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\begin{document}

\title{En bloc resection of an extremely giant mediastinal immature teratoma
with somatic-type malignancy: A case report with a brief review of the
literature}



\author[1]{qinghua zhou}%
\author[2]{kaili huang}%
\author[1]{pengfei li}%
\author[1]{hanyu deng}%
\author[1]{xiaojun tang}%
\affil[1]{West China Hospital of Sichuan University}%
\affil[2]{Sichuan University West China Hospital Lung Cancer Center}%


\vspace{-1em}



  
  \date{May 28, 2024}


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\textbf{En bloc resection of an extremely giant mediastinal immature
teratoma with somatic-type malignancy: A case report with a brief review
of the literature}

Kai-li Huang, MD\textsuperscript{1\#}, Pengfei Li,
MD\textsuperscript{1\#}, Han-Yu Deng, MD\textsuperscript{1}, Xiaojun
Tang\textsuperscript{1}, Qinghua Zhou, MD\textsuperscript{1*}

\textsuperscript{1}Lung cancer center, West China Hospital, Sichuan
University, Chengdu 610041, China

*Correspondence to: Qinghua Zhou. Lung Cancer Center, West China
Hospital of Sichuan University, No.37 Guoxue Alley, Chengdu 610041,
China. Email: prof\_qh\_zhou@126.com

\#These authors contributed equally to the study and were co-first
authors.

Conflicts of interest: The authors declare no competing interests.

Word count: 3717

\textbf{Consent statement:Written informed consent was obtained from
the patient's parents to publish this report in accordance with the
journal's patient consent policy}

\textbf{Abstract:} Primary mediastinum immature teratoma with
somatic-type malignant transformation (SM) is extremely rare, and the
clinical prognosis is poor. Immature teratoma with SM is hardly to be
eradicated by chemotherapy for the poor sensitivity, therefore surgical
resection is recommended whenever possible for it may offer a better
survival. We herein report a case of a chemotherapy-resistant and
extremely giant immature teratoma who received en bloc resection with
pathologic findings of foci of sarcoma and poorly differentiated
squamous cell carcinoma, and the literature is reviewed. To our best
knowledge, this is the largest primary mediastinum immature teratoma
with somatic-type malignant transformation treated with an en bloc
resection so far.

\textbf{Key words:} Primary mediastinum immature teratoma, somatic-type
malignant transformation, en bloc, surgery

\textbf{1. Introduction}

Germ cell tumors (GCTs) are a family of neoplasms with diverse
histopathological, clinical features and prognosis, which are widely
considered to arise from almighty primordial germ
cells\textsuperscript{(1)}. Gonads are the most common organ that GCTs
predominantly occurs, while a small proportion of GCTs primarily
develops in extra-gonad regions such as pineal gland, coccyx,
mediastinum, retroperitoneum\textsuperscript{(2)} and the anterior
mediastinum is the prior anatomical position in which approximately
10--20\% of primary extra-gonad GCTs occur\textsuperscript{(3)}.
Pathologically, GCTs are divided into two categories: pure seminomas and
non-seminomatous germ cell tumors (NSGCT)\textsuperscript{(4)}.
Teratoma, a subtype of NSGCT, accounts for about 40\% - 60\% of all
mediastinal GCTs with the majority of its histology being
mature\textsuperscript{(5)}. While the immature teratoma, a particularly
rare subtype of teratomas with poor clinical prognosis, accounts for
only approximately 1.8\% of mediastinal GCTs and about 4\% of
mediastinal teratomas\textsuperscript{(3)}. Moreover, the immature
teratoma with somatic-type malignant transformation (SM) is extremely
rare\textsuperscript{(6)}, and there are only a few cases described
about this topic\textsuperscript{(7-12)}. We herein report a case of a
chemotherapy-resistant and extremely giant immature teratoma who
received en bloc resection with pathologic findings of foci of sarcoma
and poorly differentiated squamous cell carcinoma. To our best
knowledge, this is the largest primary mediastinum immature teratoma
with somatic-type malignant transformation treated with an en bloc
resection so far.

\textbf{2. Case presentation}

An 18-year-old adolescent came to our medical center from a local
hospital for further management of a giant anterior mediastinum mass.
Four months before this admission, he made a routine health examination
at local health institution and found a huge mass in the mediastinum
without any clinical symptoms such as chest pain, dyspnea, or cough. For
further treatment, he was referred to a comprehensive oncology hospital
and malignant GCT was diagnosed by mediastinal biopsy. Therefore,
combined chemotherapy with etoposide (100 mg/m2IV on days 1--5),
bleomycin (30 units IV on days1, 8, and 15), and cisplatin (20 mg/m2IV
on days 1--5) was subsequently initiated. However, when four cycles of
chemotherapy were finished, he underwent a chest CT again which
indicated that there was no obvious improvement. Hence, he received
radiotherapy (specific dose was not known) at another oncology hospital
and the mediastinum mass failed again to respond to radiotherapy and the
tumor volume even grew since then. In our hospital, physical examination
revealed a thin-built man with normal vital signs and weight loss.
Superior vena cava syndrome (SVCs) such as facial edema and jugular vein
distention was not observed. Respiratory, cardiac, abdominal, testicular
and lymph node examination were negative.

Contrast-enhanced CT showed that a large (approximately
21.6\selectlanguage{ngerman}×12.3×10.5cm\textsuperscript{3}) solid mass with heterogeneous
enhancement and noncalcified in the anterior mediastinum. Heart and
great vessels including superior vena cava (SVC), ascending aorta,
pulmonary artery and left principal bronchus were compressed and
surrounded by the tumor with well-defined margin while mediastinal lymph
nodes were not noted (Figure 1). Brain MRI, abdominal contrast-enhanced
CT, bone scan and pulmonary function test were normal.

Laboratory investigations showed thrombocytopenia
(platelets=21×10\textsuperscript{9}/L,
normal=100\selectlanguage{english}~300x10\textsuperscript{9}/L), anemia (hemoglobin\selectlanguage{english}[Hb\selectlanguage{english}]=
92g/L, normal range=130-175g/L) and normal leukocyte count. Lactate
dehydrogenase (LDH), alpha fetoprotein (AFP), \selectlanguage{greek}β-\selectlanguage{english}human chorionic
gonadotropin(\selectlanguage{greek}β-\selectlanguage{english}HCG) and carcinoembryonic antigen (CEA) were
elevated(AFP>1210ng/ml, normal<8ng/ml; \selectlanguage{greek}β-\selectlanguage{english}HCG=270.48mIU/ml,
normal<3.81mIU/ml; CEA=3.71ng/ml, normal<3.4ng/ml). After chemotherapy
and radiotherapy, the level of AFP decreased to 69.56ng/ml and \selectlanguage{greek}β-\selectlanguage{english}HCG
decreased to normal (\selectlanguage{greek}β-\selectlanguage{english}HCG=0.26mIU/ml). Other laboratory examinations
including renal, hepatic, coagulation function were within acceptable
limits. Therefore, the patient underwent surgical resection of the tumor
after informed consent was obtained from the patient.

A giant solid mass with intact capsule was observed macroscopically. In
the mass, most of the components were solid with local necrosis and
multiple cysts. Two mediastinal lymph nodes were observed with a
diameter of about 0.8~0.9cm. At the same time, a piece of pericardium
attached to the tumor with a size of about 3.6cm\selectlanguage{ngerman}×2.2cm was also
observed. Microscopically, the tumor was consisted of epithelial tissue,
cartilage tissue, skeletal muscle tissue and other mesenchymal tissue,
part of which were presented as immature or malignant morphology (Figure
2). Immunohistochemical staining demonstrated that cytokeratin (CK),
epithelial membrane antigen (EMA), smooth muscle actin (SMA), desmin
(Des), MyoD 1 and Myogenin were positive while AFP and HCG were negative
indicating that the large mass was an immature teratoma with poorly
differentiated squamous cell carcinoma and sarcoma malignant
transformation.

\textbf{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\textsuperscript{(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\textsuperscript{(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)\textsuperscript{(15)} accounting
for about 6\% of GCTs\textsuperscript{(16)}. The SM of GCTs are most
observed in retroperitoneum and recurrent cases and it is extremely rare
in the mediastinum with immature teratoma\textsuperscript{(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 \textsuperscript{(17, 18)}. Other histology
types include squamous cell transformation, carcinoid tumors,
hemangioendothelioma, and nephroblastoma\textsuperscript{(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\textsuperscript{(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\textsuperscript{(15, 19, 20)}, most of them occurred subsequently to
chemotherapy or irradiation in young patients with a malignant GCT
initially\textsuperscript{(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\textsuperscript{(21)} and it
has been proved by Honecker F et al\textsuperscript{(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\textsuperscript{(23)}. Few
other cases of immature teratoma with somatic-type malignancy have been
reported previously (Table 1)\textsuperscript{(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\textsuperscript{(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\textsuperscript{(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\textsuperscript{(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\textsuperscript{(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\textsuperscript{(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\textsuperscript{(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\textsuperscript{(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
\selectlanguage{greek}β-\selectlanguage{english}HCG\textsuperscript{(35)}. Mediastinal nonseminomatous GCTs with
elevated AFP and \selectlanguage{greek}β-\selectlanguage{english}HCG have been previously reported in GCTs with SM,
suggesting the presence of malignance and poor
prognosis\textsuperscript{(5, 36)}. In the herein mentioned case, a high
level of AFP(>1210ng/ml) and \selectlanguage{greek}β-\selectlanguage{english}HCG(270.48mIU/ml) was observed before
treatment. After chemotherapy and radiotherapy, the level of AFP as well
as \selectlanguage{greek}β-\selectlanguage{english}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\textsuperscript{(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\textsuperscript{(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\textsuperscript{(36)}. It has been previously provided that GCTs
with SM, especially with sarcoma malignant transformation, had a poor
response to cisplatin-based chemotherapy\textsuperscript{(17, 39)}.

Orizi A et al\textsuperscript{(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\textsuperscript{(41)}. Garnick MB\textsuperscript{(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\textsuperscript{(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\textsuperscript{(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\textsuperscript{(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\textsuperscript{(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\textsuperscript{(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\textsuperscript{(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\textsuperscript{(15)}.

\textbf{Conclusion}

In summary, primary mediastinal immature teratoma with somatic-type
malignancy is extremely rare with extremely poor prognosis. When
laboratory and imaging findings are conflicting for patients with
immature teratoma after chemotherapy, somatic-type malignancy should be
considered. Due to its rarity, comprehensive reporting of clinical,
radiological and pathological features is needed for a diagnosis of an
immature teratoma with SM. We reported a primary giant mediastinal
immature teratoma with sarcoma and squamous malignant transformation
which was resistant to chemotherapy and radiotherapy but resected
completely. Rare as it is, additional cases of this pathology are needed
to add to the literature for a better understanding of somatic-type
malignancy and management of this disease.

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Figure Legends

Figure 1 A-C: Contrast-enhanced CT indicated a large mass in the
anterior mediastinum with well-defined margin and the important
structures in the mediastinum were compressed and surrounded by the
tumor; D-F: an en bloc resection of the large solid tumor with intact
capsule via a median sternotomy.

Figure 2 HE stain of somatic-type malignancies components showing: (A)
rhabdomyosarcoma; (B) chondrosarcoma; (C) fibrosarcoma; (D) poorly
differentiated carcinoma. Magnification ×200.\selectlanguage{english}
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