Germ cell tumors

1. GERM CELL TUMORS Ganesh Kumar M

2. Introduction Primary germ cell tumors (GCTs) arise by the malignant transformation of primordial germ cells Primary GCTs of testes constitute 95% of all testicular tumors Infrequently, GCTs arise from an extragonadal site

3. GERM CELL TUMORS IN MALES 90% are testicular in origin 10% are extragonadal : Mediastinal Retroperitoneal Intra-cranial(Pineal gland) Of the extragonadal sites, predominent site of occurrence is mediastinal

4. ETIOLOGY

5. Epidemiology Most commonly seen in the age group of 15-35 years Most common tumors in males in this age group Contributes to upto 10% of all cancer deaths Familial clustering has been observed, particularly among siblings

6. Risk Factors Cryptorchidism : Associated in 2% of cryptorchids Abdominal cryptorchids more likely to develop GCTs than inguinal cryptorchids Klinefelter’s Syndrome: Testicular atrophy, gynecomastia , 47XXY karyotype Increased likelihood of developing mediastinal GCT( upto 50 times normal) but not testicular tumors

7. Risk Factors(contd.) Familial predisposition: Strong familial predisposition in testicular GCT The relative risk of development of these tumors in fathers and sons of patients with testicular germ cell tumors is 4 times higher than normal, and is 8 to 10 times higher between brothers

8. Classification(in males) Seminatous GCT Seminoma Spermatocytic seminoma Non- seminomatous GCT(NSGCT) Embryonal carcinoma Yolk sac( endodermal sinus) tumor Choriocarcinoma Teratoma : mature immature with malignant transformation

9. Classification(in females)(WHO) Dysgerminoma Endodermal sinus tumor Embryonal carcinoma Polyembryoma Choriocarcinoma Immature teratoma Mature dermoid cyst with malignant transformation Monodermal and highly specialized Struma ovarii Carcinoid Struma ovarii and carcinoid Others Mixed forms

10. ITGCN Intra Tubular Germ Cell Neoplasm Considered as carcinoma-in-situ phase of GCT This phase precedes all adult cases of testicular GCT, frequently present in retroperitoneal presentations, but rarely in mediastinal presentations Cytologically , the ITGCN preceding both seminoma and nonseminoma is identical

11. SEMINOMA Accounts for approximately 50% of GCTs Most frequently appears in the fourth decade of life The typical or classic form consists of large-cell sheets with abundant cytoplasm, and round, hyperchromatic nuclei with prominent nucleoli; frequently associated with a lymphocytic infiltrate

12. Variants of Seminoma Atypical: lymphocytic infiltration absent; necrosis more common in the tumor mass; higher nucleo-cytoplasmic ratio Spermatocytic : rare variant; seen in older men; not associated with ITGCN; minimal metastatic potential

13. NSGCT Represent approx. 50% of all GCTs Most frequently present in third decade of life Most tumors show mixed histo -pathological cell types; consisting of two or more cell lines(including Seminoma )

14. NSGCT: Embryonal Carcinoma Most undifferentiated type of NSGCT Histopath : Epithelioid cells arranged in the form of nests or tubulo -glandular structures or as sheets Necrosis and hemorrhage are frequently observed in the tumor

15. NSGCT: Choriocarcinoma By definition, consists of both syncytiotrophoblasts and cytotrophoblasts Show high levels of hCG Usually associated with widespread hematogenous metastases Might result in a severe complication if hemorrhage occurs spontaneously at a metastatic site

16. NSGCT: Yolk Sac Tumor Mimics the yolk sac of an embryo Produces alpha-fetoprotein Pure yolk sac component is uncommon in adult testes, but accounts for significant percentage in primary mediastinal GCTs

17. NSGCT: Teratoma Composed of somatic cell types from two or more germ layers (ectoderm, mesoderm, or endoderm) Derived from a totipotential , malignant precursor ( embryonal carcinoma or yolk sac tumor)

18. Usually are solid or cystic in appearance Refered to as dermoid cysts if unilocular Teratomas contain elements from all three germ cell layers, with a predominance of the ectodermal component

19. Ectodermal component: skin, hair, sweat glands, sebaceous glands, and teeth Mesodermal component: fat, smooth muscle, bone, and cartilage Endodermal component: Respiratory and intestinal epithelium

20. NSGCT: Teratoma (contd.) Immature teratoma - partial somatic differentiation of these ectodermal , mesodermal or endodermal components; similar to that seen in a fetus Mature and immature teratomas are both histologically benign Teratoma with malignant transformation is a form of teratoma in which an immature or mature component histologically resembles a non-GCT somatic cancer ( leukemias , sarcomas, carcinoma)

21. Serum Tumor Markers α - FetoProtein ( α FP): A glycoprotein of 591 amino acids encoded by AFP gene on short arm of chromosome 4(4p25 ) Major fetal plasma protein produced by yolk sac and fetal liver Serum t1/2 : 5 - 7 days Normal range in adults: < 5.4 ng / mL

22. Serum Tumor Markers: α FP(contd.) Serum levels elevated in: NSGCT Hepatocellular carcinoma Omphalocele Ataxia Telangectasia Serum levels reduced in: Down syndrome

23. Serum Tumor Markers(contd.) Human Chorionic Gonadotropin A glycoprotein produced by the syncytiotrophoblast It is made up of α and β subunits α hCG - is identical to the subunit of LH, FSH, and TSH molecular weight of α hCG - is 18,000, and that of β hCG - is 28,000 Serum half-life: 36 – 72 hrs

24. Serum Tumor Markers: β hCG (contd.) Immunoassay techniques are used to quantify the presence of β subunit of the molecule Diagnosis and monitoring treatment response in germ cell tumors Also used in: Pregnancy tests Gestational trophoblastic diseases Diagnosis and post-treatment care of ectopic pregnancy As a component of ‘Triple Test ’

25. Serum Tumor Markers(contd.) Lactate dehydrogenase Increases in the serum concentration of LDH are a reflection of tumor burden, growth rate, and cellular proliferation Usually the first serum marker to show a rising trend

26. LDH(contd.) Comparison of value from one lab to another is possible by using ratios of the detected level to the upper limit of normal for the individual assay Increased serum LDH concentrations are observed in approx. 60% of NSGCT patients with advanced disease and up to 80% of patients with advanced seminoma But less specific compared to the other two seum markers

27. Risk Stratification: Seminoma Good Risk: Any hCG Any LDH Non-pulmonary Visceral Metastases absent Intermediate Risk: Any hCG Any LDH Non-pulmonary Visceral Metastases present Poor Risk: Not defined

28. Risk Stratification: NSGCT Good Risk: AFP < 1000 hCG < 5000 LDH < 1.5ULN NPVM absent Gonadal or retroperitoneal primary tumor Intermediate Risk: AFP: 1000 – 10000 hCG : 5000 – 50000 LDH 1.5 – 10ULN NPVM absent Gonadal or retroperitoneal primary tumor

29. Risk Stratification: NSGCT(contd.) Poor Risk: Mediastinal - primary site Extra pulmonary visceral mets + nt ( brain,liver,etc ) AFP > 10,000 ng / mL hCG > 50,000 mIU / mL LDH > 10ULN

30. TNM Classification: T Staging pTX Primary tumor cannot be assessed (if no radical orchiectomy has been performed, TX is used) pT0 No evidence of primary tumor (e.g., histologic scar in testis) pTis Intratubular germ cell neoplasia (carcinoma in situ) pT1 Tumor limited to the testis and epididymis without vascular/lymphatic invasion. Tumor may invade into the tunica albuginea but not the tunica vaginalis pT2 Tumor limited to the testis and epididymis with vascular/lymphatic invasion or tumor extending through the tunica albuginea with involvement of the tunica vaginalis pT3 Tumor invades the spermatic cord with or without vascular/lymphatic invasion pT4 Tumor invades the scrotum with or without vascular/lymphatic invasion

31. TNM Classification: N staging Nx Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis with a lymph node mass ≤2 cm in greatest dimension; or multiple lymph nodes, none >2 cm in greatest dimension N2 Metastasis with a lymph node mass >2 cm but not >5 cm in greatest dimension; or multiple lymph nodes, any one mass >2 cm but not >5 cm in greatest dimension N3 Metastasis with a lymph node mass >5 cm in greatest dimension

32. TNM Classification: M Staging Mx Distant metastasis cannot be assessed M0 No distant metastasis M1a Nonregional nodal or pulmonary metastases M1b Distant metastasis other than to nonregional lymph nodes and lungs

33. TNM Classification: ‘S’ Staging Stage LDH hCG AFP S1 <1.5xN <5000 <1000 S2 1.5-10xN 5000 – 50000 1000 – 10000 S3 >10xN >50000 >10000

34. Stage Grouping T N M S Stage I IA pT1 N0 M0 S0 IB pT2 – 4 N0 M0 S0 IS Any pT / pTx N0 M0 S1 – 3 Stage II IIA Any pT / pTx N1 M0 S0 – 1 IIB Any pT / pTx N2 M0 S0 – 1 IIC Any pT / pTx N3 M0 S0 – 1 Stage III IIIA Any pT / pTx Any N M1a S0 – 1 IIIB Any pT / pTx N1 - 3 M0 S2 Any pT / pTx Any N M1a S2 IIIC Any pT / pTx N1 – 3 M0 S3 Any pT / pTx Any N M1a S3 Any pT / pTx Any N M1b Any S

35. Anatomical Considerations in Staging The initial route of metastasis in seminomas is through lymphatic spread to RPLNs In non- semonomas initial route of metastasis is through hematogeneous route

36. Anatomical Considerations in Staging(contd.) The primary landing zones Lymphatic crossover Ipsilateral distribution Inguinal node involvement Cephalad spread

37. Diagnosis Testicular tumours usually present with a painless unilateral scrotal mass Approx. 10% present with dull scrotal ache, acute pain (thought to be due to haemorrhage ) A small group present with RP metastases or a disseminated disease, backache , lethargy & other systemic features

38. Management of Seminoma Surveillance: Preferred option in compliant patients avoid risk of 2nd tumours avoid risk of toxic effects of chemotherapy Adjuvant chemotherapy Adjuvant radiotherapy

39. Management of NSGCT Requires a multimodality approach including: Surveillance RPLND Chemotherapy Radiotherapy

40. Role of Imaging modalities Imaging is largely used to confirm the presence of the disease and for the assessment of its extent Various imaging modalities that are used in diagnosis and management of GCTs are: Ultrasound CT MRI PET/CT

41. Role of imaging modalities: Ultrasound Scrotal Ultrasound used for imaging in the initial diagnosis of testicular GCTs Certain types of GCT present with characteristic findings on ultrasound

42. Ultrasound: Seminoma : well-defined, homogenous, hypoechoic compared to surrounding parenchyma Embryonal cell tumor: less homogenous and well-defined in comparison with seminoma Teratoma : Characteristically of mixed echogenecity ; more likely to contain cystic spaces and calcifications

43. Scrotal Ultrasound: Seminoma

44. Scrotal Ultrasound: Teratoma

45. Ultrasound(contd.) Assessment of retroperitoneal and pelvic nodes not as reliable as compared to CT or MRI Upto 17% of small volume disease may be missed But can be useful in the assessment of solid intra-abdominal organs, e.g. Liver As a guide for needle placement during biopsy of suspicious lesions

46. Role of Imaging modalities: CT CT is used in staging of GCT as cross-sectional imaging of both mediastinum and abdomen is necessary in staging of the disease Useful method in assessing metastatic disease in thorax, abdomen and pelvis Ability of HRCT to produce thinner sections helps in increasing the sensitivity of pulmonary nodule detection

47. CT(contd.) Drawbacks: Inability of routine diagnostic CT in detecting and assessing small volume lymphadenopathy and viable tumor in normal volume lymph nodes Post-chemo/radiation imaging fails to identify viable tissue effectively as the anatomical details are hindered with post therapy fibrosis

48. CT(contd.) Unable to identify small volume disease in normal sized nodes in upto 30% of patients with GCTs Anatomical imaging modality like CT increases chances of false negative as upper limit of lymph nodes size is yet to be defined

49. Role of Imaging modalities: MRI Better soft tissue contrast compared to USG and CT More accurate in determining and defining retroperitoneal lymph nodes Detection of CNS, musculo -skeletal and hepatic metastases

50. MRI(contd.) Demonstration of IVC tumor invasion Demonstration of vascular anatomy prior to RPLN surgery As an alternative in patients in whom IV contrast cannot be given and in CT with equivocal findings

51. MRI(contd.) Drawbacks: Less accurate in demonstrating lung metastases Similar to CT, cannot identify residual viable tumor after chemotherapy

52. Role of imaging modalities: PET/CT 18F – FDG PET/CT is the main nuclear imaging modality used in the management of GCTs Being a hybrid imaging modality, carries the benefit of defining the tumor and metastases anatomically as well as in terms of identifying viable tumor foci

53. 18F-FDG PET/CT(contd.) Surveillance is one of the options proposed in the management of stage I seminomatous and NS GCT when there is only a low risk of progression More precise predictive factors of occult metastases CT and MRI for GCT detection at diagnosis may be flawed since GCT cells may be present in normal sized lymph nodes

54. 18F-FDG PET/CT in initial staging FDG-PET is a potentially useful diagnostic tool for initial staging in patients with GCTs FDG PET has been found capable of detecting metastatic disease at diagnosis that is not identifiable by other imaging modalities, with a PPV of 100% and NPV of 76 – 91%( Hain SF et al, EJNM 2000 May) However, FDG PET cannot identify mature teratomas

55. FDG PET/CT in evaluation of treatment response In GCTs the prognostic relevance of the rate of decline of serum AFP and beta-HCG for patients with nonseminomatous GCT represents an easy tool in the therapeutic management of these patients However, FDG-PET can be used as an additional useful biomarker for treatment evaluation in poor prognosis GCT patients

56. 48 year Male, Diagnosed Lt Testis GCT- 1994. Underwent Sx and Chemotherapy – 1994 Had retroperitoneal LNs recurrence –had 2 Sx 1996 and 2003 Increased AFP in 2007 – CT – 1.5 cm Rp LN FNAC- Necrosis/GCT- Rx Chemo – AFP –ve Follow-up PET-CT and AFP

57. Rakesh Kumar, AIIMS Date Size (cm) SUV AFP 17.06.08 1.0 3.2 6.43 25.08.08 1.0 1.3 6.37 08.12.08 1.2 2.9 6.96 19.05.09 1.7 8.1 9.26 11.08.09 1.9 9.4 20.1 3 Cycles of Chemotherapy Given

58. FDG PET/CT in evaluation of post – chemotherapy residual disease Residual masses remain in 30% - 40% of patients after completion of chemotherapy despite normalized tumor markers PET/CT can be used effectively as a diagnostic tool in follow-up of post-chemotherapy patients to detect any relapses

59. FDG PET/CT in evaluation of post – chemotherapy residual disease

60. 21 year Male, NSGCT anterior Mediastinum, Post chemotherapy, Tumor Markers- Negative

61. FDG PET-CT Germ Cell Tumor - Pre Rx

62. FDG PET-CT Germ Cell Tumor - Post Rx

63. Role of FDG PET/CT in decision making The optimal management of residual masses remains a controversial matter, with the two main options being surgery and surveillance Resection of residuals may be technically demanding and connected with increased morbidity;

64. Decision-making(contd.) Complications of postchemotherapy RPLND are higher than for primary RPLND, ranging from 7% to 30% and include wound infection small bowel obstruction chylous ascites renovascular injury neurologic injuries Therefore, it is reserved only for patients with a high risk of viable tumor

65. Decision-making(contd.) De Santis et al(J Clin Oncol 2001) found FDG-PET to be highly specific for residuals > 3 cm They showed that FDG-PET is the best predictor of viable neoplastic tissue in postchemotherapy seminoma residuals and can be used as a standard tool for clinical decision-making in this patient group They also showed that patients with residual lesions, even >3 cm, can safely undergo mere surveillance, provided that FDG-PET is negative

66. FDG PET/CT Drawbacks: High sensitivity but low specificity False-positive results for 18F-FDG PET during or shortly after chemotherapy, mainly due to an inflammatory process 18F-FDG is not a tumor specific agent; metabolic marker Teratomatous primary histology might be a contributing factor for the higher rate of false-negative 18F-FDG PET findings in nonseminomas

67. PET/CT: Other radiopharmaceuticals Apart from 18F – FDG, 18F – FLT( Fluorothymidine ), a cell proliferation marker, has also been used in assessment of metastatic germ cell tumors( Pfannenberg et al, JNM 2010) Thymidine kinase I (TK1) activity is thought to be proportional to cellular proliferation and DNA synthesis by the salvage pathway. Hence cells which proliferate at a more rapid rate tend to take up 18F – FLT more avidly

68. Once in the cell, FLT is a substrate for thymidine kinase I (TK1) and is phosphorylated but is not incorporated into DNA. Phosphorylated FLT cannot exit the cell. FLT is not a substrate for thymidine phosphorylase and so is not significantly degraded in vivo and is retained in the cells

69. 18F - FLT Advantages: marker of cellular proliferation more cancer-specific tracer with only low uptake in inflammatory tissue; hence lesser possibility of false positive

70. The study by Pfannenberg et al included 11 patients At the end of the study, 18F - FLT showed lower sensitivity than 18F – FDG with bulky metastases taking up lower amount of 18F – FLT as compared to 18F – FDG

71. Possible explanations for lesser uptake: Competition Active transport(Warburg effect) Uptake period

72. CONCLUSION Germ Cell tumors are diverse group of malignancies that require a multi-modality approach in their management As they carry a high cure rate of upto 95% when treated effectively, their management and follow-up involves use of multiple imaging modalities and serological marker evaluation

73. Conclusion(contd.) 18F – FDG PET/CT continues to be the primary nuclear imaging modality Plays a crucial role in the following aspects of management of GCT: Staging Early prediction of response to chemotherapy Post-treatment follow-up to detect relapses Decision-making

74. THANK YOU