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 FactorsCryptorchidism:

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

SeminomaSpermatocytic seminoma

Non-seminomatous GCT(NSGCT)Embryonal carcinomaYolk sac(endodermal sinus) tumorChoriocarcinomaTeratoma: mature

immaturewith 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 seminomaand 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, hyperchromaticnuclei 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 hematogenousmetastases

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 ectodermalcomponent

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 endodermalcomponents; similar to that seen in a fetus

Mature and immature teratomas are both histologicallybenign

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 Markersα- 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 < 1000hCG < 5000LDH < 1.5ULNNPVM absentGonadal or retroperitoneal primary tumor

Intermediate Risk:AFP: 1000 – 10000hCG: 5000 – 50000LDH 1.5 – 10ULNNPVM absentGonadal or retroperitoneal primary tumor

Risk Stratification: NSGCT(contd.) Poor Risk:

Mediastinal- primary site

Extrapulmonary visceral mets +nt (brain,liver,etc)

AFP > 10,000 ng/mLhCG > 50,000 mIU/mLLDH > 10ULN

TNM Classification: T StagingpTX 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 stagingNx 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 GroupingT 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 SeminomaSurveillance:

Preferred option in compliant patients

avoid risk of 2nd tumours

avoid risk of toxic effects of chemotherapy

Adjuvant chemotherapy

Adjuvant radiotherapy

Management of NSGCTRequires 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, hypoechoiccompared 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

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

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/CTDrawbacks: 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 thymidinekinase 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 - FLTAdvantages:

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 modalityPlays 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

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