A Glint of Hope for Treatment of Advanced Malignant Transformations of Ovarian Mature Cystic Teratomas: A Retrospective Analysis of 9 Cases

Abstract

Objective:

Malignant transformation of a mature cystic teratoma (MTMCT) of the ovary is extremely rare; the occurrence rate is ∼1%–3% of all mature cystic teratomas. Because of the rarity of MTMCT, there are many unknown aspects of its clinical findings, treatment, and prognosis. Prognosis for MTMCT is reportedly worse than that of epithelial ovarian cancer. A retrospective study was performed with 9 patients in the Gynecology Service, of the National Kyushu Cancer Center, in Fukuoka, Japan, to explore MTMCT's clinical findings and prognosis.

Materials and Methods:

This was a retrospective study of nine cases of MTMCT treated in the hospital from January 2000 to December 2017.

Results:

The median age of the 9 patients was 65. The median survival time was 20.5 months (range: 11–127 months). Among the patients, 5 (55.5%) were determined to have advanced stage III or IV MTMCT. All patients underwent hysterectomy with bilateral salpingo-oophorectomy and omentectomy. Five patients (55.5%) underwent more-extended debulking surgery, including intestinal-tract and ureter resection. All patients received postoperative adjuvant treatments. Unexpectedly, however, 3 of 5 patients with advanced disease (stage III/IV) survived for more than 5 years. None of the surviving patients developed recurrences after the initial treatment.

Conclusions:

MTMCT is a malignant disease with a poor prognosis even in the early stage. However, some patients with advanced MTMCT can have long-term survival even with poor prognostic factors, such as lymph-node metastases and intestinal invasions. The prognosis may be improved by performing maximal tumor reduction and appropriate adjuvant therapy. (J GYNECOL SURG 36:184)

Introduction

Mature cystic teratoma (MCT) of the ovary is the most-common benign tumor among ovarian germ-cell tumors. It comprises ∼10%–20% of all ovarian tumors. In contrast, malignant transformation of mature cystic teratoma (MTMCT) of the ovary is extremely rare, and its frequency is ∼1%–3% of all MCTs.^1–3 Various reports have described the clinical findings, treatment, and prognosis of this tumor, but, because of its rarity, there are still many unknown aspects. MTMCT is generally thought to have highly malignant potential and to be resistant to any postoperative adjuvant treatment. Additionally, the prognosis of MTMCT has been considered to be worse than that of epithelial ovarian cancer. Many patients die within 1 year after the diagnosis.^2,3 In 1 report, the 5-year survival rate was 48.4% overall and 75.7% for stage I cancer, 33.8% for stage II, 20.6% for stage III, and 0.0% for stage IV, indicating that cure can be expected only in the early stages.²

The current authors studied 9 patients with MTMCT of the ovary retrospectively to investigate their clinical findings and prognoses. Three patients with advanced MTMCT of the ovary had long-term survival, and the factors associated with the good prognoses of these 3 patients are discussed in this article.

Materials and Methods

From January 2000 to December 2017, 528 patients with ovarian cancer were registered and treated at the Gynecology Service, of the National Kyushu Cancer Center, in Fukuoka, Japan,. Nine patients were diagnosed with MTMCT. The clinical records of these 9 patients were evaluated retrospectively with respect to ages, symptoms, maximum sizes of their masses, surgical procedures, operative findings (dissemination and residual tumors), ascites cytology, clinical stages, histologies, adjuvant treatments, and outcomes. Surgical staging was performed using the 2014 International Federation of Gynecology and Obstetrics (FIGO) classification system.

Results

A total of 528 patients were diagnosed with ovarian cancer from January 2000 to December 2017, and MTMCT was noted in 9 patients (1.7%). The characteristics of these 9 patients and their tumors are shown in Table 1. The median age of the 9 patients was 65 (range: ages 37–69). All patients underwent primary debulking surgery. The median tumor size was 10 cm (range: 8–20 cm), and all patients had tumor sizes >8 cm. The median survival time was 20.5 months (range: 11–127 months). Almost all patients presented with abdominal pain. The clinical characteristics of the 9 patients are shown in Table 2. FIGO stage was determined in all patients; only 1patient was classified as having stage I cancer, while 5 patients (55.5%) had stage III or IV cancers.

Table 1.

Patients and tumor characteristics (N = 9)

Characteristics	n, median (range)	%
Age, years	65 (37–69)
Survival, months	20.5 (11–127)
Tumor size, cm	10 (8–20)
Tumor marker
CEA, >5.0 ng/mL	4, 15.2 (5.7–62.4)	44.4
CA125, >35 U/mL	8, 109.5 (64–239)	88.8
CA19-9, >37 U/mL	7, 179 (59–1939)	77.7
SCC, >1.5 ng/mL	6, 42.4 (6.5–132)	66.6
FIGO stage	1	11.1
I	3	33.3
II	3	44.4
III	2	11.1
IV	2	11.1
Histology
SCC	7	77.7
Adenocarcinoma	1	11.1
Chondrosarcoma	1	11.1
Surgical procedure
TAH+BSO	9	100
+OMT+PLND+PALNB	7	77.7
+Intestinal resection	5	55.5
Adjuvant treatment
Chemotherapy	9	100
Radiotherapy	3	33.3
Follow-up from date of surgery (n, mo.)
NED	4, 83(28–127)	44.4
DOD	5, 12(5–13)	55.5

SCC, squamous-cell carcinoma; TAH, total abdominal hysterectomy; BSO, bilateral salpingo-oophorectomy; OMT, omentectomy; PLND, pelvic lymph-node dissection; PALNB, para-aortic lymph node biopsy; mo, months; NED, no evidence of disease; DOD, died of disease.

Table 2.

Clinical Characteristics of 9 Patients

Pt #	Age	FIGO 2014	Histology	Surgical procedure	Ascites cytology	Extra-ovarian disease/dissemination number	Residual disease	Postoperative treatment	Follow-up from date of operation
1	68	IVB	SCC	Standard surgeryIntestinal resection	40 mLNegative	Mucosal invasion of descending colonpara-aortic lymph nodemesenteric lymph node/none	CS	PC8	127 monthsNED
2	69	IIIC	Chondrosarcoma	TAH + BSO+ OMTIntestinal resection	100 mLNegative	Ileal, peritoneal disseminationmesentery dissemination/multiple	OS < 1cm dissemination	DG6	106 monthsNED
3	58	IIIB	SCC	Standard surgery	500 mLNegative	Descending colon serosadissemination/single	CS	PC6	60 monthsNED
4	55	IC	Adenocarcinoma	Standard surgery	NoneNegative	None	CS	PC5	28 monthsNED
5	63	IIB	SCC	Standard surgeryIntestinal resectionUreter resection	Class III	Uretersigmoid colon/none	CS	PC4RT	13 monthsDOD
6	37	IIIC	SCC	Standard surgeryIntestinal resection	600 mLPositive	Rectum, appendixpara-aortic lymph node/none	OS +Pelvic	PC2RT DC4	12 monthsDOD
7	65	IVB	SCC	TAH + BSO + OMTIntestinal resection	10 mLUnknown	Multiple lung metastasis, rectumMesentery lymph node/multiple	SOS +Lung metastasis	PC1BSC	5 monthsDOD
8	62	IIB	SCC	Standard surgery	NoneNegative	Bladder, sigmoid colon/none	SOS +Pelvic	PC6RT	11monthsDOD
9	44	IIB	SCC	Standard surgery	SlightNegative	Vesicouterine excavation dissemination/single	CS	PC5CPT-P+Bev6	13 monthsDOD

FIGO 2014, International Federation of Gynecology and Obstetrics classification system for ovarian cancer 2014; SCC, squamous-cell cancer;

Standard surgery can include: TAH, total abdominal hysterectomy; + BSO, bilateral salpingo-oophorectomy; + OMT, omentectomy; + PLND , pelvic lymph-node dissection; + PALNB, para-aortic lymph node biopsy.

Treatment regimens can include: PC, paclitaxel–carboplatin regimen; DC, docetaxel–carboplatin regimen; DG, docetaxel–gemcitabine regimen; RT, radiation therapy; BSC, best supportive care.

Surgical types can include: CS, complete surgery; OS, optimal surgery; SOS, suboptimal surgery.

Outcomes can include: NED, no evidence of disease; DOD: died of disease.

All patients underwent hysterectomy with bilateral salpingo-oophorectomy and omentectomy. Seven patients (77.7%) underwent pelvic lymph-node dissection (PLND) and para-aortic lymph-node biopsy. Five patients (55.5%) underwent more-extended debulking surgery, including intestinal-tract and ureter resection. One of 5 patients had mucosal invasion of the descending colon and was restaged from IIIC to IVB (FIGO 2014). Three patients (33.3%) had intraperitoneal dissemination, and 2 had macroscopic residual tumors of <1 cm. The pathologic findings were squamous-cell carcinoma (SCC) in 7 patients, adenocarcinoma in 1, and chondrosarcoma in 1.

Adjuvant therapy involving a combination of cytotoxic drugs with or without radiation was given to all patients. All patients except the 1 with chondrosarcoma received a paclitaxel and carboplatin (PC) regimen. A gemcitabine–docetaxel regimen was chosen for the patient with chondrosarcoma. Radiotherapy was performed for patients who had worsening during chemotherapy.

Five patients (55.5%) died of MTMCT and 4 (44.4%) survived. All deaths occurred within 13 months after surgery. No patients underwent secondary debulking surgery. None of the patients who survived developed recurrences after the initial treatment. Three of 5 patients with advanced disease (stage III/IV) survived for more than 5 years, and their details are described below.

Patient 1

Patient 1 was a 68-year-old woman. A laparotomy was performed; it revealed a huge left-ovarian tumor measuring 20 cm in diameter. This tumor had become fixed to the descending colon and peritoneum. The tumor was lifted to the upper abdominal space. Approximately 30–40 mL of bloody ascites was present, but the cytology was negative for malignancy. The tumor was free of surface invasion and rupture, and no intraperitoneal dissemination was present. The para-aortic lymph nodes around the left renal vein were swollen to 5 cm in diameter. No swelling of the pelvic lymph nodes was present. The current authors performed a total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, appendectomy, para-aortic lymph node dissection, and descending colectomy. The tumor was removed without rupture; the enlarged para-aortic lymph nodes were also removed completely. No macroscopic residual lesions were present.

Histologically, the mesenteric lymph nodes and para-aortic lymph nodes were affected by metastasis, and the mucosa of the descending colon had been destroyed and replaced by SCC. The postoperative clinical diagnosis was stage IVB MTMCT according to the FIGO 2014 classification. The patient received 8 cycles of PC as adjuvant chemotherapy, was followed up for more than 10 years, and was alive without disease 127 months after the last treatment.

Patient 2

Patient 2 was a 69-year-old woman. She had a huge right-ovarian tumor measuring 18 cm in diameter, and this tumor had adhered to the ileum, omentum, and peritoneum. Disseminations of 1–2 cm were present on the mesentery, serosa of the ileum, and entire peritoneum. Approximately 100 mL of ascites was present, but the cytology was negative for malignancy. The current authors performed a total abdominal hysterectomy, bilateral oophorectomy, omentectomy, and partial ileum resection. The huge tumor was completely removed with <1 cm of residual dissemination, achieving optimal surgery.

The histologic diagnosis was chondrosarcoma of MTMCT, stage IIIC. The patient received 6 cycles of the gemcitabine–docetaxel regimen and was free of recurrence for 106 months after the last treatment.

Patient 3

Patient 3 was a 58-year-old woman. She had a left-ovarian tumor measuring 8 cm in diameter, and the tumor had adhered to the pelvic peritoneum. Disseminations of 5 mm were present on the descending colon serosa. Approximately 500 mL of ascites was present, but the cytology was negative for malignancy. The current authors performed a total abdominal hysterectomy, bilateral oophorectomy, omentectomy, PLND, and para-aortic lymph-node biopsy. No macroscopic residual tumors were present, achieving complete surgery.

The histologic diagnosis was SCC of MTMCT, stage IIIB. She received 6 cycles of the PC regimen and had no signs of recurrence 60 months after the last treatment.

Discussion

Because of the rarity of MTMCT, there are many unknown aspects regarding its clinical findings, treatment, and prognosis.^1–3 MTMCT typically occurs in postmenopausal women, and the major clinical symptoms are abdominal pain and distention. Tumors are usually large, and 78.7% of them have been reported to measure ≥10 cm.² MTMCT also often contains necrosis and hemorrhage and undergoes rapid growth. Malignancy can develop from each of the three germ cell layers; thus, adenocarcinomas, carcinoid tumors, melanomas, and sarcomas have been reported. However, the most common histology is SCC, which accounts for 80% of these tumors.^2,3 Initial treatments are often performed according to the epithelial ovarian cancer and include surgical treatment and adjuvant platinum-based chemotherapy. However, adjuvant therapy for MTMCT has not been established because the disease is rare and no large clinical trials have been performed.

In general, the prognosis of MTMCT has been considered to be worse than that of epithelial ovarian cancer. Many patients die within 1 year after the diagnosis.^2,3 Hackethal et al.¹ reported that the prognosis of MTMCT is poor and depends on the stage of the disease, with a 5-year survival rate of 95% for stage I, 80% for stage II, and 0% for stage III/IV.¹ Another review showed that the 5-year survival rate was 48.4% overall, 75.7% for stage I, 33.8% for stage II, 20.6% for stage III, and 0.0% for stage IV, indicating that cure can only be expected in the early stages.²

Prognostic risk factors, such as age, tumor size, and tumor markers, have been studied but are still controversial.^1–4 Hackethal et al.¹ reported that there is an important prognostic difference between stage I and stages II–IV, and other factors that might have an impact on the prognosis are capsular invasion, ascites, rupture or spillage, adhesions, and the surgical procedure performed. Tseng et al.⁵ reported that the ability to achieve optimal cytoreduction was associated with a statistically significant improvement in survival.

Several of the 9 patients studied had poor prognostic risk factors identified in other studies, and the patients with invasive and progressive disease required additional resection of surrounding organs. According to previous reports, the current authors expected that the prognosis of these patients would be very poor; however, 44.4% (4 of 9 patients) remained alive without recurrence after their initial treatments. All 3 patients with stage II intrapelvic disease died within 13 months, showing that this disease is very aggressive with a poor prognosis. However, 3 patients remained alive for a long period of time with advanced stage III/IV disease.

One patient had transmucosal colon invasion and para-aortic lymph node metastasis. Although this was an extremely invasive case of MTMCT, the current authors performed para-aortic lymphadenectomy and descending colon colectomy in addition to the standard operation, followed by adjuvant chemotherapy, and this patient remained alive without recurrence for more than 10 years. This patient had all risk factors for a poor prognosis including high age, large tumor size, complete intestinal invasion, and lymph-node metastasis. The intraperitoneal findings also suggested a very aggressive tumor, but long-term survival was obtained without recurrence after treatment.

The other 2 patients had intraperitoneal and mesentery dissemination, lymph-node metastasis, and adhesion around the peritoneum. The postoperative clinical diagnosis was stage III, and optimal cytoreduction surgery was performed. Postoperative chemotherapy was selected according to the epithelial ovarian cancer, except for the patient with chondrosarcoma. Such patients as the others may benefit from resection of all gross disease followed by the PC regimen.

The present study showed no clear difference between patients with poor prognoses and those with good prognoses. However, the ascites cytology was negative in all patients with good prognoses. Additionally, intestinal resection was performed to prevent residual lesions in 55.5% (5 of 9 patients).

Conclusions

It might be possible to achieve a good long-term prognosis by performing maximal cytoreductive surgery and adjuvant chemotherapy even in patients with severe progression and invasion to other organs. This study suggests that some MTMCTs might be cured by continuing treatment efforts. Accumulation of additional cases in multi-institutional clinical trials is warranted in the future.

Footnotes

Acknowledgments

The authors thank Angela Morben, DVM, ELS, from the Edanz Group, for editing a draft of this article.

Author Disclosure Statement

No financial conflicts of interest exist.

Funding Information

No funding was received for this article.

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