- Email: [email protected]
Growing Teratoma Syndrome: First Case Report in a 4-Year-Old Girl
Accepted Manuscript Growing Teratoma Syndrome: First Case Report in a four-year-old girl Paul Daher, Edward Riachy, Antoine Khoury, Lara Raffoul, Claude Sader-Ghorra, Caline Rehayem PII:
S1083-3188(14)00165-X
DOI:
10.1016/j.jpag.2014.03.003
Reference:
PEDADO 1706
To appear in:
Journal of Pediatric and Adolescent Gynecology
Received Date: 11 October 2013 Revised Date:
14 February 2014
Accepted Date: 18 March 2014
Please cite this article as: Daher P, Riachy E, Khoury A, Raffoul L, Sader-Ghorra C, Rehayem C, Growing Teratoma Syndrome: First Case Report in a four-year-old girl, Journal of Pediatric and Adolescent Gynecology (2014), doi: 10.1016/j.jpag.2014.03.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Growing Teratoma Syndrome: First Case Report in a four-yearold girl
RI PT
Paul Daher, Edward Riachy, Antoine Khoury, Lara Raffoul, Claude Sader-
M AN U
Paul Daher, MD, PhD Head of Department of Pediatric Surgery Hotel-Dieu de France University Hospital Boulevard Alfred Naccache, Achrafieh, PO Box: 16- 6830 Beirut, Lebanon E-mail: [email protected]
SC
Ghorra, Caline Rehayem
TE D
Edward Riachy, MD (Corresponding author) Department of Pediatric Surgery Hotel-Dieu de France University Hospital Boulevard Alfred Naccache, Achrafieh, PO Box: 16- 6830 Beirut, Lebanon E-mail: [email protected] Tel: +961-78-890808
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EP
Antoine Khoury, MD Department of Pediatric Surgery Hotel-Dieu de France University Hospital Boulevard Alfred Naccache, Achrafieh, PO Box: 16- 6830 Beirut, Lebanon E-mail: [email protected] Lara Raffoul, MD Department of Pediatric Surgery Hotel-Dieu de France University Hospital Boulevard Alfred Naccache, Achrafieh, PO Box: 16- 6830 Beirut, Lebanon E-mail: [email protected]
ACCEPTED MANUSCRIPT
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EP
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SC
M AN U
Caline Rehayem, MD Department of Pathology Hotel-Dieu de France University Hospital Boulevard Alfred Naccache, Achrafieh, PO Box: 16- 6830 Beirut, Lebanon E-mail: [email protected]
RI PT
Claude Sader-Ghorra, MD Department of Pathology Hotel-Dieu de France University Hospital Boulevard Alfred Naccache, Achrafieh, PO Box: 16- 6830 Beirut, Lebanon E-mail: [email protected]
ACCEPTED MANUSCRIPT
Growing Teratoma Syndrome: First Case Report in a four-year-old girl Paul Daher, Edward Riachy, Antoine Khoury, Lara Raffoul, Claude Ghorra, Caline
RI PT
Rehayem
SC
ABSTRACT
Growing teratoma syndrome (GTS) consists of germ cell tumors that grow following
M AN U
chemotherapy despite complete eradication of the malignant cells. They can metastasize to any site, particularly the retroperitoneum, mediastinum and cervical region. It typically affects young adults and adolescents. Here we describe the youngest case reported in a 4-year-old girl with an ovarian mixed germ cell tumor who underwent an oophorectomy. Her tumor markers normalized by the end of her chemotherapeutic
TE D
treatment; however, she developed a retroperitoneal mass that was subsequently resected. Histopathology revealed a mature teratoma, consisting of a GTS. We stress
EP
the need for early recognition and treatment of GTS to avoid the subsequent morbidity and mortality associated with it. Although GTS has an excellent prognosis when
AC C
completely resected, it is essential that the patient be regulary followed-up with serum tumor markers and imaging.
ACCEPTED MANUSCRIPT
INTRODUCTION
RI PT
In 1977, DiSaia was the first to publish three cases of “Chemotherapeutic Retroconversion" in which benign distant metastasis appeared following adjuvant chemotherapy for immature teratoma of the ovary (1). However, the term "Growing
SC
Teratoma Syndrome" (GTS) was first coined by Logothetis in 1982 when he described six patients with non-seminomatous germ cell tumors who subsequently presented with
M AN U
enlarging metastatic masses despite appropriate systemic chemotherapy and normalized serum markers. Their histopathology consisted of benign mature teratoma with no viable germ cell elements (2). These two phenomena are in fact the same entity whereby germ cell tumors enlarge after chemotherapy despite complete eradication of
TE D
viable malignant cells and normalization of serum tumor markers (3,4). Because mature teratoma is resistant to both chemotherapy and radiotherapy, a complete resection is warranted in order to prevent progression and offer a better prognosis (5). We herein
AC C
CASE
EP
report the youngest case described in a four-year-old girl presenting with GTS.
A 4-year-old girl presented with a one-month history of vomiting along with gradually increasing abdominal girth. Her physical examination was positive for a firm, distended abdomen with a large palpable pelvic mass. Laboratory tests were normal, except for elevated alpha-fetoprotein (AFP) and human chorionic gonadotrophin (B-HCG). An abdominal ultrasound identified the mass in the lower abdomen and pelvis. A following abdominal CT scan revealed the mass to be retro-peritoneal, but could not determine its
ACCEPTED MANUSCRIPT
origin (Figure 1). At exploratory laparotomy, a left ovarian multilobulated mass of cystic and solid nature measuring 17x12x7 cm was completely resected, along with several suspicious nodules resected within the omentum. The liver, contralateral ovary, retro-
RI PT
peritoneal and pelvic lymph nodes were inspected and no suspicious lesions were found nor biopsied. The final pathologic diagnosis was grade III malignant germ-cell tumor composed of yolk-sac tumor mixed with dysgerminoma and teratomatous
SC
elements.
M AN U
Tumor markers level normalized in the following month. Four months later, the patient had a lower abdominal discomfort with radiological recurrence of the abdominal mass. Tumor markers were again elevated, so she was started on a chemotherapy regimen based on etoposide, ifosfamide, and cisplatin. The patient remained asymptomatic during the first month, with normal serum tumor markers. However, a CT scan identified
TE D
a new perihepatic mass on the right side of the liver with extension throughout the inferior vena cava. Three months later, at the completion of her chemotherapy, a control CT scan showed a right sub-phrenic mass, along with supra-umbilical left para-median
exploratory
laparotomy
showed
multiple
implants
studding
the
right
AC C
second
EP
mass with possible peritoneal involvement. Serum tumor markers were still normal. A
subdiaphragmatic space, the omentum, the appendix, the broad ligament and the abdominal wall. The lesions were all removed and sampled for pathologic examination. Histopathology demonstrated mature teratoma of the ovary without a malignant component. The patient was discharged home and continued to do well. She was followed with serum tumor markers which remained normal, along with surveillance abdominal ultrasound. Seven months later, she complained of vague abdominal pain. Physical examination was non-significant and serum tumor markers were normal.
ACCEPTED MANUSCRIPT
Abdominal ultrasound showed an echogenic and cystic abdominal mass in the right upper quadrant, while the abdominal CT scan revealed multiple new masses containing cystic and necrotic elements surrounding the liver and extending throughout internal
RI PT
inguinal orifice (Figure 2). Tumor markers were still normal. A third laparotomy was therefore performed with resection and sampling of the lesions; mature teratoma was confirmed on histopathlogy. She was followed-up regularly with CT scans and serum
SC
tumor markers. Five months later, and at one year and eight months from the time of her initial presentation, she underwent a fourth laparotomy for similar radiological
M AN U
recurrent abdominal masses and a new cystic pelvic lesion. Resection and sampling of the implants and pelvic mass again revealed mature teratoma without malignant elements. Serum markers remained normal. At the time of this report, the patient is a healthy 5-year-old girl who is regularly monitored with abdominal ultrasound and serum
TE D
tumor markers.
SUMMARY
EP
GTS is a rare clinical phenomenon characterized by: (a) a history of a
AC C
nonseminomatous gonadal neoplasm with a teratomatous component in the primary specimen, (b) an elevated serum levels of AFP, β-hCG and /or LDH with radiologic evidence of metastatic disease, (c) a normalization of biomarkers after chemotherapy, (d) an enlargement of the metastatic masses despite normal tumor markers during or after chemotherapy, (e) and a mature teratoma in the resected metastatic specimen (6). The mechanism of progression from malignant teratoma to GTS is still uncertain. An intriguing question is whether differentiation is induced by chemotherapy or whether
ACCEPTED MANUSCRIPT
chemotherapy eradicates undifferentiated elements leaving behind pre-existing resistant benign structures (7,8).
RI PT
While GTS of the gonads has been reported in over 50 males, it is much less common in females (9). To the best of our knowledge, only 16 cases have been previously described in the ovary (3,8,10-12). Most women were either young adults or
SC
adolescents, but only two were 5 years of age (9,11), making our case the youngest case to be reported.
M AN U
The presence of an enlarging new mass after chemotherapy for malignant teratoma usually indicates recurrence or progression of malignancy, but this is not always necessary (12). GTS should also be considered in such presentation, particularly if associated with normal serum tumor markers during or after chemotherapy
TE D
(5). The GTS nodules can appear anywhere from the commencement of chemotherapy, and in some cases delayed up to 8 years, with an average interval of 8 months (13). It occurs most commonly in the retroperitoneum, followed by the lung, cervical lymph
EP
nodes, and mediastinum (10).
Although those lesions are histologically benign, their invasive growth and
AC C
aggressive local expansion can cause substantial morbidity and mortality if not surgically resected in a timely manner (2). Other indications for resection are to diminish the chances of degeneration of mature teratoma into undifferentiated tumor components and to rule out secondary malignancies that can be induced by previous chemotherapy (13,14). In some cases, multiple operations may be nesessary (12,13). Our patient needed three separate interventions in addition to her first surgery. It is imperative to perform an adequate and total resection because GTS can have a high recurrence rate
ACCEPTED MANUSCRIPT
of 72-83% in patients with partial resections versus 0-4% in those who undergo complete resections (15). With a 5-year overall survival rate of 89% in patients who
RI PT
undergo surgery, GTS has an overall good prognosis (16). Some medical therapies may play a role in reducing the size and alleviating surgical dissections (17). Interferon-α has been successfully used in unresectable tumors to stop their growth for a prolonged period of time (18-20). The administration of
SC
the humanized monoclonal antibody, Bevacizumab, also provided significant clinical
M AN U
improvement as well as growth stability of a partially resected mass (21). In a promising phase 1 trial with Palbociclib (PD-0332991), an oral and selective inhibitor of cyclin dependent kinases (CDK) 4 and 6, the disease was stabilized in three men not amenable to further surgery (22).
TE D
Regular follow-up imaging of patients with GTS is essential (17). MR imaging and CT are the preferred modalities (23). CT scan may show a low-density cystic lesion or an increase in the cystic component of the mass suggestive of teratomatous element
EP
(24). Ultrasound surveillance is made difficult by the variable appearance of these lesions and it is also less sensitive for fat than other modalities (25); but it is not
AC C
irradiating and more practical in experienced hands. More recently, 3D ultrasound has been advocated to be as sensitive as CT scan for the differential diagnosis, especially when combined with color flow Doppler scanning (26). In all cases, a rapid growth rate in the presence of normalized serum tumor markers should raise suspicion of GTS (15).
CONCLUSION
ACCEPTED MANUSCRIPT
Clinicians and radiologists should be aware of the potential occurence of GTS during or after successful chemotherapeutic treatment of germ cell tumors. GTS tumors do not respond to either chemotherapy or radiotherapy. Histological analysis of the
RI PT
specimen usually detects only mature teratoma, without active tumor evidence. Surgical exploration and complete resection is the only curative treatment. Although GTS has an excellent prognosis, regular follow-up with serum tumor markers as well as imaging is
SC
critical as very late malignant masses do occur in some patients.
M AN U
REFERENCES
DiSaia PJ, Saltz A, Kagan AR, et al. Chemotherapeutic retroconversion of immature teratoma of the ovary. Obstet Gynecol. 1977;49(3):346–350.
2.
Logothetis CJ, Samuels ML, Trindade A, et al. The growing teratoma syndrome. Cancer. 1982;50(8):1629–1635.
3.
Amsalem H. Growing teratoma syndrome vs. chemotherapeutic retroconversion Case report and review of the literature. Gynecol Oncol. 2004;92(1):357–360.
4.
Afifi HY, Bosl GJ, Burt ME. Mediastinal growing teratoma syndrome. Ann Thorac Surg. 1997;64(2):359–362.
5.
Kampan N, Irianta T, Djuana A, et al. Growing teratoma syndrome: a rare case report and review of the literature. Case Rep Obstet Gynecol. 2012;2012:134032.
6.
Feber KM, Soderdahl DW, Hansberry KL. The growing teratoma syndrome: an unusual case. Br J Urol. 1998;81(4):648.
7.
Tait D, Peckham MJ, Hendry WF, et al. Post-chemotherapy surgery in advanced non-seminomatous germ-cell testicular tumours: the significance of histology with particular reference to differentiated (mature) teratoma. Br J Cancer. 1984;50(5):601–609.
8.
Itani Y, Kawa M, Toyoda S, et al. Growing teratoma syndrome after chemotherapy for a mixed germ cell tumor of the ovary. J Obstet Gynaecol Res. 2002;28(3):166–171.
9.
Tangjitgamol S, Manusirivithaya S, Leelahakorn S, et al. The growing teratoma syndrome: a case report and a review of the literature. Int J Gynecol Cancer. 2006;16 Suppl 1:384–390.
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EP
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1.
ACCEPTED MANUSCRIPT
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(3):395– 399.
11.
Inaoka T, Takahashi K, Yamada T, et al. The growing teratoma syndrome secondary to immature teratoma of the ovary. Eur Radiol. 2003;13(9):2115–2118.
12.
Geisler JP, Goulet R, Foster RS, et al. Growing teratoma syndrome after chemotherapy for germ cell tumors of the ovary. Obstet Gynecol. 1994;84(4 Pt 2):719–721.
13.
Djordjevic B, Euscher ED, Malpica A. Growing teratoma syndrome of the ovary: review of literature and first report of a carcinoid tumor arising in a growing teratoma of the ovary. Am J Surg Pathol. 2007;31(12):1913–1918.
14.
André 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(11):1389– 1394.
15.
Spiess PE, Kassouf W, Brown GA, et al. Surgical management of growing teratoma syndrome: the M. D. Anderson cancer center experience. J Urol. 2007;177(4):1330–4– discussion 1334.
16.
Pisters L, Gorbatiy V, Spiess P. The growing teratoma syndrome: Current review of the literature. Indian J Urol. 2009;25(2):186.
17.
Byrd K, Stany MP, Herbold NC, et al. Growing teratoma syndrome: Brief communication and algorithm for management. Aust N Z J Obstet Gynaecol. 2013;53(3):318–321.
18.
Rustin GJ, Kaye SB, Williams CJ, et al. Response of differentiated but not anaplastic teratoma to interferon. Br J Cancer. 1984;50(5):611.
19.
Inoue M, Hisasue S-I, Nagae M, et al. Interferon-a Treatment for Growing Teratoma Syndrome of the Testis. Case Rep Nephrol Urol. 2013;3(1):40–45.
20.
Postovsky S, Epelbaum M, Itzhak OB, et al. Growing Teratoma syndrome treated by interferon alpha-2beta: case report and literature review. Pediatr Hematol Oncol. 2004;21(1):9–16.
21.
Mego M, Reckova M, Sycova-Mila Z, et al. Bevacizumab in a growing teratoma syndrome. Case report. Ann Oncol. 2007;18(5):962–963.
22.
Vaughn DJ, Flaherty K, Lal P, et al. Treatment of growing teratoma syndrome. N Engl J Med. 2009;360(4):423–424.
23.
Coscojuela P, Llauger J, Perez C, et al. The growing teratoma syndrome: radiologic findings in four cases. Eur J Radiol. 1991;12(2):138–140.
AC C
EP
TE D
M AN U
SC
RI PT
10.
ACCEPTED MANUSCRIPT
Moskovic E, Jobling T, Fisher C, et al. Retroconversion of immature teratoma of the ovary: CT appearances. Clin Radiol. 1991;43(6):402–408.
25.
Outwater EK, Siegelman ES, Hunt JL. Ovarian teratomas: tumor types and imaging characteristics. Radiographics. 2001;21(2):475–490.
26.
Hsieh T-Y, Cheng Y-M, Chang F-M, et al. Growing Teratoma Syndrome: An Asian Woman with Immature Teratoma of Left Ovary After Chemotherapy. Taiwan J Obstet Gynecol. 2009;48(2):186–189.
SC
RI PT
24.
M AN U
FIGURES
Figure 1 - Abdominal CT scan showing an extra-peritoneal mass of unknown origin (*)
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Figure 2 - CT scan revealing multiple new masses containing cystic and necrotic
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EP
elements surrounding the liver.
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EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
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EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S1083-3188(14)00165-X
DOI:
10.1016/j.jpag.2014.03.003
Reference:
PEDADO 1706
To appear in:
Journal of Pediatric and Adolescent Gynecology
Received Date: 11 October 2013 Revised Date:
14 February 2014
Accepted Date: 18 March 2014
Please cite this article as: Daher P, Riachy E, Khoury A, Raffoul L, Sader-Ghorra C, Rehayem C, Growing Teratoma Syndrome: First Case Report in a four-year-old girl, Journal of Pediatric and Adolescent Gynecology (2014), doi: 10.1016/j.jpag.2014.03.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Growing Teratoma Syndrome: First Case Report in a four-yearold girl
RI PT
Paul Daher, Edward Riachy, Antoine Khoury, Lara Raffoul, Claude Sader-
M AN U
Paul Daher, MD, PhD Head of Department of Pediatric Surgery Hotel-Dieu de France University Hospital Boulevard Alfred Naccache, Achrafieh, PO Box: 16- 6830 Beirut, Lebanon E-mail: [email protected]
SC
Ghorra, Caline Rehayem
TE D
Edward Riachy, MD (Corresponding author) Department of Pediatric Surgery Hotel-Dieu de France University Hospital Boulevard Alfred Naccache, Achrafieh, PO Box: 16- 6830 Beirut, Lebanon E-mail: [email protected] Tel: +961-78-890808
AC C
EP
Antoine Khoury, MD Department of Pediatric Surgery Hotel-Dieu de France University Hospital Boulevard Alfred Naccache, Achrafieh, PO Box: 16- 6830 Beirut, Lebanon E-mail: [email protected] Lara Raffoul, MD Department of Pediatric Surgery Hotel-Dieu de France University Hospital Boulevard Alfred Naccache, Achrafieh, PO Box: 16- 6830 Beirut, Lebanon E-mail: [email protected]
ACCEPTED MANUSCRIPT
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EP
TE D
SC
M AN U
Caline Rehayem, MD Department of Pathology Hotel-Dieu de France University Hospital Boulevard Alfred Naccache, Achrafieh, PO Box: 16- 6830 Beirut, Lebanon E-mail: [email protected]
RI PT
Claude Sader-Ghorra, MD Department of Pathology Hotel-Dieu de France University Hospital Boulevard Alfred Naccache, Achrafieh, PO Box: 16- 6830 Beirut, Lebanon E-mail: [email protected]
ACCEPTED MANUSCRIPT
Growing Teratoma Syndrome: First Case Report in a four-year-old girl Paul Daher, Edward Riachy, Antoine Khoury, Lara Raffoul, Claude Ghorra, Caline
RI PT
Rehayem
SC
ABSTRACT
Growing teratoma syndrome (GTS) consists of germ cell tumors that grow following
M AN U
chemotherapy despite complete eradication of the malignant cells. They can metastasize to any site, particularly the retroperitoneum, mediastinum and cervical region. It typically affects young adults and adolescents. Here we describe the youngest case reported in a 4-year-old girl with an ovarian mixed germ cell tumor who underwent an oophorectomy. Her tumor markers normalized by the end of her chemotherapeutic
TE D
treatment; however, she developed a retroperitoneal mass that was subsequently resected. Histopathology revealed a mature teratoma, consisting of a GTS. We stress
EP
the need for early recognition and treatment of GTS to avoid the subsequent morbidity and mortality associated with it. Although GTS has an excellent prognosis when
AC C
completely resected, it is essential that the patient be regulary followed-up with serum tumor markers and imaging.
ACCEPTED MANUSCRIPT
INTRODUCTION
RI PT
In 1977, DiSaia was the first to publish three cases of “Chemotherapeutic Retroconversion" in which benign distant metastasis appeared following adjuvant chemotherapy for immature teratoma of the ovary (1). However, the term "Growing
SC
Teratoma Syndrome" (GTS) was first coined by Logothetis in 1982 when he described six patients with non-seminomatous germ cell tumors who subsequently presented with
M AN U
enlarging metastatic masses despite appropriate systemic chemotherapy and normalized serum markers. Their histopathology consisted of benign mature teratoma with no viable germ cell elements (2). These two phenomena are in fact the same entity whereby germ cell tumors enlarge after chemotherapy despite complete eradication of
TE D
viable malignant cells and normalization of serum tumor markers (3,4). Because mature teratoma is resistant to both chemotherapy and radiotherapy, a complete resection is warranted in order to prevent progression and offer a better prognosis (5). We herein
AC C
CASE
EP
report the youngest case described in a four-year-old girl presenting with GTS.
A 4-year-old girl presented with a one-month history of vomiting along with gradually increasing abdominal girth. Her physical examination was positive for a firm, distended abdomen with a large palpable pelvic mass. Laboratory tests were normal, except for elevated alpha-fetoprotein (AFP) and human chorionic gonadotrophin (B-HCG). An abdominal ultrasound identified the mass in the lower abdomen and pelvis. A following abdominal CT scan revealed the mass to be retro-peritoneal, but could not determine its
ACCEPTED MANUSCRIPT
origin (Figure 1). At exploratory laparotomy, a left ovarian multilobulated mass of cystic and solid nature measuring 17x12x7 cm was completely resected, along with several suspicious nodules resected within the omentum. The liver, contralateral ovary, retro-
RI PT
peritoneal and pelvic lymph nodes were inspected and no suspicious lesions were found nor biopsied. The final pathologic diagnosis was grade III malignant germ-cell tumor composed of yolk-sac tumor mixed with dysgerminoma and teratomatous
SC
elements.
M AN U
Tumor markers level normalized in the following month. Four months later, the patient had a lower abdominal discomfort with radiological recurrence of the abdominal mass. Tumor markers were again elevated, so she was started on a chemotherapy regimen based on etoposide, ifosfamide, and cisplatin. The patient remained asymptomatic during the first month, with normal serum tumor markers. However, a CT scan identified
TE D
a new perihepatic mass on the right side of the liver with extension throughout the inferior vena cava. Three months later, at the completion of her chemotherapy, a control CT scan showed a right sub-phrenic mass, along with supra-umbilical left para-median
exploratory
laparotomy
showed
multiple
implants
studding
the
right
AC C
second
EP
mass with possible peritoneal involvement. Serum tumor markers were still normal. A
subdiaphragmatic space, the omentum, the appendix, the broad ligament and the abdominal wall. The lesions were all removed and sampled for pathologic examination. Histopathology demonstrated mature teratoma of the ovary without a malignant component. The patient was discharged home and continued to do well. She was followed with serum tumor markers which remained normal, along with surveillance abdominal ultrasound. Seven months later, she complained of vague abdominal pain. Physical examination was non-significant and serum tumor markers were normal.
ACCEPTED MANUSCRIPT
Abdominal ultrasound showed an echogenic and cystic abdominal mass in the right upper quadrant, while the abdominal CT scan revealed multiple new masses containing cystic and necrotic elements surrounding the liver and extending throughout internal
RI PT
inguinal orifice (Figure 2). Tumor markers were still normal. A third laparotomy was therefore performed with resection and sampling of the lesions; mature teratoma was confirmed on histopathlogy. She was followed-up regularly with CT scans and serum
SC
tumor markers. Five months later, and at one year and eight months from the time of her initial presentation, she underwent a fourth laparotomy for similar radiological
M AN U
recurrent abdominal masses and a new cystic pelvic lesion. Resection and sampling of the implants and pelvic mass again revealed mature teratoma without malignant elements. Serum markers remained normal. At the time of this report, the patient is a healthy 5-year-old girl who is regularly monitored with abdominal ultrasound and serum
TE D
tumor markers.
SUMMARY
EP
GTS is a rare clinical phenomenon characterized by: (a) a history of a
AC C
nonseminomatous gonadal neoplasm with a teratomatous component in the primary specimen, (b) an elevated serum levels of AFP, β-hCG and /or LDH with radiologic evidence of metastatic disease, (c) a normalization of biomarkers after chemotherapy, (d) an enlargement of the metastatic masses despite normal tumor markers during or after chemotherapy, (e) and a mature teratoma in the resected metastatic specimen (6). The mechanism of progression from malignant teratoma to GTS is still uncertain. An intriguing question is whether differentiation is induced by chemotherapy or whether
ACCEPTED MANUSCRIPT
chemotherapy eradicates undifferentiated elements leaving behind pre-existing resistant benign structures (7,8).
RI PT
While GTS of the gonads has been reported in over 50 males, it is much less common in females (9). To the best of our knowledge, only 16 cases have been previously described in the ovary (3,8,10-12). Most women were either young adults or
SC
adolescents, but only two were 5 years of age (9,11), making our case the youngest case to be reported.
M AN U
The presence of an enlarging new mass after chemotherapy for malignant teratoma usually indicates recurrence or progression of malignancy, but this is not always necessary (12). GTS should also be considered in such presentation, particularly if associated with normal serum tumor markers during or after chemotherapy
TE D
(5). The GTS nodules can appear anywhere from the commencement of chemotherapy, and in some cases delayed up to 8 years, with an average interval of 8 months (13). It occurs most commonly in the retroperitoneum, followed by the lung, cervical lymph
EP
nodes, and mediastinum (10).
Although those lesions are histologically benign, their invasive growth and
AC C
aggressive local expansion can cause substantial morbidity and mortality if not surgically resected in a timely manner (2). Other indications for resection are to diminish the chances of degeneration of mature teratoma into undifferentiated tumor components and to rule out secondary malignancies that can be induced by previous chemotherapy (13,14). In some cases, multiple operations may be nesessary (12,13). Our patient needed three separate interventions in addition to her first surgery. It is imperative to perform an adequate and total resection because GTS can have a high recurrence rate
ACCEPTED MANUSCRIPT
of 72-83% in patients with partial resections versus 0-4% in those who undergo complete resections (15). With a 5-year overall survival rate of 89% in patients who
RI PT
undergo surgery, GTS has an overall good prognosis (16). Some medical therapies may play a role in reducing the size and alleviating surgical dissections (17). Interferon-α has been successfully used in unresectable tumors to stop their growth for a prolonged period of time (18-20). The administration of
SC
the humanized monoclonal antibody, Bevacizumab, also provided significant clinical
M AN U
improvement as well as growth stability of a partially resected mass (21). In a promising phase 1 trial with Palbociclib (PD-0332991), an oral and selective inhibitor of cyclin dependent kinases (CDK) 4 and 6, the disease was stabilized in three men not amenable to further surgery (22).
TE D
Regular follow-up imaging of patients with GTS is essential (17). MR imaging and CT are the preferred modalities (23). CT scan may show a low-density cystic lesion or an increase in the cystic component of the mass suggestive of teratomatous element
EP
(24). Ultrasound surveillance is made difficult by the variable appearance of these lesions and it is also less sensitive for fat than other modalities (25); but it is not
AC C
irradiating and more practical in experienced hands. More recently, 3D ultrasound has been advocated to be as sensitive as CT scan for the differential diagnosis, especially when combined with color flow Doppler scanning (26). In all cases, a rapid growth rate in the presence of normalized serum tumor markers should raise suspicion of GTS (15).
CONCLUSION
ACCEPTED MANUSCRIPT
Clinicians and radiologists should be aware of the potential occurence of GTS during or after successful chemotherapeutic treatment of germ cell tumors. GTS tumors do not respond to either chemotherapy or radiotherapy. Histological analysis of the
RI PT
specimen usually detects only mature teratoma, without active tumor evidence. Surgical exploration and complete resection is the only curative treatment. Although GTS has an excellent prognosis, regular follow-up with serum tumor markers as well as imaging is
SC
critical as very late malignant masses do occur in some patients.
M AN U
REFERENCES
DiSaia PJ, Saltz A, Kagan AR, et al. Chemotherapeutic retroconversion of immature teratoma of the ovary. Obstet Gynecol. 1977;49(3):346–350.
2.
Logothetis CJ, Samuels ML, Trindade A, et al. The growing teratoma syndrome. Cancer. 1982;50(8):1629–1635.
3.
Amsalem H. Growing teratoma syndrome vs. chemotherapeutic retroconversion Case report and review of the literature. Gynecol Oncol. 2004;92(1):357–360.
4.
Afifi HY, Bosl GJ, Burt ME. Mediastinal growing teratoma syndrome. Ann Thorac Surg. 1997;64(2):359–362.
5.
Kampan N, Irianta T, Djuana A, et al. Growing teratoma syndrome: a rare case report and review of the literature. Case Rep Obstet Gynecol. 2012;2012:134032.
6.
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Moskovic E, Jobling T, Fisher C, et al. Retroconversion of immature teratoma of the ovary: CT appearances. Clin Radiol. 1991;43(6):402–408.
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FIGURES
Figure 1 - Abdominal CT scan showing an extra-peritoneal mass of unknown origin (*)
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Figure 2 - CT scan revealing multiple new masses containing cystic and necrotic
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elements surrounding the liver.
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