Ann Surg Oncol DOI 10.1245/s10434-015-4608-y
ORIGINAL ARTICLE – GYNECOLOGIC ONCOLOGY
Surgical Outcomes After Debulking Surgery for Intraabdominal Ovarian Growing Teratoma Syndrome: Analysis of 38 Cases Enrica Bentivegna, MD1, Henri Azaı¨s, MD1, Catherine Uzan, MD, PhD1,2, Alexandra Leary, MD, PhD3, Patricia Pautier, MD3, Clementine Gonthier, MD1, Catherine Genestie, MD4, Corinne Balleyguier, MD5, Catherine Lhomme, MD3, Pierre Duvillard, MD4, Philippe Morice, MD, PhD1,2,6, and Sebastien Gouy, MD, PhD1 Department of Gynecologic Surgery, Gustave Roussy, Villejuif, France; 2Unit INSERM 30-10, Villejuif, France; 3 Department of Medical Oncology, Gustave Roussy, Villejuif, France; 4Department of Pathology, Gustave Roussy, Villejuif, France; 5Department of Radiology, Gustave Roussy, Villejuif, France; 6University Paris Sud, Paris, France 1
ABSTRACT Background. The goal, methods, and results of surgery for growing teratoma syndrome (GTS) in men after testicular cancer have been well described. The main surgical challenge relates to the need for vascular or thoracic procedures. But little is known about GTS in women, particularly regarding the optimal management of intraabdominal disease. This study aimed to evaluate the surgical management and outcomes (recurrences and fertility) for a large series of ovarian GTS. Methods. This study retrospectively analyzed patients treated for an ovarian immature teratoma (IT) who subsequently experienced abdominal GTS requiring surgery. Results. Between 1983 and 2014, 196 cases of IT were referred to the authors’ institution or treated there, and 38 patients (19 %) subsequently experienced a GTS, including 10 cases of gliomatosis peritonei (containing exclusively pure mature glial tissue). The median age at diagnosis was 26 years (range 8–41 years), and the mean delay between IT and GTS diagnosis was 7 months (range 3–84 months). Surgical resection included peritonectomy (n = 22), diaphragmatic peritoneal resection (n = 14), bowel resection (n = 8), and splenectomy (n = 5). Conservative surgery was possible for 20 patients. Complete cytoreductive surgery was achieved for 25 patients. The mean
Presented at the International Gynaecological Cancer Society Meeting, Melbourne, Australia, 7–11 November 2014. Society of Surgical Oncology 2015 First Received: 16 January 2015 P. Morice, MD, PhD e-mail: [email protected]
follow-up period was 73 months (range 3–263 months). At least one recurrence developed for 10 patients (in the form of mature disease in all, and 8 of these patients had an initial complete resection. Five patients had a pregnancy. One patient died of complications from the disease (pulmonary embolism in a patient with bowel obstruction). Conclusions. The overall prognosis of abdominal GTS is good. The surgical procedures for GTS are similar to those used in debulking surgery for epithelial cancer. Whenever technically possible, a conservative surgery should be performed because spontaneous fertility is possible. Recurrent GTS is frequent even after complete surgery.
The development of mature teratoma in patients treated by chemotherapy for germ cell gonadal cancers is a wellknown phenomenon first described more than three decades ago.1–4 In fact, it probably involves two syndromes, chemotherapeutic retroconversion and growing teratoma syndrome, very similar in terms of natural history and therapeutic management.1,2,5 Chemotherapeutic retroconversion was first described by DiSaia et al. 2 in 1977 in patients with ovarian immature teratoma (IT) treated by chemotherapy. The authors proposed two potential mechanisms: chemotherapy could promote the conversion of immature tissue into mature disease, or chemotherapy could eradicate the immature elements and allow the mature component to flourish.2,6 Although such retroconversion was initially described in teratoma, it also is reported in other subtypes of germ cell ovarian tumor (e.g., yolk sac or dysgerminoma).7 The term ‘‘growing teratoma syndrome’’ (GTS) was proposed 5 years later by Logothetis et al.,1 who described six patients with malignant germ cell tumors (5 testicular
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and 1 ovarian) treated by surgery and chemotherapy in whom a pure mature recurrence developed in the thorax (4 patients) or the abdomen (2 patients). Theoretically, these two syndromes have potentially subtle differences. In a strict sense, GTS implies an expanding mass with the potential for local damage, whereas chemotherapeutic retroconversion does not necessarily require tumor growth.6 Nevertheless, some authors consider these two entities as very similar and probably the same.5 Another less frequent form of mature peritoneal spread associated with germ immature teratoma can arise: gliomatosis peritonei (GP). This entity often is mixed in series of GTS, but two subtle differences exist between GP and GTS according to the criteria of Logothetis et al.1 First, GP is histologically defined as the presence of pure mature glial tumor tissue in the peritoneum without any other mature nonglial components such as observed in GTS. 8–10 Second, GP could be encountered in patients not exposed to adjuvant chemotherapy after the initial management of the ovarian germ cell cancer.11–13 The treatments of GP and GTS are identical and based entirely on a surgical resection. In the current series, we included both entities under the same terminology of GTS. If these masses are not completely resected, they can enlarge and provoke compressive symptoms and exceptionally disease-related mortality (by bowel perforation or ischemia).3,14,15 Furthermore, malignant transformation also has been reported, especially in the form of carcinoid and primitive neuroectodermal tumors.8,16,17 For these reasons, the treatment of GTS requires complete resection of all visible disease.8,17–19 Because testicular cancer is more frequent than ovarian germ cell tumors, the vast majority of GTS occur in men (90 % in the series of Andre´ et al.14).20 Male GTS tend to localize to retroperitoneal or mediastinal lymph nodes where the therapeutic challenge is the requirement for vascular or complex thoracic procedures to ensure complete resection.18–22 In contrast, GTS after ovarian immature teratoma can either have a retroperitoneal nodal spread or present with diffuse peritoneal disease, similar to other ovarian malignancies.23–29 The proposed surgery usually is a so-called ‘‘debulking’’ surgery, a term conventionally used for the removal of the intraabdominal tumor in ovarian cancer, However, the literature has little data regarding the extent of surgery required, particularly the place of fertilitysparing surgery or the clinical outcome after debulking for intraabdominal GTS. Because GTS is significantly less frequent in women than in men, published series are short, and none have focused specifically on the question of surgical management and postsurgical outcomes. One series of 22 cases has been reported, but the paper is
written in Chinese.16 Except for a short series of 12 cases (none of them treated surgically) dedicated to oncologic issues, most publications about GTS in women are case reports (reporting 1–3 cases).6,15,25,26,29 We present the largest series of GTS occurring after treatment for ovarian germ cell tumors and the first series specifically dedicated to surgical considerations.
PATIENTS AND METHODS Population Patients with immature ovarian teratoma referred to our institution or treated there between 1983 and 2014 were retrospectively identified. Among these cases, patients who experienced subsequent GTS (or a chemotherapeutic retroconversion) treated surgically were included in the analysis. Patients were included in the study if they met the diagnostic criteria for GTS as defined by Logothetis et al. 1 in 1982 as well as the following additional inclusion criteria: •
• • • • •
•
Histologic review of the initial tumor by an expert pathologist, with inclusion of only GTS cases from initial immature teratoma Normalization of previously elevated serum tumor markers (aFP or hCG) Clinical or radiologic enlargement of intraabdominal disease during or after chemotherapy Surgical treatment for GTS Histologic confirmation of GTS Centralized pathologic review of the GTS specimen by an expert pathologist with exclusion of patients who had any residual immature disease in the abdomen Available posttreatment outcome data.
Patients were followed up after surgery using clinical examination, blood markers (aFP/hCG), and radiologic imaging (abdominopelvic ultrasonography, magnetic resonance imaging [MRI], or computed tomography [CT] scans depending on the use of conservative treatment of the uterus and one ovary and the degree of spread of the intraabdominal peritoneal disease). Clinical, pathologic, and prior treatment data were collected from clinical records. Precise details regarding the extent of debulking surgery performed for GTS were recorded, as were postoperative outcomes. Oncologic outcomes after the debulking surgery (delay, sites, and histotypes of recurrences) and fertility results for patients treated with a fertility-sparing surgery at the time of the GTS management (defined by preservation of the uterus and at least a part of 1 ovary) were analyzed.
Surgical Outcomes After Debulking Surgery for Intraabdominal
RESULTS During the study period, 196 patients were referred to our institution with an IT or treated there. Among them, 43 had suspicion (on clinical examination or radiologic imaging) of a GTS. Five patients were excluded from the study. Two patients were excluded because immature tissue was found at the permanent histologic analysis of the GTS specimen (in the abdomen of 1 patient and in the paraaortic node of 1 patient), and three patients were excluded due to a lack of data during the follow-up period. Two patients were excluded because immature tissue remained disease free after the surgical procedure for the GTS (18 months for a patient with immature disease in the abdomen and 180 months for a patient with immature disease in a node). Therefore, 38 patients (19 % of IT) fulfilled the inclusion criteria: 28 (14 %) in the form of GTS and 10 (5 %) in the form of GP containing then exclusively pure mature glial tissue. Intraabdominal GTS developed in 32 patients (27 GTS and 5 GP) after surgery and chemotherapy for an IT. One patient had GTS exclusively in the paraaortic node. One patient had radiologic suspicion of GTS without surgical resection during the third recurrence, but this patient had a history of two surgical resections, with mature peritoneal disease for each of them. We included this patient in this series, even if the last event had no histologic confirmation of recurrence in the form of mature disease. The initial characteristics of these 38 cases are detailed in Table 1. Preoperative imaging of some of different cases are shown in Figs. 1, 2 and 3. Initial Characteristics
TABLE 1 Characteristics of patients during initial management of the immature teratoma n = 38 Median age: years (range) \12 years
3
Blood markers Normal Abnormal aFP hCG Unknown
5 17 15 2 16
Stage (and grade for stage 1) 1
10 Grade 2 Grade 3
2 8
2
2
3
13
Unknown stage (grade 3)
13
Histologic subtypes Immature teratoma combined with mature teratoma
20
Pure immature teratoma
13
Mixed Immature teratoma with embryonal carcinoma Immature teratoma with embryonal carcinoma & yolk sac tumor
5 1 4
Characteristics of the surgical management Fertility-preserving surgery
20
Peroperative rupture (in stage 1)
4
Residual macroscopic disease (stage 2 or 3)
3
1-Step surgery
25
2-Step surgery
13
Chemotherapy (types and number of cycles)
Of the 38 patients, 3 were younger than 12 years and 10 were younger than 20 years (34 %). All the patients were treated initially for their IT with fertility-sparing surgery. For 26 % (10/38) of the patients who had presented with a stage 1 IT, adjuvant chemotherapy was offered because of pre- or peri-operative rupture or stage 1C and/or grade 3 disease. Adjuvant chemotherapy was administered to 32 patients (27 of 28 patients with GTS and 5 of 10 patients with GP). A majority of patients were treated with bleomycin, etoposide, and cisplatin (BEP), the exception being very young girls managed by pediatricians who deliver somewhat different chemotherapy regimens to reduce the potential (and theoretical) risk of alkylant-induced secondary leukemia (Table 1).30 The single GTS patient treated without adjuvant chemotherapy initially underwent a unilateral salpingooophorectomy for a mature teratoma combined with a small component of grade 3 immature teratoma without extraovarian disease. This patient had a preoperative rupture. She did not receive adjuvant treatment due to the absence of
26 (8–41)
32
BEP regimen
20
2 Cycles
3
3 Cycles
9
4 Cycles
6
Other
2
BEP followed by EP regimen (6 cycles) EP regimen
1 2
3 Cycles
1
4 Cycles
1
Other regimens
7
Unknown
2
hCG human chorionic gonadotropin, aFP alpha-fetoprotein, EP etoposide, cisplatin, BEP bleomycin, etoposide, cisplatin
macroscopic extra-ovarian disease and the small part of immature disease. For this patient, intraabdominal and wound ‘‘recurrences’’ developed 15 months later. Histologic analysis of the debulking surgery specimen (performed with a fertility-sparing debulking surgery) demonstrated that all
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FIG. 1 Computed tomography showing peritoneal lesions (with calcifications) on the right diaphragm and inside the spleen FIG. 3 Sagittal view during magnetic resonance imaging (MRI) showing a large disease in the abdominal wall and peritoneum
uterus in place and at least a part of 1 ovary) was possible for 20 patients (Table 2). A complete macroscopic resection (CC0) was performed in 25 cases. Seven patients had small residual disease smaller than 2 mm on the small intestine or mesentery (CC1). One patient had a CC2 resection, leaving a residual pelvic tumor larger than 2 mm but smaller than 5 mm in place. Two patients had a CC2 resection, leaving a residual tumor larger than 1 cm (including 1 patient with GP) in place. Among nine patients with CC1/CC2 resection, five had fertility-preserving surgery. Postoperative morbidity (Dindo classification [grade 2) 31 is presented detailed in Table 2. FIG. 2 Sagittal view during magnetic resonance imaging (MRI) showing a large disease in the abdominal wall
the intraabdominal diseases were pure mature teratoma. Immature disease was found exclusively in the abdominal wall resection. Because all the intraabdominal tumor was mature and because the surgical procedures used were similar to those for GTS, we kept this patient in the current series although in strict sense she did not fulfill the second inclusion criterion of Logothetis et al. 1 defining GTS (previous treatment by chemotherapy). Operative Management and Surgical Outcomes The factors leading to the diagnosis of GTS are presented in Table 2. The characteristics of the debulking surgery and the postoperative outcomes are detailed in Table 2. For 22 patients, peritoneal resection of the paracolic gutters or Douglas pouch was performed. Eight patients underwent bowel resections. A fertility-preserving surgery (leaving the
Recurrences During a median follow-up period of 73 months (range 3–263 months) after initial treatment of GTS, 10 (26 %) patients (1 GP and 9 GTS patients) had recurrences. The median delay between surgery of the GTS and the first recurrence was 45 months (range 2–132 months). All the recurrences were pure mature disease. Among the 10 patients with recurrence, 8 underwent complete macroscopic resection. Their first recurrence was in the peritoneum (n = 3), wound and peritoneum (n = 2), wound alone (n = 2), or ovary and peritoneum (n = 1). Five patients had one recurrence; two patients had two recurrences; and one patient had three recurrences. Among the three patients who had at least two recurrences, all the recurrences were peritoneal or in the abdominal wall. They were treated surgically. Two patients with recurrence were treated with a CC2 resection for initial management of GTS:
Surgical Outcomes After Debulking Surgery for Intraabdominal TABLE 2 Characteristics of patients at the management of the growing teratoma syndrome Characteristics
n = 38
Median delay between initial management and GTS/gliomatosis: months (range)
7 (3–84)
Median number of surgeries for the management of GTS/gliomatosis: n (range)
1 (0–5)
Mode of GTS/gliomatosis discovery Clinical examination
6
Systematic second-look or control surgery
14
Radiologic imaging
11
Ultrasonography
5
Computed tomography
5
Magnetic resonance imaging
1
Unknown
7
Surgical procedures used for debulking surgery Ovarian procedures
38
Unilateral oophorectomy
3
Unilateral salpingo-oophorectomy
17
Bilateral salpingo-oophorectomy
4
Hysterectomy and bilateral salpingo-oophorectomy
14
Ovarian cryopreservation
2
Lymphadenectomy (pelvic and/or para-aortic)
5
Complete omentectomy
19
Splenectomy
5
Appendectomy
14
Large bowel resection
6
Small bowel resection
2
Anastomosis with protective stomia
1
Diaphragmatic peritoneal resection
14
Large peritonectomies (except diaphragmatic peritoneal resection)
22
Partial bladder resection
1
Abdominal wall resection
5
With free-flap reconstruction
1
With biologic mesh reconstruction
1
Characteristics of the resection Complete macroscopic resection (CC0)
25
Macroscopic residual tumor \ 2 mm (CC1)
7
Macroscopic residual tumor [ 2 mm (CC2)
3
Unknown
3
Postoperative morbidities (Clavien Dindo classification [grade 2)
9 26
Bilateral pulmonary embolism
2
Bowel obstruction
2
Caecestomy
1
Hematoma surgically treated
1
Wound dehiscence (late)
2
Bladder self-catheterization combined with diarrhea affecting quality of life
1
GTS growing teratoma syndrome
–
The first patient experienced recurrence 7 years after the initial management in the form of a mature teratoma cyst on the retained ovary (treated using cystectomy)
–
associated with small peritoneal disease (peritoneal gliomatosis). She remained free of disease 9 years after this last recurrence. The second patient was mentioned previously. She initially underwent an emergency unilateral salpingooophorectomy for an adnexal torsion on a germ cell tumor. She experienced a peritoneal recurrence 3 months later in the form of mature and immature peritoneal spread. Four courses of platinum-based chemotherapy were administered, with normalization of alphafetoprotein in the second course. Multiple abdominal masses developed 6 months later, with two attempts at debulking surgery. For both surgeries, the histologic results demonstrated pure mature disease (GTS), but the resection was incomplete. This patient further experienced a third nonoperable recurrent disease (clinically observed and confirmed on CT scan) with bowel obstruction. She died of massive pulmonary embolism in a context of growing abdominal masses 60 months after the initial diagnosis.
The last patient with a CC2 resection was interesting as well because she had bulky peritoneal spread (diagnosis based on CA125 elevation and ascites on CT scan) with unresectable disease (miliary peritoneal implants on the mesentery). This patient underwent large biopsies and a caecostomy demonstrating histologically pure GP. She remained asymptomatic, without clinical symptomatic recurrence 65 months after this last surgical procedure. Four of the patients with GP underwent a secondary surgery (systematic second-look for 2 patients and surgery for ovarian cyst 2 and 16 months after the last surgical procedure respectively for 2 patients), which found asymptomatic quiescent gliomatosis peritonei. None of these patients had symptomatic recurrent GP. At least one patient with GP had died of an intercurrent pathology (heart disease). Among 20 patients treated with fertility-sparing surgery for GTS, two ovarian cryopreservations (technically feasible for 1 patient) had been planned during the surgery. Three patients had ovarian stimulation. Of six patients who desired a pregnancy, four had spontaneous pregnancies and one had an induced pregnancy. In this group of patients having a pregnancy, four had initial complete resection, and one had a CC1 resection (for a GP). DISCUSSION The results of the current study raise several important points for discussion. The first point concerns the true incidence of GTS (or chemotherapeutic retroconversion) after treatment for ovarian germ cell tumors. The syndrome has been estimated to occur in 1.9–7.6 % of testicular
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nonseminomatous germ cell tumors.5,32 Because ovarian germ cell tumors are less frequent in women, GTS series include mostly men.14 Very little data on the incidence of this disease in ovarian tumors are available. In the current series, 19 % of the IT developed subsequent to GTS, including 5 % in the form of pure mature glial disease (GP). These results are concordant with our previous observation.15 In the interesting series by Bonazzi et al.,24 including 32 ovarian IT, six patients (18 %) experienced chemotherapeutic retroversion or GTS (all found at secondlook surgery). The majority of the patients in the study of Bonazzi et al.24 had stage 1 disease. In the Gynecologic Oncology Group trial reported by Williams et al.23 that involved 91 patients with ovarian germ cell tumors (60 with stage 1 disease), six chemotherapeutic retroconversions in the form of pure mature disease (13 %) were found in 46 patients undergoing a reassessment laparotomy. One objective of this study was to help define the operative management of peritoneal GTS. The management of GTS is based on surgical resection of all macroscopic disease (if technically feasible) to avoid complications due to compression by the growing intraabdominal masses (such as the death related to the bowel obstruction that we reported). Other major morbidities related to the intraabdominal progression of mature GTS masses had been described. 3,14,15 The surgical procedures then are similar to those performed at the time of debulking surgery for epithelial ovarian cancers (e.g., multiple peritoneal resection, splenectomy, bowel resection). Nevertheless, compared with the surgical procedures required for epithelial ovarian cancer, one notable exception exists: if technically feasible, fertility-sparing surgery with preservation of the uterus and the remaining ovary can be proposed despite important peritoneal spread (remembering that all patients treated for GTS had a history of oophorectomy or salpingo-oophorectomy for the initial treatment of the ovarian tumor). We observed five pregnancies (4 of them spontaneous). Sometimes, this conservative approach is not technically feasible because the remaining ovary is involved in the pelvic masses of GTS. Nevertheless, when the remaining ovary has some small lesions on its surface, it is better to leave the remaining ovary in place even if a CC0 resection is not subsequently obtained rather to remove it and impair the further fertility results. The management of GP should probably be different from the treatment of ‘‘other’’ GTS diseases.11 Gliomatosis peritonei can remain quiescent for a long time.24 In the interesting series by Bonazzi et al.,24 6 (18 %) of the 32 IT cases were associated with GP, and the diagnosis of 2 were determined at the time of second-look surgery during the follow-up visit without further surgical resection. If a complete resection of peritoneal GP is feasible, it should be the first goal of the surgery to avoid misdiagnosis of small
immature residual tissue that could drastically alter survival and further management. But, unlike GTS, the majority of GP in the current study presented macroscopically with small but disseminated peritoneal implants.12 Consequently, even if a complete resection of GP is the ideal goal of surgery, it would not be achievable in patients with miliary spread. In the current series, five patients with GP and residual peritoneal disease had no further recurrence, suggesting that GP is a quiescent disease in the great majority of cases. The last surgical consideration specific to GTS concerns the high rate of wound disease related to a contamination of a laparoscopic port or a laparotomic incision. Careful clinical examination of (laparoscopic) ports and scars is important in the follow-up evaluation of patients treated for immature teratoma or GTS. Even after complete resection, GTS recurrences were frequent in the current series (32 % recurrence rate), but all of them occurred in the form of pure mature disease, raising the question of the optimal follow-up examinations after debulking surgery (in addition to the clinical exam previously mentioned). For patients treated with fertilitysparing surgery, routine pelvic ultrasound should be used. Furthermore, some relapses were diagnosed during a routine abdomino-pelvic CT scan or MRI in the current series, emphasizing the importance of systematic imaging during the follow-up visit. With regular examinations, recurrences can be detected at an early stage amenable to a less radical (and potentially conservative) surgery. In conclusion, the prognosis for GTS after the initial management of immature ovarian teratoma is good. The surgical procedures required are similar to those used in debulking surgery for epithelial cancer. Whenever technically possible, a conservative surgery should be performed because spontaneous fertility is possible. Recurrence is frequent even after complete surgery. ACKNOWLEDGMENTS We thank Dr. Aubert, Dr. Benouali, Dr. Benyounes, Dr. Bloget, Pr. Bonnier, Dr. Chouty, Dr. Declerck, Dr. Demaria, Pr. Devouassoux-Shisheboran, Dr. Dieny, Dr. Floquet, Dr. Gallon, Dr. Greget, Pr. Houvenaeghel, Dr. Kowalski, Pr. Laboisse, Dr. Magnani, Dr. Montaut, Dr. Pascau, Pr. Raudrant, Dr. Severy, Dr. Tachon, and Dr. Vannotte for updating the data of the patients. CONFLICT OF INTEREST
There are no conflicts of interest.
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Surgical Outcomes After Debulking Surgery for Intraabdominal 4. Tonkin KS, Rustin GJ, Wignall B, et al. Successful treatment of patients in whom germ cell tumour masses enlarged on chemotherapy while their serum tumour markers decreased. Eur J Cancer Clin Oncol. 1989;25:1739–43. 5. Amsalem H, Nadjari M, Prus D, et al. Growing teratoma syndrome vs chemotherapeutic retroconversion: case report and review of the literature. Gynecol Oncol. 2004;92:357–60. 6. Djordjevic B, Euscher ED, Malpica A. Growing teratoma syndrome of the ovary: review of literature and first report of a carcinoid tumor arising in a growing teratoma of the ovary. Am J Surg Pathol. 2007;31:1913–8. 7. David YB, Weiss A, Shechtman L, et al. Tumor chemoconversion following surgery, chemotherapy, and normalization of serum tumor markers in a woman with a mixed type germ cell ovarian tumor. Gynecol Oncol. 2002;84:464–7. 8. Robboy SJ, Scully RE. Ovarian teratoma with glial implants on the peritoneum: an analysis of 12 cases. Hum Pathol. 1970;1:643–53. 9. Norris HJ, Zirkin HJ, Benson WL. Immature (malignant) teratoma of the ovary: a clinical and pathologic study of 58 cases. Cancer. 1976;37:2359–72. 10. Truong LD, Jurco S III, McGavran MH. Gliomatosis peritonei: report of two cases and review of literature. Am J Surg Pathol. 1982;6:443–9. 11. Bentivegna E, Gonthier C, Uzan C, Genestie C, Morice P, Gouy S. Gliomatosis peritonei: a particular entity with specific outcomes within growing teratoma syndrome. Int J Gynecol Cancer. 2015;25:244–9. 12. Harms D, Ja¨nig U, Go¨bel U. Gliomatosis peritonei in childhood and adolescence: clinicopathological study of 13 cases including immunohistochemical findings. Pathol Res Pract. 1989;184: 422–30. 13. Nielsen SN, Scheithauer BW, Gaffey TA. Gliomatosis peritonei. Cancer. 1985;56:2499–503. 14. Andre´ F, Fizazi K, Culine S, et al. The growing teratoma syndrome: results of therapy and long-term follow-up of 33 patients. Eur J Cancer. 2000;36:1389–94. 15. Zagame L, Pautier P, Duvillard P, et al. Growing teratoma syndrome after ovarian germ cell tumors. Obstet Gynecol. 2006; 108(3 Pt 1):509–14. 16. Cheng NH, Huang HF, Lian LJ, et al. Ovarian growing teratoma syndrome clinical study of 22 cases. Zhonghua Fu Chan Ke Za Zhi. 2009;44:426–30. 17. Sella A, el Naggar A, Ro JY, et al. Evidence of malignant features in histologically mature teratoma. J Urol. 1991;146:1025–8. 18. Stella M, Gandini A, Meeus P, et al. Retroperitoneal vascular surgery for the treatment of giant growing teratoma syndrome. Urology. 2012;79:365–70.
19. Sonneveld DJ, Sleijfer DT, Koops HS, et al. Mature teratoma identified after postchemotherapy surgery in patients with disseminated nonseminomatous testicular germ cell tumors: a plea for an aggressive surgical approach. Cancer. 1998;82:1343–51. 20. Gelderman WA, Schraffordt Koops H, Sleijfer DT, et al. Results of adjuvant surgery in patients with stage III and IV nonseminomatous testicular tumors after cisplatin-vinblastine-bleomycin chemotherapy. J Surg Oncol. 1988;38:227–32. 21. Gelderman WA, Koops HS, Sleijfer DT, et al. Treatment of retroperitoneal residual tumor after PVB chemotherapy of nonseminomatous testicular tumors. Cancer. 1986;58:1418–21. 22. Loehrer PJ Sr, Hui S, Clark S, et al. Teratoma following cisplatinbased combination chemotherapy for nonseminomatous germ cell tumors: a clinicopathological correlation. J Urol. 1986;135:1183–9. 23. Williams S, Blessing JA, Liao SY, et al. Adjuvant therapy of ovarian germ cell tumors with cisplatin, etoposide, and bleomycin: a trial of the Gynecologic Oncology Group. J Clin Oncol. 1994;12:701–6. 24. Bonazzi C, Peccatori F, Colombo N, et al. Pure ovarian immature teratoma, a unique and curable disease: 10 years’ experience of 32 prospectively treated patients. Obstet Gynecol. 1994;84:598–604. 25. Geisler JP, Goulet R, Foster RS, et al. Growing teratoma syndrome after chemotherapy for germ cell tumors of the ovary. Obstet Gynecol. 1994;84(4 Pt 2):719–21. 26. Itani Y, Kawa M, Toyoda S, et al. Growing teratoma syndrome after chemotherapy for a mixed germ cell tumor of the ovary. J Obstet Gynaecol Res. 2002;28:166–71. 27. Lorusso D, Malaguti P, Trivellizzi IN, et al. Unusual liver locations of growing teratoma syndrome in ovarian malignant germ cell tumors. Gynecol Oncol Case Rep. 2011;1:24–5. 28. Lee CW, Song MJ, Park ST, et al. Residual tumor after the salvage surgery is the major risk factors for primary treatment failure in malignant ovarian germ cell tumors: a retrospective study of single institution. World J Surg Oncol. 2011;9:123. 29. Pendlebury A, Rischin D, Ireland-Jenkin K, et al. Ovarian growing teratoma syndrome with spuriously elevated a-fetoprotein. J Clin Oncol. 2014. doi:10.1200/JCO.2013.49.8998. 30. Lhomme C, Leary A, Uzan C, et al. Adjuvant chemotherapy in stage I ovarian germ cells tumors: should indications and treatment modalities be different in young girls and adults? J Clin Oncol. 2014;32(25):2815–6. 31. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205–13. 32. Jeffery GM, Theaker JM, Lee AH, et al. The growing teratoma syndrome. Br J Urol. 1991;67:195–202.
ORIGINAL ARTICLE – GYNECOLOGIC ONCOLOGY
Surgical Outcomes After Debulking Surgery for Intraabdominal Ovarian Growing Teratoma Syndrome: Analysis of 38 Cases Enrica Bentivegna, MD1, Henri Azaı¨s, MD1, Catherine Uzan, MD, PhD1,2, Alexandra Leary, MD, PhD3, Patricia Pautier, MD3, Clementine Gonthier, MD1, Catherine Genestie, MD4, Corinne Balleyguier, MD5, Catherine Lhomme, MD3, Pierre Duvillard, MD4, Philippe Morice, MD, PhD1,2,6, and Sebastien Gouy, MD, PhD1 Department of Gynecologic Surgery, Gustave Roussy, Villejuif, France; 2Unit INSERM 30-10, Villejuif, France; 3 Department of Medical Oncology, Gustave Roussy, Villejuif, France; 4Department of Pathology, Gustave Roussy, Villejuif, France; 5Department of Radiology, Gustave Roussy, Villejuif, France; 6University Paris Sud, Paris, France 1
ABSTRACT Background. The goal, methods, and results of surgery for growing teratoma syndrome (GTS) in men after testicular cancer have been well described. The main surgical challenge relates to the need for vascular or thoracic procedures. But little is known about GTS in women, particularly regarding the optimal management of intraabdominal disease. This study aimed to evaluate the surgical management and outcomes (recurrences and fertility) for a large series of ovarian GTS. Methods. This study retrospectively analyzed patients treated for an ovarian immature teratoma (IT) who subsequently experienced abdominal GTS requiring surgery. Results. Between 1983 and 2014, 196 cases of IT were referred to the authors’ institution or treated there, and 38 patients (19 %) subsequently experienced a GTS, including 10 cases of gliomatosis peritonei (containing exclusively pure mature glial tissue). The median age at diagnosis was 26 years (range 8–41 years), and the mean delay between IT and GTS diagnosis was 7 months (range 3–84 months). Surgical resection included peritonectomy (n = 22), diaphragmatic peritoneal resection (n = 14), bowel resection (n = 8), and splenectomy (n = 5). Conservative surgery was possible for 20 patients. Complete cytoreductive surgery was achieved for 25 patients. The mean
Presented at the International Gynaecological Cancer Society Meeting, Melbourne, Australia, 7–11 November 2014. Society of Surgical Oncology 2015 First Received: 16 January 2015 P. Morice, MD, PhD e-mail: [email protected]
follow-up period was 73 months (range 3–263 months). At least one recurrence developed for 10 patients (in the form of mature disease in all, and 8 of these patients had an initial complete resection. Five patients had a pregnancy. One patient died of complications from the disease (pulmonary embolism in a patient with bowel obstruction). Conclusions. The overall prognosis of abdominal GTS is good. The surgical procedures for GTS are similar to those used in debulking surgery for epithelial cancer. Whenever technically possible, a conservative surgery should be performed because spontaneous fertility is possible. Recurrent GTS is frequent even after complete surgery.
The development of mature teratoma in patients treated by chemotherapy for germ cell gonadal cancers is a wellknown phenomenon first described more than three decades ago.1–4 In fact, it probably involves two syndromes, chemotherapeutic retroconversion and growing teratoma syndrome, very similar in terms of natural history and therapeutic management.1,2,5 Chemotherapeutic retroconversion was first described by DiSaia et al. 2 in 1977 in patients with ovarian immature teratoma (IT) treated by chemotherapy. The authors proposed two potential mechanisms: chemotherapy could promote the conversion of immature tissue into mature disease, or chemotherapy could eradicate the immature elements and allow the mature component to flourish.2,6 Although such retroconversion was initially described in teratoma, it also is reported in other subtypes of germ cell ovarian tumor (e.g., yolk sac or dysgerminoma).7 The term ‘‘growing teratoma syndrome’’ (GTS) was proposed 5 years later by Logothetis et al.,1 who described six patients with malignant germ cell tumors (5 testicular
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and 1 ovarian) treated by surgery and chemotherapy in whom a pure mature recurrence developed in the thorax (4 patients) or the abdomen (2 patients). Theoretically, these two syndromes have potentially subtle differences. In a strict sense, GTS implies an expanding mass with the potential for local damage, whereas chemotherapeutic retroconversion does not necessarily require tumor growth.6 Nevertheless, some authors consider these two entities as very similar and probably the same.5 Another less frequent form of mature peritoneal spread associated with germ immature teratoma can arise: gliomatosis peritonei (GP). This entity often is mixed in series of GTS, but two subtle differences exist between GP and GTS according to the criteria of Logothetis et al.1 First, GP is histologically defined as the presence of pure mature glial tumor tissue in the peritoneum without any other mature nonglial components such as observed in GTS. 8–10 Second, GP could be encountered in patients not exposed to adjuvant chemotherapy after the initial management of the ovarian germ cell cancer.11–13 The treatments of GP and GTS are identical and based entirely on a surgical resection. In the current series, we included both entities under the same terminology of GTS. If these masses are not completely resected, they can enlarge and provoke compressive symptoms and exceptionally disease-related mortality (by bowel perforation or ischemia).3,14,15 Furthermore, malignant transformation also has been reported, especially in the form of carcinoid and primitive neuroectodermal tumors.8,16,17 For these reasons, the treatment of GTS requires complete resection of all visible disease.8,17–19 Because testicular cancer is more frequent than ovarian germ cell tumors, the vast majority of GTS occur in men (90 % in the series of Andre´ et al.14).20 Male GTS tend to localize to retroperitoneal or mediastinal lymph nodes where the therapeutic challenge is the requirement for vascular or complex thoracic procedures to ensure complete resection.18–22 In contrast, GTS after ovarian immature teratoma can either have a retroperitoneal nodal spread or present with diffuse peritoneal disease, similar to other ovarian malignancies.23–29 The proposed surgery usually is a so-called ‘‘debulking’’ surgery, a term conventionally used for the removal of the intraabdominal tumor in ovarian cancer, However, the literature has little data regarding the extent of surgery required, particularly the place of fertilitysparing surgery or the clinical outcome after debulking for intraabdominal GTS. Because GTS is significantly less frequent in women than in men, published series are short, and none have focused specifically on the question of surgical management and postsurgical outcomes. One series of 22 cases has been reported, but the paper is
written in Chinese.16 Except for a short series of 12 cases (none of them treated surgically) dedicated to oncologic issues, most publications about GTS in women are case reports (reporting 1–3 cases).6,15,25,26,29 We present the largest series of GTS occurring after treatment for ovarian germ cell tumors and the first series specifically dedicated to surgical considerations.
PATIENTS AND METHODS Population Patients with immature ovarian teratoma referred to our institution or treated there between 1983 and 2014 were retrospectively identified. Among these cases, patients who experienced subsequent GTS (or a chemotherapeutic retroconversion) treated surgically were included in the analysis. Patients were included in the study if they met the diagnostic criteria for GTS as defined by Logothetis et al. 1 in 1982 as well as the following additional inclusion criteria: •
• • • • •
•
Histologic review of the initial tumor by an expert pathologist, with inclusion of only GTS cases from initial immature teratoma Normalization of previously elevated serum tumor markers (aFP or hCG) Clinical or radiologic enlargement of intraabdominal disease during or after chemotherapy Surgical treatment for GTS Histologic confirmation of GTS Centralized pathologic review of the GTS specimen by an expert pathologist with exclusion of patients who had any residual immature disease in the abdomen Available posttreatment outcome data.
Patients were followed up after surgery using clinical examination, blood markers (aFP/hCG), and radiologic imaging (abdominopelvic ultrasonography, magnetic resonance imaging [MRI], or computed tomography [CT] scans depending on the use of conservative treatment of the uterus and one ovary and the degree of spread of the intraabdominal peritoneal disease). Clinical, pathologic, and prior treatment data were collected from clinical records. Precise details regarding the extent of debulking surgery performed for GTS were recorded, as were postoperative outcomes. Oncologic outcomes after the debulking surgery (delay, sites, and histotypes of recurrences) and fertility results for patients treated with a fertility-sparing surgery at the time of the GTS management (defined by preservation of the uterus and at least a part of 1 ovary) were analyzed.
Surgical Outcomes After Debulking Surgery for Intraabdominal
RESULTS During the study period, 196 patients were referred to our institution with an IT or treated there. Among them, 43 had suspicion (on clinical examination or radiologic imaging) of a GTS. Five patients were excluded from the study. Two patients were excluded because immature tissue was found at the permanent histologic analysis of the GTS specimen (in the abdomen of 1 patient and in the paraaortic node of 1 patient), and three patients were excluded due to a lack of data during the follow-up period. Two patients were excluded because immature tissue remained disease free after the surgical procedure for the GTS (18 months for a patient with immature disease in the abdomen and 180 months for a patient with immature disease in a node). Therefore, 38 patients (19 % of IT) fulfilled the inclusion criteria: 28 (14 %) in the form of GTS and 10 (5 %) in the form of GP containing then exclusively pure mature glial tissue. Intraabdominal GTS developed in 32 patients (27 GTS and 5 GP) after surgery and chemotherapy for an IT. One patient had GTS exclusively in the paraaortic node. One patient had radiologic suspicion of GTS without surgical resection during the third recurrence, but this patient had a history of two surgical resections, with mature peritoneal disease for each of them. We included this patient in this series, even if the last event had no histologic confirmation of recurrence in the form of mature disease. The initial characteristics of these 38 cases are detailed in Table 1. Preoperative imaging of some of different cases are shown in Figs. 1, 2 and 3. Initial Characteristics
TABLE 1 Characteristics of patients during initial management of the immature teratoma n = 38 Median age: years (range) \12 years
3
Blood markers Normal Abnormal aFP hCG Unknown
5 17 15 2 16
Stage (and grade for stage 1) 1
10 Grade 2 Grade 3
2 8
2
2
3
13
Unknown stage (grade 3)
13
Histologic subtypes Immature teratoma combined with mature teratoma
20
Pure immature teratoma
13
Mixed Immature teratoma with embryonal carcinoma Immature teratoma with embryonal carcinoma & yolk sac tumor
5 1 4
Characteristics of the surgical management Fertility-preserving surgery
20
Peroperative rupture (in stage 1)
4
Residual macroscopic disease (stage 2 or 3)
3
1-Step surgery
25
2-Step surgery
13
Chemotherapy (types and number of cycles)
Of the 38 patients, 3 were younger than 12 years and 10 were younger than 20 years (34 %). All the patients were treated initially for their IT with fertility-sparing surgery. For 26 % (10/38) of the patients who had presented with a stage 1 IT, adjuvant chemotherapy was offered because of pre- or peri-operative rupture or stage 1C and/or grade 3 disease. Adjuvant chemotherapy was administered to 32 patients (27 of 28 patients with GTS and 5 of 10 patients with GP). A majority of patients were treated with bleomycin, etoposide, and cisplatin (BEP), the exception being very young girls managed by pediatricians who deliver somewhat different chemotherapy regimens to reduce the potential (and theoretical) risk of alkylant-induced secondary leukemia (Table 1).30 The single GTS patient treated without adjuvant chemotherapy initially underwent a unilateral salpingooophorectomy for a mature teratoma combined with a small component of grade 3 immature teratoma without extraovarian disease. This patient had a preoperative rupture. She did not receive adjuvant treatment due to the absence of
26 (8–41)
32
BEP regimen
20
2 Cycles
3
3 Cycles
9
4 Cycles
6
Other
2
BEP followed by EP regimen (6 cycles) EP regimen
1 2
3 Cycles
1
4 Cycles
1
Other regimens
7
Unknown
2
hCG human chorionic gonadotropin, aFP alpha-fetoprotein, EP etoposide, cisplatin, BEP bleomycin, etoposide, cisplatin
macroscopic extra-ovarian disease and the small part of immature disease. For this patient, intraabdominal and wound ‘‘recurrences’’ developed 15 months later. Histologic analysis of the debulking surgery specimen (performed with a fertility-sparing debulking surgery) demonstrated that all
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FIG. 1 Computed tomography showing peritoneal lesions (with calcifications) on the right diaphragm and inside the spleen FIG. 3 Sagittal view during magnetic resonance imaging (MRI) showing a large disease in the abdominal wall and peritoneum
uterus in place and at least a part of 1 ovary) was possible for 20 patients (Table 2). A complete macroscopic resection (CC0) was performed in 25 cases. Seven patients had small residual disease smaller than 2 mm on the small intestine or mesentery (CC1). One patient had a CC2 resection, leaving a residual pelvic tumor larger than 2 mm but smaller than 5 mm in place. Two patients had a CC2 resection, leaving a residual tumor larger than 1 cm (including 1 patient with GP) in place. Among nine patients with CC1/CC2 resection, five had fertility-preserving surgery. Postoperative morbidity (Dindo classification [grade 2) 31 is presented detailed in Table 2. FIG. 2 Sagittal view during magnetic resonance imaging (MRI) showing a large disease in the abdominal wall
the intraabdominal diseases were pure mature teratoma. Immature disease was found exclusively in the abdominal wall resection. Because all the intraabdominal tumor was mature and because the surgical procedures used were similar to those for GTS, we kept this patient in the current series although in strict sense she did not fulfill the second inclusion criterion of Logothetis et al. 1 defining GTS (previous treatment by chemotherapy). Operative Management and Surgical Outcomes The factors leading to the diagnosis of GTS are presented in Table 2. The characteristics of the debulking surgery and the postoperative outcomes are detailed in Table 2. For 22 patients, peritoneal resection of the paracolic gutters or Douglas pouch was performed. Eight patients underwent bowel resections. A fertility-preserving surgery (leaving the
Recurrences During a median follow-up period of 73 months (range 3–263 months) after initial treatment of GTS, 10 (26 %) patients (1 GP and 9 GTS patients) had recurrences. The median delay between surgery of the GTS and the first recurrence was 45 months (range 2–132 months). All the recurrences were pure mature disease. Among the 10 patients with recurrence, 8 underwent complete macroscopic resection. Their first recurrence was in the peritoneum (n = 3), wound and peritoneum (n = 2), wound alone (n = 2), or ovary and peritoneum (n = 1). Five patients had one recurrence; two patients had two recurrences; and one patient had three recurrences. Among the three patients who had at least two recurrences, all the recurrences were peritoneal or in the abdominal wall. They were treated surgically. Two patients with recurrence were treated with a CC2 resection for initial management of GTS:
Surgical Outcomes After Debulking Surgery for Intraabdominal TABLE 2 Characteristics of patients at the management of the growing teratoma syndrome Characteristics
n = 38
Median delay between initial management and GTS/gliomatosis: months (range)
7 (3–84)
Median number of surgeries for the management of GTS/gliomatosis: n (range)
1 (0–5)
Mode of GTS/gliomatosis discovery Clinical examination
6
Systematic second-look or control surgery
14
Radiologic imaging
11
Ultrasonography
5
Computed tomography
5
Magnetic resonance imaging
1
Unknown
7
Surgical procedures used for debulking surgery Ovarian procedures
38
Unilateral oophorectomy
3
Unilateral salpingo-oophorectomy
17
Bilateral salpingo-oophorectomy
4
Hysterectomy and bilateral salpingo-oophorectomy
14
Ovarian cryopreservation
2
Lymphadenectomy (pelvic and/or para-aortic)
5
Complete omentectomy
19
Splenectomy
5
Appendectomy
14
Large bowel resection
6
Small bowel resection
2
Anastomosis with protective stomia
1
Diaphragmatic peritoneal resection
14
Large peritonectomies (except diaphragmatic peritoneal resection)
22
Partial bladder resection
1
Abdominal wall resection
5
With free-flap reconstruction
1
With biologic mesh reconstruction
1
Characteristics of the resection Complete macroscopic resection (CC0)
25
Macroscopic residual tumor \ 2 mm (CC1)
7
Macroscopic residual tumor [ 2 mm (CC2)
3
Unknown
3
Postoperative morbidities (Clavien Dindo classification [grade 2)
9 26
Bilateral pulmonary embolism
2
Bowel obstruction
2
Caecestomy
1
Hematoma surgically treated
1
Wound dehiscence (late)
2
Bladder self-catheterization combined with diarrhea affecting quality of life
1
GTS growing teratoma syndrome
–
The first patient experienced recurrence 7 years after the initial management in the form of a mature teratoma cyst on the retained ovary (treated using cystectomy)
–
associated with small peritoneal disease (peritoneal gliomatosis). She remained free of disease 9 years after this last recurrence. The second patient was mentioned previously. She initially underwent an emergency unilateral salpingooophorectomy for an adnexal torsion on a germ cell tumor. She experienced a peritoneal recurrence 3 months later in the form of mature and immature peritoneal spread. Four courses of platinum-based chemotherapy were administered, with normalization of alphafetoprotein in the second course. Multiple abdominal masses developed 6 months later, with two attempts at debulking surgery. For both surgeries, the histologic results demonstrated pure mature disease (GTS), but the resection was incomplete. This patient further experienced a third nonoperable recurrent disease (clinically observed and confirmed on CT scan) with bowel obstruction. She died of massive pulmonary embolism in a context of growing abdominal masses 60 months after the initial diagnosis.
The last patient with a CC2 resection was interesting as well because she had bulky peritoneal spread (diagnosis based on CA125 elevation and ascites on CT scan) with unresectable disease (miliary peritoneal implants on the mesentery). This patient underwent large biopsies and a caecostomy demonstrating histologically pure GP. She remained asymptomatic, without clinical symptomatic recurrence 65 months after this last surgical procedure. Four of the patients with GP underwent a secondary surgery (systematic second-look for 2 patients and surgery for ovarian cyst 2 and 16 months after the last surgical procedure respectively for 2 patients), which found asymptomatic quiescent gliomatosis peritonei. None of these patients had symptomatic recurrent GP. At least one patient with GP had died of an intercurrent pathology (heart disease). Among 20 patients treated with fertility-sparing surgery for GTS, two ovarian cryopreservations (technically feasible for 1 patient) had been planned during the surgery. Three patients had ovarian stimulation. Of six patients who desired a pregnancy, four had spontaneous pregnancies and one had an induced pregnancy. In this group of patients having a pregnancy, four had initial complete resection, and one had a CC1 resection (for a GP). DISCUSSION The results of the current study raise several important points for discussion. The first point concerns the true incidence of GTS (or chemotherapeutic retroconversion) after treatment for ovarian germ cell tumors. The syndrome has been estimated to occur in 1.9–7.6 % of testicular
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nonseminomatous germ cell tumors.5,32 Because ovarian germ cell tumors are less frequent in women, GTS series include mostly men.14 Very little data on the incidence of this disease in ovarian tumors are available. In the current series, 19 % of the IT developed subsequent to GTS, including 5 % in the form of pure mature glial disease (GP). These results are concordant with our previous observation.15 In the interesting series by Bonazzi et al.,24 including 32 ovarian IT, six patients (18 %) experienced chemotherapeutic retroversion or GTS (all found at secondlook surgery). The majority of the patients in the study of Bonazzi et al.24 had stage 1 disease. In the Gynecologic Oncology Group trial reported by Williams et al.23 that involved 91 patients with ovarian germ cell tumors (60 with stage 1 disease), six chemotherapeutic retroconversions in the form of pure mature disease (13 %) were found in 46 patients undergoing a reassessment laparotomy. One objective of this study was to help define the operative management of peritoneal GTS. The management of GTS is based on surgical resection of all macroscopic disease (if technically feasible) to avoid complications due to compression by the growing intraabdominal masses (such as the death related to the bowel obstruction that we reported). Other major morbidities related to the intraabdominal progression of mature GTS masses had been described. 3,14,15 The surgical procedures then are similar to those performed at the time of debulking surgery for epithelial ovarian cancers (e.g., multiple peritoneal resection, splenectomy, bowel resection). Nevertheless, compared with the surgical procedures required for epithelial ovarian cancer, one notable exception exists: if technically feasible, fertility-sparing surgery with preservation of the uterus and the remaining ovary can be proposed despite important peritoneal spread (remembering that all patients treated for GTS had a history of oophorectomy or salpingo-oophorectomy for the initial treatment of the ovarian tumor). We observed five pregnancies (4 of them spontaneous). Sometimes, this conservative approach is not technically feasible because the remaining ovary is involved in the pelvic masses of GTS. Nevertheless, when the remaining ovary has some small lesions on its surface, it is better to leave the remaining ovary in place even if a CC0 resection is not subsequently obtained rather to remove it and impair the further fertility results. The management of GP should probably be different from the treatment of ‘‘other’’ GTS diseases.11 Gliomatosis peritonei can remain quiescent for a long time.24 In the interesting series by Bonazzi et al.,24 6 (18 %) of the 32 IT cases were associated with GP, and the diagnosis of 2 were determined at the time of second-look surgery during the follow-up visit without further surgical resection. If a complete resection of peritoneal GP is feasible, it should be the first goal of the surgery to avoid misdiagnosis of small
immature residual tissue that could drastically alter survival and further management. But, unlike GTS, the majority of GP in the current study presented macroscopically with small but disseminated peritoneal implants.12 Consequently, even if a complete resection of GP is the ideal goal of surgery, it would not be achievable in patients with miliary spread. In the current series, five patients with GP and residual peritoneal disease had no further recurrence, suggesting that GP is a quiescent disease in the great majority of cases. The last surgical consideration specific to GTS concerns the high rate of wound disease related to a contamination of a laparoscopic port or a laparotomic incision. Careful clinical examination of (laparoscopic) ports and scars is important in the follow-up evaluation of patients treated for immature teratoma or GTS. Even after complete resection, GTS recurrences were frequent in the current series (32 % recurrence rate), but all of them occurred in the form of pure mature disease, raising the question of the optimal follow-up examinations after debulking surgery (in addition to the clinical exam previously mentioned). For patients treated with fertilitysparing surgery, routine pelvic ultrasound should be used. Furthermore, some relapses were diagnosed during a routine abdomino-pelvic CT scan or MRI in the current series, emphasizing the importance of systematic imaging during the follow-up visit. With regular examinations, recurrences can be detected at an early stage amenable to a less radical (and potentially conservative) surgery. In conclusion, the prognosis for GTS after the initial management of immature ovarian teratoma is good. The surgical procedures required are similar to those used in debulking surgery for epithelial cancer. Whenever technically possible, a conservative surgery should be performed because spontaneous fertility is possible. Recurrence is frequent even after complete surgery. ACKNOWLEDGMENTS We thank Dr. Aubert, Dr. Benouali, Dr. Benyounes, Dr. Bloget, Pr. Bonnier, Dr. Chouty, Dr. Declerck, Dr. Demaria, Pr. Devouassoux-Shisheboran, Dr. Dieny, Dr. Floquet, Dr. Gallon, Dr. Greget, Pr. Houvenaeghel, Dr. Kowalski, Pr. Laboisse, Dr. Magnani, Dr. Montaut, Dr. Pascau, Pr. Raudrant, Dr. Severy, Dr. Tachon, and Dr. Vannotte for updating the data of the patients. CONFLICT OF INTEREST
There are no conflicts of interest.
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