ORIGINAL STUDY
Gliomatosis Peritonei A Particular Entity With Specific Outcomes Within the Growing Teratoma Syndrome Enrica Bentivegna, MD,* Clementine Gonthier, MD,* Catherine Uzan, MD, PhD,* Catherine Genestie, MD,Þ Pierre Duvillard, MD,Þ Philippe Morice, MD, PhD,*þ and Sebastien Gouy, MD, PhD*
Objectives: Ovarian immature teratoma may be associated with peritoneal spread that could, after adjuvant chemotherapy, develop into disease exclusively composed of mature implants (growing teratoma syndrome) and/or gliomatosis peritonei (GP), defined as the presence of pure mature glial tissue. However, very few specific series are devoted to the outcomes of pure GP. This was the aim of the present study. Patients: From 1997 to 2013, data concerning patients treated for stage II/III immature teratoma were reviewed. All slides were reviewed by an expert pathologist. Patients with ovarian cancer associated with peritoneal spread in the form of pure GP (initially if patients were treated without adjuvant treatment or after adjuvant chemotherapy if done) were analyzed. Results: Ten patients fulfilled the inclusion criteria. The median age of patients at diagnosis was 36 years (range, 14Y41 years). Six patients had undergone a conservative treatment. Five patients had macroscopic residual disease at the end of surgery. The median duration of follow-up from the diagnosis of GP was 39 months (range, 6Y114 months). Six patients had undergone secondary surgery. Among them, 5 had incompletely resected macroscopic GP. No patients had died of their disease. All patients were asymptomatic at the time of the last consultation (1 of them with abnormal radiologic imaging). Conclusions: Gliomatosis peritonei is a particular entity of the condition described as growing teratoma syndrome because residual peritoneal disease can be asymptomatic totally stable over a long period which raises the question of a more conservative surgical approach in patients with massive peritoneal spread. Key Words: Immature ovarian teratoma, Growing teratoma syndrome, Gliomatosis peritonei, Recurrence, Follow-up Received September 10, 2014, and in revised form December 5, 2014. Accepted for publication December 7, 2014. (Int J Gynecol Cancer 2015;25: 244Y249)
Departments of *Gynecologic Surgery, and †Pathology, and ‡University Paris Sud, Gustave Roussy Cancer Campus, Villejuif, France. Copyright * 2015 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000345
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Address correspondence and reprint requests to Philippe Morice, MD, PhD, Gustave Roussy Cancer Campus, 114 rue Edouard Vaillant, 94805 Villejuif, France. E-mail: [email protected]. The authors declare no conflicts of interest.
International Journal of Gynecological Cancer
& Volume 25, Number 2, February 2015
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 25, Number 2, February 2015
immature teratoma can be associated with periO varian toneal spread in the form of immature peritoneal im-
plants that may develop after adjuvant chemotherapy into disease exclusively composed of mature implants [growing teratoma syndrome (GTS) or ‘‘chemotherapeutic retroconversion’’].1Y4 These 2 entities are very close and perhaps the same, and should be treated surgically.5 The procedure may then involve retroperitoneal surgery (resection of residual bulky nodes) and/or intra-abdominal debulking surgery, that we perform to treat epithelial ovarian cancer, because these masses can expand and provoke compressive symptoms and exceptionally, disease-related mortality (through bowel perforation or ischemia).3,6,7 This is why the cornerstone treatment of GTS (or ‘‘chemotherapeutic retroconversion’’) is based on surgical removal of all macroscopic disease (even if radical surgery is required).7 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). This entity is histologically defined as the presence of mature glial tumor tissue in the peritoneum.8Y10 Histologically, it can be pure (exclusively comprising mature glial tissue) or associated with other mature tissue components (GTS) and/or associated with immature disease. The latter case is rare (carrying a very poor prognosis) if it is diagnosed after adjuvant chemotherapy. But very few series are specifically devoted to the outcomes of pure GP.8,11Y13 Most of the reports are case studies (or very short series with a few patients) and sometimes with a mixture of GP and other nonglial mature tissues.13Y18 The aim of this study was to evaluate the specific outcomes of patients with peritoneal implants exclusively composed of mature GP.
PATIENTS AND METHODS Population Patients with immature ovarian teratoma (IOT) and/or nonepithelial cancers exhibiting teratoma patterns referred to or treated in our institution between 1997 and 2013 were retrospectively identified. Among these cases, patients with GP at histologic examination were included in the analysis. Patients were definitively included if they met the following criteria: - Centralized histologic review of the initial ovarian tumor and the subsequent GP specimen. - Surgical treatment of their GP with histologic confirmation of the entire ovarian and peritoneal tumor specimens. Patients with radiologic suspicion of GP, but without surgical management (and histologic confirmation), were excluded. - Patients presenting with a mature GP but associated with other nonglial mature tissues (GTS) were excluded. - If patients had received adjuvant chemotherapy, patients with immature tissues (associated with GP) at the time of secondary surgery were excluded. - Available posttreatment outcome data. Surgery was either a radical procedure (bilateral salpingooophorectomy with or without a hysterectomy), or a conservative
Gliomatosis Peritonei
intervention (defined as conservation of the uterus and at least a portion of one ovary). A conservative surgery was the first option when a healthy part of at least one ovary could be preserved and if the uterus had no disease on its surface. Additional surgical procedures were occasionally performed, such as peritoneal washings, omentectomy, multiple peritoneal biopsies, and pelvic and para-aortic lymphadenectomy. These surgical procedures had been performed depending on the period, macroscopic exploration, the availability of the pathological information during the operation, and the stage of the disease. Thus, surgical procedures had been performed in a 1-step operation or completed at the time of restaging surgery after complete analysis of the definitive histologic results. Some patients had undergone second-look surgery after adjuvant chemotherapy. After surgery, follow-up was based on a clinical examination and imaging (abdominopelvic ultrasonography; magnetic resonance imaging or computed tomographic (CT) scans, depending on whether conservative treatment of the uterus and one ovary had been performed and on the degree of intraabdominal peritoneal dissemination). Clinical, pathological, and prior treatment data were collected from the clinical records. The precise details regarding the extent of debulking surgery performed for GP were recorded. Outcomes after debulking surgery (interval and sites of recurrences, histologic types of these recurrences, fertility if, fertility-preserving surgery had been performed) were analyzed. According to local regulation, an institutional review board approval is not required (and so asked) in such retrospective study.
RESULTS During the study period, 10 patients fulfilled the inclusion criteria. All patients had ‘‘pure’’ GP without any other nonglial mature tissue. Detailed patient characteristics are shown in Table 1. The median age of patients at diagnosis was 36 years (range, 14Y41 years). Nine patients had undergone a 2-step operation and 1 a single procedure. Among the 9 patients having undergone a 2-step procedure, adnexal surgery during the first operation was a unilateral salpingooophorectomy in 5 (completed with a contralateral salpingooophorectomy and a hysterectomy during restaging surgery in 1), a unilateral cystectomy (completed with a unilateral salpingo-oophorectomy during restaging surgery) in 1, a unilateral salpingo-oophorectomy and a contralateral cystectomy (completed with a salpingo-oophorectomy during restaging surgery) in 1, and a bilateral salpingo-oophorectomy in 2 patients. One patient (case 4) was pregnant during her treatment. Among the additional procedures performed during the first and second surgery (if done), 6 patients had undergone a conservative treatment and 4 a bilateral salpingo-oophorectomy (with a hysterectomy in 2) (Table 1). All patients but 1 had IOT and the last one a mixed nonepithelial ovarian cancer with mature teratoma (case 8 in Table 1). Among the 9 patients treated using a 2-step surgical procedure, the diagnosis of GP had been made in 1 during the first procedure (and in the remaining 8 at the time of restaging surgery).
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IOT grade 1 and peritoneal immature gliomatosis
USO
Caecostomy
IOT grade 1 and peritoneal mature gliomatosis USO Asymptomatic Peritonectomies IOT grade 2 and peritoneal mature gliomatosis H + BSO Peritoneal gliomatosis Biopsy IOT grade 1 and peritoneal mature gliomatosis BSO Peritoneal gliomatosis Peritonectomies IOT grade 1 and peritoneal mature gliomatosis USO Abdominal CT scan normal BSO Mixed ovarian tumor with yolk sac and dysgerminoma and mature teratoma Omentectomy Peritonectomies H + BSO IOT grade 3 and peritoneal mature gliomatosis Splenectomy Gliomatosis in the wound Omentectomy Large peritonectomy Diaphragmatic resection Biopsy IOT grade 2 and peritoneal mature gliomatosis
USO Biopsy
USO Appendectomy Biopsy
USO Peritonectomies IOT grade 3 and peritoneal mature gliomatosis
IOT grade 1 and peritoneal mature gliomatosis
Yes
Yes
Yes
No
No
No
No
Yes
Yes
No
Yes diffuse
No
No
No
Yes diffuse
Yes
No
Yes diffuse
Yes diffuse
No
Residual Adjuvant Macroscopic Treatment Gliomatosis V
Location and Histology of Disease
Benign ovarian cyst
V
Recurrence
Recurrence
No
No
V
Normal
V
Normal
V
Normal
V
V
Abnormal with stable lesions
Asymptomatic Normal after recurrence
Died of cardiac disease
Asymptomatic
Asymptomatic
Asymptomatic
Recent delivery
Asymptomatic
Asymptomatic
Asymptomatic
66
69
114
36
16
94
24
41
7
6
Outcomes Posttreatment and Last Imaging (MRI Follow-up, Consultation or CT Scan) mo
Massive peritoneal Asymptomatic gliomatosis with a (unresectable) caecostomy
Abdominal scar (resected)
V
V
Ovarian cyst Benign and infertility ovarian cyst
Ovarian cyst
No
Second-look Peritoneal surgery after gliomatosis chemotherapy
Second-look Peritoneal surgery after gliomatosis chemotherapy
No
Secondary Surgery (Reason)
*Adding procedures done during the first operation and restaging surgery (if done). BSO, Bilateral salpingo-oophorectomy; H, hysterectomy; MRI, magnetic resonance imaging; USO, unilateral salpingo-oophorectomy.
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33
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Biopsy
Histologic Subtype and Grade
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Surgical Case Age, y Procedures*
TABLE 1. Patient characteristics
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Five patients had received adjuvant chemotherapy based on histologic factors identified at the time of the first operation or at restaging surgery (if done). Three of them had received their adjuvant therapy between both surgeries. Only 1 patient (case 3) exhibited immature neuroglial tissue before adjuvant chemotherapy which had transformed into mature GP at the time of second-look surgery. Gliomatosis peritonei had been unveiled during the first operation or at restaging surgery in all of the other patients. Five patients had macroscopic residual peritoneal disease after the first operation and/or at restaging surgery (if done). The median duration of follow-up from the diagnosis of GP (depending on whether disease had been diagnosed during the first operation or restaging surgery (if done) was 39 months (range, 6Y114 months). Six patients had undergone secondary surgery: - Two of them had undergone a second-look procedure 3 months after adjuvant chemotherapy. Gliomatosis peritonei had been unveiled in both patients. - Two patients had ovarian cysts (found 2 and 16 months after the last surgical procedure). Gliomatosis peritonei had been found (with benign ovarian cysts) in both of them. - Two patients had been treated for a clinical, biological, or radiological recurrence. The first one (case 9) had a wound recurrence 58 months after initial management. Elective scar revision surgery had been performed and gliomatosis had been found at the histologic analysis. This patient is currently disease free 12 months after this last procedure. The other patient (case 10) had bulky peritoneal spread (diagnosed based on CA125 elevation and ascites on CT scan) with unresectable disease (miliary peritoneal implants on the mesentery). She had undergone large biopsies (demonstrating pure GP) and
FIGURE 1. Coronal view on CT in patient 10 showing residual disease in the peritoneum (arrow).
Gliomatosis Peritonei
a caecostomy. She remains currently asymptomatic 52 months after this last surgical procedure. Her disease is still visible on the CT scan but has been stable for 5 years (Fig. 1). One patient (case 8) had died of an intercurrent pathology (heart disease). One patient had experienced a spontaneous pregnancy (Table 1).
DISCUSSION The GP entity was diagnosed more than a century ago but the first papers specifically devoted to this disease were published in the 1970s and 1980s.8,9,13 Only 2 series have reported more than 10 cases of GP and all the other papers are case reports.11,12 Gliomatosis peritonei is therefore a very rare disease, associated in most of cases with IOT (9 of cases). But, as observed in one of our cases, it can sometimes arise in patients with a benign teratoma (but in our similar case, a mixed malignant nonepithelial tumor was associated).13 This point explains why, unlike GST (or ‘‘chemotherapeutic retroconversion’’), which is, per se, observed after chemotherapy, GP, can arise in adjuvant chemotherapy-naive patients (because the primary ovarian tumor was a mature teratoma or because it was a grade 1 IOT treated exclusively with surgery). This was observed in half of our cases. The pathogenesis of this rare entity also remains debated because the initial series suggested that peritoneal spread, such as that observed in GTS, was related to ovarian tumor rupture.18 However, recent papers have suggested that GP is genetically unrelated to the ovarian tumor.19,20 Comparing series of IOT without GP to those with GP to identify characteristics of this later group, patients with GP had a larger ovarian tumor size, a trend to have more peritoneal spread and a higher level of CA125.11 Beyond the pathogenesis of this entity, which does not change anything in terms of further management, the most crucial questions concern the overall prognosis of GP and its specific treatment. In the series by Yoon et al,11 the recurrence rate was increased in patients with IOT associated with GP compared to patients with IOT devoid of glial mature tissues in the peritoneum. Among 16 patients bearing GP, 6 (37%) relapsed.11 But this higher recurrence rate had no impact on overall survival because all recurrences were composed of mature glial tissues that were removed surgically. One patient refused the surgical resection of her recurrence and died of the disease 536 days after the initial diagnosis.11 In the pediatric series reported by Harms et al12 concerning about 13 cases of GP, no patient died of the disease and only 1 developed a recurrence in the form of immature glial tissue. That patient is alive but was receiving adjuvant therapy at the time of the publication. In the review of the literature undertaken by Truong et al10 (30 cases plus their own 2 cases), ‘‘only’’ 3 deaths were observed. In those 3 cases, deaths occurred within 13 months after initial management. How should we manage patients with GP? As most of the few GP cases reported were observed in patients with an immature ovarian tumor treated with adjuvant chemotherapy, there is a tendency to consider GP as a particular entity in the
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subgroup of GTS.15 But our series suggests that the management of GP should probably be different from ‘‘other’’ GTS diseases. 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 (bowel obstruction or perforation and deaths have been described).3,6,7 The case of GP is somewhat different because, unlike GTS that may expand, GP can remain quiescent for a long time.21 In the interesting series by Bonazzi et al concerning 32 IOT, 6 (18%) were associated with GP and 2 were diagnosed at the time of second-look surgery during the follow-up and without further surgical resection. If a complete resection of peritoneal GP is feasible, it should be the first goal of the surgery. This surgery has the 2-fold objective of obtaining complete eradication of the disease (such as in GTS), and of avoiding misdiagnosis of small immature residual tissue that could drastically alter survival and further management. But, unlike GTS, most of GP presented macroscopically with small-sized but disseminated peritoneal implants measuring between 1 and 3 mm (such as miliary implants).12 Sometimes, GP was diagnosed based on systematic biopsies whereas no macroscopic lesions were found.12 Consequently, even if a complete resection would be the ‘‘ideal’’ goal of surgery, it would not be achievable in patients with miliary spread (nor in the case of patients without macroscopic peritoneal disease but with GP found at the time of the histologic analysis of random biopsies). Our results (with 5 patients with residual peritoneal disease and no further recurrence among them) suggest that GP is a quiescent disease in the most cases. Second-look surgery (with no sign of peritoneal disease on imaging before this surgery) had been performed in 4 cases in the present study and GP had been unveiled in all cases without any impact on the risk of a further recurrence. This is why in the present series, we considered those patients as having asymptomatic residual disease and not really a true recurrence, because these 4 patients had no symptoms and no peritoneal abnormalities on imaging. In fact, we observed 2 ‘‘true’’ recurrences in patients with abnormal clinical signs and/or peritoneal abnormalities on imaging (cases 9 and 10). In case 9, complete debulking surgery (with a diaphragmatic resection and a splenectomy) had been performed and the patient had relapsed later in the wound. Both of them are alive without symptomatic disease (case 10 had an abnormal CT scan for nearly 5 years after the last surgical procedure). This finding is important because, unlike the strategy applied in the management of GTS, if a complete macroscopic resection cannot be achieved in GP (or is feasible but at the price of excessively radical debulking surgery such as a bowel resection or radical treatment in young patients desiring fertility preservation), the simple follow-up of patients is acceptable because peritoneal GP may remain stable for a long time without any impact on patient outcomes. Nevertheless, we need to have sufficiently large peritoneal biopsy specimens allowing us to confirm the presence of pure mature disease (GP) and to exclude the rare event of associated immature peritoneal disease which then requires specific management. We need to follow up patients bearing GP (particularly in the case of residual disease and/or abnormal postoperative
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imaging) because rare cases of malignant transformation have been described.22Y24 The question we now need to address concerns the optimal follow-up modalities (together with the clinical examination which remains the first step): simple imaging procedures with or without second-look surgery? In the series by Harms et al,12 among 6 second-look surgeries, 2 unveiled GP disease. In the present series, as we previously mentioned, all 4 patients who had undergone second-look surgery without abnormal peritoneal disease on preoperative imaging had peritoneal GP and no recurrence, but this disease had no impact on further patient management. In conclusion, GP is a particular entity in the condition described as GTS because residual peritoneal disease can be asymptomatic and totally quiescent over a long period, raising the question of a more conservative surgical approach in patients with massive peritoneal spread.
REFERENCES 1. Logothetis CJ, Samuels ML, Trindade A, et al. The growing teratoma syndrome. Cancer. 1982;50:1629Y1635. 2. DiSaia PJ, Saltz A, Kagan AR, et al. Chemotherapeutic retroconversion of immature teratoma of the ovary. Obstet Gynecol. 1977;49:346Y350. 3. Kattan J, Droz JP, Culine S, et al. The growing teratoma syndrome: a woman with nonseminomatous germ cell tumor of the ovary. Gynecol Oncol. 1993;49:395Y399. 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;25:1739Y1743. 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;92:357Y360. 6. 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;36:1389Y1394. 7. Zagame L, Pautier P, Duvillard P, et al. Growing teratoma syndrome after ovarian germ cell tumors. Obstet Gynecol. 2006;108:509Y514. 8. Robboy SJ, Scully RE. Ovarian teratoma with glial implants on the peritoneum. An analysis of 12 cases. Hum Pathol. 1970;1:643Y653. 9. Norris HJ, Zirkin HJ, Benson WL. Immature (malignant) teratoma of the ovary: a clinical and pathologic study of 58 cases. Cancer. 1976;37:2359Y2372. 10. Truong LD, Jurco S3rd, McGavran MH. Gliomatosis peritonei. Report of two cases and review of literature. Am J Surg Pathol. 1982;6:443Y449. 11. Yoon NR, Lee JW, Kim BG, et al. Gliomatosis peritonei is associated with frequent recurrence, but does not affect overall survival in patients with ovarian immature teratoma. Virchows Arch. 2012;461:299Y304. 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;184:422Y430. 13. Nielsen SN, Scheithauer BW, Gaffey TA. Gliomatosis peritonei. Cancer. 1985;56:2499Y2503. 14. Hamada Y, Tanano A, Sato M, et al. Ovarian teratoma with gliomatosis peritonei: report of two cases. Surg Today. 1998;28:223Y226. * 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
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15. Umekawa T, Tabata T, Tanida K, et al. Growing teratoma syndrome as an unusual cause of gliomatosis peritonei: a case report. Gynecol Oncol. 2005;99:761Y763. 16. Mu¨ller AM, So¨ndgen D, Strunz R, et al. Gliomatosis peritonei: a report of two cases and review of the literature. Eur J Obstet Gynecol Reprod Biol. 2002;100:213Y222. 17. Chuang JH, Chen L. Ovarian teratoma with gliomatosis peritonei. J Pediatr Surg. 1992;27:662Y664. 18. Favara BE, Franciosi RA. Ovarian teratoma and neuroglial implants on the peritoneum. Cancer. 1973;31:678Y681. 19. Kwan MY, Kalle W, Lau GT, et al. Is gliomatosis peritonei derived from the associated ovarian teratoma?. Hum Pathol. 2004;35:685Y688. 20. Best DH, Butz GM, Moller K, et al. Molecular analysis of an immature ovarian teratoma with gliomatosis peritonei and
21.
22.
23.
24.
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recurrence suggests genetic independence of multiple tumors. Int J Oncol. 2004;25:17Y25. 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;84:598Y604. Shefren G, Collin J, Soriero O. Gliomatosis peritonei with malignant transformation: a case report and review of the literature. Am J Obstet Gynecol. 1991;164:1617Y1620. Dadmanesh F, Miller DM, Swenerton KD, et al. Gliomatosis peritonei with malignant transformation. Mod Pathol. 1997;10:597Y601. Mengshol SC, Demars LR, Schned AR. Gliomatosis peritonei and teratomatous implant with carcinomatous transformation presenting 54 years following oophorectomy for dermoid cyst. Gynecol Oncol. 2004;92:353Y356.
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Gliomatosis Peritonei A Particular Entity With Specific Outcomes Within the Growing Teratoma Syndrome Enrica Bentivegna, MD,* Clementine Gonthier, MD,* Catherine Uzan, MD, PhD,* Catherine Genestie, MD,Þ Pierre Duvillard, MD,Þ Philippe Morice, MD, PhD,*þ and Sebastien Gouy, MD, PhD*
Objectives: Ovarian immature teratoma may be associated with peritoneal spread that could, after adjuvant chemotherapy, develop into disease exclusively composed of mature implants (growing teratoma syndrome) and/or gliomatosis peritonei (GP), defined as the presence of pure mature glial tissue. However, very few specific series are devoted to the outcomes of pure GP. This was the aim of the present study. Patients: From 1997 to 2013, data concerning patients treated for stage II/III immature teratoma were reviewed. All slides were reviewed by an expert pathologist. Patients with ovarian cancer associated with peritoneal spread in the form of pure GP (initially if patients were treated without adjuvant treatment or after adjuvant chemotherapy if done) were analyzed. Results: Ten patients fulfilled the inclusion criteria. The median age of patients at diagnosis was 36 years (range, 14Y41 years). Six patients had undergone a conservative treatment. Five patients had macroscopic residual disease at the end of surgery. The median duration of follow-up from the diagnosis of GP was 39 months (range, 6Y114 months). Six patients had undergone secondary surgery. Among them, 5 had incompletely resected macroscopic GP. No patients had died of their disease. All patients were asymptomatic at the time of the last consultation (1 of them with abnormal radiologic imaging). Conclusions: Gliomatosis peritonei is a particular entity of the condition described as growing teratoma syndrome because residual peritoneal disease can be asymptomatic totally stable over a long period which raises the question of a more conservative surgical approach in patients with massive peritoneal spread. Key Words: Immature ovarian teratoma, Growing teratoma syndrome, Gliomatosis peritonei, Recurrence, Follow-up Received September 10, 2014, and in revised form December 5, 2014. Accepted for publication December 7, 2014. (Int J Gynecol Cancer 2015;25: 244Y249)
Departments of *Gynecologic Surgery, and †Pathology, and ‡University Paris Sud, Gustave Roussy Cancer Campus, Villejuif, France. Copyright * 2015 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000345
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Address correspondence and reprint requests to Philippe Morice, MD, PhD, Gustave Roussy Cancer Campus, 114 rue Edouard Vaillant, 94805 Villejuif, France. E-mail: [email protected]. The authors declare no conflicts of interest.
International Journal of Gynecological Cancer
& Volume 25, Number 2, February 2015
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 25, Number 2, February 2015
immature teratoma can be associated with periO varian toneal spread in the form of immature peritoneal im-
plants that may develop after adjuvant chemotherapy into disease exclusively composed of mature implants [growing teratoma syndrome (GTS) or ‘‘chemotherapeutic retroconversion’’].1Y4 These 2 entities are very close and perhaps the same, and should be treated surgically.5 The procedure may then involve retroperitoneal surgery (resection of residual bulky nodes) and/or intra-abdominal debulking surgery, that we perform to treat epithelial ovarian cancer, because these masses can expand and provoke compressive symptoms and exceptionally, disease-related mortality (through bowel perforation or ischemia).3,6,7 This is why the cornerstone treatment of GTS (or ‘‘chemotherapeutic retroconversion’’) is based on surgical removal of all macroscopic disease (even if radical surgery is required).7 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). This entity is histologically defined as the presence of mature glial tumor tissue in the peritoneum.8Y10 Histologically, it can be pure (exclusively comprising mature glial tissue) or associated with other mature tissue components (GTS) and/or associated with immature disease. The latter case is rare (carrying a very poor prognosis) if it is diagnosed after adjuvant chemotherapy. But very few series are specifically devoted to the outcomes of pure GP.8,11Y13 Most of the reports are case studies (or very short series with a few patients) and sometimes with a mixture of GP and other nonglial mature tissues.13Y18 The aim of this study was to evaluate the specific outcomes of patients with peritoneal implants exclusively composed of mature GP.
PATIENTS AND METHODS Population Patients with immature ovarian teratoma (IOT) and/or nonepithelial cancers exhibiting teratoma patterns referred to or treated in our institution between 1997 and 2013 were retrospectively identified. Among these cases, patients with GP at histologic examination were included in the analysis. Patients were definitively included if they met the following criteria: - Centralized histologic review of the initial ovarian tumor and the subsequent GP specimen. - Surgical treatment of their GP with histologic confirmation of the entire ovarian and peritoneal tumor specimens. Patients with radiologic suspicion of GP, but without surgical management (and histologic confirmation), were excluded. - Patients presenting with a mature GP but associated with other nonglial mature tissues (GTS) were excluded. - If patients had received adjuvant chemotherapy, patients with immature tissues (associated with GP) at the time of secondary surgery were excluded. - Available posttreatment outcome data. Surgery was either a radical procedure (bilateral salpingooophorectomy with or without a hysterectomy), or a conservative
Gliomatosis Peritonei
intervention (defined as conservation of the uterus and at least a portion of one ovary). A conservative surgery was the first option when a healthy part of at least one ovary could be preserved and if the uterus had no disease on its surface. Additional surgical procedures were occasionally performed, such as peritoneal washings, omentectomy, multiple peritoneal biopsies, and pelvic and para-aortic lymphadenectomy. These surgical procedures had been performed depending on the period, macroscopic exploration, the availability of the pathological information during the operation, and the stage of the disease. Thus, surgical procedures had been performed in a 1-step operation or completed at the time of restaging surgery after complete analysis of the definitive histologic results. Some patients had undergone second-look surgery after adjuvant chemotherapy. After surgery, follow-up was based on a clinical examination and imaging (abdominopelvic ultrasonography; magnetic resonance imaging or computed tomographic (CT) scans, depending on whether conservative treatment of the uterus and one ovary had been performed and on the degree of intraabdominal peritoneal dissemination). Clinical, pathological, and prior treatment data were collected from the clinical records. The precise details regarding the extent of debulking surgery performed for GP were recorded. Outcomes after debulking surgery (interval and sites of recurrences, histologic types of these recurrences, fertility if, fertility-preserving surgery had been performed) were analyzed. According to local regulation, an institutional review board approval is not required (and so asked) in such retrospective study.
RESULTS During the study period, 10 patients fulfilled the inclusion criteria. All patients had ‘‘pure’’ GP without any other nonglial mature tissue. Detailed patient characteristics are shown in Table 1. The median age of patients at diagnosis was 36 years (range, 14Y41 years). Nine patients had undergone a 2-step operation and 1 a single procedure. Among the 9 patients having undergone a 2-step procedure, adnexal surgery during the first operation was a unilateral salpingooophorectomy in 5 (completed with a contralateral salpingooophorectomy and a hysterectomy during restaging surgery in 1), a unilateral cystectomy (completed with a unilateral salpingo-oophorectomy during restaging surgery) in 1, a unilateral salpingo-oophorectomy and a contralateral cystectomy (completed with a salpingo-oophorectomy during restaging surgery) in 1, and a bilateral salpingo-oophorectomy in 2 patients. One patient (case 4) was pregnant during her treatment. Among the additional procedures performed during the first and second surgery (if done), 6 patients had undergone a conservative treatment and 4 a bilateral salpingo-oophorectomy (with a hysterectomy in 2) (Table 1). All patients but 1 had IOT and the last one a mixed nonepithelial ovarian cancer with mature teratoma (case 8 in Table 1). Among the 9 patients treated using a 2-step surgical procedure, the diagnosis of GP had been made in 1 during the first procedure (and in the remaining 8 at the time of restaging surgery).
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IOT grade 1 and peritoneal immature gliomatosis
USO
Caecostomy
IOT grade 1 and peritoneal mature gliomatosis USO Asymptomatic Peritonectomies IOT grade 2 and peritoneal mature gliomatosis H + BSO Peritoneal gliomatosis Biopsy IOT grade 1 and peritoneal mature gliomatosis BSO Peritoneal gliomatosis Peritonectomies IOT grade 1 and peritoneal mature gliomatosis USO Abdominal CT scan normal BSO Mixed ovarian tumor with yolk sac and dysgerminoma and mature teratoma Omentectomy Peritonectomies H + BSO IOT grade 3 and peritoneal mature gliomatosis Splenectomy Gliomatosis in the wound Omentectomy Large peritonectomy Diaphragmatic resection Biopsy IOT grade 2 and peritoneal mature gliomatosis
USO Biopsy
USO Appendectomy Biopsy
USO Peritonectomies IOT grade 3 and peritoneal mature gliomatosis
IOT grade 1 and peritoneal mature gliomatosis
Yes
Yes
Yes
No
No
No
No
Yes
Yes
No
Yes diffuse
No
No
No
Yes diffuse
Yes
No
Yes diffuse
Yes diffuse
No
Residual Adjuvant Macroscopic Treatment Gliomatosis V
Location and Histology of Disease
Benign ovarian cyst
V
Recurrence
Recurrence
No
No
V
Normal
V
Normal
V
Normal
V
V
Abnormal with stable lesions
Asymptomatic Normal after recurrence
Died of cardiac disease
Asymptomatic
Asymptomatic
Asymptomatic
Recent delivery
Asymptomatic
Asymptomatic
Asymptomatic
66
69
114
36
16
94
24
41
7
6
Outcomes Posttreatment and Last Imaging (MRI Follow-up, Consultation or CT Scan) mo
Massive peritoneal Asymptomatic gliomatosis with a (unresectable) caecostomy
Abdominal scar (resected)
V
V
Ovarian cyst Benign and infertility ovarian cyst
Ovarian cyst
No
Second-look Peritoneal surgery after gliomatosis chemotherapy
Second-look Peritoneal surgery after gliomatosis chemotherapy
No
Secondary Surgery (Reason)
*Adding procedures done during the first operation and restaging surgery (if done). BSO, Bilateral salpingo-oophorectomy; H, hysterectomy; MRI, magnetic resonance imaging; USO, unilateral salpingo-oophorectomy.
41
33
2
Biopsy
Histologic Subtype and Grade
International Journal of Gynecological Cancer
10
38
1
Surgical Case Age, y Procedures*
TABLE 1. Patient characteristics
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Five patients had received adjuvant chemotherapy based on histologic factors identified at the time of the first operation or at restaging surgery (if done). Three of them had received their adjuvant therapy between both surgeries. Only 1 patient (case 3) exhibited immature neuroglial tissue before adjuvant chemotherapy which had transformed into mature GP at the time of second-look surgery. Gliomatosis peritonei had been unveiled during the first operation or at restaging surgery in all of the other patients. Five patients had macroscopic residual peritoneal disease after the first operation and/or at restaging surgery (if done). The median duration of follow-up from the diagnosis of GP (depending on whether disease had been diagnosed during the first operation or restaging surgery (if done) was 39 months (range, 6Y114 months). Six patients had undergone secondary surgery: - Two of them had undergone a second-look procedure 3 months after adjuvant chemotherapy. Gliomatosis peritonei had been unveiled in both patients. - Two patients had ovarian cysts (found 2 and 16 months after the last surgical procedure). Gliomatosis peritonei had been found (with benign ovarian cysts) in both of them. - Two patients had been treated for a clinical, biological, or radiological recurrence. The first one (case 9) had a wound recurrence 58 months after initial management. Elective scar revision surgery had been performed and gliomatosis had been found at the histologic analysis. This patient is currently disease free 12 months after this last procedure. The other patient (case 10) had bulky peritoneal spread (diagnosed based on CA125 elevation and ascites on CT scan) with unresectable disease (miliary peritoneal implants on the mesentery). She had undergone large biopsies (demonstrating pure GP) and
FIGURE 1. Coronal view on CT in patient 10 showing residual disease in the peritoneum (arrow).
Gliomatosis Peritonei
a caecostomy. She remains currently asymptomatic 52 months after this last surgical procedure. Her disease is still visible on the CT scan but has been stable for 5 years (Fig. 1). One patient (case 8) had died of an intercurrent pathology (heart disease). One patient had experienced a spontaneous pregnancy (Table 1).
DISCUSSION The GP entity was diagnosed more than a century ago but the first papers specifically devoted to this disease were published in the 1970s and 1980s.8,9,13 Only 2 series have reported more than 10 cases of GP and all the other papers are case reports.11,12 Gliomatosis peritonei is therefore a very rare disease, associated in most of cases with IOT (9 of cases). But, as observed in one of our cases, it can sometimes arise in patients with a benign teratoma (but in our similar case, a mixed malignant nonepithelial tumor was associated).13 This point explains why, unlike GST (or ‘‘chemotherapeutic retroconversion’’), which is, per se, observed after chemotherapy, GP, can arise in adjuvant chemotherapy-naive patients (because the primary ovarian tumor was a mature teratoma or because it was a grade 1 IOT treated exclusively with surgery). This was observed in half of our cases. The pathogenesis of this rare entity also remains debated because the initial series suggested that peritoneal spread, such as that observed in GTS, was related to ovarian tumor rupture.18 However, recent papers have suggested that GP is genetically unrelated to the ovarian tumor.19,20 Comparing series of IOT without GP to those with GP to identify characteristics of this later group, patients with GP had a larger ovarian tumor size, a trend to have more peritoneal spread and a higher level of CA125.11 Beyond the pathogenesis of this entity, which does not change anything in terms of further management, the most crucial questions concern the overall prognosis of GP and its specific treatment. In the series by Yoon et al,11 the recurrence rate was increased in patients with IOT associated with GP compared to patients with IOT devoid of glial mature tissues in the peritoneum. Among 16 patients bearing GP, 6 (37%) relapsed.11 But this higher recurrence rate had no impact on overall survival because all recurrences were composed of mature glial tissues that were removed surgically. One patient refused the surgical resection of her recurrence and died of the disease 536 days after the initial diagnosis.11 In the pediatric series reported by Harms et al12 concerning about 13 cases of GP, no patient died of the disease and only 1 developed a recurrence in the form of immature glial tissue. That patient is alive but was receiving adjuvant therapy at the time of the publication. In the review of the literature undertaken by Truong et al10 (30 cases plus their own 2 cases), ‘‘only’’ 3 deaths were observed. In those 3 cases, deaths occurred within 13 months after initial management. How should we manage patients with GP? As most of the few GP cases reported were observed in patients with an immature ovarian tumor treated with adjuvant chemotherapy, there is a tendency to consider GP as a particular entity in the
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subgroup of GTS.15 But our series suggests that the management of GP should probably be different from ‘‘other’’ GTS diseases. 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 (bowel obstruction or perforation and deaths have been described).3,6,7 The case of GP is somewhat different because, unlike GTS that may expand, GP can remain quiescent for a long time.21 In the interesting series by Bonazzi et al concerning 32 IOT, 6 (18%) were associated with GP and 2 were diagnosed at the time of second-look surgery during the follow-up and without further surgical resection. If a complete resection of peritoneal GP is feasible, it should be the first goal of the surgery. This surgery has the 2-fold objective of obtaining complete eradication of the disease (such as in GTS), and of avoiding misdiagnosis of small immature residual tissue that could drastically alter survival and further management. But, unlike GTS, most of GP presented macroscopically with small-sized but disseminated peritoneal implants measuring between 1 and 3 mm (such as miliary implants).12 Sometimes, GP was diagnosed based on systematic biopsies whereas no macroscopic lesions were found.12 Consequently, even if a complete resection would be the ‘‘ideal’’ goal of surgery, it would not be achievable in patients with miliary spread (nor in the case of patients without macroscopic peritoneal disease but with GP found at the time of the histologic analysis of random biopsies). Our results (with 5 patients with residual peritoneal disease and no further recurrence among them) suggest that GP is a quiescent disease in the most cases. Second-look surgery (with no sign of peritoneal disease on imaging before this surgery) had been performed in 4 cases in the present study and GP had been unveiled in all cases without any impact on the risk of a further recurrence. This is why in the present series, we considered those patients as having asymptomatic residual disease and not really a true recurrence, because these 4 patients had no symptoms and no peritoneal abnormalities on imaging. In fact, we observed 2 ‘‘true’’ recurrences in patients with abnormal clinical signs and/or peritoneal abnormalities on imaging (cases 9 and 10). In case 9, complete debulking surgery (with a diaphragmatic resection and a splenectomy) had been performed and the patient had relapsed later in the wound. Both of them are alive without symptomatic disease (case 10 had an abnormal CT scan for nearly 5 years after the last surgical procedure). This finding is important because, unlike the strategy applied in the management of GTS, if a complete macroscopic resection cannot be achieved in GP (or is feasible but at the price of excessively radical debulking surgery such as a bowel resection or radical treatment in young patients desiring fertility preservation), the simple follow-up of patients is acceptable because peritoneal GP may remain stable for a long time without any impact on patient outcomes. Nevertheless, we need to have sufficiently large peritoneal biopsy specimens allowing us to confirm the presence of pure mature disease (GP) and to exclude the rare event of associated immature peritoneal disease which then requires specific management. We need to follow up patients bearing GP (particularly in the case of residual disease and/or abnormal postoperative
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imaging) because rare cases of malignant transformation have been described.22Y24 The question we now need to address concerns the optimal follow-up modalities (together with the clinical examination which remains the first step): simple imaging procedures with or without second-look surgery? In the series by Harms et al,12 among 6 second-look surgeries, 2 unveiled GP disease. In the present series, as we previously mentioned, all 4 patients who had undergone second-look surgery without abnormal peritoneal disease on preoperative imaging had peritoneal GP and no recurrence, but this disease had no impact on further patient management. In conclusion, GP is a particular entity in the condition described as GTS because residual peritoneal disease can be asymptomatic and totally quiescent over a long period, raising the question of a more conservative surgical approach in patients with massive peritoneal spread.
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