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).