Originally published as JCO Early Release 10.1200/JCO.2008.16.0622 on June 9 2008

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Mature and Immature Extracranial Teratomas in Children: The UK Children's Cancer Study Group Experience

Jillian R. Mann, Elizabeth S. Gray, Claire Thornton, Faro Raafat, Kathleen Robinson, Gary S. Collins, Peter Gornall, Simon N. Huddart, Juliet P. Hale, Anthony Oakhill

From the Departments of Pediatric Oncology, Histopathology, Pediatric Surgery, Birmingham Children's Hospital, Birmingham; Department of Pathology, Medical School, University of Aberdeen; Department of Histopathology, Institute of Clinical Sciences, Belfast; The Children's Cancer and Leukaemia Group Data Centre and University of Leicester, Leicester; Centre for Statistics in Medicine, University of Oxford, Oxford; University Hospital of Wales, Cardiff; Department of Pediatric Oncology, Royal Victoria Infirmary, Newcastle-upon Tyne; and the Department of Pediatric Oncology, Royal Hospital for Children, Bristol, United Kingdom
Deceased

Corresponding author: Jillian R. Mann, FRCPCH, Oncology Department, Birmingham Children's Hospital, Steelhouse Lane, Birmingham, B4 6NH, United Kingdom; e-mail: jillmann{at}doctors.org.uk

	ABSTRACT

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Purpose The purpose of this article is to describe the features, treatment, and risk factors for relapse of children with mature teratoma (MT) and immature teratoma (IT) to assist future treatment plans.

Patients and Methods Patients were younger than 16 years of age and referred to the UK Children's Cancer Study Group centers with biopsy-proven extracranial MT and IT and no prior chemotherapy. Complete excision, with the coccyx in sacrococcygeal patients, and follow-up, including serum alpha-fetoprotein monitoring for early detection of malignant yolk sac tumor (YST) recurrence, were recommended. Carboplatin, etoposide, and bleomycin (JEB) were given for YST relapse, whereas relapsed MT and IT were treated at clinicians’ discretion, usually surgically. Pathology was reviewed and treatments, outcome, and prognostic features assessed.

Results There were 351 patients, 227 with MT, 124 with IT. Tumor sites were: testis (n = 53), ovary (n = 130), sacrococcygeal region (n = 98), thorax (n = 23), and other (n = 47). Surgical resection was incomplete in 26% of MT and 40% of IT patients; 5-year event-free survival was 92.2% and 85.9%, respectively, and 5-year overall survival was 99% and 95.1%. Poorer outcome occurred with incomplete resection, tumor rupture, nongonadal site (particularly sacrococcygeal), young age, higher stage and grade, and gliomatosis peritonei, but not with cyst fluid aspiration/spillage, tumor enucleation, nodal gliomatosis, or microfoci of YST in the tumor (Heifetz lesions). JEB was effective for YST recurrence, but not for MT or IT.

Conclusion Treatment remains primarily surgical, with JEB chemotherapy for YST relapse. No definite response followed JEB for pure MT and IT. Adjuvant chemotherapy after surgery for sacrococcygeal patients is not advocated.

	INTRODUCTION

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Teratomas are derived from the three germinal layers. Tissues are differentiated in mature teratoma (MT) which generally behaves benignly after complete resection. Immature teratoma (IT) is characterized by containing immature neural tissue and greater propensity for recurrence.^1,2

Sacrococcygeal teratomas occur mostly in neonates and infants, testicular ones mainly in the first 5 years of life and ovarian mostly between 5 and 15 years of age.^3,4,5,6

Complete surgical resection without damaging vital structures is preferred. Recurrence may be benign (MT or IT), malignant (mostly yolk sac tumor [YST]), occasionally other malignant germ cell tumor (GCT) types, or malignant non-GCT. The place of chemotherapy is unclear, except for YST recurrence, when platinum-based chemotherapy is usually successful.^5,6,7,8

Prognostic markers were described in 135 American children with completely resected IT, of whom 75 had Heifetz lesions (HL) in their tumors, whereas 60 had pure IT without any malignant components.² The presence of HL correlated with higher stage and grade, raised alpha-fetoprotein (AFP) levels and higher likelihood of recurrence.

The German group excluded patients with malignant microfoci from their series if serum markers were above the age-adapted range. In their remaining 270 MT and IT patients, risk of recurrence was positively correlated with incomplete resection, higher grade, and sacrococcygeal site. Among 240 patients treated without adjuvant chemotherapy 14 developed benign and 14 malignant YST relapse, whereas in 40 who received chemotherapy, there were seven benign but no malignant relapses. Gobel et al are doing a randomized study of adjuvant chemotherapy in children scoring as high risk.¹

We describe patients with MT and IT registered in the UK Children's Cancer Study Group's (UKCCSG) second GCT study, including prognostic features and therapy.

	PATIENTS AND METHODS

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Patients
Patients younger than 16 years of age with biopsy-proven extracranial MT or IT, but no prior chemotherapy, referred to UKCCSG centers, were eligible. Patients with malignant GCT, even when tumors contained MT or IT elements, were not eligible. Patients whose tumors contained HL were not excluded.

Investigations
Before surgery imaging studies and serum for AFP and human chorionic gonadotropin (HCG) measurement were obtained. Surgical and histology reports were examined to judge completeness of resection.

Staging
This was performed as in the second UKCCSG GCT study⁹ (Appendix Table A1, online only). Ovarian tumors with gliomatosis peritonei (GP) were designated stage III.

Histopathologic Classification
Dehner's method, slightly modified, was used^3,9 and Norris's for grading IT¹⁰ (Table 1). The identification of microfoci of YST (HL) was based on Heifetz's article.² He did not precisely define a microfocus. For our study, microfoci were reported when one or more microfoci were seen, each occupying not more than two adjacent high-power fields (HPF; x 40 objective). When YST foci bigger than two adjacent HPF were found, the tumor was classified as malignant teratoma. Three authors (F.R., E.G., C.T.) reviewed the sections.

Although chemotherapy was suggested only for malignant recurrence, a few patients received this. Its efficacy was assessed from follow-up data forms: no benefit was assumed when no response was recorded or when there was subsequent recurrence.

Follow-Up
The surgeon and/or pediatric oncologist undertook this. Bimonthly serum AFP monitoring for 2 years was recommended for early detection of YST recurrence.

Treatment of Recurrence
For YST recurrence, after investigations including biopsy, carboplatin, etoposide, and bleomycin (JEB) chemotherapy was given, as in the concurrent UKCCSG protocol for malignant GCTs,⁹ then further surgery if needed.

Other recurrences were treated at the clinician's discretion, usually surgically. In girls with ovarian tumors, the development of another teratoma in the contralateral ovary was not counted as recurrence.

Statistical Methods
Data were collected on disease status and morbidities annually. Event-free survival (EFS) and overall survival (OS) were measured from the date of diagnosis to the date of first relapse or death. Survival probabilities and curves were estimated using the Kaplan-Meier method. The Cox proportional hazards model was used for univariate and multivariate analyses. A multivariate prognostic model for EFS was produced by generating 2,000 bootstrap samples from the data.¹¹ For each bootstrap sample, a stepwise selection multivariate Cox proportional hazards model was created based on Akaike's, with a penalty score accounting for model complexity. Prognostic importance of each factor is assessed by the percentage inclusion of a factor in the bootstrap resampling; a cutoff value of 60% was used for inclusion in the final multivariate model, the higher the value the higher the prognostic importance of a particular factor.

Ethical Approval
Institutions obtained approval as required by their local district research ethics committees. Informed consent was obtained from each patient and/or his/her legal guardian.

	RESULTS

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Patients’ Characteristics
The study was open from January 1989 to April 2005 and evaluated in July 2006. Fifteen of 368 patients registered were excluded because tumor material was unavailable for histology review. Two girls with bilateral ovarian tumors were excluded, one because she had preoperative chemotherapy without prior biopsy and another because, although one tumor was MT, the other was stage III YST. Thus, 351 patients were eligible, 227 with MT and 124 with IT.

Patients’ characteristics are presented in Table 2and Appendix Figure A1 (online only). Generally testicular tumors presented before the fifth birthday, ovarian between 5 and 15 years, and sacrococcygeal tumors at birth or in infancy. Thoracic tumors occurred throughout infancy and childhood, those at other sites mainly during infancy. The high proportion of females is due to ovarian tumors and female preponderance in sacrococcygeal teratomas (male 22, female 76).

AFP and HCG were incorporated in risk analyses only in children age older than 1 year, because infants have higher levels.^12,13 None with MT had AFP higher than 50 kU/L, whereas 11 with IT had modest elevation (106 to 778 kU/L). None had HCG above 10 U/L.

In IT, the presence of HL was significantly associated with raised AFP: one of 40 children with normal AFP (data missing in two) had HL compared with four of 11 with raised AFP (data missing in one; P = .004).

Initial Treatment and Primary Site
Initial treatment is summarized in the following text and in Table 2, which presents figures for perioperative tumor rupture, type of operation, cyst fluid aspiration/spillage and, for gonadal tumors, torsion. Additional details are shown in the Appendix (online only).

Testis
There were no bilateral testicular tumors; one boy had a cyst in the contralateral testis and three had undescended testis. The surgical approach was inguinal in 42, scrotal in three, abdominal in three, both in two and unrecorded in three. Radical orchidectomy was performed in 48, but in five patients with MT the tumor was enucleated, preserving residual testicular tissue.

Ovary
Four girls had bilateral ovarian tumors (two with MT and two with IT—the courses of two patients, numbers 578 and 290, are presented in Table 3) and unfortunately all four needed bilateral oophorectomy. Of the 126 girls with unilateral tumors, two had preoperative biopsy then laparotomy and oophorectomy and one (with MT) had laparoscopic tumor enucleation. The remaining 123 had laparotomy and oophorectomy (n = 113), laparotomy and tumor enucleation (n = 8: seven with MT, one with IT) or procedure unrecorded (n = 2). Two girls with ovarian MT and 11 with IT had GP and six with IT had nodal gliomatosis.

Thorax
The tumor arose in or near the thymus in 15 patients, esophagus (n = 1), pericardium (n = 2), aorta (n = 1), paraspinal area (n = 1), or elsewhere (n = 3). Two patients had biopsy before definitive surgery.

The surgical approach reflected the site and in three cases included oesophagectomy, gastric pull-through and left lower lobectomy; or thoracotomy and spinal surgery; or cardiopulmonary bypass.

Other Sites
These tumors arose in the head and/or neck (12 MT, eight IT), the abdomen - stomach, intestines, liver, kidney, adrenal, abdominal wall or retroperitoneum (12 MT, 13 IT), or the cauda equina or a myelocoele (both MT). The surgical approach reflected the site.

Survival and Risk Factors for Relapse
Median duration of follow-up was 4.98 years (range, 0 to 18.76), 4.48 for MT (range, 0 to 18.76) and 5.44 for IT (range, 0 to 12.75).

For MT (227 patients), 5-year EFS was 92.2% (95% CI, 88.4% to 96.3%) and 5-year OS was 99% (95% CI, 97.7% to 100%). For IT (124 patients), 5-year EFS was 85.9% (95% CI, 79.9% to 92.3%) and 5-year OS was 95.1% (95% CI, 91.4% to 99.0%). The better outcome for MT was significant, P values were .0341 for EFS and .0196 for OS.

Sixteen patients relapsed with MT or IT (Table 3) and nine with YST (Table 4). Among the nine with YST, six were diagnosed as a result of AFP monitoring, which showed rising levels or persistent elevation above age-related normal values (two presented clinically, and information was incomplete for one). Only eight patients died (Table 5), seven of tumor-associated problems and/or surgery or prematurity and one after recurrence (plus patient 81 who died after the analyses were done).

For MT and IT, young age and nongonadal site were not independent risk factors for EFS.

Among the criteria for incomplete resection was perioperative tumor rupture, absent in testicular patients. In the others (excluding six who died pre- or perioperatively) six of 45 with, and 18 of 246 without tumor rupture relapsed. Also, in sacrococcygeal patients, among 64 with MT who survived surgery, seven of 56 with excised coccyx relapsed (two with YST), whereas two of three where it was not removed, and three of five with no record relapsed. In 30 patients with IT who survived surgery, 29 had the coccyx removed and six relapsed (three with YST).

GP was present in two girls with ovarian MT; neither relapsed. Three of 10 with ovarian IT and GP relapsed compared with two of 44 without GP (P = .0389). None of six patients with nodal gliomatosis from ovarian (n = 5) or sacrococcygeal (n = 1) primaries relapsed.

Enucleation of gonadal tumors was not considered incomplete resection and no relapses followed this in five boys with MT, and nine girls (eight with MT, one with IT). Similarly, only one of 12 patients whose cysts were aspirated during surgery (patient 83; Table 4) and one of two aspirated antenatally (patient 724; Table 3) relapsed. Likewise, among 35 patients with intraoperative spillage of cyst fluid only three sacrococcygeal patients relapsed, of whom two also had tumor rupture and one had only biopsy.

Efficacy of Chemotherapy
JEB was effective in the nine patients with YST relapse, all achieving complete remission, mostly without further surgery; one had another relapse many years later (Table 4).

Although chemotherapy was not recommended for patients with MT and IT, a few received this. Its efficacy in these benign tumors was difficult to assess, but we had no definite evidence of benefit after JEB therapy, whether given preoperatively (two patients), as adjuvant therapy after surgery (six patients) or for benign relapse (two patients; Table 3). Another patient, with ovarian IT, was given nine cycles of the SIOP 95 MMT 6-drug regimen¹⁴ for relapse because her original ovarian tumor had a major neuroectodermal element of aggressive appearance and is in complete remission (Table 3); however, as there was no biopsy at relapse, its precise histology is unknown.

Late Effects
Information is subject to ongoing study. Among 95 survivors of sacrococcygeal tumors, at least 10 have neuropathic bladder and two have weak legs. Of 130 ovarian tumor survivors, one with spina bifida is paraplegic, four are infertile after bilateral oophorectomy, and one has cerebral palsy. A survivor of nasopharyngeal/orbital teratoma has hydrocephalus, developmental delay, and unilateral visual loss. A survivor of a teratoma in a meningo-myelocoele is paraplegic.

	DISCUSSION

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The 351 patients with extracranial MT and IT described herein were registered after referral to the major pediatric surgery centers of the United Kingdom, where the UKCCSG centers are also situated. They are probably representative of pediatric teratomas but, as not all are registered with cancer registries, this is uncertain. The distribution of patients by site and age was similar for MT and IT and to that described previously, as was female predominance for sacrococcygeal tumors.^3-6

Our results confirmed significantly better EFS and OS in MT than IT, the greater risk of recurrence for sacrococcygeal than ovarian or testicular tumors and that complete resection is important.^1,2 There were no events or deaths in the testicular and no deaths in the ovarian patients (Table 6). Completeness of resection was defined as in Germany,¹ except that no distinction was made between blunt and sharp dissection, and GP was coded as incomplete resection in British but not German patients. The data confirm increased risk after tumor rupture and support removing the coccyx with sacrococcygeal tumors, to reduce risk. They also suggest that in ovarian IT GP increases risk; a larger series is needed to confirm this. None of six patients with nodal gliomatosis relapsed. Cyst fluid aspiration or spillage during surgery, which were not coded as incomplete resection, were not generally associated with relapse, as reported for spillage elsewhere.⁷

The results are consistent with reports that higher grade IT are more likely to recur than lower^1,4,10 and that the presence of HL is associated with raised AFP², but unlike the American experience,² HLs were not predictive of relapse. Differences between the studies included inclusion of only children with completely resected IT in the American series, but of all stages in the British. Also patients with ovarian tumors comprised 64% of American but 37% of British patients. It is possible that the American series included cases that in the United Kingdom would have been considered malignant, as HLs were identified in only 15% of United Kingdom compared with 56% of American patients, and whereas 96% of 44 American girls with ovarian HL-containing IT had AFP elevation (80 to > 20,000 ng/dL), only 11 (20%) of all the 56 evaluated British IT patients had elevated AFP (106 to 778, none above 1,000 kU/L). Serum AFP level was not an eligibility criterion for the UKCCSG's second GCT study, but after considering the findings reported herein, in UKCCSG's third study (2005) patients with IT with AFP higher than 1,000 kU/L are treated as malignant GCTs.

Enucleation of benign teratomas to preserve gonadal function, not discussed in previous pediatric publications, might be considered if feasible and safe (especially in girls with bilateral ovarian tumors) as none of five boys and eight girls with MT or one girl with IT whose tumors were enucleated relapsed.

While there were no relapses among five boys who had scrotal incisions, we recommend inguinal incision for every testicular lesion if the operator cannot be sure it is not malignant. All girls with ovarian tumors had laparotomy, except one who had laparoscopic enucleation of her tumor. However, while laparoscopy is useful for evaluating abdominal lesions, it may not be valuable for excising most ovarian teratomas.

Although surgical resection was incomplete in 26% of 227 MT and 40% of 124 IT patients, the 5-year EFS rates were 92.2% and 85.9%, respectively, so relapse was not inevitable after incomplete resection. Moreover, the OS rates of 99% and 95.1%, respectively, indicate that treatments for relapse, mainly surgery for nonmalignant relapse, and JEB for YST, were effective; only one of nine children with YST recurrence of sacrococcygeal teratomas had further relapse (Table 4).

We examined the causes of eight deaths, and were unsure whether the survival of the six neonates could have been improved.

The efficacy of chemotherapy in MT and IT was difficult to assess, as few patients received this. JEB appeared ineffective, whether given preoperatively (two patients), as adjuvant therapy after surgery (six patients), or for benign relapse (two patients). Only one girl, whose original tumor had aggressive neuroectodermal elements, achieved complete remission after six-drug chemotherapy for relapse. Therefore, we remain reluctant to use adjuvant chemotherapy after surgery. This is being studied in the German case-control trial MAKEI 2004¹⁵ for high-risk sacrococcygeal teratomas, aiming to prevent YST relapse. However, we do recommend close oncological follow-up, including AFP monitoring, of all patients with sacrococcgeal teratoma to permit early diagnosis and treatment of YST recurrence (reported in some 10% of patients¹⁶) and for all other patients except those with completely resected gonadal tumors and normal preoperative AFP and HCG.

Our late effects data are incomplete and subject to ongoing study. While many patients are in excellent health, some have substantial morbidity, as reported from the Netherlands in 79 survivors of sacrococcygeal teratomas.¹⁷

In conclusion, in pure MT and IT, surgery should remain the mainstay of treatment. While for YST recurrence, JEB is highly effective, for pure MT and IT, no clear benefit from JEB chemotherapy has been demonstrated. Careful follow-up is recommended, with AFP monitoring, especially for sacrococcygeal tumors.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Jillian R. Mann, Anthony Oakhill

Administrative support: Jillian R. Mann, Kathleen Robinson

Provision of study materials or patients: Jillian R. Mann, Elizabeth S. Gray, Claire Thornton, Faro Raafat, Peter Gornall, Anthony Oakhill

Collection and assembly of data: Jillian R. Mann, Elizabeth S. Gray, Claire Thornton, Faro Raafat, Juliet P. Hale, Anthony Oakhill

Data analysis and interpretation: Jillian R. Mann, Elizabeth S. Gray, Claire Thornton, Faro Raafat, Kathleen Robinson, Gary S. Collins, Peter Gornall, Simon N. Huddart

Manuscript writing: Jillian R. Mann, Faro Raafat, Gary S. Collins, Simon N. Huddart, Juliet P. Hale

Final approval of manuscript: Jillian R. Mann, Elizabeth S. Gray, Claire Thornton, Faro Raafat, Kathleen Robinson, Gary S. Collins, Peter Gornall, Simon N. Huddart, Juliet P. Hale

	Appendix

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Initial Treatment and Primary Site
Table 2 shows figures for perioperative tumor rupture, type of operation, cyst fluid aspiration/spillage, or for gonadal tumors, torsion.

Testis (mature teratoma 42, immature teratoma 11). None had bilateral tumors, one with mature teratoma (MT) had a cyst in the contralateral testis, three with MT had undescended testis (UDT)—one with torsion. The surgical approach was inguinal in 42, scrotal in three (diagnosis was torsion, hydrocoele, or cyst), abdominal in three (for UDT, torsion, or both), combined scrotal and inguinal in two (diagnosis was hydrocoele or cyst), and unrecorded in three. Forty-eight boys had radical orchidectomy but five with MT had tumor enucleation with preservation of residual testicular tissue.

Ovary. Seventy-six had MTs. Of 74 girls with unilateral MT, one had preoperative biopsy, then laparotomy and oophorectomy. Another had laparoscopic tumor enucleation. The others had laparotomy and either oophorectomy (65 girls) or enucleation (n = 7). The teratoma was discovered during surgery for appendicitis in two. Two girls had GP.

Two girls had bilateral ovarian MT. One had oophorectomy for torsion of the left MT and later oophorectomy for torsion of the right. The other had oophorectomy for the right MT and biopsy of the left, and later oophorectomy.

Fifty-four had immature teratomas (ITs). One of 52 girls with unilateral tumors had preoperative biopsy, then laparotomy and oophorectomy. The rest had laparotomy and oophorectomy (n = 48), enucleation (n = 1) or no record (n = 2). Eleven had gliomatosis peritonei (GP) and six had nodal gliomatosis.

Two girls had bilateral tumors and GP. Patient 290's details are presented in Table 3. Patient 482, with AFP 722, had left oophorectomy for ruptured IT, then three cycles of JEB; 3 months after oophorectomy she had biopsy of a right ovarian MT, which was removed after torsion 7 months later.

Sacrococcygeal region (MT 66, IT 32). The surgical approach was sacrococcygeal in 72 patients, abdominal in five, both in 16, and biopsy only in one (unrecorded in four). The coccyx was removed in 89, not removed in four (unrecorded in five).

Thorax (MT 17, IT 6). The tumor arose in or near the thymus in 15 patients, in the esophagus (n = 1), pericardium (n = 2), aorta (n = 1), paraspinal area (n = 1), or elsewhere (n = 3). Two patients had biopsy before definitive surgery. The surgical approach reflected the site and in three cases included oesophagectomy, gastric pull-through and left lower lobectomy, or thoracotomy and spinal surgery, or cardiopulmonary bypass.

Other sites (MT 26, IT 21). These tumors arose in the head and/or neck (12 MT, 8 IT), the abdomen—stomach, intestines, liver, kidney, adrenal, abdominal wall or retroperitoneum (12 MT, 13 IT)—or the cauda equina or a myelocoele (both MT). The surgical approach reflected the site.

Efficacy of Chemotherapy
Nine patients had JEB chemotherapy for YST relapse. All achieved complete remission, mostly without additional surgery, although one had another relapse many years later (Table 4).

There were a few other patients who also had chemotherapy and we tried to assess its effect. We recognize that our evaluation lacks rigor because there were no guidelines in the protocol regarding assessment of response after chemotherapy for these patients. We have therefore tried to do this by using the clinical information that we could obtain, summarized as follows.

Nine patients had chemotherapy as part of their initial treatment. Patient 465, a girl with sacrococcygeal MT and intraspinal extension to T4, had biopsy and three cycles of JEB without any clinical response; she survives with paraplegia. Patient 148, a boy with sacrococcygeal IT had six cycles of JEB, with no clinical response, and then incomplete resection followed by OJEC chemotherapy. Patient 538 had carboplatin and etoposide for thoracic MT with intraspinal extension and paraplegia; there was no response to one course and, despite surgical debulking, she died. Patient 249 with ovarian IT had two cycles of JEB with no clinical response and then multiple abdominal recurrences and resections (and 1.5 courses of VIP with no response; Table 3). Patient 290 had bilateral ovarian tumors and received four cycles of JEB but, although her AFP level then fell to normal, shortly afterward she developed two recurrences of IT that were treated surgically (Table 3). Patient 482 had ruptured left ovarian IT removed with some GP nodules and then three cycles of JEB, but 2 months later had additional nodules removed and a right ovarian MT biopsied (removed 2.5 years later). Patient 534 had four cycles of JEB for nodal gliomatosis from ovarian IT but had abdominal recurrences more than 2 years later that were treated surgically (Table 3). Patient 618 had six cycles of JEB for nodal gliomatosis from ovarian IT but it was not possible to assess response; she had no recurrences. Patient 62 with sacrococcygeal IT had four cycles of JEB after surgical resection, because of nodal gliomatosis; it was not possible to assess response, but she had no recurrence. All of these patients except patient 538 survive.

Five patients had chemotherapy for non-YST relapse (Table 3). Four patients (patients 249, 290, 327, and 572) with IT had JEB or VIP without response, although there was partial recovery of lower limb movement in patient 572, which could have resulted from surgery. Patient 276, whose original ovarian IT had a major neuroectodermal element, had a complete response to the SIOP MMT95 six-drug regimen with no surgery or other therapy. All of these patients survive.

In summary, apart from the patients with YST recurrences, and patient 276 with recurrent ovarian IT which was not biopsied, we cannot demonstrate that any of the patients benefited from the chemotherapy that they received.

View larger version (22K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Ages at diagnosis of patients with mature and immature teratomas.

	NOTES

 
published online ahead of print at www.jco.org on June 9, 2008

Supported by Cancer Research UK (for data management).

Presented in part at the Germ Cell Tumours IV meeting, in Leeds, United Kingdom, November 1998.

The UK Children's Cancer Study Group is now the Children's Cancer and Leukaemia Group.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
1. Gobel U, Calaminus G, Blohm M, et al: Extracranial non-testicular teratoma in childhood and adolescence: Introduction of a risk score for stratification of therapy. Klin Padiatr 209:228-234, 1997[Medline]

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4. Gobel U, Calaminus G, Engert J, et al: Teratomas in infancy and childhood. Med Pediatr Oncol 31:8-15, 1998[CrossRef][Medline]

5. Mann JR, Raafat F, Robinson K, et al: Mature and immature extracranial teratomas in children: The UK Children's Cancer Study Group's experience, in Jones WG, Appleyard I, Harnden P, et al (eds): Germ Cell Tumours IV. London, United Kingdom, John Libbey and Co Ltd, 1998, pp 237-246

6. Harms D, Zahn S, Gobel U, et al: Pathology and molecular biology of teratomas in childhood and adolescence. Klin Padiatr 218:296-302, 2006[CrossRef][Medline]

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9. Mann JR, Raafat F, Robinson K, et al: The United Kingdom Children's Cancer Study Group's Second Germ Cell Tumor Study: Carboplatin, etoposide and bleomycin are effective treatment for children with malignant extracranial germ cell tumors, with acceptable toxicity. J Clin Oncol 18:3809-3818, 2000[Abstract/Free Full Text]

10. O'Connor DM, Norris HJ: The influence of grade on outcome of stage I immature (malignant) teratomas and the reproducibility of grading. Int J Gynae Pathol 13:283-289, 1994

11. Sauerbrei W, Schumacher M: A bootstrap resampling procedure for model building: Application to the Cox regression model. Stat Med 11:2093-2109, 1992[Medline]

12. Tsuchida Y, Endo Y, Saito S, et al: Evaluation of alpha-fetoprotein in early infancy. J Pediatr Surg 13:155-156, 1978[CrossRef][Medline]

13. Wu JT, Book L, Sudar K: Serum alpha-protein (AFP) levels in normal infant. Pediatr Res 15:50-52, 1981[Medline]

14. Stevens M, Rey A, Bouvet N, et al: SIOP MMT 95: Intensified 6 drug versus standard (IVA) chemotherapy for high risk non metastatic rhabdomyosarcoma (RMS). J Clin Oncol 22:802s, 2004 (abstr 8515)

15. Calaminus G, Schmidt P, Schneider DT, et al: Factors influencing outcome of teratoma in infancy and childhood: Results of the German cooperative trials MAHO 92-98/MAKEI 96 and further stratification in MAKEI 2004. Abstracts of SIOP XXXVI, Oslo, September 2004, Ped Blood and Cancer 43:377-378, 2004

16. Huddart SN, Mann JR, Robinson K, et al: Sacrococcygeal teratomas: The UK Children's Study Group's experience I. Neonatal. Pediatr Surg Int 19:47-51, 2003[Medline]

17. Derikx JPM, De Backer A, Van de Schoot L, et al: Long-term functional sequelae of sacrococcygeal teratoma: A national study from the Netherlands. J Pediatr Surg 42:1122-1126, 2007[CrossRef][Medline]

Submitted January 3, 2008; accepted April 9, 2008.

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