Testicular tumors-Cassification, Biomarkers and Staging by Dr Rajesh

TESTICULAR TUMORS-
Biomarkers and staging
Dr Rajesh Kumar
ATRCTRI
BIKANER

DICTUM FOR ANY SOLID SCROTAL SWELLINGS
All patients with a solid, Firm
Intratesticular Mass that cannot
be Transilluminated should be
regarded as Malignant unless
otherwise proved.

Important facts about testicular
tumors in Asian countries
 Uncommon, incidence: 1/100,000 men
 1% of all malignancies in men
 Peak: 30-40 years, rare in prepubertal children & elderly
 >95% are of germ cell origin.
 Serum tumor markers found in 50% of patients. Eg: AFP,
hCG
 In 2013 our institute, 43 new case of testicular tumors
registered.
 Total Male cancer patients: 4118, thus 1.04% of all male
patients.

I. Primary Neoplasma of Testis.
A. Germ Cell Tumour
B. Non-Germ Cell Tumour
II. Secondary Neoplasms.
III. Paratesticular Tumours.

A. Germinal Neoplasms : (90 - 95 %)
1. Seminomas - 40%
(a) Classic Typical Seminoma
(b) Anaplastic Seminoma
(c) Spermatocytic Seminoma
2. Embryonal Carcinoma - 20 - 25%
3. Teratoma - 25 - 35%
(a) Mature
(b) Immature
4. Choriocarcinoma - 1%
5. Yolk Sac Tumour

B. Nongerminal Neoplasms : ( 5 to 10% )
1. Specialized gonadal stromal tumor
(a) Leydig cell tumor
(b) Other gonadal stromal tumor
2. Gonadoblastoma
3. Miscellaneous Neoplasms
(a) Adenocarcinoma of the rete testis
(b) Mesenchymal neoplasms
(c) Carcinoid
(d) Adrenal rest “tumor”

A. Adenomatoid
B. Cystadenoma of Epididymis
C. Mesenchymal Neoplasms
D. Mesothelioma
E. Metastases
II. SECONDARY NEOPLASMS OF TESTIS
A. Reticuloendothelial Neoplasms
B. Metastases
III. PARATESTICULAR NEOPLASMS

Staging A or I - Tumour confined to testis.
Staging B or II - Spread to Regional nodes.
IIA - Nodes <2 cm in size or ≤ 5 Positive Nodes
IIB - 2 to 5 cm in size or > 5 Positive Nodes
IIC - Large, Bulky, abdominal mass usually > 5 to 10
cm
Staging C or III - Spread beyond retroperitoneal
Nodes or Above Diaphragm or visceral disease

Diagnostic Work-up For Tumors of the Testis
A complete history should be taken, including information about previous
inguinal or scrotal surgery for cryptorchidism, retractile testes, and
orchiopexy.
Specifically, the abdomen should be examined to rule out the presence of
large abdominal masses, and both supraclavicular regions should be
palpated to rule out supraclavicular metastases.
The contra lateral testis should be examined clinically.
The presence or absence of gynecomastia is an important observation

Presentation
 Painless swelling/mass with or without hydrocele (5-10%)
 30-40% report dull/aching sensation
 10% present with metastatic symptoms
 More common on the right Neck Mass / Cough / Anorexia /
Vomiting / Back Ache/ Lower limb swelling
 Gynecomastia
 5% germ cell
 30-50% Sertoli/Leydig
 1-2% have bilateral disease at diagnosis
 Cutaneous atypical nevi. It has been claimed that multiple
cutaneous atypical nevi occur with increased frequency in
patients with testicular germ cell tumors and that they could
represent a marker for this disease.

Bilaterality
 Bilateral testicular involvement by germ cell tumors is seen
in 1.0–2.7% of the cases according to the different series.
 The risk of bilaterality rises to 15% if both testes are
undescended.
 The most common situation is bilateral spermatocytic or
classic seminoma.
 In the presence of bilateral testicular tumors in an elderly
individual, the most likely diagnosis is malignant
lymphoma

 Telomerase activity is present in all types of testicular
germ cell tumors except for mature teratomas.
 Spermatocytic seminoma shows completely different
genetic features. Isochromosome 12p is not found.
 Numerical chromosomal aberrations are common, and
gain of chromosome 9 is characteristic.

Symptoms
 a painless enlargement of
the testis
 usually gradual, and a
sensation of testicular
heaviness .
 typical delay in treatment
from initial recognition of
the lesion by the patient to
definitive therapy
(orchiectomy) ranges from
3 to 6 months.

Signs
 testicular mass or diffuse
enlargement
 typically firm and
nontender and the
epididymis should be
easily separable from it
 Hydrocele may
accompany the testicular
tumor and help to
camouflage it

1. Ultrasound - Hypoechoic area
2. Chest X-Ray - PA and lateral views
3. CT Scan
4. MRI
5. PET CT
6. Tumour Markers
- AFP
-  HCG
- LDH
- PLAP

Laboratory
 Anemia may be detected in
advanced disease.
 Liver function-may be elevated
 Renal function may be diminished
(elevated serum creatinine) if
ureteral obstruction secondary to
bulky retroperitonealdisease is
present.
 The assessment of renal function
(creatinine clearance) is mandatory
in patients with advanced disease
who require chemotherapy.
 AFP
 Found in several NSGCT
 Rarely in Seminomas
 hCG
 Elevated in NSGCT
 7% Seminomas
 LDH
 Elevation of total serum LDH
and in particular isoenzyme-I
was shown to correlate with
tumor burden in NSGCTs.
LDH may also be elevated in
seminoma.

Imaging
 Ultrasonography scrotum-
 1.Scrotal swelling
 2. without s swelling-Young
male with RPLN or visceral
mass, increased AFP/HCG,
infertility.
 determine whether the mass
is truly intratesticular, can be
used to distinguish the tumor
from epididymal pathology,
and may also facilitate
testicular examination in the
presence of a hydrocele.

Testicular microlithiasis
 Associated with increased risk of testicular in situ
carcinoma(TIN).
 Most common in GCT & their family members.
 Need further investigations( biopsy or monitoring
) if microlithiasis is-
 in b/l testes,
 in subfertile male,
 in c/l of GCT testes
 Atrophy( vol≤ 12 ml)
 inhomogeneous parenchyma

 Once the diagnosis of testicular cancer has been
established by inguinal orchidectomy, careful clinical
staging of disease is mandatory.
 Chest radiographs (postero-anterior and lateral) and
computed tomography (CT scan) of the abdomen and
pelvis are used to assess the 2 most common sites of
metastatic spread, namely, the lungs and
retroperitoneum.

Diagnostic Radiology
Computed tomography (CT) scan of
abdomen and pelvis :- to identify
metastatic involvement above and below
the diaphragm.
Sensitivity-40%, specificcity-95%
CT scan of chest for nonseminomas and
stage II seminomas.
lymph node SIZE- 1 to 2 cm in a
primary landing zone are involved by
GCT -70%
If 0.4 to 1 cm positive in -50%

 Magnetic resonance imaging appears equivalent to CT in
determining the size and location of retroperitoneal
adenopathy. MRI of the scrotum offers a sensitivity of
100% and a specificity of 95-100%, but its high
 cost does not justify its use for diagnosis.
 Positron emission tomography (PET) has been shown to
improve on the diagnostic accuracy of CT in early stage
testicular cancer. It has a higher sensitivity (70%) and
specificity (up to 100%) than CT . It is unable to detect
lesions <5 mm in size or teratomas of any size due to
their very low metabolic activity. PET is useful in the
detection of residual viable seminoma in patients
with masses greater than 3 cm in diameter after
chemotherapy.

Special Studies:-
 Bipedal lymphangiography has a greater sensitivity than
CT (71%) but a lower specificity (60%). It does not add to the
diagnostic accuracy of a positive CT, but is able to
demonstrate architectural abnormalities within normal-size
lymph nodes.
 Pulmonary function test-
 Semen analysis and banking of sperm

Differential Diagnosis
Torsion
Epididymitis
Epididimo-orchitis
Hydrocele
Hernia
Haematoma
Spermatocele
Syphilitic gumma

Classification of Germ-Cell Tumors of the Testis
 Intratubular germ-cell neoplasia
 Seminoma :
a) Classic type b) Spermatocytic type
 Nonseminomatous germ-cell tumors
a) Embryonal carcinoma
b) Yolk sac (endodermal sinus) tumor
c) Teratoma: Mature, Immature, Teratoma with
malignant transformation, d) Choriocarcinoma
e) Mixed germ-cell tumors
 Other than GCT :- Sex-Cord Stromal Tumors

 Classification of Sex-Cord Stromal Tumors
a) Leydig cell tumor
b) Sertoli cell tumor
c) Granulosa cell tumor
d) Fibroma-thecoma stromal tumor
e) Sex cord-stromal tumor with annular tubules
f) Gonadoblastoma
g) Sex cord-stromal tumor unclassified type

95% germ cell tumours – malignant, but curable
 Seminomas (40%)
 Nonseminomatous germ cell tumors (NSGCT)
(40%)
 15% of tumors have both seminomatous &
nonseminomatous elements.
 Nonseminomatous elements are more malignant,
therefore such tumors are clinically treated as
NSGCT.
5% non-germ cell (aka sex cord stromal) tumours –
usually benign, sometimes presenting hormonally.

Diagram showing relationships between various types of germ cell tumors

Seminoma Nonseminoma Age of presentation
• 3rd and 4th decade
 Presentation
• present with uniform
testicular swelling
 Serum markers are
rarely elevated. AFP
never rises.
 Lymphatic spread
• Good prognosis
• 2nd and 3rd decade
• present with
multinodular testicular
swelling
• Serum markers are
commonly elevated.
• Lymphatic as well as
hematogenous
• Worse prognosis

Dixon and Moore classification
Based on histology & has prognostic importance &
described in 1952
Group-1 seminoma pure.
Group-2 embryonal carcinoma pure, or with seminoma.
Group-3 teratoma pure, or with seminoma.
Group-4 teratoma with embryonal ca. and/ or
choriocarcinoma with or without seminoma.
Group-5 choriocarcinoma pure, or with embryonal
carcinoma and or seminoma.

For the purpose of treatment planning GCT may be
divided into 2 categories.
1 -pure seminoma
2 -all other histologic types(group 2 to 5), thereafter
referred to as
Mixed tumors

Immunochemical markers
 CD117 :- Seminoma, negative in
embryonal carcinoma
Loss of cKit asso. With more aggressive
phenotype.
 SOX2 and CD30 :- Embryonal
carcinoma, negative in seminoma.
 OCT ¾- positive in seminoma &
embryonal carcinoma
 Placental alkaline phosphatase (PLAP) is
positive in a membranous pattern in up to
98% of seminomas.

SEMINOMA
 IMMUNOHISTO CHEMISTRY
 Cells are OCT4+ve,
 PLAP +ve, &
 c-kit +ve
 Contains cytokeratins, although only
36 % cases are +ve
 EMA -ve

SPERMATOCYTIC SEMINOMA
 Cells are PLAP –ve,
 vimentin –ve,
 muscle marker –ve,
 cytokeratin –ve, AFP –ve,
 HCG –ve,
 EMA –ve
 NY-ESO 1 +ve
 SCP-1 +ve

EMBRYONAL CARCINOMA
 Tumor cells are CD 30 +ve, a finding unique to
Embryonal carcinoma, and useful in ruling out solid
pattern of Embryonal carcinoma, which can simulate
Seminoma .
 OCT 4 +ve,
 PLAP +ve,
 cytokeratin +ve,
c-kit –ve, and EMA -ve

YOLK SAC TUMOR
 AFP + ( focal or patchy ),
 cytokeratin +ve,
 PLAP variable,
 EMA –ve, CD 30 -ve

SERTOLI CELL TUMOR
 Inhibin –+ve, but less consistently than in leydig cell
tumor & can be +ve with chromogranin,
 S-100 proteins, synaptophysin, and cytokeratin AE1/3 &
CAM 5.2 in 64-100 % cases
 MIS & CD99 +ve

IHC OF TESTICULAR GERM CELL TUMORS
Seminoma Spermato.
Seminoma
Embryonal
carcinoma
Yolk sac
tumor
Teratoma Choriocarci
noma
OCT-4
+ - + - - -
CD117
+ -/+ - - - -
CK
-/+ - + + + +
VIMENTIN
+ - - + + -
PLAP
+ - + + + +
AFP
- - + + + +
HCG
+ - + - + +
CD30
+ - + - - -
PAS
+ - - + - -

Testicular Tumour & Molecular Biology
Seminoma &
Embryonal - N-myc expression
Carcinoma
Seminoma - c-ras expression
Immature
Teratomas - c-erb expression
PROTO-ONCOGENES in Germ Cell Tumours (Shuin et al)

Testicular Tumor & Molecular Biology
(Recent Advances)
Testicular germ cell tumor show consistent
expression of both:
 Parental alleles of H19
 IGF-2 genes.

Definition:
Biomarker is a substance used as an indicator of a biologic state
Existence of living organisms or biological process.
A particular disease state
A fragment of DNA sequence
Proteins
Nucleic acids
Carbohydrate
Lipids

Detection of biomarker
Detection of biomarker
Quantitative
a link between quantity of the marker and disease
Qualitative
a link between exist of a marker and disease
Detection of biomarker – diagnosis
e.g enzymatic activities
Antibodies, IHC, ELISA

Enzymes –PSA - prostate specific antigen (serine protease),
NSE (neurospecific isoenzyme of enolase), TK (thymidine
kinase), LDH
Hormones - GH, prolactin, calcitonin, parathormon (PTH),
gastrin, hCG
Imunoglobulines – IgG, IgM, IgA, IgD, IgE, 2-microglobulin
Glycoproteines, :- AFP, beta-hCG, CA 125
Glycolipides:- CA 19-9
Tumor markers are

Testicular tumors
TWO MAIN CLASSES
 Onco-fetal Substances : AFP & HCG
 Cellular Enzymes : LDH & PLAP
 Hormones : Testosterone, estradiol,
Androstenidione, Inhibin
( AFP and b-HCG Trophoblastic Cells)

Common Serum Markers for Cancer
Diagnosis/prognosis
AFP CEA CA15-3 CA19-9 CA125 PSA PLAP hTG HCGb NSE B2M LDH
Lung x x x x x x
Pancreas x x x x x
Kidney x x x x
Breast x x x
Ovarian x x x x x x
Cervical x x
Uterine x x x x
Prostate x x
Liver x x x x x
Gastro x x x
Colon x x x x
Bladder x
Lymphom
a
x
Myeloma x
Thyroid x x
Testicular x x x x

Common Biomarker for testicular Cancer
AFP (10-15 ng/ml)
 Alpha-fetoprotein (AFP) is the major protein of fetal serum but falls to
an undetectable level after birth.
 A glycoprotein, MW 70.000, discovered in 1956 in foetal serum
described as a tumour-associated protein in 1964 synthesised in the liver
and yolk sac of the foetus.
 Because of the association of the rapid cell growth, this fetal protein is
also used as a tumor marker.
 AFP is secreted into serum, reaching maximum levels at week 13 of
pregnancy. (Particularly very high if the pregnancy is complicated by a spinal cord defect or other
abnormality)

 Normal adult concentration less than 15 ng/ml. Normal half life is 5 to 7 days.
 The primary malignancies associated with AFP elevations are
Hepatocellular carcinoma
Nonseminomatous germ cell tumor:-
Pure embryonal carcinoma, Teratocarcinoma ,Yolk sac Tumor
 Other gastrointestinal cancers occasionally (but rarely to greater than 1,000 ng
per mL)
 AFP levels are abnormal in 80 percent of patients with hepatocellular carcinoma
and exceed 1,000 ng / mL in 40 percent of patients with this cancer.
 An AFP level above 500 ng /mL is often used in lieu of biopsy to diagnose HCC.
 Seminomas and Dysgerminomas are always AFP-negative
 AFP level, (together with hCG level), is established regimen for monitoring
patients with non-seminomatous.

Non cancerous diseases
 Cirrhosis
 Viral hepatitis
 Marijuana abuser
(although usually less than 500 ng/mL)
 AFP rise in: Non seminomatous germ cell tumor . Direct relationship
exists between AFP level and disease stage of non-seminomatous testicular
carcinoma.
Stage I - 10-20%
Stage II – 20% - 40%
Stage III – 40 – 60%

AFP and b-HCG Levels in Germ Cell Tumors and Gestational Trophoblastic
Disease
Tumor AFP elevation hCG elevation
 Seminoma and dysgerminoma Never Occasional, minimal
 Embryonal cell carcinoma Yes Yes
 Choriocarcinoma No Yes
 Yolk sac tumors Yes No
 Teratoma No No
 Gestational trophoblastic disease No Yes
AFP values in excess of 10,000 ng/mL or hCG levels above 50,000 mIU per mL
at initial diagnosis portend a poor prognosis, with a five-year survival rate of 50
percent. Similarly staged patients with lower AFP and -hCG levels have a cure
rate higher than 90 percent.
 Use of AFP or beta-hCG elevation
Recurrence and assess response to treatment.

HCG (10 mIU/ml )
 The hormone HCG is secreted at the time of implantation by the syncytio
trophoblast cells (which later becomes the placenta), when the embryo attaches to
the uterine wall.
 Main role : to maintain the corpus luteum (whose role is to secrete
progesterone) which is necessary for implantation of the embryo.
 The protein can be detected in serum or urine.
 Half life of HCG is 18 - 36 hours.
 beta HCG promotes the maintenance of the corpus luteum during the beginning
of pregnancy, causing it to secrete the hormone progesterone. Progesterone enriches
the uterus with a thick lining of blood vessels and capillaries so that it can sustain
the growing foetus.
 This is first hormone that detects pregnancy as it is present in the blood about
ten days after fertilization, and in the urine a few days later.
 The most sensitive, accurate and reliable pregnancy test is a blood test for the
presence of beta HCG .

 Beta HCG levels vary according to the gestational age.
 Non-malignant elevations may be observed in pregnancy and cirrhosis. Levels of
HCG are useful in monitoring the effectiveness of treatment.
 Beta-HCG are typically about 100 mIU/ml 14 days after ovulation in a healthy
singleton pregnancy. They should double every 48- 72 hours in a healthy pregnancy.
 The test for HCG to diagnose pregnancy, as well as other problems of pregnancy is
done by determining the levels of β-subunit of hCG.
 The HCG hormone has 2 sub units- namely the ALPHA AND BETA sub-units.
 The alpha sub-unit has components identical to that of luteinizing hormone
(LH), follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH)
 The beta subunit is unique to only to hCG.

Importance :
 Confirmation of pregnancy
 Tumor marker
 Human chorionic gonadotropin can be used as a tumor marker, as its β
subunit is secreted by some cancers.
 The normal range for men is between 0-5 mIU/mL. Combined with
alpha-fetoprotein, β-HCG is an excellent tumor marker for the monitoring
of germ cell tumors.
 The -hCG level is used to diagnose gestational trophoblastic disease, a
rare neoplastic complication of pregnancy.
 Choriocarcinoma may produce high levels of βhCG (due to the presence
of syncytialtrophoblasts- part of the villi that make up the placenta)
despite the absence of an embryo.
 Non seminomatous germ cell tumor
Stage I - 10-20%
Stage II – 20% - 30%
Stage III – 40%

 Also increase in 15 – 20% of advanced pure seminoma.
Non cancerous conditions
 abnormal pregnancies i.e. ectopic pregnancies and potential miscarriages.
 It is also used as part of a screening test for Down Syndrome. Where it is decrease.
 150,000 mIU/ml is strongly indicative of an ectopic pregnancy..
 Multiple Pregnancy
 Gestational trophoblastic disease like Hydatidiform moles ("molar pregnancy")

Lactate Dehydrogenase
 Increased in 60% of advanced NSGCT and in 80% of
advanced seminoma.
 LDH level reflects tumor burden, growth rate and
cellular proliferation.

 Yolk Sac Tumor is almost invariably associated with
production of large amounts of alpha-fetoprotein
(AFP) and also alpha-1 antitrypsin.

To properly Stage Testicular Tumours following
are pre-requisites:
(a) Pathology of Tumour Specimen
(b) History
(c) Clinical Examination
(d) Radiological procedure - USG / CT /
MRI / Bone Scan
(e) Tumour Markers -  HCG, AFP
Requirements for staging

Serum tumor markers
LDH HCG
Miu/ml
AFP
Ng/ml
S0 N N N
S1 <1.5 x N < 5000 < 1000
S2 1.5-10x N 5000 to
50000
1000 to
10000
S3 >10x N > 50000 >10000

Prognostic factors in testicular
cancer(EAU)
 For seminoma For non-seminoma
 Pathological (for stage I)
 Histopathological type •
 Tumour size (> 4 cm)
 • Invasion of the rete testis
 • Vascular/lymphatic in or peri-tumoural invasion
 • Proliferation rate > 70%
 • Percentage of embryonal carcinoma > 50%
 Clinical (for metastatic disease)
 • Primary location
 • Elevation of tumour marker levels
 • Presence of non-pulmonary visceral metastasis
According to CMR invasion of testicular veins or lymphatics,
absence of yolk sack elements, and presence of embryonal cell
carcinoma.

Q 1. With respect to clinical staging of germ cell tumors of
the testis, which of the following statements is incorrect?
A. Modern staging techniques have reduced the false-
negative staging error in clinical staging of T1N0M0 to
approximately 20%
B. Approximately 10-15% of patients with clinical stage
T1N0M0 seminoma harbor occult retroperitoneal metastases
C. In general, 5% of patients with clinical stage I germ cell
tumors harbor occult disease in extragonadal sites
D. Abdominal and pelvic MRI scans have a significant
advantage over CT scans with respect to diagnosing
micrometastatic disease.
E. Spermatic cord involvement increased the likelihood of
metastatic involvement.

Answer: D
MRI offers no advantage over CT for imaging and
staging the retroperitoneum in patients with testis
cancer.

Q 2. In NSGCTs, all of the following prognostic factors
are used to determine risk of metastatic disease except
which one?
A. T stage
B. Embryonal cell carcinoma (>40%)
C. Teratoma (>50%)
D. Vascular invasion
E. Absence of yolk sac elements

Answer: C
Six factors have been analyzed in many of these
studies and include stage of the primary tumor (pT
</= 2); vascular (including lymphatic) invasion;
presence of embryonal carcinoma; absence of yolk
sac elements; and elevated preorchiectomy
markers. In the Medical Research Council series,
four were independently predictive of relapse;
invasion of testicular veins or lymphatics, absence
of yolk sack elements, and presence of embryonal
cell carcinoma. Of the 259 patients, 55 patients
had three or four factors and a relapse rate of 58%;
89 had two factors and a relapse rate of 24%; 81
had one factor and a relapse rate of 10%; and 8
patients had no factors and no relapses.

Q. 3. With respect to lymphatic drainage of the testis, which one
of the following statements is correct?
A. The primary drainage of the right testis is usually located
within the group of lymph nodes in the left para-aortic region.
B. The spermatic cord contains four to eight lymphatic
channels that traverse the inguinal canal and peritoneal space.
C. The spermatic vessels cross dorsal to the ureter, whereas the
testicular lymphatics cross ventrally.
D. Lymphatic drainage has been shown to cross over from right
to left and therefore cross-metastasis occur more commonly in
patients with right sided tumors.
E. Suprahilar lymph node spread is invariable in stage N1
disease.

Answer: D
Cross-metastases were reported to occur more
commonly in patients with right sided tumors,
because of lymphatic drainage from right to left.
These observations have been important for the
surgical management of testis cancer.

Testicular tumors-Cassification, Biomarkers and Staging by Dr Rajesh

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