Mediastinal Germ Cell Tumors Anja C. Roden, M.D. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA 2018 MFMER slide-1
Disclosure I have no relevant financial relationships to disclose. I will not discuss off label use and/or investigational use in my presentation. 2018 MFMER slide-2
Outline Mediastinal GCT Introduction Demographics, clinical features Unique histologic features Molecular studies Differential diagnosis Outcome 2018 MFMER slide-3
Introduction Described since beginning of 20 th century Thought to be metastatic or subtype of thymoma Seminoma-like tumor, seminomatous thymoma 1970s-1980s primary mediastinal GCT recognized Roden AC. Arch Pathol Lab Med. 2017.141(2):232-46. 2018 MFMER slide-4
Introduction Histology / immunophenotype / ultrastructure similar to GCT elsewhere Differences in - Presentation - Morphologic features - Distribution of GCT subtypes - Differential diagnosis - Outcome 2018 MFMER slide-5
Demographics Rare; 1-15% of mediastinal neoplasms 2-7% of GCT Age: Neonatal peak Incidence abruptly increases at puberty Mean age depends on tumor type - Seminomas 30 yo - Non-seminomatous tumors 25 yo Sudour-Bonnange H et al. Pediatr Blood Cancer 2017; 64:e26494. Stang A et al. Int J Androl 2012; 35:616-25. Rusner C et al. Cancer Epidemiol 2013;37:370-3. 2018 MFMER slide-6
Clinical Features Anterior mediastinum (82%) (thymus) Sometimes incidental Symptoms: Cough, chest pain, hemoptysis, dyspnea, SVC syndrome, trichoptysis, fistulas Moeller KH et al. AJR 1997;169:985-90. Pulmonary Anatomy (Thorax) flashcards/ Quizlet 2018 MFMER slide-7
Type I GCT Primary Mediastinal GCT 2-3% of extragonadal type I GCT anterior originating from thymus; rarely posterior Slight female preponderance Progression to YST in up to 30% 2018 MFMER slide-8
Primary Mediastinal GCT Type II GCT 50-70% of extragonadal type II GCT Anterior mediastinum associated with thymus Early- and postpubertal patients Seminomas 55%, non-seminomas 45% Males >> females 2018 MFMER slide-9
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Histologic Classification - WHO Frequency in Mediastinum(%) Teratoma 43-75 Seminoma 10-37 Non-seminomatous tumors - Mixed GCT 16-34 - Yolk sac tumor 2-12 - Embryonal carcinoma 2-8 - Choriocarcinoma 2 Moran CA et al. Cancer 1997;80:681-90. Takeda S et al. Cancer 2003; 97:367-76. 2018 MFMER slide-11
N=31 Teratoma Mature + sarcomatoid comp Immature Seminoma Mixed PMGCT N (%) 13 (42) 1 (3) 1 (3) 5 (16) 11 (35) Age (yrs), median 37 (2d-49) 50 23 34 (20-67) 27 (12-51) Symptoms, % 57 100 100 60 100 Tumor size (cm), median 10 (5-17) Liu L et al. Mod Pathol. 2016 Feb; 29:475A 8 unknown 10 (2.1-14.5) 7 (4-21) 2018 MFMER slide-12
60-yo male 14 cm anterior mediastinal mass identified during preop w/u for foot surgery 2018 MFMER slide-13
Mature Teratoma 2018 MFMER slide-14
Teratoma Mature Immature Teratoma with other mal. comp. 63% 4% 33% Sarcoma, other GCT, carcinoma, hematologic malignancy 2018 MFMER slide-15
Teratoma with other malignant component (seminoma nonseminomatous GCT) 2018 MFMER slide-16
Klinefelter syndrome 8-33% of male patients with PMGCT Danish cytogenetic register (696 pts with KFS): Male with KFS - 67x risk for non-seminomatous PMGCT Younger patients (median age, 15 vs 28 yrs) Cytogenetic analysis in young male with PMGCT Sudour-Bonnange H et al. Pediatr Blood Cancer 2017; 64:e26494. Hasle H et al. Br J Cancer 1995;71:416-20. Nichols et al. J Clin Oncol. 1987.5:1290-4. 2018 MFMER slide-17
GCT Subtypes Klinefelter Syndrome Frequency (%) KS (N=41) PMGCT (Immature) Teratoma 29 43-75 Seminoma 0 10-37 Non-seminomatous tumors - Mixed GCT 44 16-34 - Yolk sac tumor 2 2-12 - Embryonal carcinoma 10 2-8 - Choriocarcinoma 15 2 Volkl TM et al. Am J Med Genet 2006; 471-81. 2018 MFMER slide-18
12 yo male with chest pain, SOB Recently diagnosed with Klinefelter syndrome 11.8 cm anterior mediastinal mass 2018 MFMER slide-19
Mixed GCT CD117 Glyp 3 2018 MFMER slide-20
Seminoma Anterior mediastinum Men Mean age, 30 (11-79 yo) Napieralska A et al. J Thorac Dis 2018; 10:4335-41. Moran CA et al. Cancer 1997;80:691-8. Aygun C et al. Urology 1984;23:109-117. Sung MT et al. AJSP 2008;32:146-55. 2018 MFMER slide-21
Mediastinal Seminomas % cases Lymphocytic infiltration 100 Fibrous septa/stroma 91 Prominent tumor cell nucleoli 91 Clear tumor cell cytoplasm 87 Distinct tumor cell borders 87 Non-necrotizing granulomas 46-74 Thymic remnants 27 Prominent cystic changes 8 Moran CA et al. Cancer 1997; 80:691-8. Sung MT et al. AJSP 2008; 32:146-55. 2018 MFMER slide-22
20 yo male Right shoulder pain and swelling 8 cm anterior mediastinal mass Bx 2018 MFMER slide-23
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CD117 OCT4 Keratin 2018 MFMER slide-25
PMGCT with Solid Somatic-Type Malignancy 10-20% of non-seminomas Rhabdomyosarcoma most common Mediastinum - tumors grow larger before symptoms Potential for malignant transformation Complete resection difficult 2018 MFMER slide-26
4x 2018 MFMER slide-27
High grade pleomorphic sarcoma with Desmin rhabdomyoblastic differentiation Myogenin arising in teratoma 2018 MFMER slide-28
PMGCT with Hematologic Malignancy 2-6% Associated with mediastinal YST or mixed nonseminoma with YST component Megakaryoblastic leukemia most frequent 2018 MFMER slide-29
Molecular Studies in PMGCT Seminomas mostly aneuploid, few near-tetraploid i(12p) most common structural aberration in type II GCT Chr 12p abnormalities in 22 (of 23) mediastinal seminoma (12p amplification [87%], i12p [65%]) 9 (of 13) PMGCT had i12p by karyotype analysis Chaganti RSK et al. Lancet 1994;343:1130-2. Sung MT et al. AJSP 2008;32:146-55. 2018 MFMER slide-30
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Molecular Studies Gain in chr 12p [in particular i(12p)] in solid and hematologic somatic-type malignancies prove origin from GCT Gains in chr 21 and X, loss of chr 13 Seminomas: activating KIT mutations (38%), KRAS mutation (8%) Przygodzki RM et al. Lab Investig 2002; 82:1369-75. Przygodzki RM et al. Hum Pathol 1996; 27:975-9. 2018 MFMER slide-32
PMGCT Differential Diagnoses Metastases Bronchogenic cyst, thymic cyst, other cysts Pleuropulmonary blastoma Thymic carcinoma Lymphomas Sarcomas 2018 MFMER slide-33
Metastases from Gonads 16 extragonadal GCT (4 mediastinal) - no palpable or subsequent testicular lesion in mediastinal GCT 2/20 autopsy cases of PMGCT testes with occult tumor or well-defined testicular scar 78 autopsies of testicular GCTs none with sole met to anterior mediastinum Mets from gonads - rare but can occur workup White JE et al. Am J Med Sci 1991;301:182-5. Bohle A et al. J Urol 1986;135:939-43. Luna MA et al. Am J Clin Pathol 1976;65:450-4. Johnson DE et al. Urology 1976;8:234-9. 2018 MFMER slide-34
Bronchogenic Cyst Might mimic mature teratoma Respiratory epithelium, smooth muscle, mature cartilage, mucous glands No enteric-type epithelium, immature elements, atypia, tumor necrosis CK7+ / CDX2- bronchogenic cyst CDX2+ / TTF-1+ teratoma. Roma A et al. Am J Clin Pathol 2008;130:265-73. 2018 MFMER slide-35
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Diagnosis OCT4 Distinctive Features Seminoma +++ Chr 12p alterations Thymoma - Lobulated, p40+ Thymic Ca - Commonly p40+ NUT Ca - NUT+; t(15;19) Metast. Ca - Morphology, immunophenotype Lymphoma - Immunophenotype, flow, molecular 2018 MFMER slide-38
Outcome Treatment: Neoadjuvant chemo (platinum-based) +/- resection +/- radiation, occasional initial resection Outcome depends on histologic subtype 5-yr survival 58-82% Metastases/relapse 19-57%, lungs, LN, liver, CNS, bone marrow Sudour-Bonnange H et al. Pediatr Blood Cancer 2017; 64:e26494. Hurt RD et al. Cancer 1982;49:1658-63. Bokemeyer C et al. Cancer 2001;91:1394-401. Stang A et al. Int J Androl. 2012;35:616-25. 2018 MFMER slide-39
GCT with Sarcomatoid Component Mediastinal Gonadal Died (%) 82 (1-37 mos) 44 (5-96 mos) Metastases (%) 18 75 Mediastinum: Unresponsive to conventional chemotherapy Death due to compromise of vital structures Malagon HD et al. AJSP 2007;31:1356-62 2018 MFMER slide-40
Treated with platinum-based chemo Seminoma Nonseminomatous 5-yr survival (%) 90-100 44-48 Worse prognosis >35 yo; Present with fever, SVC syndrome, supraclavicular/ cervical LA, widespread disease, hilar disease (CT) Napieralska A et al. J Thorac Dis 2018; 10:4335-41. Bokemeyer C et al. JCO 2002;20:1864-73. Hurt RD et al. Cancer 1982;49:1658-63 2018 MFMER slide-41
Summary Mediastinal GCT Rare but need to be considered in DD Young male - exclude Klinefelter syndrome Cytogenetic studies might help to distinguish sarcoma from solid-somatic component of GCT PMGCT with sarcomat. comp., non-seminomatous PMGCT - worse outcome than in gonads Larger molecular studies needed 2018 MFMER slide-42