CLINICAL AND LABORATORY OBSERVATIONS

Germ Cell Tumors in Atypical Locations: Experience

of the TGM 95 SFCE Trial
He´le`ne Sudour-Bonnange, MD,* Daniel Orbach, MD,w Nicolas Kalfa, MD, PhD,z
Sylvie Fasola, MD,y and Catherine Patte, MD8

The management in the TGM 95 trial involves surgical

Summary: The yolk sac tumor is one of the most common malig- removal when possible, which is followed by chemotherapy.
nant germ cell tumors in young children and typically occurs in the When surgery is not possible, neoadjuvant chemotherapy is
gonads. We report 6 cases of children less than 30 months old with necessary and is followed by surgical removal of the
extragonadal atypical locations of yolk sac tumor. These rare
residual tumor. The type of chemotherapy given depends
diagnoses were established by raised serum a-fetoprotein levels and
biopsies. These patients were treated according to the French TGM on the risk group as defined by the a-fetoprotein (AFP)
95 trial. All the patients are alive disease-free after Z2.5 years of level (AFP > 15000 or <15000 ng/mL), operability, and
follow-up. We want to highlight the importance of measuring the staging.3 The management included a “watch and wait”
a-fetoprotein levels in very young children presenting with any strategy for low risk, a vinblastin, bleomycin, cisplatin
midline tumor, even if the tumor is not located in the typical regimen (VBP) for intermediate risk, and a VIP regimen
extragonadal sites such as the sacrococcyx, mediastinum, retro- (etoposide, ifosfamide, cisplatin) for high risk.
peritoneum, or vagina.
Key Words: yolk sac tumors, atypical location, risk-factor adapted OBSERVATIONS
strategy All the 6 cases are summarized in the Table 1.
(J Pediatr Hematol Oncol 2014;36:646–648) Case Report 1
A newborn presented with a large tumor of the naso-
pharynx. He underwent a complete surgery and was diag-
nosed with a teratoma without a malignant component.
T he yolk sac tumor (YST) is one of the most common
malignant germ cell tumors (GCTs) in children, occur-
ring mainly in the gonads (in more than half of cases).1
When he was 41 months old, the patient presented with a
hemorrhagic lesion of his left-sided nasal cavity. Computed
Extragonadal tumors are rarer and typically occur in mid- tomography (CT) of the face revealed a large nasopharynx
line locations: nonmalignant GCTs and usually occur in the mass with lysis of the pterygoid bone and involvement of
midline sacrococcyx, mediastinum, retroperitoneum, and the pterygoid muscle and the cavernous sinus. A biopsy
central nervous system.2 Other sites have rarely been revealed a GCT with a vitelline pattern. An elevated serum
described. We were interested to know more on these AFP level of 61681 ng/mL supported the diagnosis of an
unusual sites, in term of frequency, initial features, man- YST. There was no metastatic location. The final diagnosis
agement, and outcome. was a localized high-risk YST (because of the high AFP
We reviewed the clinical, pathological and therapeutic level) of the nasopharynx. The patient received 5 courses of
features of 351 children with a GCT or a sex cord tumor VIP. He experienced a dramatic response with regression of
treated in the TGM 95 trial in SFCE (Société Franc¸aise des the mass, and the AFP level decreased to the normal range.
Cancers de l’Enfant) centers between 1995 and December He underwent surgery of the residual lesion. The histo-
2010. Two hundred and seventy-one had a non-semi- pathologic examination revealed no residual malignant
nomatous GCT. After exclusion of the pure immature tumor. At the last follow-up, 2.5 years after the diagnosis,
teratomas, there were 239 patients; among these, 6 pre- he remained free of disease.
sented with extragonadal tumors in atypical locations. All
the patients had an YST. The tumors were orofacial in 3 Case Report 2
patients, preputial in 1, located in the buttock for 1, and in A 17-month-old girl presented with progressive fati-
the intra-abdominal region (omentum) for 1. gue, anorexia, and growth failure. She then developed a
palsy of the right third cranial nerve and decreased visual
acuity. CT and magnetic resonance imaging (MRI) revealed
a large mass involving the pterygopalatine fossa, ethmoidal,
Received for publication May 13, 2013; accepted November 12, 2013.
sphenoidal, and cavernous sinuses with lysis of the orbital
From the *Pediatric Oncology Department, Oscar Lambret Center, floor. No metastatic site was diagnosed on bone scintig-
Lille Cedex; wPediatric Hematology-Oncology Unit, Curie Insti- raphy, and thoracic or abdominal CT. Two biopsies were
tute; yPediatric Hematology-Oncology Department, Armand unsuccessful. Laboratory studies revealed an elevated
Trousseau Hospital, Paris Cedex; zPediatric Urologic Surgery Unit,
Lapeyronie Hospital, CHU de Montpellier, Montpellier Cedex; and
serum AFP level of 7477 ng/mL and a human chorionic
8Pediatric Oncology Department, Gustave Roussy Institute, Ville- gonadotropin level of <0.1 mIU/mL. These results sup-
juif Cedex, France. ported the diagnosis of a localized high-risk secreting
The authors declare no conflict of interest. malignant GCT primarily in the orofacial region. Because
Reprints: Hélène Sudour-Bonnange, MD, Département d’oncologie
pédiatrique, Centre Oscar Lambret, 3 rue Frederic Combemales,
of the threat to the patient’s vision, front-line radiotherapy
Lille Cedex 59020, France (e-mail: [email protected]). (6 Gy) was performed. Chemotherapy (4 VIP) was then
Copyright r 2013 by Lippincott Williams & Wilkins used and yielded a very good partial regression of the mass,

646 | www.jpho-online.com J Pediatr Hematol Oncol  Volume 36, Number 8, November 2014
J Pediatr Hematol Oncol  Volume 36, Number 8, November 2014 Atypical Locations of Germ Cell Tumors in TGM 95

TABLE 1. Summary of Patients’ Clinical Presentation, Pathology Results, Treatment, and Follow-up
aFP (ng/mL)
Case HCG Follow-
No. Age (mo) Sex Presentation Site Histology (mIU/mL) Treatment up
1 41 (neonatal M Respiratory distress Nasopharynx Yolk sac tumor 61681 Chemotherapy, ANED
teratoma) < 0.1 surgery 2.5 y
2 17 F AGS, anorexia Right Malignant without 7477 Chemotherapy, ANED
Right cranial nerve pterygopalatine other specification < 0.1 radiotherapy, 7y
number 3 paralyzed fossa surgery
3 25 M Mass of preputial Penile shaft Yolk sac tumor 2 (4 mo after Surgery, ANED
sulcus surgery) chemotherapy 10 y
NS
4 10 F Palate swelling Palate Yolk sac tumor 21140 Chemotherapy, ANED
< 1.5 surgery 10 y
5 15 F Fever, AGS, Omentum Yolk sac 52000 Chemotherapy, ANED
hematuria, tumor + immature NS surgery 8y
abdominal pains teratoma
6 25 F Buttock swelling Buttock Yolk sac tumor 1823 Chemotherapy, ANED
<2 surgery 5y
AGS indicates altered general status; ANED, alive with no evidence of disease; HCG, human chorionic gonadotropin; NS, nonspecified.

and the AFP level decreased to the normal range. Treatment was continued with 2 more VIP courses. She
Unfortunately, no success on the vision was observed. A then underwent complete surgical excision of the residual
complete excision of the residual mass was successfully mass. The histopathologic examination revealed some
performed. The histopathologic examination revealed no residual malignant components on 2/8 analyzed pieces but
residual malignant tumor. She was disease free at the 7-year showed complete removal. No additional treatment was
follow-up point, with residual bilateral blindness. performed. She had disease-free survival at her 10-year
follow-up and had epilepsy as a neurological sequela.
Case Report 3
A 21-month-old boy presented with penile swelling Case Report 5
and pain. A penile contusion was suspected, and he A 15-month-old girl presented with fever, altered
underwent surgery, which revealed a tumor lesion of the health, hematuria, and abdominal pain. A clinical exami-
penile shaft. The histopathologic examination showed nation found a mass on the left flank. Echography and
vascular dysplasia and an incomplete excision. When he abdominal CT revealed a very large solid mass in the upper
was 25 months old, he underwent a second surgery because intraperitoneal cavity, which was associated with liver
of a local relapse. The new histopathologic examination metastatic nodules and an intraperitoneal effusion. The
showed vitelline and tubular patterns. The immunohis- tumor likely first occurred in the greater omentum. A
tochemistry (IHC) results were positive for AFP. The serum thoracic CT found no suspicious lesions. A biopsy of some
AFP level was normal (after the complete excision), but the of the peritoneal granulations revealed GCT with a vitelline
patient was diagnosed as definitely having a localized YST pattern mixed with an immature teratoma. The serum AFP
originating in the penis, and the tumor had been completely level was 52000 ng/mL. The final diagnosis was a metastatic
resected. A “watch and wait” strategy was initiated with high-risk YST of the omentum. She received 5 courses of
monthly clinical examinations and AFP level measurement. VIP. Because the AFP level did not completely decrease, a
Four months later, he presented with a second local relapse second round of chemotherapy with 1 course of bleomycin,
(histopathologically confirmed). A complete excision was carboplatin, and adriamicyn was administered. Surgery of
performed and the AFP level after surgery decreased to the residual abdominal lesions consisted of an omentec-
within the normal range. Chemotherapy was initiated tomy and excision of all the supramillimetric granulations.
according to the intermediate-risk group, with 3 courses of The AFP level decreased to within the normal range. The
VBP. No further relapses were observed. He was disease histopathologic examination revealed tumor necrosis
free at his 10-year follow-up. without residual malignant cells. She had disease-free sur-
vival at her 8-year follow-up.
Case Report 4
A 10-month-old girl presented with increasing palatine Case Report 6
swelling. MRI revealed a large tumor on the left side of the A 25-month-old girl presented with buttock swelling,
palatine space with extension up to the orbital floor and located remotely from the sacrococcyx. An MRI revealed
lysis of the left maxillary bone. A biopsy revealed a tumor a solid mass that had developed in the left buttock. A
with a vitelline pattern (IHC positive for AFP). Laboratory thoracic CT revealed metastatic nodules in the right lung
studies found an elevated serum AFP level of 21140 ng/mL. parenchyma. A biopsy showed a tumor with a vitelline
This supported the diagnosis of a localized unresectable pattern, and AFP staining was present on IHC. The serum
high-risk YST of the palatine. With 4 courses of VIP, the AFP level was 1823 ng/mL. For this metastatic high-risk
mass and AFP progressively decreased. Chemotherapy was YST of the buttock, the patient received 4 courses of VIP.
complicated by a herpetic encephalopathy with seizures. The tumor volume was significantly reduced, and the AFP

r 2013 Lippincott Williams & Wilkins www.jpho-online.com | 647

Sudour-Bonnange et al J Pediatr Hematol Oncol  Volume 36, Number 8, November 2014

level decreased to within the normal range. Surgery resulted very complex surgery. In orofacial tumors the need for
in a complete excision of the residual buttock mass and all complete excision may require the collaboration of facial
the pulmonary residual nodules. The histopathologic and neurosurgeons. No recurrences were observed. For the
examination revealed no residual malignant tumor. She third patient, surgery of the mass was possible and adjuvant
remained disease free at her 5-year follow-up. chemotherapy was performed because of a second relapse.
No further recurrences were observed. These results dem-
DISCUSSION onstrate that the risk factor adapted strategy of the TGM
Malignant pediatric GCTs account for 3% to 4% of 95 SFCE protocol for nonseminomatous GCTs can
all childhood malignancies.4 These tumors share a common be successfully used for extragonadal YSTs. The prognosis
origin of pluripotent primordial germ cells, but they com- of these atypical tumors appears to be no worse because
prise a markedly heterogeneous group of neoplasms with all 6 of our patients are alive without disease after a long
variability in the clinical, biological, and histologic features. follow-up period.
The degree and direction of differentiation determine the To conclude, it is important to perform AFP meas-
histologic subtype; YST is the most common pure malig- urements in cases for which there is no obvious diagnosis in
nant subtype in the pediatric population.5 very young children presenting with any midline tumor,
GCTs predominantly arise from the testes and ovaries; even if the tumor is not located in the typical extragonadal
but a significant subset (10% to 60% depending on the age) sites, such as the sacrococcyx, mediastinum, retro-
of these tumors is of an extragonadal origin and occurs peritoneun, or vagina.
predominantly in the midline of the human body.6 These
tumors are thought to develop from the same primordial ACKNOWLEDGMENT
germ cells, which can be misplaced during the long trip to
the gonads.7 The mediastinum, sacrococcygeal, and retro- The authors thank Dr Didier Frappaz for his exceed-
peritoneal location are well described,3,8 but a literature ingly helpful advice that he provided regarding this paper.
research revealed only a small number of case reports of
other sites of extragonadal YSTs; these tumors have been REFERENCES
reported in the orbit, parotid gland, ear, nasal cavity, scalp,
penile shaft, omentum, and mesentery. It is important to 1. Baranzelli MC, Kramar A, Bouffet E, et al. Prognostic factors
in children with localized malignant nonseminomatous germ
consider the diagnosis of a GCT for many sites in children
cell tumors. J Clin Oncol. 1999;17:1212–1218.
younger than 30 months. In the TGM 95 trial, it represents 2. Horton Z, Schlatter M, Schultz S. Pediatric germ cell tumors.
2.5% of the secreting nonseminomatous GCTs. The serum Surg Oncol. 2007;16:205–213.
AFP, a useful marker in the diagnosis and follow-up of 3. De Corti F, Sarnacki S, Patte C, et al. Prognosis of
gonadal YSTs, is generally increased in the patients with malignant sacrococcygeal germ cell tumours according to their
extragonadal YSTs.9,10 In our 6 patients, the serum AFP natural history and surgical management. Surg Oncol. 2012;21:
level was increased in 5/6 cases. For the third case, labo- 31–37.
ratory studies were performed after surgery, which explains 4. Gobel U, Schneider DT, Calaminus G, et al. Germ cell tumors
the negative results, but the tumor showed positive immu- in childhood and adolescence. Ann Oncol. 2000;11:263–271.
nostaining for AFP and AFP was increased at the relapse. 5. Cushing B, Perlman EJ, Marina NM, et al. Germ cell tumors.
In: Pizzo PA, Poplacck DG, eds. Principles and Practice of
In the atypical locations, it is important to consider GCTs, Pediatric Oncology. 4th ed. Philadelphia: Lippincott Williams
and the level of AFP could lead to a rapid diagnosis. In our and Wilkins; 2002:1094.
second case, the diagnosis was supported by the highly 6. Rescorla FJ. Pediatric germ cell tumors. Semin Surg Oncol.
increased AFP level, and 2 successive biopsies did not 1999;16:144–158.
contribute to the diagnosis. The interpretation of AFP 7. Ueno T, Tanaka YO, Nagata M, et al. Spectrum of germ cell
values depends on the age and kinetics.11 The anatomo- tumors: from head to toe. Radiographics. 2004;24:387–404.
pathologic result was an YST GCT in the 6 patients in our 8. Bokemeyer C, Nichols CR, Droz JP, et al. Extragonadal germ
report. The patients were all younger than 30 months, cell tumors of the mediastinum and retroperitoneum: results
from an international analysis. J Clin Oncol. 2002;20:1864–1873.
which is typical for this histiotype. According to the TGM
9. Kiratli H, Erkan Balci K, Güler G. Primary orbital endoder-
95 trial strategy, 5 of our 6 patients were initially treated mal sinus tumor. J AAPOS. 2008;12:623–625.
with chemotherapy, according to their risk group. They 10. Xinghui Y, Jing H, Mingju L, et al. Endodermal sinus tumour
showed a marked improvement with regression of the of the omentum in a child. J Pediatr Surg. 2001;36:1602–1603.
masses and decreased AFP levels. Surgery on the residual 11. Tsuchida Y, Endo Y, Saito S, et al. Evaluation of alpha-
tumors could be performed successfully, sometimes with fetoprotein in early infancy. J Pediatr Surg. 1978;13:155–162.

648 | www.jpho-online.com r 2013 Lippincott Williams & Wilkins