanghai Medical College, Fudan University, Shanghai, China

Received October 18, 2015; accepted January 9, 2016; Epub February 15, 2016; Published February 29, 2016

Abstract: Growing Teratoma Syndrome (GTS) is defined as the occurrence of a tumor mass consisting exclusively of mature teratoma, combined with normal tumor marker levels, during or after chemotherapy in patients with Non Seminomatous Germ Cell Tumors (NSGCT). We report two cases of GTS. Case 1 is a woman with concomitant retroperitoneal mass invading the muscular layer of abdominal wall, and scattered nodules fixed on the diaphragm following a primary ovarian immature teratoma within 9 months during chemotherapy. No macroscopic deposit was left at the end of last surgery, and pathologic diagnosis showed mature teratoma. The serum level of CA19-9 elevated through the course of disease even four months after the radical operation of GTS when blood amylase and CT scan were negative, and electronic gastroscopy showed chronically congestive and exudative gastritis. We consider the elevated CA19-9 is mainly due to gastritis or only reactive peritoneal mesothelial cells. Case 2 is a woman with scattered nodules fixed on the pelvic peritoneal following a primary ovarian immature teratoma within 3 months during chemotherapy, which is proved to be mature teratoma with mature gliacyte by pathologic diagnosis. The tumor markers are all negative after that and another ovarian mass is found 6 months later. We also reviewed relevant literature and distinguished GTS from chemotherapeutic retroconversion (CR), and gliomatosis peritonei (GP). Optimal cytoreduction with no macroscopic residual disease is essential for GTS with subsequent favorable prognosis. Regular follow-up is recommended.

Keywords: Growing teratoma syndrome, ovarian immature teratoma, chemotherapeutic retroconversion, gliomato-sis peritonei

Introduction

The ovarian teratoma are considered the most common germ cells neoplasm represented by mature, immature, and monodermal types. The immature teratoma (IT) of the ovary constitutes about 1% to 2% of all ovarian teratoma. According to WHO, IT is defined as a teratoma containing a variable amount of immature embryonal type (generally) neuroectodermal tissue [1]. And tumor grading is based on the amount of immature neuroepithelium presence.

Growing teratoma syndrome (GTS) is a clinico-pathological presentation during/post-chemo-therapy in malignant ovarian germ cell tumor where mature teratoma grows and requires complete surgical excision. The incidence of

GTS is estimated to be 1.9 to 7.6% in testicu- lar Non Seminomatous Germ Cell Tumours (NSGCT) and is even rarer in women [2].

Here we report a case of GTS with concomitant retroperitoneal and diaphragm distribution in a woman with a primary ovarian immature teratoma.

Case description

Case 1

In June 2014, a 35-year-old parous lady with a regular menstrual cycle underwent investiga-tions for recent subtle discomfort of lower abdomen. Her family histories were all unre-markable. A 11 cm pelvic mass was diagnosed. Serum tumor marker study showed elevated

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Carbohydrate antigen 19-9 (CA19-9, 66.17 IU/mL) and α-foetoprotein (AFP, 140.56 ng/ml). Laparoscopic evaluation confirmed a smooth tumor in the right ovary and a right cystectomy was done. Pathologic diagnosis of frozen sec-tion showed mature teratoma without any immature neural tissue, but with mesenchymal tissue which was not fully mature. Then a right salpingo-oophorectomy was done at the same day, and the pathologic diagnosis of paraffin section was immature teratoma G2 (Figure 1A). Immunohistochemistry showed CK-pan (+), CD9-9 (+), S-100 (+), vimentin (+), and glial fibril-lary acidic protein (GFAP) (+).

Sixteen days later, a following radical resection was done, which included total hysterectomy, left salpingo-oophorectomy, right ovarian vas-cular resection, omentectomy and appendec-tomy. There was no ascitic fluid or positive find-ing about abdominal or pelvic organs. The pathologic diagnosis of paraffin section showed no tumor.

Four months later, October 2014, a follow-up positron emission tomography and computer

tomography (PET/CT) scan showed planting metastasis at the left and middle part of deep abdominal wall, and also under the liver cap-sule of right posterior lobe (6.6*4.3 cm). Serum tumor marker study showed elevated CA19-9 (191.96 IU/mL) and AFP (>2000 ng/ml). Four courses of chemotherapy with a triple associa-tion (bleomycin-etoposide-cisplatin) were given. AFP level was 18.90 ng/ml right after the fourth chemotherapy, and 5.20 ng/ml one month later. CA19-9 level was 184.21 IU/mL right after the fourth chemotherapy, and 143.90 IU/mL one month later with computer tomography (CT) scan showing planting metastasis at abdominal cavity and at the liver (9.2 cm in diameter). So in February 2015, the patient received the third operation which showed a giant and hard-textured retroperitoneal mass (15*12 cm) between the liver and kidney, invad-ing the muscular layer of abdominal wall, and with scattered nodules fixed on the diaphragm and the largest one was about 4*3 cm. No macroscopic deposit was left at the end of sur-gery (radical operation, RO state), 1000 mg flu-orouracil was used to flush abdominal cavity, and another 1000 mg fluorouracil was kept in

Figure 1. A. Pathologic diagnosis of paraffin sec-tion of salpingo-oophorectomy showed immature teratoma G2 (case 1). B. Pathologic diagnosis of paraffin section of radical operation showed ma-ture teratoma (retroperitoneal mass) (case 1). C. Pathologic diagnosis of paraffin section of radical operation showed gliacyte (nodules on the perito-neum and diaphragm) (case 1).

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abdominal cavity. Pathologic diagnosis of par-affin section showed mature teratoma (retro-peritoneal mass, showed as Figure 1B) and gli-acyte (nodules on the peritoneum and dia-phragm, showed as Figure 1C), and no imma-ture elements or viable carcinoma were seen in any of the sections studied, which was con-firmed by six senior pathologists. Immu- nohistochemistry showed CK (+), CD34 (+), SMA (+), Desmin (+), NSE (+), S-100 (+), vimen-tin (-), CD68 (-), CD117 (-), LCA (-) and ChrA (-).

Six months after the third operation, AFP level was 2.00 ng/ml, and CA19-9 level was 80.22 IU/mL. The variation of serum tumor markers was showed as Table 1. The serum level of CA19-9 elevated through the course of disease in this case, even six months after the radical operation of GTS when blood amylase and CT scan were negative. Electronic gastroscopy showed chronically congestive and exudative gastritis. The patient received no further thera-py and was still on close follow-up.

Case 2

In April 2012, a 29-year-old parous lady with a regular menstrual cycle was found to have a pelvic mass about 14 cm in diameter when she received regularly medical checkup. Her family histories were all unremarkable. Serum tumor marker study showed elevated Carbohydrate antigen 125 (CA125, 157.30 IU/mL) and α-foetoprotein (AFP, 128.86 ng/ml). Abdominal

laparotomy confirmed a ruptured tumor about 14 cm in diameter in the left ovary, two masses about 0.5 cm in diameter in the right ovary and a few nodules on the peritoneal. Then a left salpingo-oophorectomy was done, and all the masses and nodules were removed at the same time. The pathologic examination showed that the mass of the left ovary was immature teratoma G2, the masses of the right ovary were mature teratoma, and the nodules on the peritoneal were mature gliacyte, shown as Figure 2A, 2B. Immunohistochemistry of imma-ture teratoma showed AFP (focally+), CD9-9 (+), ki67 (10%+), Inhibin-a (-), S-100 (focally +) and vimentin (+). Three courses of chemotherapy with a triple association (vincristine-cisplatin-bleomycin) were given. Serum AFP decreased to normal level, CA125 showed a trend of decreasing but still elevated (51.04 IU/mL).

But after the third cycle of chemotherapy, CA125 was 73.35 IU/mL and pelvic MRI showed a complex mass which was removed and proved to be mature teratoma with mature glia-cyte. The patient received the fourth cycle of chemotherapy with the same chemotherapy regimens, and was kept on close follow-up.

The serum tumor marker was negative after that, but a slowly enlarging mass was found in the right ovary. Six months later, March 2013, laparoscopic examination showed a 5 cm smooth mass in the right ovary and a few nod-

Table 1. The variation of serum tumor markers (case 1)AFP

(ng/mL)CEA

(ng/mL)SCC

(ng/mL)CA19-9 (U/mL)

CA125 (U/mL)

CA153 (U/mL) Notes

2014-6-27 140.56↑ 1.31 0.90 66.17↑ 7.93 6.40 Before 1st operation2014-6-30 103.51↑ NA NA 65.62↑ NA NA After 1st operation2014-10-15 1860.07↑ 1.97 1.20 136.58↑ 12.76 8.01 After 2nd operation, and before 1st chemotherapy2014-11-6 1036.76↑ 2.36 1.10 160.18↑ 17.49 7.92 Before 2nd chemotherapy2014-11-10 784.62↑ NA NA 163.81↑ NA NA After 2nd chemotherapy2014-11-29 108.73↑ 3.00 2.30↑ 137.37↑ 17.02 9.76 Before 3rd chemotherapy2014-12-22 18.90↑ 4.21 4.10↑ 184.21↑ 18.27 10.56 Before 4th chemotherapy2015-1-15 7.36 5.30↑ 6.60↑ 227.67↑ 24.33 9.36 After 4th chemotherapy, and before 3rd operation2015-3-6 3.17 2.12 1.20 120.67↑ 29.40 11.78 1 month after 3rd operation2015-3-30 2.41 1.63 0.90 69.10↑ 9.90 8.60 2 months after 3rd operation2015-4-23 2.21 1.33 1.10 72.35↑ 9.80 8.30 3 months after 3rd operation2015-4-27 2.26 1.53 0.90 94.70↑ 9.00 7.70 3 months after 3rd operation2015-5-31 1.99 1.61 0.80 103.63↑ 7.90 7.50 4 months after 3rd operation2015-6-28 2.26 NA NA 83.52↑ NA NA 5 months after 3rd operation2015-8-3 2.00 NA NA 80.22↑ NA NA 6 months after 3rd operationNotes: NA means not available, ↑ means higher than standard value.

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ules on the peritoneal, which were all removed and proved to be mature teratoma with mature gliacyte. The patient received no further thera-py and was well during follow-up.

Discussion

Mature teratomas (MT) are benign tumors often composed of derivatives of two or three germ cell layers. Immature teratomas (IT) are malignant ovarian tumors defined as a tumor containing immature embryo components, usu-ally immature primitive neuroectodermal tissue [3]. Immature elements represent the evolution of a malignant clone, and the prognosis relates to the amount of this component [4].

The ovarian GTS is a rare condition among patients with primary NSGCT presenting with enlarging masses during or after appropriate chemotherapy in the context of normalized serum markers. GTS is usually diagnosed in the twenties and may occur after a primary pure immature teratoma or a mixed NSGCT [5]. Three criteria are mandatory to define GTS: (1) an evolving tumor mass or finding a new tumor mass during or after chemotherapy for NSGCT, (2) the regression of previously increased tumor markers (AFP, hCG or both), and (3) the pres-ence of only mature teratoma on the final his-tology [6, 7].

The aetiology of GTS remains unclear. Main hypotheses are that chemotherapy may selec-tively inactivate the immature elements with subsequent growth of the remaining mature tumor cells or may change the cells behavior

with immature germ cells transforming into benign teratomatous elements [8]. In many cases, GTS nodules exist in the pelvis, abdo-men, or retroperitoneum, with the most fre-quent site of metastasis being the peritoneum. Only one group reported an ovarian GTS patient with GTS nodules in the neck lymph nodes and lungs [9]. There was a case of GTS of the ovary showing three patterns of metastasis: dissemi-nation, lymphogenous metastasis, and hema-togenous metastasis [10]. The patient initially presented 5 years ago with a mixed germ cell tumor of the left ovary and positive cytology of ascites. After surgery and chemotherapy, mature teratomas recurred as pelvic peritoneal dissemination, a para-aortic lymph node mass, and a lung mass, which suggested that chemo-therapy influenced the differentiation potency and induced the malignant cell differentiation of an immature into a mature teratoma, but the possible existence of micrometastases could not be denied. There were two case reports of subsequent abdominal port-site GTS of two patients taken in charge by laparoscopy [11, 12], which suggested the importance of an optimal surgical approach for all suspicious complex adnexal masses, and the potential iatrogenic role of unsafe and inadequate surgery in terms of increased risk of GTS sec-ondary to abdominal wall implants. Mass rup-ture, incomplete resection and tumor cells spill-age must be avoided as much as possible because it worsens the patient prognosis and may result in iatrogenic GTS requiring aggres-sive surgical management to obtain complete cytoreduction.

Figure 2. A. The pathologic examination showed that the mass of the left ovary was immature teratoma G2 (case2). B. The pathologic examination showed that the nodules on the peritoneal were mature gliacyte (case2).

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Table 2. Clinical features of 24 patients from 19 series with GTS or CR and with primary diagnosis of immature teratoma

Author Cases Age Stage Grade AFP when IT (ng/mL)

Time of GTS after IT

AFP when GTS (ng/

mL)GTS site

Byrd K [16] 1 48 NA I NA 11 years NA Uterus

Daher P [17] 1 4 NA III Elevated 7 months Normal Pelvic, omentum, appendix, broad ligament, abdominal wall

Djordjevic B [5] 1 19 IIIc III 2839 7 months Normal Periaortic, peripancreatic, perisplenic, omental, transverse colon, sigmoid, mesenteric

Han NY [18] 3 13, 13, 37 years I*1, III*2 NA Elevated 5, 16, 83 months NA 1 pelvic, 1 perihepatic space, pelvic, 1 subphrenic space, splenic hilum, paracolic gutter, rectouterine pouch

Hariprasad R [9] 3 18, 26, 27 NA III*2, NA*1 560, 1462, 6000 11 months, NA, NA NA 1 abdomino-pelvic, uterus, rectum, sigmoid colon, calcifi cation, 1 pelvic, 1 pelvic and liver

Kampan N [19] 1 17 Ia I NA 1 year NA Bilateral adnexal, uterus

Kato N [20] 2 30, 22 NA III Normal 8, 22 years Normal 1 retroperitoneum, nodules in pelvic cavity, 1 peritoneal cavity

Kikawa S [21] 1 36 Ic II 11.9 9 months Normal Pelvic masses, peritoneum

Kurata A [22] 1 15 Ia II 107.3 19 months 20.1 Brain, liver, lung

Lorusso D [23] 1 19 Ia III 105 4 months NA Liver

Matsushita H [24] 1 30 IIIa II 343 97 months Normal Superior pole of kidney

Morency EG [25] 1 20 IIIb III 400 18 months Normal Pelvic, liver

Mrabti H [26] 1 18 NA NA 210 6 months Normal Abdominopelvi, peritoneum

Pendlebury A [27] 1 21 Ic III 86 kU/L 2 months 20 kU/L Serosal surface of liver, hemidiaphragm, pelvic peritoneum

Rashmi [28] 1 19 Ia III 5378.4 3 years Normal Omentum, peritoneum, bowel loops

Sengar AR [12] 1 26 I I 265.7 4 months 2,375.98 Pelvic, abdominal wall

Tangjitgamol S [15] 1 5 Ia III >900 5 months Normal Mass beneath diaphragm, cul-de-sac

Tejura H [29] 1 21 NA NA 154 1 year NA Pelvic, adnexal, para-aortic lymph

Tzortzatos G [30] 1 20 Ic II NA 2 years NA Sacrouterina ligaments, fossa DouglasiNotes: NA means not available.

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There is no consensus regarding the necessary conditions underlying the development of GTS. Primary peritoneal involvement as well as the existence of mainly immature neuroectodermal elements in the primary neoplasm may be nec-essary [6]. The risk factors for the development of GTS may include (1) the presence of mature teratoma in a nonseminomatous germ cell tumor; (2) no reduction in the size of metasta-ses during chemotherapy; and (3) the presence of mature teratoma in postchemotherapy resid-ual masses [8]. If there are no abdominal, pel-vic, or retroperitoneal recurrences within 24 months of the original presentation of an ovar-ian teratoma or mixed germ cell tumor, GTS is unlikely to occur, and as ovarian GTS nodules rarely arise above the diaphragm, patients could be spared chest-imaging studies, unless they are symptomatic [5]. AFP levels, if initially elevated, may be used to monitor therapeutic response [5].

Chemotherapeutic retroconversion (CR) is a chemotherapy-mediated transformation of a metastatic immature teratoma into mature ter-atoma, which was first defined in 1977 by DiSaia and colleagues in the context of imma-ture ovarian teratoma [13]. There are 2 possi-ble mechanisms for CR: chemotherapy either promotes the conversion of immature tera-tomatous tissue into mature tissue or chemo-therapy destroys only the immature compo-nent, leaving the mature tissue behind [13]. Strictly speaking, CR meets only 2 of the 3 cri-teria for GTS. In GTS, not only must the mature teratoma nodules have undergone CR, but also must have the ability to grow, whereas in CR the nodules do not increase in size, which speaks to the proliferative ability of the GTS cells despite being terminally differentiated. It is also noteworthy that CR, as it was defined, refers only to immature teratomas of the ovary and has not been applied by subsequent authors to mixed germ cell tumors of either the ovary or the testis. But Amsalem concluded that GTS and chemotherapeutic retroconver-sion were probably the same phenomenon [14].

There was one paper of 2006 searched the English literature for the cases reported under the term CR or GTS and found 23 patients from 10 series with such diagnoses and with prima-ry diagnosis of IT [15]. Here we report this case

of GTS with concomitant retroperitoneal and diaphragm distribution in a woman following primary ovarian IT within 9 months during che-motherapy. We also searched the English litera-ture of recent 10 years for the cases reported under the term CR or GTS and found 24 patients from 19 series with such diagnoses and with primary diagnosis of IT. Their clinical features are summarized and shown in Table 2 [5, 8, 12, 15-30].

Another form of peritoneal spread can arise with nonepithelial ovarian tumors (mainly in cancer but also more exceptionally in benign teratoma), namely, gliomatosis peritonei (GP) [31, 32]. This entity is histologically defined as the presence of mature glial tumor tissue in the peritoneum, which can be pure (exclusively comprising mature glial tissue) or associated with other mature tissue components (GTS) and/or associated with immature disease. GST is observed after chemotherapy, but GP can arise in adjuvant chemotherapy-naive patients (the primary ovarian tumor was a mature tera-toma or it was a grade 1 immature ovarian tera-toma treated exclusively with surgery).

Among all the tumor markers, most reports of GTS focus on AFP, hCG, LDH and CA125, only a few reports mentioned CA19-9. Patients have normal CA19-9 during the whole time [22], or elevated CA19-9 when diagnosed with IT or GTS and normal CA19-9 after operation or che-motherapy [10, 21, 24]. The serum level of CA19-9 was normal CA19-9 during the whole time in our case 2, but elevated through the course of disease, even six months after the radical operation of GTS when blood amylase and CT scan were negative in case 1. What does this mean? CA19-9 is commonly ex- pressed by adenocarcinoma cells of the ovary, pancreas, and gastrointestinal tract. Electronic gastroscopy shows chronically congestive and exudative gastritis in case 1, and we have not found any evidence of recurrence or retaining of teratoma, or tumor of other organs, we con-sider that the elevated CA19-9 is mainly due to gastritis or only reactive peritoneal mesothelial cells, and keep the patient on close follow-up without further therapy.

Conclusions

The ovarian GTS is a rare entity but should be suspected when tumor masses persist or

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develop with normal tumor markers, during or after adjuvant chemotherapy for NSGCT. The diagnosis requires histologic confirmation with presence of mature teratomatous elements exclusively. Optimal cytoreduction with no mac-roscopic residual disease is essential for GTS with subsequent favorable prognosis. Regular follow-up is recommended. But IT has sensitive tumor markers, and there are some cases of mass with normal tumor markers, and other cases of slightly elevated tumor markers with no suspicious lesions. What should we do about these cases? Second look operation, chemo-therapy or only close following-up? There is still no consensus about it and further clinical researches are needed.

Acknowledgements

This study was supported by National Natural Science Foundation of China (Grant No. 31371452 to Hua Jiang) and Foundation from Science and Technology Commission of Shanghai Municipality (Grant No. 15JC1403202 to Hua Jiang).

Disclosure of conflict of interest

None.

Address correspondence to: Hua Jiang, Depart- ment of Gynecology, OB/GYN Hospital, Shanghai Medical College, Fudan University, 419 Fangxie Road, Shanghai 200011, China. Tel: +86 21 63455090; Fax: +86 21 63455090; E-mail: jiang-hua@fudan.edu.cn

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