© 2011 The Korean Academy of Medical Sciences.
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Development of Acute Megakaryoblastic Leukemia with
Isochromosome (12p) after a Primary Mediastinal Germ Cell
Tumor in Korea
The association of hematological malignancies with a mediastinal germ cell tumor (GCT) is
very rare. We report one case of a young adult male with primary mediastinal GCT who
subsequently developed acute megakaryoblastic leukemia involving isochromosome (12p).
A 25-yr-old man had been diagnosed with a mediastinal GCT and underwent surgical
resection and adjuvant chemotherapy. At 1 week after the last cycle of chemotherapy, his
peripheral blood showed leukocytosis with blasts. A bone marrow study confirmed the
acute megakaryoblastic leukemia. A cytogenetic study revealed a complex karyotype with
i(12p). Although additional chemotherapy was administered, the patient could not attain
remission and died of septic shock. This case was definitely distinct from therapy-related
secondary leukemia in terms of clinical, morphologic, and cytogenetic features. To our
knowledge, this is the first case report of a patient with mediastinal GCT subsequently
developing acute megakaryoblastic leukemia involving i(12p) in Korea.
Key Words: Mediastinal Germ Cell Tumor; Acute Megakaryoblastic Leukemia;
Nae Yu1, Hye Ryoun Kim1,
Young-Joo Cha1, Eun Kyung Park2
and Jeong Wook Kim2
Departments of 1Laboratory Medicine and 2Internal
Medicine, Chung-Ang University College of Medicine,
Received: 14 March 2011
Accepted: 8 June 2011
Address for Correspondence:
Hye Ryoun Kim, MD
Department of Laboratory Medicine, Chung-Ang University
College of Medicine, 29 Heukseok-ro, Dongjak-gu, Seoul
Tel: +82.2-6299-2718, Fax: +82.2-6298-8630
DOI: 10.3346/jkms.2011.26.8.1099 • J Korean Med Sci 2011; 26: 1099-1102
Oncology & Hematology
Germ cell tumors (GCTs) account for 2% of human malignan-
cies, but are the most common tumors in males 15-35 yr old (1).
Mediastinal GCTs occur predominantly within the anterior me-
diastinum, which account for 1%-4% of mediastinal tumors, and
that have different clinical characteristics from testicular GCTs
(2, 3). The association between hematological malignancies and
mediastinal GCT was first reported in 1983 (4) and more than
50 cases have been published since (5-9). Most often, the mega-
karyocytic lineage of hematopoiesis is involved in hematologic
malignancy, resulting in acute megakaryoblastic leukemia, my-
elodysplsia with abnormal megakaryocytes, or idiopathic throm-
bocytopenia, essential thrombocythemia. Other hematologic
diagnoses included acute lymphocytic or acute myeloid leuke-
mia (AML) and, in rare cases, malignant histiocytosis or system-
ic mastocytosis (4-7, 9). A total of 64 cases of hematologic malig-
nancies with mediastinal GCT cases have been published (1,
4-9) and only one case has reported bone marrow involvement
in a mediastinal GCT case in Korea (10). Here we present a case
in which a patient developed acute megakaryoblastic leukemia
involving i(12p) after a primary mediastinal GCT.
A 25-yr-old man presenting with chest pain was admitted to
Chung-Ang University Hospital (Seoul, Korea) because of an ab-
normal mass in the anterior mediastinal area. He had no remark-
able past medical and familial history. He had been diagnosed
with a malignant mediastinal GCT (immature teratoma 80%,
embryonal carcinoma 10%, seminoma 5%, yolk sac tumor 5%)
in January 2010. Peripheral blood examination showed the fol-
lowing: Hb level, 14.5 g/dL; leukocyte count, 10,770/μL (neutro-
phil 70%, lymphocyte 21%, no blasts); and platelet count, 257,000/
μL. Serum alpha-fetoprotein (AFP), beta-human chorionic go-
nadotropin (hCG), and lactate dehydrogenase (LDH) were 11,680
ng/mL, 0.847 mIU/mL, and 187 IU/L, respectively. After surgi-
cal resection of the tumor, the patient received four cycles of ad-
juvant chemotherapy with bleomycin, etoposide, and cisplatin
between February and April 2010. During routine follow-up in
August 2010, a persistent tumor lesion was found and the patient
received three cycles of adjuvant chemotherapy with pacilitaxel,
ifosfamide, and cisplatin between August and October 2010. A
peripheral blood examination performed in October 2010 showed
pancytopenia without blasts.
After 1 week of the last chemotherapy cycle, the patient visit-
ed the emergency room with a fever. Peripheral blood examina-
tion showed the following: Hb level, 5.9 g/dL; leukocyte count,
12,920/μL with 16% neutrophils, 22% lymphocytes, 57% blasts;
5 nucleated red cells per hundred white blood cells; and platelet
count, 6,000/μL (Fig. 1A). Serum AFP and LDH levels were 234
ng/mL and 2,964 IU/L, respectively. Based on these findings,
Yu N, et al. • Development of AML with i(12p) after a GCT in Korea
acute leukemia was suspected and a bone marrow examination
was performed in November 2010. In the bone marrow aspira-
tion, about 40.4% of all nucleated cells were blasts. The blasts
were medium to large-size with round, slightly irregular nuclei
and one to three nucleoli. The cytoplasm of blasts was basophil-
ic and might show distinct bleb or pseudopod formation (Fig.
1B). The dysplastic features of a megakaryocytic lineage (e.g. mi-
cromegakaryocytes and hypolobulation of the nucleous) were
found in more than 30% of 30 megarkaryocytes (Fig. 1C). Cyto-
chemical staining showed that the cells had dot-like positivity
for periodic acid-Schiff (Fig. 1D) and acid phosphatase, in con-
trast, negativity for myeloperoxidase, α-naphthyl acetate ester-
ase and α-naphthyl butyrate esterase. The bone marrow biopsy
showed about 90%-100% cellularity (Fig. 1E). Immunopheno-
typing showed positivity for CD13, CD33, CD117, MPO, CD7,
CD61, and HLA-DR, and was negative for CD2, CD3, CD5, CD19,
CD20, cCD22, cCD79a, CD10, CD14, and TdT. Cytogenetic ex-
amination revealed a 46,XY,add(5)(q11.2),del(10)(p11.2), -17,
der(18)t(17;18) (q11.2;q21), +i(12p) karyotype (Fig. 2). FISH
analysis using AML1/ETO, BCR/ABL, MLL, PML/RARA, and
CBFB gene probes (Vysis, Downers Grove, IL, USA) demonstrat-
ed no abnormalities. After conferring a diagnosis of acute mega-
karyoblastic leukemia, chemotherapy with idarubicin and ara-
C was administered and the patient showed pancytopenia. The
patient was then treated with mitoxantrone and ara-C, and bone
marrow examination was performed that showed severe hypo-
cellular marrow and reactive increase of histiocytes and plasma
cells. Despite the additional chemotherapy, the disease not go
into remission and the patient died of septic shock 1 month af-
ter the diagnosis of leukemia had been made. A summary of the
clinical course is shown in Table 1.
This case concurs with previous evidence of an association be-
tween hematological malignancies and mediastinal GCTs in
young males (5-9). Hematological malignancies associated with
mediastinal GCTs must be distinguished from therapy-related
secondary leukemia. Leukemia associated with the use of alkylat-
ing agents usually occurs after an average interval of 5-7 yr, often
Fig. 1. (A) Peripheral blood smear showing blasts (57% of nucleated cells). (B) Bone marrow smear revealed many medium-sized myeloblasts (about 40.4% of all nucleated
cells). (C) Dysplasic megakaryocyte. (D) PAS positivity (granular pattern). Wright-Giemsa stain, × 1,000 magnification. (E) Bone marrow biopsy showing compact marrow with
increased dysplastic megakaryocytes (H&E, × 400 magnification).
Fig. 2. Giemsa-banded karyotype showing 46,XY,add(5)(q11.2),del(10)(p11.2),
Yu N, et al. • Development of AML with i(12p) after a GCT in Korea
preceded by a preleukemic period with myelodysplasia and fre-
quently progressing to AML with French-American-British clas-
sification (FAB) subtypes M1 or M2 (11). Topoisomerase II in-
hibitor-related secondary leukemia is generally diagnosed 2-3
yr after chemotherapy and most commonly exhibit FAB M4 or
M5 phenotypes. While the latter type of leukemia is frequently
associated with translocations of the long arm of chromosome
11 (11q23) (12-15), leukemia that appears after treatment with
alkylating agents displays alterations in chromosome 5 or 7 in a
high proportion of patients (60%-90%) (5).
In contrast, leukemia associated with mediastinal germ cell
tumors appears to have no consistent cytogenetic abnormali-
ties (9). However, in some cases, immunohistochemical and cy-
togenetic evidence, especially presence of i(12p) chromosome,
had previously suggested the clonal relationship between the
mediastinal GCTs and the hematologic malignancy (16). Also,
two cases of leukemia have been reported in which i(12p) was
found and both of these leukemia patients had mediastinal GCTs
(17). The most common karyotypic abnormality in a mediasti-
nal GCT and in the associated leukemic blasts was i(12p), sug-
gested that i(12p) was might be a potential predictive marker
for development of acute megakaryoblastic leukemia. Although
our patient was treated with an alkylating agent (ifosfamide), the
interval period between mediastinal GCT and the development
of acute leukemia was only 10 months, the leukemia phenotype
expressed in bone marrow and peripheral blood was that of acute
megakaryoblastic leukemia, and a characteristic chromosomal
abnormality i(12p) was also found in this case. Therefore, the
clinical, morphologic, and cytogenetic features of the leukemia
in our case are definitely different from therapy-related acute
leukemia although the patient received seven cycles of chemo-
The most possible explanation for the association between
mediastinal GCTs and acute megakaryoblastic leukemia was
suggested by Nichols et al. (9) who found that hematologic neo-
plasm is a consequence of multipotential differentiation of ma-
lignant germ cells. Presumptive corroboration of this theory is
Table 1. Summary of the clinical data for the patient with acute megakaryoblastic leukemia and a primary mediastinal GCT
Primary mediastinal GCT
Four cycles of bleomycin, etoposide and cisplatin
Three cycles of pacilitaxel, ifosfamide and cisplatin
5.9 g/dL-12,920/µL-6,000/µL (57% blasts)
Acute megakaryoblastic leukemia
R/O hypocellular marrow and reactive increase of histiocytes and plasma cells
Interval period (months)
First and second
PB, peripheral blood; BM, bone marrow.
provided by the finding of i(12p) as a marker chromosome in the
cytogenetic analysis of bone marrow in a patient with a medias-
tinal GCT and leukemia.
Hematologic neoplasms with primary mediastinal GCT pos-
sess a very aggressive clinical course. Patients tend to die before
treatment, do not respond to anti-leukemic therapy, or achieve
only short remissions. Allogenic bone marrow transplantation
may be the only curative strategy despite one report with two pa-
tients who failed to respond to this treatment (5). However, a sub-
group of patients with platelet disorders seemed to have a slight-
ly better prognosis (4, 6). The patient in our case also showed
very aggressive clinical course and little response to chemother-
apy. His survival period after AML diagnosis was only 2 months.
There has been one report showing and association between
mediastium and hematological diseases in Korea which present-
ed a case of a primary mediastinal GCT with bone marrow in-
volvement (10). However, this case did not present either acute
megakaryoblastic leukemia or leukemia involving i(12p); rather,
this group reported acute undifferentiated leukemia with triso-
my 8 and concurrent mediastinal GCT. It remains unclear why
some patients with non-seminomatous mediastinal GCTs de-
velop a hematologic disorder whereas the majority of patients
are unaffected. Based on cytogenetic findings (high incidence
of i[12p]) and there is a short interval between the treatment of
GCT and being diagnosed with leukemia, no relationship appar-
ently exists between the treatment of GCTs and the development
of leukemia (5).
This is the first report of a patient with a mediastinal GCT who
subsequently developed acute megakaryoblastic leukemia with
i(12p) in Korea. Future studies on pathogenesis of the association
between these diseases are needed. Furthermore, improved strat-
egies for treating hematological disorders in patients with medi-
astinal GCTs should be another area of further investigation.
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