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2011/12/21
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王韋淯王韋淯王韋淯王韋淯12121212、、、、姜乃榕姜乃榕姜乃榕姜乃榕12121212、、、、吳尚殷吳尚殷吳尚殷吳尚殷1111、、、、陳雅萍陳雅萍陳雅萍陳雅萍1111、、、、蘇文彬蘇文彬蘇文彬蘇文彬1111、、、、林鵬展林鵬展林鵬展林鵬展1111、、、、顏家瑞顏家瑞顏家瑞顏家瑞1111、、、、蘇五洲蘇五洲蘇五洲蘇五洲1111、、、、陳彩雲陳彩雲陳彩雲陳彩雲1111
1111國立成功大學附設醫院國立成功大學附設醫院國立成功大學附設醫院國立成功大學附設醫院 內科部內科部內科部內科部 血液腫瘤科血液腫瘤科血液腫瘤科血液腫瘤科
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
2011/12/21
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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.