ORIGINAL STUDY
A Series of Malignant Ovarian Cancers Arising From Within a Mature Cystic Teratoma A Single Institution Experience Jonathan D. Black, MD, MPH,* Dana M. Roque, MD,Þ Monica C. Pasternak, MD,þ Natalia Buza, MD,§ Thomas J. Rutherford, MD, PhD,* Peter E. Schwartz, MD,* Shirley McCarthy, MD,|| and Elena Ratner, MD*
Background: Mature cystic teratoma (MCT) is the most common germ cell tumor. It accounts for 10% to 20% of all ovarian masses. The likelihood of malignancy arising from within an MCT is low, and prognosis is poor. Methods: A single-institution retrospective chart review was completed of all cases of MCT from 2004 to 2012. Multiple variables were examined including procedure performed, residual disease after surgery, surgical stage, histologic type, site of primary disease, date of recurrence, whether or not adjuvant chemotherapy was given, and whether or not there was death secondary to disease. Results: During the study period, 1.2% of MCTs exhibited malignant transformation. The average age at presentation was 53.7 years. Mean follow-up time was 23 months. The most common presenting symptoms were bloating and abdominal pain. The average tumor size was 18 cm. Of note, 33% of cases were at least surgical stage IIIC at the time of presentation, whereas the remainder were stage IC or lower. Four (44.4%) of the 9 cases were identified as mucinous adenocarcinoma in addition to 1 case each of malignant melanoma, squamous cell carcinoma, and poorly differentiated adenocarcinoma. Only 1 patient experienced recurrence. One patient had a known MCT that was being managed expectantly and exhibited malignant transformation to a mucinous adenocarcinoma. Conclusions: A large ovarian mass that is suspected to be a mature teratoma should be managed more aggressively in older patients. Our data suggest that although malignancy arising from mature teratomas is rare, it is more likely when patients are older than 40 years, the mass is greater than 18 cm, and there is any suspicion for a mucinous tumor. Like most ovarian tumors, these tumors most often present at later stages and, thus, can be difficult to treat. It is unclear what role chemotherapy or radiation plays in the management of these tumors. Key Words: Mature cystic teratoma, Dermoid, Malignant transformation, Mucinous adenocarcinoma Received September 17, 2014, and in revised form February 5, 2015. Accepted for publication February 5, 2015. (Int J Gynecol Cancer 2015;25: 792Y797)
*Section of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT; †Section of Gynecologic Oncology, University of Copyright * 2015 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000431
792
Maryland Medical Center, Baltimore, MD; and ‡Departments of Obstetrics, Gynecology, and Reproductive Sciences, §Pathology, and ||Diagnostic Radiology, Yale School of Medicine, New Haven, CT. Address correspondence and reprint requests to Jonathan D. Black, MD, MPH, 333 Cedar St, New Haven, CT 06515. E-mail: [email protected]. The authors declare no conflicts of interest.
International Journal of Gynecological Cancer
& Volume 25, Number 5, June 2015
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 25, Number 5, June 2015
cystic teratoma (MCT) is the most common type M ature of ovarian germ cell tumor. It accounts for 10% to 20%
of all ovarian masses and is most common during the childbearing years. They are composed of mature tissue from ectoderm, mesoderm, and/or endoderm and form as a result of failure of meiosis II or from preYmeiotic cells in which meiosis I has failed.1 The incidence of MCT ranges from 1.2 to 14.2 cases per 100,000 per year.2 Malignancy arising from the MCT can occur, being more likely among older, postmenopausal women. The likelihood of malignancy within a teratoma is very low, with a reported rate of 0.17% to 2%; the prognosis is usually poor.2Y5 Common symptoms and preoperative findings in cases of malignancy arising from and MCT are abdominal pain,3,6,7 mass greater than 9.9 cm,7,8 constipation, vaginal bleeding, weight loss, urinary frequency, and fever.3Y5,7,9 More than 80% of cases of malignancy arising from an MCTare thought to be squamous cell carcinoma (SCC).2 Adenocarcinoma, carcinoid tumor, melanoma, and other tumors have also been reported.2,3,8Y10 Identification of the clinical, pathologic, and radiographic characteristics of malignancy arising from an MCT remains key to early detection. Because of the rarity of this entity, guidance for optimal management is lacking. In this report, we describe the institutional experience with this rare entity and summarize the existing literature. It is often impossible to distinguish malignant transformation from de novo coexisting disease arising within an MCT. For this reason, in much of the existing literature as well as the present article, these terms are used interchangeably.
METHODS Approval for the study was obtained from the institutional review board. Single-institution retrospective chart review was completed to identify all cases of malignancy arising from an MCT of the ovary diagnosed from 2004 to 2014 at Yale University hospitals. Clinical information was obtained from the medical records and pathology reports. Surgical staging in most cases included hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and pelvic and para-aortic lymphadenectomy. Surgical stage was reported using the 1988 International Federation of Gynecology and Obstetrics staging system.11 Multiple variables were examined including age, presenting symptoms, procedure performed, residual disease after cytoreductive surgery, surgical stage, histologic type, date of recurrence, adjuvant chemotherapy regimen, and whether or not there was death secondary to disease. Survival time was measured as time from the initial diagnosis to the time of death or last contact. Statistical analyses were computed using GraphPad Prism version 6 (GraphPad Software, San Diego CA).
Ovarian Cancers Arising From Within MCTs
the time of presentation, all of the patients reported abdominal pain and bloating. Available imaging revealed masses with both solid and cystic components in all cases (Fig. 1). Of the patients who presented with symptoms, only 1 (11.1%) had a known MCT; the remainder were new presentations. Finally, none of the patients had a prior surgical procedure for an MCT. All patients went to the operating room and had surgical resection. Eight patients (88.8%) had frozen sections completed at the time of surgery. All of these (100%) successfully identified malignancy within the MCT. Most (88.8%) of patients underwent complete surgical staging (total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymph node dissection, and omentectomy) after an intraoperative frozen section diagnosis confirming malignancy (Table 1). On final pathology, 4 (44.4%) of the 9 cases were identified as mucinous adenocarcinoma, 2 as carcinoid tumor (22.2%), and 1 case each of malignant melanoma (11.1%), SCC (11.1%), and poorly differentiated adenocarcinoma (11.1%). In one case, surgical staging was not completed. In this case, the malignant component was a carcinoid tumor, which typically does not need to be surgically staged and the patient also desired fertility preservation. The second carcinoid was completely staged as it exhibited an insular morphologic pattern with variable lumen formation, features that can be associated with more malignant behavior. Approximately 33% of the cases were at least surgical stage IIIC at the time of presentation, whereas the remainder were stage IC or lower. The average tumor size was 18.0 cm (range, 7-29 cm). Both carcinoid tumors were smaller than the other tumors, each being 7 cm. The next closest tumor size was 18 cm (Table 1). On immunohistochemistry, all of the mucinous tumors stained positive for CK20 and CDX2, and MUC2 immunostains
RESULTS Between 2004 and 2014, there were 9 (1.2%) of 729 mature teratoma specimens that exhibited a malignant component. The average age at presentation was 53.7 years (range, 22-74 years). In terms of racial demographics, 66% of the patients were white and the remainder were African American. At
FIGURE 1. Malignant melanoma: solid component (white arrow) and mural thickening (red arrow) worrisome for malignant transformation.
* 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
793
794
IIIC
IA
IC
IA
IIIC
IIIC
Unstaged
IA
IA
65
40
74
70
45
58
22
50
59
7
20
7
20
29
18
29
19
20
Tumor Size, cm Frozen Section
LSO, PPaLND, infracolic omentectomy TAH, BSO, PLND, omentectomy
None
Carboplatinum/Paclitaxel 4 cycles, then cisplatinum/ifosfamide FOLFOX 10 cycles
None
FOLFOX 6 cycles
Adjuvant Treatment
Mucinous adenocarcinoma Gemcitabine and oxaliplatin 1 cycle Carcinoid None
Malignant melanoma
Mucinous adenocarcinoma
SCC
Mucinous borderline
Mucinous adenocarcinoma
Pathology
Mucinous tumor, probably Mucinous adenocarcinoma None borderline, in association with teratoma Favor sex cord stromal Carcinoid None tumor
TAH, BSO, PPaLND, Adenocarcinoma, favor appendectomy, mucinous omentectomy adenocarcinoma TAH, BSO, PPaLND, Melanoma arising in omentectomy teratoma, lymph node positive for melanoma TAH, BSO, Mucinous adenocarcinoma omentectomy LSO No frozen completed
TAH, BSO, PPaLND, Adenocarcinoma, favor appendectomy, endometrioid omentectomy TAH, BSO, PPaLND, Mucinous borderline appendectomy, omentectomy TAH, BSO, PPaLND, Malignant neoplasm omentectomy
Surgery
1
21
18
1
18
13
7
42
68
Alive
Alive
Alive
Dead
Dead
Alive
Dead
Alive
Alive
Follow-Up, Disease mo Status
International Journal of Gynecological Cancer
BSO, bilateral salpingoophorectomy; FOLFOX, folinic acid, fluorouracil, oxaliplatin; LSO, left salpingoophorectomy; PPaLND, pelvic and para-aortic lymph node dissection; TAH, total abdominal hystrectomy.
Stage
Age, y
TABLE 1. Demographics and patient characteristics
Black et al
& Volume 25, Number 5, June 2015
* 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 25, Number 5, June 2015
when it was evaluated. Half of the mucinous tumors also stained positive for CK7. The carcinoid tumors stained positive for chromogranin and synaptophysin (Fig. 2). One (11.1%) patient with mucinous adenocarcinoma had an elevated serum CA-125 and CA 19-1 levels of 665 U/mL and 205 ng/mL, respectively. Four patients (44.4%) received adjuvant chemotherapy. Two of the patients died within 6 months of initiation of treatment. One of them had stage IC poorly differentiated SCC and had received carboplatinum plus paclitaxel for 4 cycles, continued to exhibit progression of disease, and then received 1 cycle of cisplatinum plus ifosfamide before care was withdrawn. The other patient who died had stage IIIC mucinous adenocarcinoma with residual disease after staging; she received gemcitabine plus oxaliplatin for 1 cycle before care was withdrawn. Another patient was staged in 2009 as IIIC mucinous adenocarcinoma with no residual disease. She received folinic acid, fluorouracil, oxaliplatin (FOLFOX)-4 for 6 cycles and has had a disease-free interval of 68 months. The fourth patient who received chemotherapy was staged at IA mucinous adenocarcinoma in 2012, received 10 cycles of FOLFOX-4 adjuvant chemotherapy, and is currently disease-free. Mean and median follow-up times were 23 and 18 months, respectively. There was 1 case of recurrence in a patient with malignant melanoma arising from within an MCT, which occurred 328 days after the initial diagnosis.
DISCUSSION A large ovarian mass that is suspected to be a mature teratoma should be surgically excised in older patients. Our
Ovarian Cancers Arising From Within MCTs
data confirm that although a malignancy within an MCT is rare, it is more likely in older, white patients. Previous studies report that suspicion for malignancy should be raised when an MCT is larger than 9.9 cm.7,8 Our average tumor size was slightly larger (18 cm). In addition, any imaging that identifies mixed solid and cystic components should heighten concern. The sonographic appearance of MCT is quite variable,12 whereas they are readily diagnosed on magnetic resonance imaging, despite complications such as hemorrhage or torsion.13,14 Gross fat has a characteristic appearance on magnetic resonance imaging and computed tomography, although computed tomography is far less accurate in the differential diagnosis of an adnexal mass.15 Rarely, MCT may exhibit little identifiable fat but can show signal behavior indicative of MCT.16,17 Immature teratomas are easily distinguished from MCT because they are solid masses with small irregular foci of fat and calcification16 and MCTwith a malignant component is typically a mass with the appearance of a cystic teratoma but a significant solid component. In one series,18 5 of 6 tumors had an obvious solid component that was relatively large. Four of the 5 solid components exhibited transmural extension. Squamous cell carcinoma tended to extend along the capsule through the cyst wall and directly invaded the surrounding organs. In 43 cases of MCT,19 2 exhibited obvious malignant components manifested by the MCT containing a solid mass greater than 5 cm, with an irregular border forming an obtuse angle with the inner wall of the cyst and contrast uptake in 1 case. The solid component in MCTs with a malignant component appears different from the frequently present frond-like, benign solid component in an MCT called the Rokitansky
FIGURE 2. Representative microscopic images of malignancy arising in MCTs (all hematoxylin and eosin stained, original magnification 40). A, Mucinous adenocarcinoma (arrow indicates cyst lining). B, Carcinoid tumor. C, SCC. D. Malignant melanoma (arrow indicates cyst lining). * 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
795
International Journal of Gynecological Cancer
Black et al
protuberance or dermoid plug. Gadolinium enhancement within the MCT should raise the possibility of malignancy.20 Although a frozen section is not the gold standard for patients undergoing a routine procedure for an MCT, it is a valuable tool and should be strongly considered if the patient or tumor exhibit any of the characteristics discussed above. In our series, a malignant component within an MCT was diagnosed on frozen section in 100% of cases. All of those patients subsequently underwent complete surgical staging. Thus, completing a frozen section allowed these patients to avoid a second procedure, one which would have been necessary if the surgeons had forgone a frozen section and sent the specimen for permanent section alone. Although existing literature reports that up to 80% of malignancies arising from MCTs are SCC,2 our data suggest a higher incidence of transformation, approximately 50%, to mucinous adenocarcinoma of the ovary. This is significant clinically because if identified by frozen section, an appendectomy would be completed as part of surgical staging, whereas it would not be necessary with other types of malignancy. Furthermore, close attention should be paid to MCTs that are thought to exhibit a carcinoid tumor as the malignant component. Although patients with carcinoid tumors do not need to be fully staged, some carcinoid tumors can exhibit an insular morphology and these tumors have a higher likelihood of exhibiting malignant behavior and are associated with carcinoid syndrome.21 Up to 25% of insular carcinoids arising from an MCT can exhibit carcinoid syndrome.22 Thus, in the case of an insular carcinoid, complete surgical staging should be completed, as it was in our patients’ case. Like most ovarian cancers, these malignancies most often present at later stages and can be difficult to treat. Our data suggest that optimal tumor debulking and adjuvant chemotherapy with FOLFOX could benefit patients who have mucinous adenocarcinoma as the malignant component of an MCT. This is consistent with preclinical data in mucinous ovarian cancer cell lines and xenografts.23,24 In this series, FOLFOX was only used with mucinous histologies; therefore, the role of FOLFOX in treating other histologic subtypes of malignancy arising from an MCT is unknown and further research is needed. FOLFOX-4 has shown activity in platinum/ taxane-resistant heavily pretreated ovarian cancers across serous, mucinous, endometrioid, clear cell, and undifferentiated histologies.25Y27 It is unclear what role, if any, radiation plays in the management of these tumors. In conclusion, an ovarian mass that has characteristics of an MCT in a patient older than 40 years, especially when the mass is larger than 18 cm, is newly identified, and/or has mixed solid and cystic components, should raise suspicion for malignancy. In such instances, preoperative imaging and tumor markers can be considered. This additional information can aid in counseling and perioperative management. Intraoperative frozen sections should be scrutinized in these cases so that proper staging can be completed as necessary.
REFERENCES 1. Caspi B, Lerne-Geva L, Dahan M, et al. A possible genetic factor in the pathogenesis of ovarian dermoid cysts. Gynecol Obstet Invest. 2003;56:203Y6.
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2. Hackethal A, Brueggmann D, Bohlman MK, et al. Squamous-cell carcinoma in mature cystic teratoma of the ovary: systematic review and analysis of published data. Lancet Oncol. 2008;9:1173Y80. 3. Rim SY, Kim SM, Choi HS. Malignant transformation of ovarian mature cystic teratoma. Int J Gynecol Cancer. 2006;16:140Y4. 4. Dos Santos L, Mok E, Iasonos A, et al. Squamous cell carcinoma arising in mature cystic teratoma of the ovary: a case series and review of the literature. Gynecol Oncol. 2007;105:321Y4. 5. Tangjitgamol S, Manusirivithaya S, Sheanakul C, et al. Squamous cell carcinoma arising from dermoid cyst: case reports and review of literature. Int J Gynecol Cancer. 2003;13:558Y63. 6. Sanghera P, El Modir A, Simon J. Malignant transformation within a dermoid cyst: a case report and literature review. Arch Gynecol Obstet. 2006;274:178Y80. 7. Bal A, Mohan H, Singh SB, et al. Malignant transformation in mature cystic teratoma of the ovary: report of five cases and review of the literature. Arch Gynecol Obstet. 2007;275:179Y82. 8. Park JY, Kim DY, Kim JH, et al. Malignant transformation of mature cystic teratoma of the ovary: experience at a single institution. Eur J Obstet Gynecol Reprod Biol. 2008; 141:173Y8. 9. Sakuma M, Otsuki T, Yoshinaga K, et al. Malignant transformation arising from mature cystic teratoma of the ovary: a retrospective study of 20 cases. Int J Gynecol Cancer. 2010;20:766Y71. 10. Chen RJ, Chen KY, Chang TC, et al. Prognosis and treatment of squamous cell carcinoma from a mature cystic teratoma of the ovary. J Formos Med Assoc. 2008;107:857Y68. 11. Odicino F, Pecorelli S, Zigliani L, et al. History of the FIGO cancer staging system. Int J Gyncol Obstet. 2008;101: 205Y10. 12. Sheth S, Fishman K, Buck JL, et al. The variable sonographic appearances of ovarian teratomas: correlation with CT. AJR Am J Roentgenol. 1988;151:331Y334. 13. Stevens SK, Hirack H, Campos Z. Teratomas versus cystic hemorrhagic adnexal lesions: differentiation with proton-selective fat-saturation MR imaging. Radiology. 1993;186:481Y488. 14. Rha SE, Byun JY, Jung SE, et al. Pictorial essay, atypical CT and MRI manifestations of mature ovarian cystic teratomas. AJR Am J Roentgenol. 2004;183:743Y750. 15. Guinet C, Ghossain MA, Buy JN, et al. Mature cystic teratomas of the ovary: CT and MR findings. Eur J Radiol. 1995;20:137Y143. 16. Troiano RN, Parkash V, Scoutt L, et al. Mature cystic teratoma of the ovary. J Womens Imaging. 2000;2:57Y62. 17. Yamashita Y, Hatanaka Y, Torashima M, et al. Mature cystic teratomas of the ovary without fat in the cystic cavity: MR features in 12 cases. AJR Am J Roentgenol. 1994;16: 613Y616. 18. Kido A, Togashi K, Konishi I. Original report: dermoid cysts of the ovary with malignant transformation: MR appearance. AJR Am J Roentgenol. 1999;172:445Y449. 19. Buy JN, Ghossain MA, Moss AA, et al. Cystic teratoma of the ovary: CT detection. Radiology. 1989;171:697Y701. 20. Maslin P, Luchs JS, Haas J, et al. Ovarian teratoma with malignant transformation: CT diagnosis. AJR Am J Roentgenol. 2002;178:1574. * 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 25, Number 5, June 2015
21. Talerman A. Carcinoid tumors of the ovary. J Cacer Res Clin Oncol. 1984;107:125Y135. 22. Davis KP, Hartmann LK, Keeney GL, et al. Primary ovarian carcinoid tumors. Gynecol Oncol. 1996;61:259Y265. 23. Sato S, Itamochi H, Kigawa J, et al. Combination chemotherapy of oxaliplatin and 5-fluorouracil may be an effective regimen for mucinous adenocarcinoma of the ovary; a potential treatment strategy. Cancer Sci. 2009;100:546Y51.22. 24. Brown J, Fromovitz M. Mucinous tumors of the ovary: current thoughts on diagnosis and management. Curr Oncol Rep. 2014;16:389Y97.
Ovarian Cancers Arising From Within MCTs
25. Pectasides D, Pectasides M, Farmakis D, et al. Oxaliplatin plus high-dose leucovorin and 5-fluorouracil (FOLFOX 4) in platinum-resistant and taxane-pretreated ovarian cancer: a phase II study. Gynecol Oncol. 2004;95:165Y72. 26. Sholi A, Martino MA, Pirigyi A, et al. Mucinous adenocarcinoma of the ovary. Semin Oncol. 2010;37: 314Y20. 27. Lee HJ, Lee HJ, Lee HJ, et al. Feasibility of oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX-4) chemotherapy in heavily pretreated patient with recurrent epithelial ovarian cancer. Cancer Res Treat. 2013;45:40Y7.
* 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
797
A Series of Malignant Ovarian Cancers Arising From Within a Mature Cystic Teratoma A Single Institution Experience Jonathan D. Black, MD, MPH,* Dana M. Roque, MD,Þ Monica C. Pasternak, MD,þ Natalia Buza, MD,§ Thomas J. Rutherford, MD, PhD,* Peter E. Schwartz, MD,* Shirley McCarthy, MD,|| and Elena Ratner, MD*
Background: Mature cystic teratoma (MCT) is the most common germ cell tumor. It accounts for 10% to 20% of all ovarian masses. The likelihood of malignancy arising from within an MCT is low, and prognosis is poor. Methods: A single-institution retrospective chart review was completed of all cases of MCT from 2004 to 2012. Multiple variables were examined including procedure performed, residual disease after surgery, surgical stage, histologic type, site of primary disease, date of recurrence, whether or not adjuvant chemotherapy was given, and whether or not there was death secondary to disease. Results: During the study period, 1.2% of MCTs exhibited malignant transformation. The average age at presentation was 53.7 years. Mean follow-up time was 23 months. The most common presenting symptoms were bloating and abdominal pain. The average tumor size was 18 cm. Of note, 33% of cases were at least surgical stage IIIC at the time of presentation, whereas the remainder were stage IC or lower. Four (44.4%) of the 9 cases were identified as mucinous adenocarcinoma in addition to 1 case each of malignant melanoma, squamous cell carcinoma, and poorly differentiated adenocarcinoma. Only 1 patient experienced recurrence. One patient had a known MCT that was being managed expectantly and exhibited malignant transformation to a mucinous adenocarcinoma. Conclusions: A large ovarian mass that is suspected to be a mature teratoma should be managed more aggressively in older patients. Our data suggest that although malignancy arising from mature teratomas is rare, it is more likely when patients are older than 40 years, the mass is greater than 18 cm, and there is any suspicion for a mucinous tumor. Like most ovarian tumors, these tumors most often present at later stages and, thus, can be difficult to treat. It is unclear what role chemotherapy or radiation plays in the management of these tumors. Key Words: Mature cystic teratoma, Dermoid, Malignant transformation, Mucinous adenocarcinoma Received September 17, 2014, and in revised form February 5, 2015. Accepted for publication February 5, 2015. (Int J Gynecol Cancer 2015;25: 792Y797)
*Section of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT; †Section of Gynecologic Oncology, University of Copyright * 2015 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000431
792
Maryland Medical Center, Baltimore, MD; and ‡Departments of Obstetrics, Gynecology, and Reproductive Sciences, §Pathology, and ||Diagnostic Radiology, Yale School of Medicine, New Haven, CT. Address correspondence and reprint requests to Jonathan D. Black, MD, MPH, 333 Cedar St, New Haven, CT 06515. E-mail: [email protected]. The authors declare no conflicts of interest.
International Journal of Gynecological Cancer
& Volume 25, Number 5, June 2015
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 25, Number 5, June 2015
cystic teratoma (MCT) is the most common type M ature of ovarian germ cell tumor. It accounts for 10% to 20%
of all ovarian masses and is most common during the childbearing years. They are composed of mature tissue from ectoderm, mesoderm, and/or endoderm and form as a result of failure of meiosis II or from preYmeiotic cells in which meiosis I has failed.1 The incidence of MCT ranges from 1.2 to 14.2 cases per 100,000 per year.2 Malignancy arising from the MCT can occur, being more likely among older, postmenopausal women. The likelihood of malignancy within a teratoma is very low, with a reported rate of 0.17% to 2%; the prognosis is usually poor.2Y5 Common symptoms and preoperative findings in cases of malignancy arising from and MCT are abdominal pain,3,6,7 mass greater than 9.9 cm,7,8 constipation, vaginal bleeding, weight loss, urinary frequency, and fever.3Y5,7,9 More than 80% of cases of malignancy arising from an MCTare thought to be squamous cell carcinoma (SCC).2 Adenocarcinoma, carcinoid tumor, melanoma, and other tumors have also been reported.2,3,8Y10 Identification of the clinical, pathologic, and radiographic characteristics of malignancy arising from an MCT remains key to early detection. Because of the rarity of this entity, guidance for optimal management is lacking. In this report, we describe the institutional experience with this rare entity and summarize the existing literature. It is often impossible to distinguish malignant transformation from de novo coexisting disease arising within an MCT. For this reason, in much of the existing literature as well as the present article, these terms are used interchangeably.
METHODS Approval for the study was obtained from the institutional review board. Single-institution retrospective chart review was completed to identify all cases of malignancy arising from an MCT of the ovary diagnosed from 2004 to 2014 at Yale University hospitals. Clinical information was obtained from the medical records and pathology reports. Surgical staging in most cases included hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and pelvic and para-aortic lymphadenectomy. Surgical stage was reported using the 1988 International Federation of Gynecology and Obstetrics staging system.11 Multiple variables were examined including age, presenting symptoms, procedure performed, residual disease after cytoreductive surgery, surgical stage, histologic type, date of recurrence, adjuvant chemotherapy regimen, and whether or not there was death secondary to disease. Survival time was measured as time from the initial diagnosis to the time of death or last contact. Statistical analyses were computed using GraphPad Prism version 6 (GraphPad Software, San Diego CA).
Ovarian Cancers Arising From Within MCTs
the time of presentation, all of the patients reported abdominal pain and bloating. Available imaging revealed masses with both solid and cystic components in all cases (Fig. 1). Of the patients who presented with symptoms, only 1 (11.1%) had a known MCT; the remainder were new presentations. Finally, none of the patients had a prior surgical procedure for an MCT. All patients went to the operating room and had surgical resection. Eight patients (88.8%) had frozen sections completed at the time of surgery. All of these (100%) successfully identified malignancy within the MCT. Most (88.8%) of patients underwent complete surgical staging (total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymph node dissection, and omentectomy) after an intraoperative frozen section diagnosis confirming malignancy (Table 1). On final pathology, 4 (44.4%) of the 9 cases were identified as mucinous adenocarcinoma, 2 as carcinoid tumor (22.2%), and 1 case each of malignant melanoma (11.1%), SCC (11.1%), and poorly differentiated adenocarcinoma (11.1%). In one case, surgical staging was not completed. In this case, the malignant component was a carcinoid tumor, which typically does not need to be surgically staged and the patient also desired fertility preservation. The second carcinoid was completely staged as it exhibited an insular morphologic pattern with variable lumen formation, features that can be associated with more malignant behavior. Approximately 33% of the cases were at least surgical stage IIIC at the time of presentation, whereas the remainder were stage IC or lower. The average tumor size was 18.0 cm (range, 7-29 cm). Both carcinoid tumors were smaller than the other tumors, each being 7 cm. The next closest tumor size was 18 cm (Table 1). On immunohistochemistry, all of the mucinous tumors stained positive for CK20 and CDX2, and MUC2 immunostains
RESULTS Between 2004 and 2014, there were 9 (1.2%) of 729 mature teratoma specimens that exhibited a malignant component. The average age at presentation was 53.7 years (range, 22-74 years). In terms of racial demographics, 66% of the patients were white and the remainder were African American. At
FIGURE 1. Malignant melanoma: solid component (white arrow) and mural thickening (red arrow) worrisome for malignant transformation.
* 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
793
794
IIIC
IA
IC
IA
IIIC
IIIC
Unstaged
IA
IA
65
40
74
70
45
58
22
50
59
7
20
7
20
29
18
29
19
20
Tumor Size, cm Frozen Section
LSO, PPaLND, infracolic omentectomy TAH, BSO, PLND, omentectomy
None
Carboplatinum/Paclitaxel 4 cycles, then cisplatinum/ifosfamide FOLFOX 10 cycles
None
FOLFOX 6 cycles
Adjuvant Treatment
Mucinous adenocarcinoma Gemcitabine and oxaliplatin 1 cycle Carcinoid None
Malignant melanoma
Mucinous adenocarcinoma
SCC
Mucinous borderline
Mucinous adenocarcinoma
Pathology
Mucinous tumor, probably Mucinous adenocarcinoma None borderline, in association with teratoma Favor sex cord stromal Carcinoid None tumor
TAH, BSO, PPaLND, Adenocarcinoma, favor appendectomy, mucinous omentectomy adenocarcinoma TAH, BSO, PPaLND, Melanoma arising in omentectomy teratoma, lymph node positive for melanoma TAH, BSO, Mucinous adenocarcinoma omentectomy LSO No frozen completed
TAH, BSO, PPaLND, Adenocarcinoma, favor appendectomy, endometrioid omentectomy TAH, BSO, PPaLND, Mucinous borderline appendectomy, omentectomy TAH, BSO, PPaLND, Malignant neoplasm omentectomy
Surgery
1
21
18
1
18
13
7
42
68
Alive
Alive
Alive
Dead
Dead
Alive
Dead
Alive
Alive
Follow-Up, Disease mo Status
International Journal of Gynecological Cancer
BSO, bilateral salpingoophorectomy; FOLFOX, folinic acid, fluorouracil, oxaliplatin; LSO, left salpingoophorectomy; PPaLND, pelvic and para-aortic lymph node dissection; TAH, total abdominal hystrectomy.
Stage
Age, y
TABLE 1. Demographics and patient characteristics
Black et al
& Volume 25, Number 5, June 2015
* 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
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& Volume 25, Number 5, June 2015
when it was evaluated. Half of the mucinous tumors also stained positive for CK7. The carcinoid tumors stained positive for chromogranin and synaptophysin (Fig. 2). One (11.1%) patient with mucinous adenocarcinoma had an elevated serum CA-125 and CA 19-1 levels of 665 U/mL and 205 ng/mL, respectively. Four patients (44.4%) received adjuvant chemotherapy. Two of the patients died within 6 months of initiation of treatment. One of them had stage IC poorly differentiated SCC and had received carboplatinum plus paclitaxel for 4 cycles, continued to exhibit progression of disease, and then received 1 cycle of cisplatinum plus ifosfamide before care was withdrawn. The other patient who died had stage IIIC mucinous adenocarcinoma with residual disease after staging; she received gemcitabine plus oxaliplatin for 1 cycle before care was withdrawn. Another patient was staged in 2009 as IIIC mucinous adenocarcinoma with no residual disease. She received folinic acid, fluorouracil, oxaliplatin (FOLFOX)-4 for 6 cycles and has had a disease-free interval of 68 months. The fourth patient who received chemotherapy was staged at IA mucinous adenocarcinoma in 2012, received 10 cycles of FOLFOX-4 adjuvant chemotherapy, and is currently disease-free. Mean and median follow-up times were 23 and 18 months, respectively. There was 1 case of recurrence in a patient with malignant melanoma arising from within an MCT, which occurred 328 days after the initial diagnosis.
DISCUSSION A large ovarian mass that is suspected to be a mature teratoma should be surgically excised in older patients. Our
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data confirm that although a malignancy within an MCT is rare, it is more likely in older, white patients. Previous studies report that suspicion for malignancy should be raised when an MCT is larger than 9.9 cm.7,8 Our average tumor size was slightly larger (18 cm). In addition, any imaging that identifies mixed solid and cystic components should heighten concern. The sonographic appearance of MCT is quite variable,12 whereas they are readily diagnosed on magnetic resonance imaging, despite complications such as hemorrhage or torsion.13,14 Gross fat has a characteristic appearance on magnetic resonance imaging and computed tomography, although computed tomography is far less accurate in the differential diagnosis of an adnexal mass.15 Rarely, MCT may exhibit little identifiable fat but can show signal behavior indicative of MCT.16,17 Immature teratomas are easily distinguished from MCT because they are solid masses with small irregular foci of fat and calcification16 and MCTwith a malignant component is typically a mass with the appearance of a cystic teratoma but a significant solid component. In one series,18 5 of 6 tumors had an obvious solid component that was relatively large. Four of the 5 solid components exhibited transmural extension. Squamous cell carcinoma tended to extend along the capsule through the cyst wall and directly invaded the surrounding organs. In 43 cases of MCT,19 2 exhibited obvious malignant components manifested by the MCT containing a solid mass greater than 5 cm, with an irregular border forming an obtuse angle with the inner wall of the cyst and contrast uptake in 1 case. The solid component in MCTs with a malignant component appears different from the frequently present frond-like, benign solid component in an MCT called the Rokitansky
FIGURE 2. Representative microscopic images of malignancy arising in MCTs (all hematoxylin and eosin stained, original magnification 40). A, Mucinous adenocarcinoma (arrow indicates cyst lining). B, Carcinoid tumor. C, SCC. D. Malignant melanoma (arrow indicates cyst lining). * 2015 IGCS and ESGO
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protuberance or dermoid plug. Gadolinium enhancement within the MCT should raise the possibility of malignancy.20 Although a frozen section is not the gold standard for patients undergoing a routine procedure for an MCT, it is a valuable tool and should be strongly considered if the patient or tumor exhibit any of the characteristics discussed above. In our series, a malignant component within an MCT was diagnosed on frozen section in 100% of cases. All of those patients subsequently underwent complete surgical staging. Thus, completing a frozen section allowed these patients to avoid a second procedure, one which would have been necessary if the surgeons had forgone a frozen section and sent the specimen for permanent section alone. Although existing literature reports that up to 80% of malignancies arising from MCTs are SCC,2 our data suggest a higher incidence of transformation, approximately 50%, to mucinous adenocarcinoma of the ovary. This is significant clinically because if identified by frozen section, an appendectomy would be completed as part of surgical staging, whereas it would not be necessary with other types of malignancy. Furthermore, close attention should be paid to MCTs that are thought to exhibit a carcinoid tumor as the malignant component. Although patients with carcinoid tumors do not need to be fully staged, some carcinoid tumors can exhibit an insular morphology and these tumors have a higher likelihood of exhibiting malignant behavior and are associated with carcinoid syndrome.21 Up to 25% of insular carcinoids arising from an MCT can exhibit carcinoid syndrome.22 Thus, in the case of an insular carcinoid, complete surgical staging should be completed, as it was in our patients’ case. Like most ovarian cancers, these malignancies most often present at later stages and can be difficult to treat. Our data suggest that optimal tumor debulking and adjuvant chemotherapy with FOLFOX could benefit patients who have mucinous adenocarcinoma as the malignant component of an MCT. This is consistent with preclinical data in mucinous ovarian cancer cell lines and xenografts.23,24 In this series, FOLFOX was only used with mucinous histologies; therefore, the role of FOLFOX in treating other histologic subtypes of malignancy arising from an MCT is unknown and further research is needed. FOLFOX-4 has shown activity in platinum/ taxane-resistant heavily pretreated ovarian cancers across serous, mucinous, endometrioid, clear cell, and undifferentiated histologies.25Y27 It is unclear what role, if any, radiation plays in the management of these tumors. In conclusion, an ovarian mass that has characteristics of an MCT in a patient older than 40 years, especially when the mass is larger than 18 cm, is newly identified, and/or has mixed solid and cystic components, should raise suspicion for malignancy. In such instances, preoperative imaging and tumor markers can be considered. This additional information can aid in counseling and perioperative management. Intraoperative frozen sections should be scrutinized in these cases so that proper staging can be completed as necessary.
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