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REVIEW ARTICLE |
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| Year : 2014 | Volume
: 19
| Issue : 4 | Page : 189-194 |
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Gonadal germ cell tumors in children and adolescents
Giovanni Cecchetto
Department of Women's and Children's Health, Pediatric Surgery Unit, University Hospital of Padua, Padua, Italy
| Date of Web Publication | 30-Sep-2014 |
Correspondence Address:
Giovanni Cecchetto
Department of Women's and Children's Health, Pediatric Surgery Unit, University Hospital of Padua, Padua
Italy
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0971-9261.141995
 Abstract | | |
Pediatric germ cell tumors (GCT) are rare tumors: 80% are benign, 20% malignant (2-3% of all malignant pediatric tumors). The gonadal sites (ovary and testis) account for 40% of cases. Ovarian GCTs: Represent 30% of GCTs and 70% of neoplastic ovarian masses, being the most common ovarian neoplasms in children and teenagers. Benign and immature forms (teratomas) constitute about 80% of all ovarian GCTs, malignant forms represent 20% increasing during adolescence. The most common malignant entity in children is the yolk sac tumors (YST); dysgerminoma is frequent during adolescence and being bilateral in 10% of cases. Presentation is similar in malignant and benign lesions; abdominal pain (70-80%) and lower abdominal mass are common symptoms. Evaluation of alpha-fetoprotein (αFP) or beta subunit of human chorionic gonadotropin (βHCG) is essential to address the nature of the tumors: Their elevation means presence of malignancy. Surgery includes intraoperative staging procedures and requires ovariectomy or ovarosalpingectomy for malignant lesions, but may be conservative in selected benign tumors. Since malignant GCTs are very chemosensitive, primary chemotherapy is recommended in metastatic or locally advanced tumors. Testicular GCT: Represent 10% of pediatric GCT, and about 30% of malignant GCT with two age peaks: Children <3 years may experience mature teratoma and malignant GCTs, represented almost exclusively by YST, while adolescents may also show seminomas or other mixed tumors. The main clinical feature is a painless scrotal mass. Surgery represents the cornerstone of the management of testicular GCTs, with an inguinal approach and a primary high orchidectomy for malignant tumors, while a testis-sparing surgery can be considered for benign lesions. A retroperitoneal lymph node (LN) biopsy may be necessary to define the staging when the involvement of retroperitoneal LN is uncertain at imaging investigations. Conclusion: Patients with gonadal malignant GCTs fare better than those with extragonadal mediastinal germ cell tumors (MGCTs) and survival rate exceeds 90% in localized forms. Chemotherapy has significantly improved the outcome of malignant forms since the introduction of platinum based regimens. The surgical procedure has to be performed in agreement with the ongoing protocols.
Keywords: Children, germ cell tumors, gonadal
How to cite this article:
Cecchetto G. Gonadal germ cell tumors in children and adolescents
. J Indian Assoc Pediatr Surg 2014;19:189-94 |
| Introduction | |  |
Pediatric germ cell tumors (GCTs) are rare tumors. Their overall incidence can be estimated as 0.9/100.000 children up to 15 years. They arise due to variation from normal differentiation of germ cells and include a heterogeneous group of neoplasms with remarkable variability concerning histology and site of presentation: Benign, malignant and immature GCTs can be observed in children and adolescents with different rates, also according to age. [1],[2]
In general, 80% of GCTs are benign while only 20% are malignant (representing about 2-3% of all malignant pediatric tumors). [2] Teratoma is the most common variety with benign (mature) or immature histological features in most cases, but also with malignant characteristics more rarely. It is classified as mature teratoma if it is composed of highly differentiated tissue from one or more embryonic germ layers, or immature teratoma when it contains mature tissue and also immature epithelial (neural or blastemal) or stromal tissue, being graded from I to III according with different grading score systems. [3] The higher is the grade of the mass, more aggressive the behavior is expected. Malignant GCTs are represented by different histotypes besides malignant teratoma. [4] Yolk sac tumor (YCT), also known as endodermal sinus tumor (EST), is the most frequent and aggressive malignant entity in young children that can be found in all sites and can metastasize to regional lymph nodes (LNs), liver, lung and brain. It is characterized by secretion of alpha-fetoprotein (αFP), a α1-globulin with a half life of 5 days, which represents a very important serum marker at diagnosis, during and after the treatment. However, it has to be emphasized that αFP is normally elevated in newborns, decreasing within the first 5-6 months of life. Other malignant histotypes are less frequent: Germinomas, also termed seminoma in males and dysgerminoma in females, are undifferentiated GCTs typical of adolescents; embrional carcinoma and choriocarcinoma are rare differentiated forms in pediatric age and commonly are a feature of mixed histological subtypes; trophoblastic elements included in choriocarcinoma may secrete a specific serum marker, beta subunit of human chorionic gonadotropin (βHCG), that has a 16 hours half life. [5] It is important to underline that different histologic patterns (benign immature and malignant) may coexist in the same GCT. The presence of just isolated microfoci of YST in benign or immature forms may determine a malignant behavior.
GCTs are also characterized by a variability concerning the site of presentation. The extragonadal sites (brain, neck, mediastinum, retroperitoneum and sacro-coccyx) represents about 60% of cases, being the sacrococcigeal the most frequent localization, while the gonadal sites (ovary and testis) account for 40% of cases in pediatric age. [4],[5],[6] The aim of this paper is to highlight the main clinical features and treatment of gonadal GCTs.
Ovary
Ovarian GCTs account for about 30% of GCTs and 70% of all neoplastic ovarian masses, being the most common ovarian neoplasms in children and teenagers. The peak of incidence is in early adolescence. The remaining 30% of ovarian neoplasms are represented by sex cord stromal tumors mainly represented by granulose cell tumors and Sertoly-Leydig tumors and by epithelial tumors, which are extremely rare before menarche. [5]
Pathology
All the histological subtypes of GCTs may be represented in the ovary. Benign and immature teratomas constitute about 80% of all ovarian GCTs and are bilateral in 5% of cases, whereas the incidence of malignant forms is reported in about 20% and increases during adolescence. [4],[5] The most common malignant entity in young population is the YSCT; dysgerminoma is the most frequent ovarian malignant GCTs during adolescence, and may be bilateral in 10% of cases. Gonadoblastoma is a rare GCT that is observed in girls with dysgenetic gonads and male pseudohermaphroditism. The tumor exhibits benign behavior, but may be associated with malignant histotypes: For this reason bilateral oophorectomy is recommended in cases with dysgenetic gonads to prevent the development of malignant changes. [7]
Clinical characteristics
Presentation of patients with ovarian GCTs can be similar both in malignant and in benign lesions; abdominal pain (70-80%) and lower abdominal mass are the most common symptoms. The tumor is often asymptomatic until it reaches a very large size with compression of the neighboring structures. Constipation, amenorrhea, vaginal bleeding are less frequent. [4] Tumors with trophoblasic cells may produce βHCG, that causes premature breast enlargement and pubic hair. The pattern of regional spread of tumors with malignant components often includes ascites and peritoneal metastases. On the other hand, neuroglial implants on the peritoneal surface are associated with mature or immature teratomas and don't affect prognosis. About 10% of cases present as acute abdomen due to torsion, infarction or spontaneous rupture of the mass.
The diagnostic work-up usually begins with ultrasound scan which shows a solid-cystic lesion, and plain abdominal x-rays that often shows calcifications; these investigations are followed by abdominal CT/MRI scan, which are necessary to define the size, the structure of the mass and the involvement of neighboring structures. Benign and malignant entities may have similar imaging features with solid and cystic components. Cystic components are more frequent in benign forms, however, caution is recommended in all cases because the hystologic subtype is not predictable at imaging evaluation. [2],[3],[4],[5],[6],[7]
Evaluation of serum markers is essential to address the nature of the tumors: Elevation of αFP or βHCG means the presence of malignancy. αFP is raised in over 90% of children with malignant GCTs while βHCG is elevated in 30% of cases. Also, other markers as LDH and NSE or those typical for epithelial tumors (CEA, Ca-125) may be slightly elevated in patients with mixed tumors. [7]
Metastatic spread has to be considered when a malignant tumor is suspected. In these cases thoracic and abdominal CT scan are required to evaluate involvement of the lungs, the liver and the retroperitoneal LNs.
Treatment of malignant GCT
Surgery has an important role in the treatment of patients with malignant GCTs which mainly consists in ovariectomy or ovarosalpingectomy. However, since malignant GCTs are very chemosensitive, primary excision should be attempted only when the surgeon thinks it constitutes a complete but non-mutilating procedure. [3],[4],[5],[6],[7],[8] With an accurate preoperative evaluation of the imaging investigations the feasibility of the resection can be defined.
The surgical approach can be performed through a Pfannestiel or a transverse infraumblical incision or a midline approach, depending on the size of the lesion and the likelihood of malignancy. Independently from the approach the surgeon should be prepared to perform a cancer operation, since malignant and benign forms cannot be distinguished at macroscopic evaluation. The use of laparoscopy to remove highly suspected malignant lesions is usually discouraged due to the size of the mass and its invasiveness: Actually the violation of the capsule or the rupture of the mass can result in upstaging the tumor. Furthermore, the procedures required during the operation may be difficult with mini invasive surgery. On the other hand, the removal of the tumor with an open surgery is very straightforward, because the mass, even if large, is encapsulated and often removable from the abdomen. The operation should include well defined intraoperative staging procedures: [3],[4],[5],[6],[7],[8],[9]
- Inspection and palpation of the contralateral ovary with a biopsy of suspected areas.
- Collect peritoneal fluid for cytology (or washing if no fluid is present).
- Intact removal of the ovary without violation of the tumor capsule. Sparing the fallopian tube only if not adherent.
- Examination of the omentum, the peritoneal surface and liver with removal of any abnormal areas. Peritoneal implants (gliomatosis peritonei) may be associated with mature or immature teratomas.
- Examination of iliac and aorto-caval nodes with biopsy of any abnormal nodes.
If imaging investigations show involvement of neighboring organs (i.e., bladder, uterus and vagina) or in case of bilateral malignant GCTs, a tumor biopsy is the best option. The biopsy may be "open," with laparoscopic technique ore with Tru-cut needle. Multiple needle-core biopsies in different areas of the mass, under ultrasound scan guidance, serve for histological diagnosis as well as for biological studies. However, a biopsy is not always required because the malignant nature of the mass can be established if the serum αFP or βHCG levels are high. When the initial surgical approach has been a biopsy or an excision with micro/macroscopic residues or in patients with metastatic disease, neoadjuvant chemotherapy is delivered. Generally, the mass becomes surgically resectable after chemotherapy. [8] Also, this operation usually is not demolitive; in case of bilateral tumors most authors recommend to attempt ovarian preservation if possible on the least involved side; mutilating excisions and bilateral ovariectomies are accepted only when chemotherapy has been proven not effective.
Staging of malignant GCTs
An accurate tumor staging with imaging and during the operation plays a crucial role in determining the following treatment. There are two main staging systems adopted for pediatric ovarian malignant tumors: The staging system suggested by the Children's Oncology Group (COG) which is summarized in [Figure 1] and the International Federation of Gynecology and Obstetrics (FIGO) staging system. Both of them are based on the results of the imaging investigations and on the findings of the first surgical approach. [4],[5],[6],[7]
Chemotherapy
Mediastinal germ cell tumors (MGCTs) are very chemosensitive and chemotherapy has dramatically improved the 5 year survival of these tumors. Combination chemotherapy based on vincristine, dactinomycin and cyclophosphamide (VAC) sometimes with other drugs were adopted since the 1970s; then cisplatin containing regimens were introduced achieving survival rates from 70% to 90% in different studies. At present bleomycin, etoposide with cisplatinum, (PEB) or with carboplatinum (JEB) are the most common regimens, showing the second a reduced toxicity. [3],[4],[5],[6],[7],[8],[9],[10]
At present most studies do not recommend further treatment after the complete removal of the tumor, with the contemporaneous absence of intraperitoneal dissemination and decrease of tumor markers (St. I). Patients with incomplete removal or biopsy at initial surgery or with distant metastases receive chemotherapy: The treatment utilized by COG suggests PEB x3 cycles for St. II-III patients (intermediate risk tumors) and PEB x4 cycles for St. IV patients (high risk tumors). The outcome is excellent in St. I patients, very good also for intermediate risk tumors and exceeds a survival of 80% also in metastatic patients.
Treatment of benign and immature GC
They are generally well defined masses, with larger cystic components as compared with malignant forms and don't show elevated levels of αFP or βHCG.
In the first months of life most ovarian lesions are benign and often detected at antenatal ultrasound. [11] Most of them can be observed for some months after birth until the spontaneous regression, while a more aggressive therapeutic approach is recommended in very huge (more than 5 cm in size) or symptomatic lesions.
The only effective therapy for a benign and immature GCT is the complete removal. [12] If histological completeness has not been achieved at primary surgery, a reoperation is suggested. The procedure often requires the ovariectomy, due to the size of the mass or uncertainty of diagnosis, however in selected cases with small tumors the enucleation of the lesion can be feasible and many authors advocate ovary-sparing operations with unilateral appearing lesions. [13],[14] On the other hand, every effort should be made to preserve hormonal and reproductive functions in patients with bilateral benign GCTs. Since most GCTs have a mixed structure, immature and malignant elements may coexist also without high levels of serum markers and it is sometime impossible to know whether the lesion is malignant or not before surgery; for this reason the surgical approach should always be very cautious and if any doubt arises on the nature of the mass, intraoperative staging procedures are recommended. Gliomatosis peritonei does not upstages the disease. If the diagnostic suspicion for malignancy is low and the pediatric surgeon is expert in minimally invasive surgery, a laparoscopic approach may be considered in cases with small or cystic masses. [12],[13],[14],[15],[16] Avoidance of tumor spill can be assured utilizing different techniques: The cystic mass can be placed in a retrieval bag, firstly punctured and then removed without spill within the bag;
Chemotherapy may be suggested only after relapse of mature or immature GCTs, especially in cases with high graded immature teratomas or if an increase of tumor markers raise the suspect of malignant transformation. The same regimens utilized for malignant GCTs are recommended. [10]
Treatment of ovarian masses associated with an ovarian torsion or incidentally found Approximately 10% of ovarian tumors present as an acute abdomen secondary to torsion or rupture of the tumor mass. The incidence of malignancy in children with ovarian torsion is low; most solid ovarian masses associated with torsion are benign. [13] Ovarian torsions require an emergent procedure and usually a laparoscopic procedure is preferred. The ovary can be excised or detorsed depending on the intraoperative findings. If a tumor is suspected at operation and the ovary is viable after the detorsion, an immediate ovariectomy should be avoided if clear signs of malignancy are not evident. [15] A re-operation will be planned on the basis of accurate imaging and serologic assessment. Immediate ovariectomy may be necessary only in the setting of an ischemic or necrotic ovary.
When a mixed or a solid mass is found incidentally at the time of an abdominal operation, accurate inspection of all abdominal contents is recommended to differentiate benign from malignant masses. [17] The presence of extra-ovarian spread, external ovarian vegetations, size >8 cm with evidence of numerous vessels predict malignancy. A second procedure after tumor markers evaluation is recommended.
Testis
Testicular GCTs represent about 10% of all pediatric GCTs, but about 30% of malignant GCTs. Bilateral forms are exceptional. Testicular GCTs have two age peaks: Children under 3 years may experience both mature teratoma and malignant GCTs represented almost exclusively by YST, while adolescents may have also seminomas or other mixed tumors often with delayed diagnosis and more advanced disease. [1],[2],[3]
The occurrence of GCTs is increased in patients with undescended testes and the risk is higher with intra-abdominal testes. The most common histological subtype is seminoma, which occur in adolescents or young adults. The effect of orchiopexy on testicular cancer is not completely known. [5]
Clinical characteristics
The main clinical feature is a painless scrotal mass; however, the tumor may appear as an emergent situation with pain and inflammatory characteristics and hydrocele. Diagnostic pitfalls are testicular torsion, epididymo-orchitis or post-traumatic hematoma, which show different aspects at history and diagnostic evaluation. Also, paratesticular rhabdomyosarcoma has to be considered in the diagnostic work-up. In a patient with a testicular mass, serum markers measurement represents the first diagnostic step to verify a possible malignant GCT. [4],[5] The scrotal ultrasound scan is the preferred imaging investigation to evaluate the testicular lesion. Sometimes it may be difficult to differentiate a testicular mass from a lesion of the paratesticurar tissues. Teratomas are usually cystic or partially solid and multicystc, whereas YST is solid. If the aspect of the lesion is suspected for a testicular neoplasm, no other imaging studies are necessary and a surgical approach on the tumor is recommended as soon as possible. In patients with a suspected malignant GCT at diagnostic work-up a thoraco-abdominal CT scan is recommended to evaluate possible metastatic spread, especially on the lungs and on the retroperitoneal LNs.
Treatment of malignant GCT
Surgery represents the cornerstone of the management of testicular GCTs. Ongoing protocols recommend an inguinal approach with vascular control before mobilization of the testis. [18],[19] If a malignant GCT is proven by frozen section examination of a biopsy of the mass, en bloc resection of testis and spermatic structures with ligation of the cord at the internal inguinal ring is required. [5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20] A complete removal of the tumor is feasible in most cases and the postoperative decrease of αFP will confirm the absence of disease in localized GCTs. Patients with scrotal skin involvement and those operated or biopsied through a scrotal approach should undergo hemiscrotectomy to ensure the local control; some authors state that when a scrotal orchiectomy has been performed without violation of the tumor capsule and the tumor markers decrease after the operation, hemiscrotectomy can be avoided assuming negative margins; however, the proximal cord structures should be resected up to the internal ring with an inguinal approach. If the initial scrotal operation was a biopsy the scrotum is considered contaminated and the patient should undergo hemiscrotectomy or upstaged to St. II receiving chemotherapy. [3] Primary orchiofunicolectomy is recommended also when distant metastases have been diagnosed. Primary retroperitoneal LN dissection is not recommended in prepubertal boys, since malignant GCTs are highly chemosensitive tumors. [21] Limited biopsy may be necessary to define the staging when the involvement of retroperitoneal LN is uncertain at imaging investigations. However, retroperitoneal LN dissection can be required when enlarged nodes remain after chemotherapy. Inguinal nodes exploration is indicated only in patients with scrotal involvement.
Staging of malignant GCT
According to the COG Staging system for childhood testicular GCTs the staging can be done after initial surgery [Figure 2]. Excellent survival is reported with surgery alone in St. I patients. [3],[4] They are managed by clinical and αFP monitoring. About 15% develop clinical evidence of relapse, mainly on the retroperitoneal nodes and can be successfully treated with further multidisciplinary treatment. Chemotherapy is recommended in patients with incomplete initial surgery or with distant metastases at diagnosis. The suggested combinations are the same recommended for all MGCTs, mainly based on cisplatin-containing regimens. COG suggests PEBx3 cycles for St. II-III-IV patients.
Treatment of benign GCT
Inguinal orchiectomy is usually recommended also for mature and immature GCTs. [22] However, when preoperative normal levels of AFP and other investigations address toward a benign GCT, a testis-sparing surgery through an inguinal approach can be taken into consideration. The feasibility of a conservative excision of the mass (tumorectomy) depend upon its size and site in the gonad. If residuals are evident or suspected at histologic evaluation after the enucleaction of the tumor, a re-excision with inguinal orchiectomy will be necessary.
| Conclusive remark | | |
GCTs are the most common tumors of the gonads in children and adolescents: They include a variety of histological entities with different incidence by age and behavior. An accurate diagnostic work-up can give important information on the nature of the tumor. Patients with gonadal MGCTs fare better than those with extragonadal MGCTs and survival rate exceeds 90% in localized forms. Chemotherapy has significantly improved the outcome of malignant forms since the introduction of platinum based regimens. Primary surgery still represents a crucial moment for ovarian and testicular GCTs. The surgical procedure has to be performed in agreement with the ongoing protocols both to directly achieve the cure and to obtain all the information necessary for the subsequent therapy.
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