3. Discussion
GCTs are a group of neoplasms that stem from different anatomic sites and in different age group. They are mainly located along the middle line of the body with the gonads being the most frequent involving organ and the mediastinum being the most common site of extragonadal GCTs(2, 13). The majority of GCTs contain mixed components and about 15% of them have the potential to be malignant but rarely do these tumors actually undergo malignant degeneration(14). Tumor malignant transformation (TMT) refers to that a non-germ cell tumor malignant component could be found within the bulk of a GCT or in its metastatic foci, which is called as GCT with somatic-type malignancy (SM)(15) accounting for about 6% of GCTs(16). The SM of GCTs are most observed in retroperitoneum and recurrent cases and it is extremely rare in the mediastinum with immature teratoma(6, 17).
Probably because the components of GCTs have pluripotency, varies types of histological malignant transformation may occur simultaneously within a GCT, of which sarcoma (predominantly rahbdomyosarcoma) is the most frequent histological type of SM followed by adenocarcinoma and primitive neuroectodermal tumors while the melanocytic neuroectodermal transformation is the rarest (17, 18). Other histology types include squamous cell transformation, carcinoid tumors, hemangioendothelioma, and nephroblastoma(18). In our case, the immature tumor was proved to have a SM, and the histological types were squamous cell tumor and sarcoma(rhabdomyosarcoma, chondrosarcoma and fibrosarcoma) while the lymph node metastasis was found to be squamous cell tumor malignant transformation, which meant a higher recurrence rate and aggressiveness than teratomas without malignant transformation(17). GCTs that developed SM naturally had been reported rarely, and they were seen more frequently in older patients with the peak age at 50 to 60 years old(15, 19, 20), most of them occurred subsequently to chemotherapy or irradiation in young patients with a malignant GCT initially(15). Therefore, it could explain that our case with initially a malignant GCT developed SM at last after chemotherapy and irradiation. However, the specific mechanisms of GCTs with SM are poorly understood and two pathogenesis were assumed. Firstly, chromosomal abnormalities have been detected such as isochromosome 12p or rearrangement of 2q(21) and it has been proved by Honecker F et al(22)that mature teratoma cells could undergo de-differentiate in vitro into malignant tissues, Secondly, a totipotential embryonal carcinoma cell transformed to a neoplasm of the somatic type through malignant de-differentiation could also be related with this phenomenon(23). Few other cases of immature teratoma with somatic-type malignancy have been reported previously (Table 1)(24-28). To our best knowledge, this is the largest primary mediastinum immature teratoma with somatic-type malignant transformation which received an en bloc resection so far.
Clinically, due to the mediastinal structures can accommodate large teratomas and their insidious growth, the manifestation of symptoms are not obvious even though GCTs with SM tend to be more symptomatic than those without SM, but the symptoms are rarely indistinguishable when they were present(29). However, several syndromes have been identified in association with nonseminomatous mediastinal GCTs that may aid diagnosis, such as Klinefelter’s syndrome and Hematologic neoplasms(30). As our case, the patient did not find the pretty large solid mass in the anterior mediastinum until he conducted a physical examination without presentation any anomalous symptoms. Symptoms such as cough, chest pain, dyspnea, heart failure, dysphagia, hemoptysis, hoarseness, postobstructive pneumonia and et al could arise when the tumor invaded or compressed the surrounding organs in the mediastinum(31), but these symptoms are not specific. Even though teratomas could grow extremely large, patients with superior vena cava syndrome (SVC) were rarely observed, accounting for no more than 10% of the cases(32). Radiologically, due to coexistence of tumor cells with different proliferation rates, attenuation heterogeneity is a common characteristic of the mass and GCTs with SM could present as solid mass along with areas of teratomatous, necrotic, or hemorrhagic zones in the contrast-enhanced CT scan(33). However, it did not suggest a particular subtype of malignant transformation which was mainly diagnosed based on the histological analysis via a biopsy or surgical specimen(34). But contrast-enhanced CT scanning is useful to determine whether the adjacent structures such as great vessels, heart and lung are invaded by the tumor or whether tumors metastasize to regional lymph nodes or other organs such as lung, brain, liver and spleen as well as tumors recurrence(27). In the case we reported herein, multiple characteristics were demonstrated in the contrast-enhanced CT scanning. Laboratory examination could find that serum tumor markers such as AFP and LDH are frequently elevated in 80% of patients with primary non-seminoma mediastinal GCTs, however, there are only about 30% to 35% of the patients with elevated β-HCG(35). Mediastinal nonseminomatous GCTs with elevated AFP and β-HCG have been previously reported in GCTs with SM, suggesting the presence of malignance and poor prognosis(5, 36). In the herein mentioned case, a high level of AFP(>1210ng/ml) and β-HCG(270.48mIU/ml) was observed before treatment. After chemotherapy and radiotherapy, the level of AFP as well as β-HCG decreased and neither AFP or HCG producing cells were confirmed in the resected specimens indicating that necrosis or de-production in the AFP and HCG-producing cells were induced by pre-operative chemotherapy and radiotherapy(37). However, the patient clinical presentation was getting deterioration with tumor growing rapidly and larger than before, which was not deemed as teratoma syndrome characteristically seen in mature mediastinal teratomas(38). In this case, the rapid tumor aggression is more likely due to the underlying aggressive nature of the non-GCTs malignant transformation components, especially sarcoma(36). It has been previously provided that GCTs with SM, especially with sarcoma malignant transformation, had a poor response to cisplatin-based chemotherapy(17, 39).
Orizi A et al(40) found that hematopoietic stem cells could exist in mediastinal GCTs which might cause hematologic derangements and it was associated with nontreatment-related blood malignance(41). Garnick MB(42) et al also found that primary mediastinal GCTs were associated with thrombocytopenia. This might explain the continued reduction of platelet occurred in our patient. Another explanation for this phenomenon might be myelo-suppression caused by chemotherapy or radiotherapy before surgery but we failed to conduct a bone marrow biopsy to further find out the pathogeny of this phenomenon. It is worth noting that GCTs may induce thrombotic events, especially during chemotherapy, and pulmonary embolism (PE) might be suspected when a sudden hemoptysis occurred(43).
Currently, the standard treatment for nonseminoma GCTs is chemotherapy followed by surgical resection of residual mass, however, radiotherapy is not recommended for it is invalid in treating primary mediastinal nonseminoma GCTs. The recommended chemotherapy is 4 courses of bleomycin, etoposide, and cisplatin(2). Given the poor sensitivity to chemotherapy, immature teratoma with SM is hardly to be eradicated by cisplatin-based chemotherapy, and an aggressive surgical resection is recommended whenever possible for it may offer a better survival(44). Nonetheless, Teratomas with SM presented in the mediastinum essentially have an aggressive course, high recurrence rate, and poor prognosis and are always fatal within a few months after initial diagnosis(15). As our case demonstrated, the tumor was resistant to standard chemotherapy and showed progression in size after chemotherapy, therefore a primary mediastinal GCT with SM might be suspected(15) and surgical intervention instead of any other treatments should be considered firstly whenever possible.
Generally, primary mediastinal teratomas with SM have an extremely poor prognosis for the malignant transformation components in term of chemotherapy resistance, high recurrence and more invasiveness and sometimes even sudden death(20, 45). Several indicators may relate with poor prognosis for GCTs which included as follow: (1) persistent germ cell tumor in the residual mass; (2) elevated LDH; (3) GCTs with thrombocytopenia; (4) somatic-type transformation; (5) post-chemotherapy AFP level greater than 1001 ng/ml(46, 47). Our patient had a number of poor indicators, including elevated LDH, thrombocytopenia and somatic-type transformation. Even though complete resection of the tumor had been achieved, he finally died after 5 months after the initial diagnosis, which was consistent with previous study(15).