Ganesh Kumar M

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

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
ETIOLOGY
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
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
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
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
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
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
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
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
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)
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
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
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
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)
 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
 Ectodermal component: skin, hair, sweat glands,
sebaceous glands, and teeth

 Mesodermal component: fat, smooth muscle, bone,

and cartilage

 Endodermal component: Respiratory and intestinal

epithelium
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)
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

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

Serum levels reduced in:

 Down syndrome
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

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’
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

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

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
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
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
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
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
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
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
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
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
Anatomical Considerations in
Staging(contd.)
 The primary landing zones

 Lymphatic crossover

 Ipsilateral distribution

 Inguinal node involvement

 Cephalad spread
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
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
Management of NSGCT
Requires a multimodality approach including:

 Surveillance

 RPLND

 Chemotherapy

 Radiotherapy
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
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
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
Scrotal Ultrasound: Seminoma
Scrotal Ultrasound: Teratoma
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
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
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
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
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
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
MRI(contd.)
Drawbacks:

 Less accurate in demonstrating lung metastases

 Similar to CT, cannot identify residual viable tumor

after chemotherapy
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
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
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

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
 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
3 Cycles of Chemotherapy Given

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 Rakesh Kumar,
9.4 AIIMS
20.1
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
FDG PET/CT in evaluation of post –
chemotherapy residual disease
21 year Male, NSGCT anterior Mediastinum,
Post chemotherapy, Tumor Markers- Negative
FDG PET-CT Germ Cell Tumor - Pre Rx
FDG PET-CT Germ Cell Tumor - Post Rx
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;
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
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
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
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
 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
18F - FLT
Advantages:

 marker of cellular proliferation

 more cancer-specific tracer with only low uptake in

inflammatory tissue; hence lesser possibility of false
positive
 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
Possible explanations for lesser uptake:

 Competition

 Active transport(Warburg effect)

 Uptake period
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
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
THANK YOU