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Ann Oncol-2002-Schmoll-265-72 PDF
Ann Oncol-2002-Schmoll-265-72 PDF
1093/annonc/mdf669
according to this hypothesis extragonadal tumors would also molecular profiling, CGH analysis, etc. Of particular interest
be of gonadal origin [10]. The potential development of malig- is an amplification of the proximal 12p11.2-12 region which
nant gonadal and extragonadal germ cell tumors is described includes the genes ras-k2, SOX5 and JAW1, as well as cycline
in Figure 1, which has been adapted from Chaganti et al. [6]. CCND2 mapped to the 12p13 region, which could be the best
However, neither of these two series explain the striking pre- candidate for the 12p3 gene in normal testicular genesis and
dominance of malignancy in male EGGCTs in comparison malignant germ cell development [12] and growth. The most
with females who predominantly have EGGCTs and germ cell likely target cell for transformation during germ cell develop-
tumors of the ovaries that are benign [11]. ment may be a cell with replicated chromosomes that
TIN (or carcinoma in situ, cis) cells are regarded as the pre- expresses wild-type p53, harbors DNA breaks and which may
cursors of all male germ cell tumors; however, it is unclear be prone to apoptosis. Such a stage is represented by the
how cis cells undergo the molecular changes leading to high zytogene-pachytene spermatocyte at which a ‘recombination
DNA content and the typical chromosomal aberrations seen checkpoint’ appears to operate which can provide an apoptotic
in this cancer. The molecular changes associated with the trigger in the presence of an unresolved DNA double-strand
development of germ cell tumors are still not clearly under- break. This stage is temporally the longest phase during
stood. However, it is clear from the universal cytogenetic find- spermatogenesis with the cell cycle machinery halted to allow
ing of increased 12p copy number that this chromosomal the recombinational events to complete. It also contains repli-
Figure 1. Genetics and biology of male germ cell (GC) tumors [7]. A diagrammatic representation of male GC development during a normal life span
and the proposed model of GC transformation. The key genetic events that underlie normal male GC fate and embryonal development are shown with
respect to their spatial and temporal relationships. Germ cell tumor development is depicted in the context of normal GC biology.
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aberrant chromatid exchange events associated with crossing with primary mediastinal or primary retroperitoneal semino-
over the zytogene-pachytene may lead to increased 12p copy matous or nonseminomatous extragonadal germ cell tumors.
number and overexpression of cyclin D2. Such a cell may
escape a recombination checkpoint-associated apoptotic
response through the oncogenic effect of cycline D2, leading
Clinical presentation
to aberrant re-initiation of cell cycle and genomic instability. The most common localization of EGGCTs is in the mediast-
In germ cells that have, under follicle-stimulating hormone inum and retroperitoneum. Beyond this the tumors can arise in
(FSH) stimulation, re-entered the cell cycle after cycline D2 the pineal region, sacrococcygeal region and also in the pros-
activation, downstream events such as a loss of tumor suppres- tate, vagina, orbita, liver and gastrointestinal tract (Table 2).
sor genes induced by genomic instability could lead to neo- Because of the rarity of the other localizations of EGGCTs,
plastic progression. Candidate suppressor genes are Rb1, this chapter only reports on primary mediastinal and retro-
DCC and NME (for a review see Chaganti and Houldsworth peritoneal EGGCTs.
[6]). An overview of this hypothetical development of germ The most conclusive data regarding clinical presentation
cell tumors is given in Figure 1. and treatment results derive from a recent meta-analysis rep-
Except for a few described cases of germ cell tumors diag- resenting the largest published series of EGGCTs with
nosed in fathers and twins, there is no evidence for familiar 635 patients [13]. Patients with mediastinal EGGCT had in
particular dyspnea (25%), chest pain (23%) and cough (17%)
38% with elevated HCG, whereas 50% of the primary retro- lymph nodes in 6%, whereas retroperitoneal nonsemino-
peritoneal tumors have elevated AFP, but 74% have elevated matous tumors have a high frequency of lung metastases
HCG (Tables 3 and 4). The size of the mediastinal tumor is (49%), abdominal (34%), or cervical lymph nodes (18%) and
nearly double that of nonseminomatous tumors, 9 cm (range liver metastases (25%). The proportion of patients with two or
7–30) in comparison with 5 cm (range 1–20) in mediastinal more metastatic sites follows the patients with primary
seminoma, whereas the size of retroperitoneal EGGCTs is gonadal origin and typical pattern of poor prognosis germ cell
comparable in both histologies. Metastases are less frequent at tumors, with 48% in retroperitoneal nonseminomas EGGCTs
diagnosis with seminomatous EGGCTs (40% of patients) versus 15% in retroperitoneal seminomas. Accordingly about
compared with nonseminomatous EGGCTs (50% for 90% of patients with seminomatous EGGCTs have good
mediastinal and 76% for retroperitoneal nonseminomatous prognosis [International Germ Cell Cancer Collaboration
EGGCTs). The pattern of metastases outside of the primary Group (IGCCCG) classification] whereas about 50% of the
tumor location varies depending on the location of the primary primary retroperitoneal nonseminomatous tumors present
tumor and its histology; mediastinal seminomas mostly have with poor prognostic features.
metastatic deposits in the cervical lymph nodes whereas
mediastinal nonseminoma is associated in particular with lung
metastases in 27% of patients. Retroperitoneal seminoma is
Diagnosis
Mediastinal Retroperitoneal
seminoma seminoma Table 4. Characteristics of 524 patients with extragonadal
nonseminomatous germ cell cancer [13]
No. of patients 51 52
Size of primary, cm (range) 4.6 (1–20) 7.2 (1–25) Mediastinal Retroperitoneal
Age, years (range) 33 (18–65) 41 (23–70) nonseminoma nonseminoma
Testicular biopsy
A testis primary is excluded by sonographic investigation of
the testis. Several reports have described the presence of a
testicular intraepithelial neoplasia (TIN) or microscopic scar
in the testis of patients with EGGCT. The largest biopsy series
is reported in the above-mentioned meta-analysis [13] with 71
patients (11% of the whole series) undergoing biopsy. Three
per cent showed a sertoli cell only syndrome, 31% athrophic
or fibrotic testis and in 9% TIN was evident with a higher
Table 5. Treatment outcome in a cumulative series of 635 patients with EGGCT [13]
No. of patients CR/PR (%) Relapse (%) 5-year OS (%) 5-year PFS (%)
Mediastinal seminoma 48 94 6 88 88
Retroperitoneal seminoma 46 88 17 88 77
Mediastinal nonseminoma 286 64 52 45 44
Retroperitoneal nonseminoma 226 68 50 62 45
CR, complete response, OS, overall survival; PR, partial response; PFS, progression-free survival.
270
the results probably reflect the true situation better than single of otherwise untreatable disease, e.g. definitive progression
center studies; however, most studies reported results which under chemotherapy, radiotherapy is the treatment of choice
are relatively consistent with these data [16–22]. and will be actively used—at least for sometime—in the
The conclusions from the data are as follows: majority of patients. Salvage radiotherapy is therefore an
important measure for some patients with otherwise refractory
• Patients with seminomatous EGGCTs should be treated
disease suffering from locoregional problems, such as super-
according to their prognostic classification (IGCCCG),
ior vena cava obstruction, bronchus obstruction, cases of resi-
with three cycles of cisplatin, etoposide, bleomycin (PEB)
dual disease after salvage surgery, as well as CNS metastases.
for good prognosis patients and four cycles of PEB for
intermediate prognosis patients.
• Patients with nonseminomatous EGGCTs, retroperitoneal The role of secondary surgery
location and good/intermediate prognosis (IGCCCG)
should be treated with three cycles of PEB, and patients Due to poor prognosis in many patients with retroperitoneal
with poor prognosis with four cycles of PEB. EGGCTs and the specific localization of primary mediastinal
• Patients with nonseminomatous EGGCTs and a medi- EGGCT, surgery is a very important part of the treatment
astinal location all belong to the poor prognosis group and strategy. In the above-mentioned series [13] secondary sur-
should be treated accordingly with four cycles of PEB. gery after chemotherapy has been performed in about 50% of
14. Hartmann JT, Fossa SD, Nichols CR et al. Incidence of metachronous 23. Bokemeyer C, Kollmannsberger C, Meisner C et al. First-line high-
testicular cancer in patients with extragonadal germ cell tumors. dose chemotherapy compared with standard-dose PEB/VIP chemo-
J Natl Cancer Inst 2001; 93: 1733–1737. therapy in patients with advanced germ cell tumors: a multivariate
15. Bokemeyer C, Droz JP, Horwich A et al. Extragonadal seminoma: an and matched-pair analysis. J Clin Oncol 1999; 17: 3450–3456.
international multicenter analysis of prognostic factors and long term 24. Vuky J, Bains M, Bacik J et al. Role of postchemotherapy adjunctive
outcome. Cancer 2001; 91: 1394–1401. surgery in the management of patients with nonseminoma arising
16. Raghavan D, Boyer MJ. Malignant extragonadal germ cell tumors from the mediastinum. J Clin Oncol 2001; 19: 682–688.
in adult. In Horwich A (ed.): Testicular Cancer: Investigation 25. Hartmann JT, Einhorn L, Nichols CR et al. Second-line treatment in
and Management, 2nd edition. London: Chapman & Hall 1996; patients with relapsed extragonadal nonseminomatous germ cell
345–367. tumors: results of an international multicenter analysis. J Clin Oncol
17. Greco FA, Hainsworth JD. Management of extragonadal germ-cell 2001; 19: 1641–1648.
tumors. In Ernstoff MS, Heaney JA, Peschel RE (ed.): Urologic 26. Rosti G, Pico J-L, Wandt H et al. High-dose chemotherapy (HDC) in
Cancer. Oxford: Blackwell Science 1997; 618–626. the salvage treatment of patients failing first-line platinum-based
18. Droz JP, Horwich A. Extragonadal germ cell tumors. In Vogelzang chemotherapy for advanced germ cell tumors (GCT); first results of a
NJ, Scardino PT, Shipley WU, Coffey DS (ed.): Comprehensive prospective randomised study of the European Group for Blood and
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