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To review the experience with the diagnosis and management of extragonadal germ cell tumors (GCT) with a subset analysis of those with atypical features.
A retrospective chart review of patients of extragonadal germ cell tumors between 2000 and 2010 was carried out.
Fifteen children aged 7 days to 15 years (median, 1.5 years) were included. Three had an antenatal diagnosis (one sacrococcygeal, one retrobulbar, one retroperitoneal tumor) and were operated in the neonatal period. The locations were distributed between the retrobulbar area (1), anterior neck-thyroid gland (1), mediastinum (4), abdominothoracic extending through the esophageal hiatus (1), retroperitoneal (4) and sacrococcygeal (4). On histological examination, five harbored immature elements while two were malignant; the latter children received postexcision adjuvant chemotherapy. There was no mortality. At a median follow-up of 4.5 years (6 months to 8 years), 14/15 have had an event-free survival. One immature mediastinal teratoma that recurred locally 7.5 years after the initial operation was excised and adjuvant chemotherapy instituted.
Extragonadal GCTs in children are uncommon and occasionally present with atypical clinical, radiological and histological features resulting in diagnostic and therapeutic dilemmas.
Germ cell tumors (GCT) in children are relatively uncommon. They account for approximately 3% of pediatric malignancies.[1,2] Extragonadal GCTs constitute only 1–5% of all GCTs. Occasionally, they may present with atypical clinical, radiological or pathological features. This series presents our experience with the diagnosis and management of extragonadal GCT and elaborates six cases with atypical features in particular.
A retrospective chart review of patients operated for extracranial extragonadal GCTs between 2000 and 2010 was carried out. The details regarding demography, clinical presentation, tumor location, tumor markers, imaging, operative findings, histopathology, follow-up and outcome were analyzed. The postoperative adjuvant chemotherapy with five or six cycles of Cisplatin–Etoposide–Bleomycin (PEB) was administered if the histology was reported as malignant GCT or immature teratoma, Norris Grade 3. All were followed-up with clinical evaluation, tumor marker estimation and imaging closely till the elevated tumor markers normalized and annually thereafter. Descriptive analysis was done.
Fifteen patients (10 males, five females) of extragonadal GCTs were included in this review [Table 1]. Their age at presentation ranged from 7 days to 15 years (median, 1.5 years). One tumor was retro-orbital, one located in the anterior neck with thyroidal involvement, one an abdominothoracic mass extending across the esophageal hiatus and involving the gastroesophageal junction and four each of mediastinal, sacrococcygeal and retroperitoneal teratomas. An antenatal diagnosis was made in three (retro-orbital tumor, one sacrococcygeal teratoma, one retroperitoneal tumor); the first two presented in the neonatal period while the latter child reported at 6 years of age. Three of 15 were operated in their first month of life and 6/15 in infancy.
Most of the cases presented with predictable clinical features depending on their location and size. Two cases presented with atypical clinical features that are detailed below.
One with a left anterior mediastinal teratoma (Case 1) presented with a combination of acute respiratory symptoms attributable to the mass effect of the tumor in the chest. In addition, he had developed behavioral and psychiatric symptoms since 4 months. He had been diagnosed with schizophrenia and was on antipsychotic therapy. The psychiatric symptoms resolved 6 months after surgical extirpation of the mass and his medications were discontinued. He had a recurrence 7.5 years later, but did not manifest psychiatric symptoms again.
The other atypical clinical presentation was seen in a preterm, low-birth weight newborn who presented with an absent anal opening and a sacrococcygeal mass (Case 13). At exploration, the tumor was seen fungating into the lumen of the blind rectal pouch through a well-defined opening in the rectal wall [Figure 1].
On contrast-enhanced computerized tomography (CECT), most of the tumors were heterogeneous, solid-cystic masses with characteristic patchy enhancement and variable areas of calcification. Atypical radiological features were noted in two cases.
One child with a retroperitoneal teratoma who presented with an asymptomatic fullness of the right side of the abdomen (Case 7) had a thin-walled cystic swelling occupying the entire right retroperitoneum, displacing the right kidney inferiorly and inferior vena cava to the left. The cyst had a few thin septations; however, a small nondescript focus of calcification in the superomedial part overlying the T 12 vertebra was missed. A preoperative diagnosis of a retroperitoneal lymphatic cyst was made. At laparotomy, the tumor resembled a large thin-walled cyst containing clear fluid with a few incomplete septa, thereby morphologically mimicking a lymphatic cyst. A small area containing pultaceous matter, calcific elements and hair in the superomedial portion of the tumor abutting the right crus of the diaphragm was found only after complete excision of the mass.
Case 2 had a large left-sided thoracic mass arising from the mediastinum and occupying the entire left hemithorax. On imaging, the caudal part of the mass appeared to contain two curvilinear calcific shadows morphologically resembling ribs. The differentiation into rib-like structures was further borne out on gross and microscopic examination [Figure 2].
Histologically, the tumors were classified as mature, immature, malignant mixed germ cell and malignant pure yolk sac tumors. Eight of 15 were mature teratomas that showed various derivatives of ectoderm, mesoderm and endoderm. In addition, the anterior cervical teratoma (Case 15) showed thyroid follicles and retinal anlage. Five of 15 were immature teratomas; all had primitive neuroepithelium in various proportions, two in addition had immature glomeruli [Figure 3]. Of the five immature teratomas, one was Norris Grade 1 while four were Norris Grade 2. Case 2 was a malignant mixed GCT with mature teratomatous elements and yolk sac components; this case in addition showed two rib-like structures. Contiguous infiltration into the periaortic tissue and lung and mediastinal lymph nodal metastases was also noted. Finally, one case was a pure yolk sac tumor and sacrococcygeal in location. Few unusual pathological observations are elaborated below.
In Case 5, the abdominothoracic mass extended into the posterior mediastinum through the esophageal hiatus and seemed to grossly involve the gastroesophageal junction. A complete excision of the tumor necessitated contiguous excision of the gastroesophageal junction and lower esophagus with gastroesophageal anastomosis to restore bowel continuity. Focal ossification with primitive neuroepithelium was seen on the serosal aspect of the gastroesophageal junction; however, the stomach and lower esophagus were not involved [Figure 4].
In addition to primitive neuroepithelium and glomeruli, one retroperitoneal teratoma (Case 8) featured an entire wall of the colon on gross and microscopy [Figure 5].
Two children with malignant tumors received adjuvant chemotherapy with the PEB schedule; the child with thyroidal teratoma and near-total thyroidectomy is on thyroxine supplementation. The duration of follow-up ranged from 6 months to 8 years (median, 4.5 years). There has been no mortality in this series. All are well and asymptomatic except Case 1, who presented with a local recurrence 7.5 years after the initial operation. The histological features of the recurrence were identical to the original tumor. After a recent excision of the recurrent tumor, he is now on adjuvant chemotherapy with PEB.
GCTs may occur in gonadal or extragonadal sites. In children younger than 15 years, the most common primary sites of GCT are the ovary (26%), coccyx (24%), testis (18%) and brain (18%). Extragonadal teratoma is the most common congenital tumor and, in infancy, sacrococcygeal tumors predominate, other extragonadal sites being mediastinum (4%), retroperitoneum (4%) and vagina (2%). Extragonadal GCTs are rare and constitute only 1–5% of all GCTs. Mediastinal GCTs presenting during childhood are extremely rare and immature teratomas are the rarest, accounting for only about 1% of mediastinal teratomas. Anterior mediastinum is the more common site and posterior mediastinal teratomas are occasional, with 18 cases reported till 2000.
Extragonadal GCTs usually arise as a result of aberrant migration of the progenitor germ cell. In spite of a common origin, these tumors demonstrate diverse clinical, radiological, morphological and histological variations. Of the 15 cases included in this review, six have presented with features not commonly associated with GCTs, some not reported in the published English literature.
Neuropsychiatric paraneoplastic syndromes have been described with virtually all tumors, but most commonly with small cell lung cancers. Such syndromes are usually due to immune-mediated encephalitis[11–13] and are occasionally seen with gonadal GCTs, but are unusual in extragonadal GCTs. The details regarding the initial presentation of Case no. 1 have been previously reported elsewhere. Most of the patients who have developed immune-mediated encephalitis in conjunction with GCTs have demonstrated resolution of neurological symptoms either with tumor extirpation or with immunosuppressive therapy.[11–13] It is interesting that these symptoms did not reappear with the histologically similar recurrence years thereafter.
The most common extragonadal GCT in young children is a sacrococcygeal tumor. These tumors are seen in conjunction with low-anorectal malformations as part of the Currarino triad, which always comprises a certain degree of sacral hypoplasia. One study has included a few children in this syndrome despite the presence of a normal sacrum because they had a HLXB9 mutation characteristic of Currarino's syndrome. A high-anorectal malformation is unusual in children with sacrococcygeal teratoma (Case 13) with or without Currarino's syndrome.[16–19]
The radiological characteristics of GCT are generally predictable; these tumors appear as complex masses with solid and cystic areas with variable amounts of fat, fluid and calcification. The presence of fat–fluid levels has been said to be highly specific for teratomas.[20,21] The presentation as a predominantly thin-walled large cyst with nonenhancing walls, few incomplete thin septae and containing clear fluid (Case 7) is unusual. This tumor had a very small solid component with minimal calcification that was overlooked and a strong possibility of a retroperitoneal lymphatic cyst was entertained preoperatively. Intraoperative aspiration of the cyst yielded a clear watery fluid that further strengthened the possibility of lymphatic cyst.
Tumoral calcification in GCT may resemble bone formation, more commonly in benign (up to 76%) than in malignant teratomas (up to 25%). Toothlike calcification or rim calcification is seen in approximately 56% of GCT. Recognisable teeth may be present in up to 29% of benign ovarian teratomas. Although tooth-like differentiation is common, osseous organoid differentiation as in Case 2 is only sporadically reported.
Teratomas are tumors composed of a variety of cell types derived from more than one germ layer; they can occur in any region of the body, commonly in the paraxial and midline location. They are thought to arise from totipotent cells that differentiate along various tissue lines such as skin, muscle, fat, cartilage, etc. These structures are usually admixed haphazardly and rarely form well-defined gross anatomical structures such as the colonic wall seen in one of our cases (Case 8). Mature teratomas behave in a benign fashion in contrast to immature teratomas, which may be clinically malignant in behavior. Histologically, the latter contain “immature” elements, such as immature neuroepithelium or immature mesenchymal tissue. Rarely, immature metanephric elements such as glomeruli-like structures may also be seen as in two cases in this series (Cases 8 and 10). The risk of recurrence can be estimated from parameters such as primary site of tumor, histological grade of immaturity and completeness of tumor excision. Malignant GCT s (teratomas, yolk sac tumors, embryonal carcinomas and dysgerminomas) are characterized by an infiltrative growth pattern and lymphogenous/hematogenous spread.[5,8] They account for 2.9% of all malignant tumors of children younger than 15 years of age, and more than half occur at extragonadal sites. Two of our cases (Cases 2 and 11) showed yolk sac tumors, one of these (Case 2) in association with teratomatous elements (malignant mixed germ cell tumor).
El Kalla et al., reported a case of benign posterior mediastinal teratoma infiltrating the lower third of the esophagus. This was a dumbbell like extension of a posterior mediastinal teratoma protruding through the esophageal hiatus. In Case 5, the infiltration of the immature teratoma was limited to the serosa microscopically. However, on gross examination, the gastroesophageal junction was encased by the tumor and the surgeons felt it necessary to resect it with the tumour to achieve complete excision.
Mature teratomas have been reported to demonstrate a high degree of differentiation often resembling tissues of normal organs. Instances of a mature cystic teratoma of the ovary associated with a complete colonic wall and colonic type adenocarcinoma arising in a primary retroperitoneal mature cystic teratoma have been reported in adults. Well differentiated colonic mucosa has been observed in an infant with sacrococcygeal teratoma and associated anorectal malformation; another sporadic report details the presence of colonic loops in a mature teratoma. Yet, it is not very common for these tumours to demonstrate organoid development; in Case 8, the immature retroperitoneal teratoma harbored a colonic wall in entirety. The mucosa, muscularis mucosa, submucosa, both layers of muscularis propria and both submucosal and myenteric plexii with clusters of ganglion cells were clearly identifiable.
Complete surgical excision is effective for children with immature teratomas with/without malignant elements (POG/CCG intergroup study), and salvage chemotherapy has been successful in those with recurrent disease. Except one (Case 1), all cases of immature teratomas in this series have undergone only complete surgical excision and have not recurred. Case 1 was an immature teratoma (Norris Gr 2) who presented with a recurrence 7.5 years after initial surgical excision; the recurrence was histologically similar to the primary tumor. It is unclear why this tumor behaved differently from other immature teratomas. Considering the aggressive tumor behavior, he received platinum-based chemotherapy after the excision of the recurrence.
Extragonadal GCTs in children are uncommon. These tumors can present at times with atypical features not commonly described elsewhere, resulting in diagnostic and therapeutic difficulties. Awareness of the extreme diversity of clinical, radiological, morphological and histological diversity with which these tumors may present is helpful in planning appropriate management.
Source of Support: Nil
Conflict of Interest: None declared.