58 Management of Residual Disease after Therapy for Mediastinal Germ Cell Tumor and Normal Serum Markers

(1)

474

58

Management of Residual Disease after Therapy for Mediastinal Germ Cell Tumor and Normal Serum Markers

Luis J. Herrera and Garrett L. Walsh

cult, and the indication and timing for surgery is tailored to the individual patient and tumor biology. Given the rarity of this disease, the literature consists of retrospective series accumulated over several decades in selected high-volume centers. Due to the lack of controlled trials, deﬁ n- itive recommendations for the management of mediastinal germ cell tumors are based on these small case series only. Furthermore, patient diversity in terms of the extent of disease makes cohort studies or controlled trials difﬁ cult.

This chapter focuses on the management of PMNSGCT, with a focus on the role of surgery for the treatment of residual disease after chemotherapy with normalization of serum tumor markers, based on the best available evidence to date. Other histological types of germ cell tumors often occur in the mediastinum, including teratoma, seminoma, and metastatic gonadal germ cell tumor. This chapter primarily focuses on the management of the primary tumors of the mediastinum of nonseminomatous histology.

58.1. Clinical Evidence: Surgical Management of Primary Mediastinal Nonseminomatous Germ Cell Tumors

Primary mediastinal nonseminomatous germ cell tumors are the most malignant subgroup of germ cell tumors, with poor prognosis despite aggressive therapy. PMNSGCT are classiﬁ ed as Primary mediastinal nonseminomatous germ

cell tumors (PMNGCT) are rare, representing less than 6% of all germ cell tumors (GCT) and 10%

to 20% of all anterior mediastinal masses.^1,2 These tumors can be biologically aggressive, with regional involvement of adjacent structures and a high metastatic potential. The biology of extragonadal GCT is often different than their gonadal counterparts, despite having similar histological features (Table 58.1).^3,4

Due to the aggressive behavior of these tumors, a multimodality approach is the most effective treatment strategy. Controversy still exists regarding the optimal chemotherapy regimen and the timing and indications for surgical intervention. One complex feature of PMNSGCT is the unpredictability of tumor response to induction treatment when based solely on radiographic evaluation and serum tumor marker analysis. In resected specimens after chemotherapy, tumors may exhibit extensive necrosis, teratoma, persistent malignant cells, or malignant transformation, regardless of the serum tumor marker status and the radiographic tumor response in imaging studies.^5–8

Signiﬁ cant advances have occurred in the treatment of germ cell tumors over the past 30 years using multimodality therapy, with high chemotherapy response rates and dramatic improvement in long-term survivors. In most cases, surgical resection of residual disease still plays an important role in the overall management of these patients. The decision to resect residual disease after chemotherapy can be difﬁ -

(2)

poor prognosis germ cell tumors by the Interna- tional Germ Cell Cancer Collaborative Group consensus classiﬁ cation based solely on the mediastinal location and regardless of any other variable.⁹

After confi rmation of the diagnosis with serum tumor markers and, if possible with tumor biopsy, chemotherapy is the fi rst-line treatment modality for these malignancies. Initial surgical resection or debulking of anterior mediastinal NSGCT are not indicted because it rarely achieves complete resection due to the infi ltrative nature of these tumors. This will also have the negative conse- quence of delaying the initiation of chemotherapy. Cisplatin-based chemotherapy is standard induction therapy. First-line therapy usually consists of a combination of cisplatin with etoposide and bleomycin (BEP).² The response rates after chemotherapy for PMNSGCT are much lower than for the testicular malignant germ cell tumors.

Serum tumor markers (STM) consist of α fetopro- tein (AFP), β-human chorionic gonadotropin (β- HCG), and lactate dehydrogenase (LDH). They are elevated in up to 90% of patients with PMNSGCT.¹⁰ Normalization of STM after chemotherapy occurs in approximately 45% to 90% of patients, with other patients demonstrating persistently elevated tumor markers and persistent disease in the mediastinum.^6,11 Normalization of STM is not necessarily associated with a complete

radiographic resolution of the mediastinal mass because persistent viable tumor, residual teratoma, or necrosis can still be present in the mediastinum after induction therapy with marker stabilization or normalization.⁸

After chemotherapy, the stage of the disease is reassessed with repeat imaging and STM. Patients may either have: (1) complete radiologic and serologic response; (2) complete serologic response but with a residual mediastinal tumor; (3) growth of the tumor with normalization of STM; or (4) growth of tumor with persistently elevated markers. Surgery is felt to play an important role in groups 2 and 3, but perhaps is less warranted in groups 1 and 4. Surgery can be an adjunct to chemotherapy to achieve a complete response and it can also evaluate the nature and viability of residual masses in order to guide further therapy. In addition, the resection of residual teratomatous elements halts tumor growth and minimizes possible future complications related to growing teratoma syndrome with tumor compression or invasion of vital structures.

Because of the rarity of these tumors, no controlled or randomized clinical trials are available and perhaps will never be performed. The literature regarding PMNSGCT consists of case series reviewed retrospectively over decades (Table 58.2). Nevertheless, important points can be gathered from the available literature in order to base clinical decisions. Based on the reported literature, the ideal candidate with PMNSGCT for surgical resection has normalization of STM after fi rst-line chemotherapy, has a residual and resectable mediastinal mass on imaging, has no evidence of extramediastinal metastatic disease, and has good performance and physiologic status (Figure 58.1). Nevertheless, many patients evaluated for surgery after fi rst-line chemotherapy do not fulfi ll these criteria but may still benefi t from surgical resection. Several factors must be considered prior to surgery after the completion of fi rst-line chemotherapy: (1) the radiographic response to chemotherapy; (2) the level of serum tumor markers; (3) the presence of extramediastinal metastatic disease; (4) the extent and resectability of the residual tumor;

and (5) the physiological reserve of the patient and estimated morbidity of the planned operation.

TABLE 58.1. Pathological classification of primary mediastinal germ cell tumors.

Teratomatous tumors Benign

Mature teratomas (well differentiated, mature elements; benign) Immature teratomas (immature mesenchymal or neuroepithelial tissue)

Malignant

Teratoma with additional malignant components (germ cell elements, epithelial cancer, sarcoma)

Nonteratomatous tumors Seminomas Nonseminomatous Yolk sac tumors Embryonal carcinomas Choriocarcinomas

Mixed nonseminomatous and seminomatous tumor Source: Modified from Moran et al.⁴

(3)

Anterior mediastinal mass

STM+/– core biopsy PMNSGCT

First line platinum based chemotherapy STM: normal

STM: elevated, trend down

STM: elevated, trend up

STM: elevated, no improvement Second line chemotherapy Imaging: CR

Observe

Recurrence

Unresectable disease

Salvage chemotherapy Necrosis Teratoma

Resection

Malignant transformation Viable NSGCT

Salvage chemotherapy Unresectable, progressive disease Resectable mediastinal disease

Observe Adjuvant chemotherapy

Imaging: PR Imaging: SD or PD Growing teratoma

FIGURE 58.1. Algorithm for management of PMNSGCT.

TABLE 58.2. Summary of published series of PMNSGCT treated with chemotherapy followed by surgery of residual disease.

References PMNSGCT (n) Year Patients resected n (%) Preoperative NL STM Overall survival Level of evidence

Schneider¹⁵ 47 1987–2002 47 (100%) 21 (45%) 3 year, 30% 4

Takeda¹⁹ 8 1986–2000 7 (87%) 7 (100%) 5 year, 43% 4

Bokemeyer¹¹ 287 1975–1996 145 (49%) 124 (45%) 5 year, 45% 4

Vuky⁷ 49 1979–1999 32 (65%) 19 (59%) 2 year, 40% 4

Ganjoo⁵ 75 1983–1997 62 (82%) 44 (70%) 5 year, 48% 4

Walsh⁶ 20 1993–1998 11 (55%) 10 (91%) 2 year, 68% 4

Kesler⁸ 92 1981–1998 79 (86%) 50 (63%) 5 year, 56% 4

Bacha²¹ 14 1979–1995 6 (43%) 8 (57%) 5 year, 48% 4

Hidalgo²⁰ 27 1978–1995 6 (22%) na 5 year, 31% 4

Lemarie²² 64 1983–1990 22 (49%) na 2 year, 53% 4

Gerl¹⁶ 12 1981–1994 12 (100%) na 5 year, 56% 4

Wright¹⁰ 28 1976–1988 16 (57%) 22 (78%) 5 year, 57% 4

Abbreviations: na, not available; NL STM, normalization of serum tumor markers; PMNSGCT, primary mediastinal nonseminomatous germ cell tumor;

Rec, level of recommendation.

(4)

58.1.1. Radiographic Response to Chemotherapy

After completion of chemotherapy, repeat imaging is obtained to reassess the extent of residual disease. In radiographic complete response with no residual tumor, observation alone is indicated. Patients with a partial response and residual resectable tumor can then be considered for surgery, particularly if STM have normalized. For patients with stable disease or disease progression that does not appear to be completely resectable, consideration to further chemotherapy is warranted.

58.1.2. Level of Serum Tumor Markers

The impact of STM levels at the time of surgical intervention for patients with PMNSGCT who have had ﬁ rst-line induction chemotherapy has not been well studied, but several case series have illustrated important points in the management of this disease.

Vuky and colleagues from Memorial Sloan- Kettering Cancer Center published a retrospective study of 32 patients with PMNSGCT who underwent surgical resection over a 20-year period.⁷ After induction chemotherapy, normalization of STM occurred in 19 of the 32 patients (59%), but having an elevated STM level at the time of surgery did not exclude patients for resection. Patients with normal STM had less residual viable tumor (56% vs. 77%). However, in patients with persistently elevated STM, a complete surgical resection was achieved in 10 patients (77%).

There was a trend towards decreased survival in patients with increasing STM at the time of surgery compared with patients with STM normalization (p = 0.09). Similarly, in our study at M.D. Anderson Cancer Center, all patients resected postchemotherapy had normalization of STM, and the one patient with persistent elevation had rapid progression of disease postoperatively.^6,7

In another study, Kesler and colleagues reported a retrospective review of 92 patients with PMNSGCT, 79 of whom underwent surgery after platinum-based chemotherapy over a 16-

year period.⁸ Levels of STM normalized in 50 of the 79 patients (63%), with those patients who had normal levels at the time of resection having decreased incidence of viable NSGCT in the resected specimen when compared with patients with elevated STM (18% vs. 52%). On multivariate analysis, a signifi cantly elevated AFP level (>1000ng/mL) after fi rst-line chemotherapy showed an associated relative risk of death of 6.5 [95% confi dence interval (95% CI), 1.3–33.2; p = 0.03), however, AFP levels less than 1000ng/mL had no apparent signifi cant impact on survival.

It is unclear from the reviewed literature what is the optimal timing and role of surgery in a patient who has persistent elevation of STM after ﬁ rst-line chemotherapy. Several factors must be considered: (1) the absolute level and trend of STM elevation; (2) the resectability of the residual tumor; (3) the radiographic response; and (4) the feasibility of further chemotherapy cycles or alternate agents. It is important to consider that the outcome of patients treated with salvage chemotherapy due to residual disease after ﬁ rst-line therapy is poor, with long-term survival attain- able in less than 7% of patients.¹² Such dismal results would favor surgical resection of residual tumor in selected patients, despite persistently elevated STM.

58.1.2. Impact of Extramediastinal Metastatic Disease

Patients with PMNSGCT often present with metastatic disease outside the mediastinum. As many as 15% to 65% of patients can have distant disease in the liver, bone, spine, brain, and lungs.^6,7,13,14 Intuitively, it would seem that patients with metastatic disease would fare much worse than patients with isolated medi astinal masses, but this has been varably described. In a study by Ganjoo and colleagues, of the 75 patients with PMNSGCT, 19 (25%) had visceral metastasis at the time of pre- sentation.⁵ Five-year disease-free survival was 37% for patients with metastatic disease versus 55% for patients without metastases (p = 0.042).

Trends towards decreased survival in patients with metastatic disease has been reported in other

(5)

studies, but statistically signi ﬁ cant differences have not been consistently found.^6–8,10,15

Patients with elevated STM after induction therapy who also present with extramediastinal disease present a particular challenge for sur- geons. If the mediastinal disease is the most feasible site to resect or if it is causing local compression symptoms, it is reasonable to proceed with resection of the mediastinal tumor to assess tumor viability and guide further therapy for the other extramediastinal lesions.

All disease that is amenable to resection, including lung metastases, should be resected subse- quently or concomitantly. In cases of widespread metastatic disease, surgery is at times indicated as a means for tissue procurement to establish the histology of residual disease in order to guide further therapy. The most accessible or the most symptomatic site of disease is surgically resected.

If possible, an aggressive approach with resection of metastatic sites is performed if the estimated morbidity is acceptable.

58.1.4. Resectability and Extent of Resection

Surgical resection of mediastinal germ cell tumors can be challenging. These tumors tend to develop an intense desmoplastic reaction, obscur- ing all tissue planes, and making safe dissection around vascular structures, lung, and cardiac chambers difﬁ cult. If the disease is completely resectable, en bloc resection of the mass and any invaded structures is performed, including resection of vascular structures, a phrenic nerve, lung, partial cardiac chambers, and chest wall. At times, en bloc resection of these tumors is not feasible due to encircling of both phrenic nerves, or involvement of multiple mediastinal structures. In some cases, bisecting the tumor allows safer access to the thoracic great vessels for better vascular control and delineation of the anatomy.

Some authors recommend four quadrant epicen- ter biopsies with frozen section evaluation, and if no viable tumor is present, near total endole- sional resection with preservation of lung, phrenic nerves, and vascular structures is performed.⁸ If at all possible, every effort should be made to preserve lung parenchyma because many

of these patients have limited pulmonary reserve secondary to bleomycin toxicity.

58.1.5. Physiological Reserve and Estimated Morbidity

A careful physiological evaluation is performed in these patients, who, although young, can have sig- niﬁ cant compromise in their respiratory function due to chemotherapy-related toxicity. Complete pulmonary function testing including ventilation/

perfusion scans and evaluation of diffusion capacity (DLCO) is necessary. The risk of the planned operation is assessed based on the patient’s performance status, comorbidities, and functional reserve. These patients often develop a persistent postoperative sinus tachycardia that is not related to their volume status, hemoglobin, or pain level which may take several days to resolve.

58.1.6. Prognosis and Impact of Postresection Tumor Histology

One of the most interesting aspects of the biology of PMNSGCT is the diversity of histological features and the capacity for cellular transformation after chemotherapy. It has been shown that the histology of the residual mediastinal mass is an important predictor of survival and disease recurrence. The histology in the pathology of the resected masses may reveal necrosis (24%–27%), residual teratoma only (35%–45%), viable NSGCT (10%–26%), or malignant transformation to carcinoma or sarcoma (5%–10%).^5,6,8 Patients with necrosis have an excellent survival (mean, 139 months), compared to an intermediate survival of patients with teratoma (mean, 111 months), and the decreased but still acceptable survival of patients with residual malignant NSGCT (mean, 52 months). Malignant transformation into sarcoma has the worst prognosis with few patients alive past 57 months (Figure 58.2).⁸ Current recommendations support the addition of adjuvant chemotherapy for patients with residual viable tumor in the resected specimen consisting of at least two cycles of chemotherapy. The ﬁ nding of malignant transformation to an epithelial histology or to a sarcoma warrants a change in chemotherapy regimens.

(6)

58.2. Current Evidence-Based Management of Primary Mediastinal Nonseminomatous Germ Cell Tumors

Overall, PMSCGCT have a poor prognosis when compared with testicular NSGCT; however, important advances have been made in the management of these aggressive malignancies. Due to the rarity of these tumors, few centers have accumulated signiﬁ cant experience with this disease, and prospective trials are not available to gener- ate clear recommendations for treatment. With multimodality therapy, including resection of residual masses after chemotherapy, 5-year survival rates of 30% to 57% can be achieved (Table 58.2).5–8,11,15–23

Deﬁ nite improvements have been made over the last two decades with the addition of cisplatin-based chemotherapy and surgical resection of residual disease, with much higher rates of long- term survivors. Due to limited number of cases, the basis for current practice is derived from small case series reported to date (Figure 58.1).

58.2.1. Surgical Resection of Residual Tumor after Completion of Initial Chemotherapy

Once initial chemotherapy is completed, evaluation of response is performed. There is enough literature available to support the role of surgical

resection of residual mediastinal disease after induction therapy; however, the level of evidence is low due to retrospective studies of small number of patients in several series accumulated over many years. Normalization of STM is indicative of a good response and it seems clear that if the disease is resectable, surgery should be performed in physiologically ﬁ t patients with isolated mediastinal tumors (level of evidence 4;

recommendation grade C). Patients with STM levels that decrease, but remain elevated, after initial chemotherapy display a trend of decreased survival after resection but some authors still recommend resection due to the low speciﬁ city of STM elevation and the poor results of salvage or second line chemotherapy (level of evidence 4 to 5; insufﬁ cient data to make a recommendation).^7,8

0 100 200

0.0 0.2 0.4 0.6

Cumulative Survival

0.8

1.0 Necrosis (n = 19)

p < 0.01 vs Rest

Teratoma (n = 28) p < 0.01 vs GCT & Sarc Carcinoma

(n = 3)

Persistent GCT (n = 24)

Sarcoma (n = 5)

Months 2

2 12

18

8

6 FIGURE 58.2. Kaplan–Meier survival curve based

on postoperative pathological category. Numbers represent the patients at risk for death. (Reprinted from Kesler KA, Rieger KM, Ganjoo KN, et al. Primary mediastinal nonseminomatous germ cell tumors: the influence of postchemotherapy pathology on long- term survival after surgery. J Thorac Cardiovasc Surg 1999;118:692–700, with permission from Elsevier.)

Normalization of serum tumor markers is indicative of a good response to systemic therapy; if the residual disease is resectable, surgery should be performed in physiologically ﬁ t patients with isolated mediastinal tumors (level of evidence 4; recommendation grade C).

Patients with serum tumor marker levels that remain elevated after initial chemotherapy display a trend of decreased survival after resection; resection may be appropriate due to the poor results of salvage or second-line chemotherapy (level of evidence 4 to 5; insufﬁ - cient data to make a recommendation).

(7)

The resectability of disease is important, and a complete resection of the disease is the goal and may require en bloc resections of vascular structures, phrenic nerve, adjacent lung, and chest wall, but this must be balanced against the morbidity associated with extensive resections.

Extended resections including pneumonecto- mies, bilateral phrenic nerves, recurrent laryn- geal nerves, or multiple vascular structures should not be performed, particularly if only teratoma or necrosis is found on tumor intraoperative biopsy, as advocated by Kesler and colleagues.⁸ Patients who have other sites of metastatic disease, including lung, brain, spine, and liver, should also be considered for resection or further chemotherapy, especially if the mediastinal mass has evidence of viable tumor.

58.3. Clinical Evidence Versus Practice: Current Standard of Care and Clinical Trends in the

Management of Primary Mediastinal Nonseminomatous Germ Cell Tumors

The patient with an anterior mediastinal mass and suspected germ cell tumor requires confi r- mation of the diagnosis in most cases. In an emergent situation, initiation of therapy based on STM elevation alone is adequate, but when- ever feasible, core biopsy of the tumor has a high yield for histological confi rmation. Baseline pulmonary function tests and laboratories and a search for metastatic disease are performed. The initial management of PMNSGCT consists of induction chemotherapy, disease restaging with STM, and repeat imaging and surgical resection of residual mediastinal masses. However, there is signifi cant variability between patients and extent of disease, making standardized patient selection for surgery diffi cult. Clinical judgment and discussion in a multidisciplinary conference helps defi ne which patients would benefi t from resection. The decision of when to proceed with surgical resection will depend on the overall status of the patient and the availability of further chemotherapy at individual institutions.

The surgical approach is most commonly via a sternotomy, sternotomy with ipsilateral thora-

cotomy (hemi-clamshell), or bilateral anterior thoracosternotomy (clamshell), depending on tumor features and location. If the tumor cannot be completely resected en bloc, intraoperative biopsies with near complete resections is acceptable for nonmalignant tumors. Judicious use of intravenous ﬂ uids and low oxygen concentra- tions can help minimize pulmonary complications in these patients.

Signiﬁ cant improvements have occurred in the management of this disease, but the outcomes of patients with progression or recurrence of disease is poor. Several unanswered questions remain. Multi-institutional trials may be needed in order to developed a more standardized staging system and better deﬁ ne the role and timing of surgery, in particular for those patients with metastatic disease and persistently elevated STM.

Improvement in salvage chemotherapy regimens would likely have a signiﬁ cant impact in the overall outcome of these patients. Subsequent development of hematogenous malignancies, in particular acute megakaryocytic leukemia, also limits long-term survival in some of these patients after they have overcome their initial malignancy, and better understanding and treatment of this process will likely improve outcomes as well.

References

1. Toner GC, Geller NL, Lin SY, Bosl GJ. Extrago- nadal and poor risk nonseminomatous germ cell tumors. Survival and prognostic features. Cancer 1991;67:2049–2057.

2. Hainsworth JD, Greco FA. Extragonadal germ cell tumors and unrecognized germ cell tumors. Semin Oncol 1992;19:119–127.

3. Moran CA, Suster S. Primary germ cell tumors of the mediastinum. Cancer 1997;80:681–690.

4. Moran CA, Suster S, Koss MN. Primary germ cell tumors of the mediastinum: III. Yolk sac tumor, embryonal carcinoma, choriocarcinoma, and combined nonteratomatous germ cell tumors of the mediastinum – a clinicopathologic and immu- nohistochemical study of 64 cases. Cancer 1997;

80:699–707.

5. Ganjoo KN, Rieger KM, Kesler KA, Sharma M, Heilman DK, Einhorn LH. Results of modern therapy for patients with mediastinal nonsemino- matous germ cell tumors. Cancer 2000;88:1051–

1056.

(8)

6. Walsh GL, Taylor GD, Nesbitt JC, Amato RJ. Inten- sive chemotherapy and radical resections for primary non-seminomatous mediastinal germ cell tumors. Ann Thorac Surg 2000;69:337–344.

7. Vuky J, Bains M, Bacik J, et al. Role of postchemotherapy adjunctive surgery in the management of patients with nonseminoma arising from the mediastinum. J Clin Oncol 2001;19:682–688.

8. Kesler KA, Rieger KM, Ganjoo KN, et al. Primary mediastinal nonseminomatous germ cell tumors:

the inﬂ uence of postchemotherapy pathology on long-term survival after surgery. J Thorac Cardio- vasc Surg 1999;118:692–700.

9. International Germ Cell Consensus Classiﬁ cation:

a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol 1997;15:594–603.

10. Wright CD, Kesler KA, Nichols CR, et al. Primary mediastinal nonseminomatous germ-cell tumors – results of a multimodality approach. J Thorac Cardiovasc Surg 1990;99:210–217.

11. Bokemeyer C, Nichols CR, Droz JP, et al. Extrago- nadal germ cell tumors of the mediastinum and retroperitoneum: results from an international analysis. J Clin Oncol 2002;20:1864–1873.

12. Saxman SB, Nichols CR, Einhorn LH. Salvage chemotherapy in patients with extragonadal nonseminomatous germ cell tumors: the Indiana University experience. J Clin Oncol 1994;12:1390–

1393.

13. Fizazi K, Culine S, Droz JP, et al. Primary mediastinal nonseminomatous germ cell tumors: results of modern therapy including cisplatin-based che- motherapy. J Clin Oncol 1998;16:725–732.

14. Bokemeyer C, Hartmann JT, Fossa SD, et al.

Extragonadal germ cell tumors: relation to testic- ular neoplasia and management options. APMIS 2003;111:49–63.

15. Schneider BP, Kesler KA, Brooks JA, Yiannoutsos C, Einhorn LH. Outcome of patients with residual germ cell or non-germ cell malignancy after resection of primary mediastinal nonseminomatous germ cell cancer. J Clin Oncol 2004;22:1195–

1200.

16. Gerl A, Clemm C, Lamerz R, Wilmanns W. Cispla- tin-based chemotherapy of primary extragonadal germ cell tumors – a single institution experience.

Cancer 1996;77:526–532.

17. Nichols CR, Saxman S, Williams SD, et al. Primary mediastinal nonseminomatous germ cell tumors:

a modern single institution experience. Cancer 1990;65:1641–1646.

18. Bukowski RM, Wolf M, Kulander BG, Montie J, Crawford ED, Blumenstein B. alternating combination chemotherapy in patients with extragonadal germ-cell tumors – a Southwest Oncology Group Study. Cancer 1993;71:2631–2638.

19. Takeda S, Miyoshi S, Ohta M, Minami M, Masaoka A, Matsuda H. Primary germ cell tumors in the mediastinum – a 50-year experience at a single Japanese institution. Cancer 2003;97:367–376.

20. Hidalgo M, PazAres L, Rivera F, et al. Mediastinal non-seminomatous germ cell tumours (MNSGCT) treated with cisplatin-based combination chemo- therapy. Ann Oncol 1997;8:555–559.

21. Bacha EA, Chapelier AR, Macchiarini P, Fadel E, Dartevelle PG. Surgery for invasive primary medi- astinal tumors. Ann Thorac Surg 1998;66:234–

239.

22. Lemarie E, Assouline PS, Diot P, et al. Primary malignant germ-cell tumors of the mediastinum – the results of a national retrospective inquiry.

Revue des Maladies Respiratoires 1992;9:235–

243.

23. Wright CD, Kesler KA, Nichols CR, et al. Primary mediastinal nonseminomatous germ cell tumors.

J Thorac Cardiovasc Surg 1990;99:210–217.