Mediastinal Germ Cell Tumors
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1 Mediastinal Germ Cell Tumors Anja C. Roden, M.D. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA 2018 MFMER slide-1
2 Disclosure I have no relevant financial relationships to disclose. I will not discuss off label use and/or investigational use in my presentation MFMER slide-2
3 Outline Mediastinal GCT Introduction Demographics, clinical features Unique histologic features Molecular studies Differential diagnosis Outcome 2018 MFMER slide-3
4 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 (2): MFMER slide-4
5 Introduction Histology / immunophenotype / ultrastructure similar to GCT elsewhere Differences in - Presentation - Morphologic features - Distribution of GCT subtypes - Differential diagnosis - Outcome 2018 MFMER slide-5
6 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:e Stang A et al. Int J Androl 2012; 35: Rusner C et al. Cancer Epidemiol 2013;37: MFMER slide-6
7 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: Pulmonary Anatomy (Thorax) flashcards/ Quizlet 2018 MFMER slide-7
8 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
9 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
10 2018 MFMER slide-10
11 Histologic Classification - WHO Frequency in Mediastinum(%) Teratoma Seminoma Non-seminomatous tumors - Mixed GCT Yolk sac tumor Embryonal carcinoma Choriocarcinoma 2 Moran CA et al. Cancer 1997;80: Takeda S et al. Cancer 2003; 97: MFMER slide-11
12 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) (20-67) 27 (12-51) Symptoms, % Tumor size (cm), median 10 (5-17) Liu L et al. Mod Pathol Feb; 29:475A 8 unknown 10 ( ) 7 (4-21) 2018 MFMER slide-12
13 60-yo male 14 cm anterior mediastinal mass identified during preop w/u for foot surgery 2018 MFMER slide-13
14 Mature Teratoma 2018 MFMER slide-14
15 Teratoma Mature Immature Teratoma with other mal. comp. 63% 4% 33% Sarcoma, other GCT, carcinoma, hematologic malignancy 2018 MFMER slide-15
16 Teratoma with other malignant component (seminoma nonseminomatous GCT) 2018 MFMER slide-16
17 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:e Hasle H et al. Br J Cancer 1995;71: Nichols et al. J Clin Oncol : MFMER slide-17
18 GCT Subtypes Klinefelter Syndrome Frequency (%) KS (N=41) PMGCT (Immature) Teratoma Seminoma Non-seminomatous tumors - Mixed GCT Yolk sac tumor Embryonal carcinoma Choriocarcinoma 15 2 Volkl TM et al. Am J Med Genet 2006; MFMER slide-18
19 12 yo male with chest pain, SOB Recently diagnosed with Klinefelter syndrome 11.8 cm anterior mediastinal mass 2018 MFMER slide-19
20 Mixed GCT CD117 Glyp MFMER slide-20
21 Seminoma Anterior mediastinum Men Mean age, 30 (11-79 yo) Napieralska A et al. J Thorac Dis 2018; 10: Moran CA et al. Cancer 1997;80: Aygun C et al. Urology 1984;23: Sung MT et al. AJSP 2008;32: MFMER slide-21
22 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 Thymic remnants 27 Prominent cystic changes 8 Moran CA et al. Cancer 1997; 80: Sung MT et al. AJSP 2008; 32: MFMER slide-22
23 20 yo male Right shoulder pain and swelling 8 cm anterior mediastinal mass Bx 2018 MFMER slide-23
24 2018 MFMER slide-24
25 CD117 OCT4 Keratin 2018 MFMER slide-25
26 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
27 4x 2018 MFMER slide-27
28 High grade pleomorphic sarcoma with Desmin rhabdomyoblastic differentiation Myogenin arising in teratoma 2018 MFMER slide-28
29 PMGCT with Hematologic Malignancy 2-6% Associated with mediastinal YST or mixed nonseminoma with YST component Megakaryoblastic leukemia most frequent 2018 MFMER slide-29
30 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: Sung MT et al. AJSP 2008;32: MFMER slide-30
31 2018 MFMER slide-31
32 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: Przygodzki RM et al. Hum Pathol 1996; 27: MFMER slide-32
33 PMGCT Differential Diagnoses Metastases Bronchogenic cyst, thymic cyst, other cysts Pleuropulmonary blastoma Thymic carcinoma Lymphomas Sarcomas 2018 MFMER slide-33
34 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: Bohle A et al. J Urol 1986;135: Luna MA et al. Am J Clin Pathol 1976;65: Johnson DE et al. Urology 1976;8: MFMER slide-34
35 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: MFMER slide-35
36 2018 MFMER slide-36
37 2018 MFMER slide-37
38 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
39 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:e Hurt RD et al. Cancer 1982;49: Bokemeyer C et al. Cancer 2001;91: Stang A et al. Int J Androl. 2012;35: MFMER slide-39
40 GCT with Sarcomatoid Component Mediastinal Gonadal Died (%) 82 (1-37 mos) 44 (5-96 mos) Metastases (%) Mediastinum: Unresponsive to conventional chemotherapy Death due to compromise of vital structures Malagon HD et al. AJSP 2007;31: MFMER slide-40
41 Treated with platinum-based chemo Seminoma Nonseminomatous 5-yr survival (%) 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: Bokemeyer C et al. JCO 2002;20: Hurt RD et al. Cancer 1982;49: MFMER slide-41
42 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
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