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２２２２國家衛生研究院國家衛生研究院國家衛生研究院國家衛生研究院 癌症研究所癌症研究所癌症研究所癌症研究所

Initial presentation � 22 y/o young man, with progressive shortness of breath for 2 weeks

� PH: nil

� Chest pain(+), weakness(+), fever(-)

� PE: anemic conjunctiva(+), decreased breathing sound over left lung(+)

� Chest CT: left hemothrax

� Lab data

● WBC: 11100 /μL with blast 5%, band 2%, seg 77%, mono 4%, lymph 9%, Hgb: 12.1 g/dL, PLT: 31000/μL

● Cr: 1.02 mg/dL, AST/ALT: 99/62 U/L, LDH: 6360 U/L

� Analysis of pleural effusion

● Hemothorax (HgbPE/Hgb: 6.2/12.1 > 50%)

● Cytology: negative for malignancy

BM smear

Liu’s stain 200X, Blasts 47.5% Liu’s stain 1000X

POX: 0 % ANBE: 1% PAS: 24%

BM Bx H&E 400X

60~79,XXYY,-X[3],-2[11],-3[11],-3[6],-4[11],-4[11],-5 [10],-5[3],+6[3],-7[3],-8[4],-9[10],-9[5],?i(9)(p10) [8],-10[4],-11[11],-11[11],-12[6],?i(12)(p10)x2[5],?i(12)(p10)[4],-13[11],-13[10],-14[3],-15[11],-15[7],-16 [9],-17[9],-17[4],-18[11],-18[4],+19[2],-19[4],+20[3], -20[3],+21[8],+21[7],+21[2],+mar[3][cp11]/46,XY[9]

Cytogenetic analysis

Flow cytometry: CD13: 26%, CD33: 22%, cMPO:8%, TdT: 0%CD41: 83%, CD61: 83%,CD117: 67%,CD41(cy): 58%, CD61(cy): 99%

i(12p)

� Tumor markers

● AFP: 3840 ng/ml, HCG: 469.2 mIU/ml

CT-guided biopsy of mediastinal tumor: tumor necrosis

Final diagnosis: Mediastinal germ cell tumor with acute megakaryoblastic leukemia

� a left lobulated cystic anterior mediastinal tumor (12 x 6.5 cm) with left hemothrax

2011/12/21

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0

1000

2000

3000

4000

5000

AFP HCG

Treatment course

9/2 I3A7 + EP

9/23 BEP

10/28 I3A7 + BEP

BM blasts (%)

47.5% 4.4%

LDH(U/L) 6360 1324 475 556 1114 547 359

I3A7: Idarubicin 12 mg/m2 D1-3 + Ara-C 100 mg/m2 D1-7EP: Etoposide 100 mg/m2 D1-5 + Cisplatin 20 mg/m2 D1-5BEP: Etoposide 100 mg/m2 D1-5 + Cisplatin 20 mg/m2 D1-5

+ Bleomycin 30 mg

� Partial remission

Febrile neutropeniaGr2 diarrheaGr1 N/V

Febrile neutropenia

Febrile neutropeniaGr2 N/V

46.4% (11/29)

Mediastinal GCT vs. hematological maligancies:

introduction

Nichols CR et al (16 cases) Hartmann JT et al (17 cases)

41%

12%6%

29%

12%

AML(M7: 5/7)

AUL

Malignant histiocytosis

MDS with abnormal megaMast cell leukemia

Mediastinal nonseminomatous GCT have been reported to be associated with hematological malignancies since 1985.

54%

13%

7%

13%

13%

AML(M7: 6/8)

AUL

MDS with abnormal megaMegakaryocytic myelosis

ET

Nichols CR et al, N Engl J Med 1990;322: 1425-9Hartmann JT et al, JNCI 2000;92:54-61

Mediastinal GCT vs. hematological maligancies:

clinical characteristics

Nichols CR et al (16 cases) Hartmann JT et al (17 cases)

Characterisctics Value

Median age - yr 22

Histologic diagnosisTeratocarcinomaEndodermal sinus tumorOthers

1123

AFP% of elevated pts 15/16(94)

HCG% of elevated pts 6/16 (38)

Time to Dx of hemetologictumor

Simultaneous diagnosis Median(range)--mo

56(0-122)

Characterisctics Value

Median age – yr 23

Histologic diagnosisTeratocarcinomaEndodermal sinus tumorOthers

1043

AFP% of elevated pts 14/17(82)

HCG% of elevated pts 7/17(41)

Anatomic localiaztion of GCTMediastinalRetroperitoneal

17(100%)0

The Incidence of hematological malignancies in primary mediastinal NSGCT: 2%

Nichols CR et al, N Engl J Med 1990;322: 1425-9Hartmann JT et al, JNCI 2000;92:54-61

Mediastinal GCT vs. hematological maligancies:

diagnosis Features of therapy-related leukemia

Causative agents

Alkylating agents Topoisomerase II inhibitors

Chromosome abnormalities del(5q),-5,del(7q),-7 11q23

Preleukemia phase MDS None

FAB morphology Usually M1, M2 Usually M4, M5

Latency 5 – 7 years 6 months to 3 years

� Cytogenetics:

(1) Typical marker chromosome abnormalities of GCT: isochromosome i(12p)

(2)XXY or trisomy 21

�mediastinal GCT & Klinefelter’s syndrome

or Down syndrome

Anne Moore et al, ASCO SEP 2nd edition p374Hartmann JT et al, JNCI 2000;92:54-61

Mediastinal GCT vs. hematological maligancies:

pathogenesis � Nonseminomatous GCTs have the capacity to display

totipotential differentiation:

Pluripotentialembryonalcarcinoma

Extraembryonic

cell type

Somatic cell type

yolk sac tumorchoriocarcinoma

Mature teratomaImmature teratoma

Malignant transformation: sarcoma, adenocarcinoma, leukemia….

MediastinalNSGCT

Often containyolk sac tumor component Mesenchyme-

like pluripotentcomponent

tend to develop hematological disorders

Ikdahl T et al, Acta Oncol. 2008;47(3):466-9Hartmann JT et al, JNCI 2000;92:54-61

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Mediastinal GCT vs. hematological maligancies:

prognosis

� Allogeneic BMT may be the only curative strategy.

� Favorable prognosis: patients with platelet disorders

Nichols CR et al (16 cases) Hartmann JT et al (17 cases)

Median survival afterDx of hematological malignancies

< 1 month 5 months

Very aggressive clinical courses

patients died before treatment

not respond to antileukemic therapy

achieve only short remission

Nichols CR et al, N Engl J Med 1990;322: 1425-9Hartmann JT et al, JNCI 2000;92:54-61

Treatment � Therapeutic strategy:

target the hematological malignancy as well as the GCT

13 y/o boy

cytarabine + etoposide + mitoxantrone CR

high dose Ara-C +etoposide + idarubicin + mitoxantrone + cisplatin CBT

Free from disease 3.5 yrs after Dx

Induction C/T

Intensive C/T x 5

Ikdahl T et al, Acta Oncol. 2008;47(3):466-9BMT(2008) 41, 907-908

Conclusion

� A mediastinal GCT with a hematological malignancy is a poor prognostic syndrome with short survival time.

� It is distinguishable from therapy-related myeloid neoplasms by the simultaneous presentation of two rare malignant disorders without previous chemotherapy or the associated cytogenetic abnormalities.

� no well-established treatment guideline

� The therapeutic regimens are suggested to target the hematological malignancy as well as the GCT by the previous literature.

� We report here induction chemotherapy with I3A7 plus etoposide/cisplatin with partial response and well tolerated toxicity.