educational purpose

1. 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

12. 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

13. 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

14. 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)

15. 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

16. 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

17. 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

18. 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)

19.  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

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

21. 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)

22. Serum Tumor Markers
α- FetoProtein(αFP):
 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

23. Serum Tumor Markers: αFP(contd.)
Serum levels elevated in:
 NSGCT
 Hepatocellular carcinoma
 Omphalocele
 Ataxia Telangectasia
Serum levels reduced in:
 Down syndrome

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

25. Serum Tumor Markers:
βhCG(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’

26. 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

27. 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

28. 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

29. 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

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

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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

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

40. 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

41. 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

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

43. 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

44. 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

45. 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

46. Scrotal Ultrasound: Seminoma

47. Scrotal Ultrasound: Teratoma

48. 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

49. 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

50. 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

51. 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

52. 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

53. 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

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

55. 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

56. 18F-FDG PET/CT(contd.)
 Surveillance is one of the options proposed in the
management of stage I seminomatous and NSGCT
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

57. 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

61. 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

62.  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

63. 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

64. 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

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

66. 21 year Male, NSGCT anterior Mediastinum,
Post chemotherapy, Tumor Markers- Negative

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

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

69. 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;

70. 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

71. 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

72. 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

73. 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

74.  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

75. 18F - FLT
Advantages:
 marker of cellular proliferation
 more cancer-specific tracer with only low uptake in
inflammatory tissue; hence lesser possibility of false
positive

76.  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

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

78. 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

79. 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

80. THANK YOU