1. الدكتور مُحَمَّد يحيى كويفَاتيِّة اختصاصي في طب الأورام ومعالجتها Oncologist ألمانيـا طبيب في قسم الأورام – مستشفى زاهي أزرق

3. Question For Cancer Patient: 1)Are we sure of the diagnosis? 2) What is the stage of disease? 3)Can this patient be cured? 4)If can’t be cured, How can we help the patient the most? 5)Can this patient participate in clinical trial?

4. Case Report Male, 31 years old, smoker came on 5.4.2007 suffered from Chest pain and dyspnea. Biopsy from Mediastinal mass with CT guided : small cell carcinoma.

5. Chest CT

6. Chest X-ray:

7. Radiology: CT Chest : huge mass in mediastinum measured about 15 cm CT Abdomen, Pelvis: normal CT Brain : normal.

8. Differentional Diagnosis of Mediastinal : Germ cell tumors Thymic tumors Mesenchymal tumors Lymphomas Neurogenic tumors

9. Extra gonadal Germ Cell Tumor Carcinoma Syndrome : 1) It occurs in young men( younger than 50 years) 2) The tumors are located predominantly in the medline ( Mediastinum, Retroperitoneum) 3) History of rapid tumor growth, the symptom interval is short fewer than 3 months 4) Serum levels of BCGH, AFP are elevated 5) Good Response to Chemotherapy

10. Labor: BHCG: 0,46 normal AFP <1000 diluted 10 times 27000 LDH: 882,3 CEA: 3,82

11. Testis examine was normal Pathology: AFP: positive CK positive

12. :Diagnosis Extragonadal Germ Cell Tumor Carcinoma : Stage I or II Mediastinal primary tumor AFP: >1000 = 27000 : poor prognosis according to International Germ Cell Cancer Collaborative Group

13. Plane: curable Cancer. Extra gonadal Germ Cell Tumor Carcinoma : poor prognosis Chemotherapy: 4xBEP doses. salvage (VIP) etoposide, ifosfamide, and cisplatin If the serum tumor markers remain elevated If the CT scan shows residual disease without tumor marker elevation, perform surgical resection. Additional postoperative chemotherapy is given if the patient is found to have viable tumors

14. Treatment: From 15.5.2007 till 6.8.2007 he was taking three cycles BEP, and two cycles EP chemotherapy After the second cycle AFP was 71.7 the third was 19.3 fourth was 12.3

15. On 19.8.2007, mass was executed through lung Pathology: Necrosis, Fibrosis, and a little bit tumor cells. Chest CT : Case after operation no Mass. On 30.8.2007 AFP 2.17 normal From 1.9.2007 till 22.10.2007 he took another three cycles EP. After the last cycle AFP was 1.81 normal 19.9.2010 AFP: 1.94

16. Extragonadal Germ Cell Tumors Introduction (EGGCTs) are rare tumors that predominantly affect young males. The only known risk factor for (EGGCTs) is Klinefelter syndrome(47XXY), which is associated with mediastinal nonseminomatous germ cell tumors. They are characterized by their location on the midline from the pineal gland to the coccyx. In (EGGCTs), no evidence of a primary malignancy is present in either the testes or ovaries by radiologic imaging or physical examination. (EGGCTs) produce a rich symptomatology and may reach large volumes if they arise in silent areas. Histologically, they mirror their gonadal counterparts with which they share the same chemosensitivity and radiosensitivity. Modern approaches to diagnosis and treatment can result in high rates of long-term survival and even cure.

17. Frequency : In United States (EGGCTs) represent 5-10% of all germ cell tumor (GCTs), predominantly affect young males Seminomas account for 30-40% of these tumors, and nonseminomatous germ cell tumors (NS-GCTs) account for 60-70%. Nonseminomatous germ cell tumors include yolk-sac tumors, embryonal carcinomas, choriocarcinomas, teratomas, and nonteratomatous combined germ cell tumors. Pathology of postchemotherapy residual masses reveals necrosis in 24%, teratoma in 45%, sarcoma in 5%, and viable germ cell cancer in 26%. Sex In children, (EGGCTs) occur equally in males and females. In adults, more than 90% of (EGGCTs) occur in males.

18. Clinical Symptoms vary depending on the site and the size of the tumor. Those arising in nonvital organs can reach large sizes before becoming symptomatic. Mediastinal germ cell tumors The mediastinum is the most common site of (EGGCTs) 50-70% Retroperitoneal germ cell tumors The second most common site of (EGGCTs) (30-40%), (RGCTs) represent 10% of all malignant primary retroperitoneal tumors. Often patients with retroperitoneal germ cell tumors present late, after their tumors have reached large dimensions. symptoms are abdominal mass with or without pain, backache, and weight loss. Intracranial germ cell tumors (ICGCTs) are localized preferentially to the pineal and suprasellar regions. Pineal tumors present with headache, nausea, and vomiting because of increased intracranial pressure; they require early ventriculoperitoneal (VP) shunting. Sacrococcygeal germ cell tumors In the literature to date, 17 cases have been reported. Pain and bowel habit change are the main symptoms.

19. Mediastinal germ cell tumors: Mediastinal germ cell tumors account for 10-15% of adult anterior mediastinal tumors. Mature teratomas represent 60-70% of mediastinal germ cell tumors. Malignant mediastinal germ cell tumors (30-40%) are divided between seminomas (40%) and nonseminomatous germ cell tumors (60%).. Although their incidence peaks in the third decade, several cases have been reported in patients older than 60 years. Patients may present with chest pain (39%), dyspnea (29%), cough (22%), weight loss (19%), superior vena cava syndrome (12%), Nausea (6%), fever (6%), postobstructive pneumonia, weight loss, night sweats, dysphagia, shoulder or arm pain, vocal cord paralysis, and hoarseness.

20. Mediastinal germ cell tumors: In one third of patients the anterior mediastinal mass is an incidental finding of a routine chest radiograph (in most of these cases, a benign tumor is found). Metastases to locoregional lymph nodes or to distant sites, such as the lungs, liver, or bone, may be present in 20-50% of cases on presentation. Mature teratoma rupture, teratoma with malignant transformation, and hematologic malignancies may complicate mediastinal germ cell tumors Growing teratoma syndrome is the increase in tumor size during or after chemotherapy, surgical resection is the treatment of choice.

21. Extragonadal germ cell cancer syndrome: Midline fast-growing tumors (eg, of the mediastinum, retroperitoneum) occur in young males. Histologically, these tumors are poorly differentiated carcinomas with atypical features. The germ cell origin of these tumors is suggested by the typical abnormalities of chromosome 12 and the elevation of beta human chorionic gonadotropin (bhCG) and/or alpha-fetoprotein (AFP).

22. Laboratory Studies Tumor markers provide diagnostic, staging, and prognostic information. Check these levels before and then at regular intervals after therapy. Choriocarcinoma, embryonal carcinoma, and a minority of seminomas (<10%) produce bhCG Serum AFP elevations are seen in yolk-sac tumors and embryonal carcinoma. AFP, bhCG, or both are elevated in approximately 85% of extragonadal nonseminomatous germ cell tumors. Small increases in serum beta-hCG can be seen in up to 50% of patients with disseminated seminoma. (LDH) is a nonspecific marker. Its level correlates well with the tumor burden and with the number of i(12p) copies. Tumor marker elevation in the appropriate clinical setting makes the diagnosis of germ cell tumors highly likely. Chemotherapy can be initiated in these cases without tissue diagnosis if a need for immediate treatment is present Cytogenetic analysis of patients with mediastinal germ cell tumors (MGCTs) reveals trisomy 8 in 16% of cases and Klinefelter syndrome (XXY) in 14-20% of cases. However, the most common karyotype abnormality is i(12p), present in 38% of patients. The presence of this abnormality helps identify midline germ cell tumors presenting as poorly differentiated carcinomas with atypical features.

23. Imaging Studies: Testicular ultrasound: This should be ordered to rule out a gonadal primary site. CT scan of the chest, abdomen, and pelvis Mature teratomas appear as heterogeneous cystic, well-defined, anterior mediastinal masses with walls of different thicknesses. Calcifications are present in approximately one quarter, with a bone or a tooth rarely identifiable. The combination of fluid, soft tissue, calcium, and/or fat attenuation in an anterior mediastinal mass is highly specific for mature teratoma. Seminomas present as bulky, lobulated, homogeneous, anterior mediastinal masses. Although invasion of adjacent organs is uncommon, metastases to regional lymph nodes and bone can be seen. Calcifications are rare. Nonseminomatous mediastinal germ cell tumors (NS-MGCTs) appear as irregular, anterior mediastinal masses, often with extensive, central heterogeneous areas of low attenuation caused by necrosis, hemorrhage, and/or cyst formation. Adjacent organ involvement and metastases to regional lymph nodes as well as to distant sites may occur.

24. positron emission tomography (PET- CT Scan) Studies have suggested that PET may be more sensitive than CT, disease smaller than 0.5 cm was not detected. In patients with nonseminomatous germ cell tumors (NSGCT), PET has not been consistently able to identify residual viable malignant germ cell tumors (GCTs) and also does not detect teratoma. One study has shown that PET is useful in the detection of residual viable seminoma in patients with masses larger than 3 cm in diameter after chemotherapy

25. Staging Clinical staging of mediastinal germ cell tumors (MGCT) Stage I - Well-circumscribed tumor with or without focal adhesions to the pleura or pericardium but without microscopic evidence of invasion into adjacent organ Stage II - Tumor confined to the mediastinum with macroscopic and/or microscopic evidence of infiltration into adjacent structures Stage III - Tumor with metastases Stage IIIA - With metastases to intrathoracic organs Stage IIIB - With extrathoracic metastases

26. Treatment Treatment modality is determined by the site and the histologic type of the primary tumor. Mature teratomas are relatively insensitive to both chemotherapy and radiation therapy therefore surgery is the only treatment for teratomas seminoma of the mediastinum: Treatment with 4 cycles of bleomycin, etoposide, and cisplatin (BEP) is the current standard of care. Radiotherapy can be used after chemotherapy in bulky mediastinal seminomas. 14 In nonseminomatous mediastinal germ cell tumors (NS-MGCT), 4 cycles of (BEP) also are recommended. If the serum tumor markers remain elevated, give salvage chemotherapy etoposide, ifosfamide, and cisplatin (VIP),. If the CT scan shows residual disease without tumor marker elevation, perform surgical resection, Additional postoperative chemotherapy is given if the patient is found to have viable tumors.

27. Prognosis Classification system by the International Germ Cell Collaborative Group (IGCCG). Nonseminoma : Good prognosis is indicated by all of the following: Testis/retroperitoneal primary No nonpulmonary visceral metastases Good markers - AFP <1000 ng/mL, bhCG <10000 IU/L, and LDH <1.5 X upper limit of normal (N) Includes 56% of nonseminomas, which have a 5-year progression-free survival rate (PFS) of 89% and 5-year survival rate of 92% Intermediate prognosis is indicated by all of the following: Testis/retroperitoneal primary No nonpulmonary visceral metastases Any of AFP >1000 and 5000 and 1.5 X N and <10 X N Includes 28% of nonseminomas, which have a 5-year PFS of 75% and 5-year survival rate of 92% Poor prognosis is indicated by any of the following: Mediastinal primary Nonpulmonary visceral metastases Poor markers - Any of AFP >10,000 ng/mL, bhCG >50,000 IU/L, or LDH >10 X N Includes 16% of nonseminomas, which have a 5-year PFS of 41% and 5-year survival rate of 48%

28. Prognosis Classification system by the International Germ Cell Collaborative Group (IGCCG). Seminoma Good prognosis is indicated by the following: Any primary site No nonpulmonary visceral metastases Normal AFP, any bhCG, any LDH Includes 90% of seminomas, which have a 5-year PFS of 92% and 5-year survival rate of 88% Intermediate prognosis is indicated by the following: Any primary site Nonpulmonary visceral metastases Normal AFP, any bhCG, any LDH Includes 10% of seminomas, which have a 5-year PFS of 67% and 5-year survival rate of 72% Poor prognosis: No patients are classified as having poor prognosis.

29. Follow-up: Detection of late recurrences (>2 y after treatment discontinuation) development of testicular tumors several years after the initial diagnosis of (EGGCTs) treatment-related complications justify prolonged periods of follow-up care with clinical evaluation, tumor markers, and imaging studies.

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