Germ cell tumors
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Transcript of Germ cell tumors
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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