Testicular Cancer

Sarah J. McAleer
March 5, 2003
 Epidemiology
• 2-3 new cases per 100,000 US males per
year
• Marked variation in incidence among
different countries/races
• 90-95% are germ cell
• Most common solid tumor in males ages
15-35
 Risk Factors
• Cryptorchidism: 7-10% of patients with
testicular cancer have a history of
cryptorchidism
• Abnormal germ cell morphology
• Elevated temperature
• Interference with normal blood supply
– 5-10% of patients with testicular cancer and a
history of cryptorchidism develop cancer in
the contralateral testis
– Orchidopexy does not prevent development of
cancer – just allows for detection
• Gonadal Dysgenesis
– 20-30% develop cancer (gonadoblastoma)
• Trauma
– prompts evaluation
• Hormones
– DES/OCP probably do not increase risk
• Atrophy (nonspecific vs. mumps orchitis)
– Speculative
 Presentation
• Painless swelling/mass with or without
hydrocele (5-10%)
• 30-40% report dull/aching sensation
• 10% present with metastatic symptoms
• Gynecomastia
– 5% germ cell
– 30-50% Sertoli/Leydig
• 1-2% have bilateral disease at diagnosis
• More common on the right
 Differential Diagnosis
• Torsion • Hematoma
• Epididymitis • Spermatocele
• Epididimoorchitis • Syphilitic gumma
• Hydrocele
• Hernia
 Work-up
• Exam
• U/S
• CXR +/- Chest CT
• Abdominal CT
– Can identify small nodal deposits <2 cm
– MRI and PET scan no advantage over CT
• Markers
– Elevation after orchiectomy generally
represents metastatic disease
– Conversely normalization does not rule out
metastatic disease
 Alpha-Fetoprotein
• Expressed by the early embryo (also liver
and GI tract)
• Single chain
• Half-life: 5-7 days
• Produced by pure embryonal,
teratocarcinoma, yolk sac, mixed tumors
(NOT pure choriocarcinoma or seminoma)
• Falsely elevated in liver dysfunction, viral
hepatitis and ETOH
 Human Chorionic Gonadotrophin
• Secretory product of the placenta
• Alpha unit (LDH,FSH,TSH) and beta unit
• Half-life: 24-36 hours
• Produced by syncytiotrophoblastic tissue
• All choriocarcinomas, 40-60% embryonal,
5-10% seminoma
• Falsely elevated in hypogonadism and
marijuana use
• Lactic Acid Dehydrogenase
– Presents normally in smooth, cardiac and
skeletal muscle, liver and brain
– Most useful in advanced seminoma or tumors
where other markers are not elevated
– Many false positives
• PLAP
• GGTP
• CD30
 Primary Testicular Cancer
GERM CELL NONGERM CELL
• Seminoma 30-60% • Leydig 1-3%
• Embryonal 3-4% • Sertoli <1%
• Yolk sac • Gonadoblastoma 0.5%
• Teratoma 5-10%
• Choriocarcinoma 1%
• Mixed 40%
Radical Orchiectomy
• Inguinal approach
• Avoid seeding the
scrotum and
disrupting lymphatics
• Wait 5 half lives
before rechecking
markers
Staging
 Seminoma

• Most common germ cell tumor

• Pure seminomas never secrete AFP
• 5-10% secrete HCG (usually classic)
• At diagnosis:
– 65-75% confined to the testis
– 10-15% with regional retroperitoneal nodes
– 5-10% with advanced juxtorenal or visceral
disease
• Classic 82-85%
– Age 30s
– Islands/sheets of cells with syncytiotrophoblasts
(5-10%)
• Anaplastic 5-10%
– Stage for stage no different than classic
• Spermatocytic 2-12%
– Low metastatic potential
– Older population (>50)
– 6% bilateral (as opposed to 2% of classic
seminomas)
Treatment: Seminoma
 Treatment: Stage I
• XRT
– 20% of clinical stage I have pathologic stage II
– 2500 cGy to paraaortic nodes
– Minimal acute morbidity
– Long term concerns: infertility, GI
manifestations, secondary malignancies
– Relapse rate 5% (rare after 5 years): usually
outside of retroperitoneum
– Salvage chemotherapy after relapse
• Surveillance
– Indicated only for compliant patients
– Favorable tumors:
• Tumors <6cm
• Absence of lymphatic or vascular invasion
• Normal post orchiectomy tumor markers
• Pure spermatocytic seminomas
– Relapse rate 15% (90% in retroperitoneum)
– After relapse treat with XRT or chemo
 Treatment : Stage IIa, IIb
• XRT to the ipsilateral external iliac,
bilateral common iliac, paracaval,
paraaortic and cisterna chyli
• Bulky IIb disease or disease close to the
kidney – chemotherapy first

• If history of herniorriphy or orchidopexy

should also do XRT to the inguinal region
(shield contralateral testis)
 Treatment: Stage IIC, III
• Cisplatin based chemo (4 cycles of EP or
3 cycles of BEP)
• 90% will have a complete response
• Residual retroperitoneal masses are
usually fibrosis
– RPLND warranted if >3cm and well
circumscribed
 NSGCT
• Embryonal
– Peak age 25-35
– May secrete both AFP and B-HCG
– Metastatic deposits usually contain teratoma (80%)
– Epitheloid cells in glands or tubules with pale
cytoplasm, 1+ nucleoli and giant cells
• Choriocarcinoma
– Peak age 20-30
– Worst prognosis of all testis tumors
– Hematogenous spread (especially to lungs)
– Always secrete B-HCG
– Central hemorrhage, syncytiotrophoblasts
(eosinophilic cytoplasm) and cytotrophoblasts (closely
packed, clear cytoplasm, single nuclei)
• Yolk Sac (Infantile embryonal)
– Peak age: infants and children
– Also may spread hematogenously
– Secretes AFB and B-HCG
– Epithelial like cells arranged in glands with vacuolated
cytoplasm
– Embryoid bodies (Schiller-Duvall bodies) resemble 1-
2 week old embryos surrounded by
syncytiotrophoblasts and cytotrophoblasts
• Teratoma
– Peak age 25-35
– Poor response to chemotherapy and XRT
– Pure forms should not secrete AFB or B-HCG
– Can arise from malignant transformation after
chemotherapy for NSGCT
– Contains all 3 germ layers in the mature form and is
undifferentiated in immature form
Treatment: NSGCT
 Treatment: Stage I
• RPLND
– Allows for more accurate staging
• 30% clinical stage I is pathologic stage II
– Definitive treatment for N1
• N2 will need post RPLND chemotherapy
– Relapse rate 5-13% (5-10% outside of
RPLND field: primarily in the lungs)
– Treat relapses with chemotherapy (BEP/EP)
 RPLND

• Major morbidity is ejaculatory dysfunction

• Modified nerve sparing RPLND preserves
function in 90-99%
– Identify the sympathetic nerves
– Dissection is limited to below the level of the IMA on
the ipsilateral side only
 Surveillance
• Appropriate for:
– Compliant patient
– Tumor confined to tunica albuginea
– No vascular/lymphatic invasion
– Normal markers after orchiectomy
– No further disease seen on radiographic
imaging
– Absence of embryonal cell
– Presence of yolk sac elements
 Surveillance
• F/U: PE, CXR, markers
– Monthly for 1 year
– Bimonthly for 1 year
– Every 3-6 months for 5-10 year (no precise end point)
– CT scan every 2-3 months for first 2 years then every
6 months
• Relapse rate 25% and usually occurs in first 8-
10 months (commonly outside of the
retroperitoneum)
• No economic difference between modified
RPLND, chemotherapy or surveillance
• XRT
– New data suggests that XRT may have value
– XRT dose 4000-5000 cGY
• Greater dose than used for seminoma
• Higher rate of complications (5-10%) including
radiation enteritis, bowel obstruction, bone marrow
suppression and secondary malignancies
• Chemotherapy
– Traditionally not used for lower stages
– 2 cycles of BEP
– Added advantage of treating metastatic
disease that RPLND misses
– Initial data promising but long term
unconfirmed
 Treatment IIA-IIB
• RPLND
– Advocated for lower volume disease
– Cures 50-70% of stage IIa/b without further intervention
• Chemotherapy
– Favored for patients with nodes >3cm
– If markers normalize but residual mass is seen on CT,
RPLND is advocated
• 20% residual cancer
• 40% teratoma
• 40% fibrosis
• Relapse or residual cancer is treated with salvage
chemotherapy (VIP X4)
 Treatment IIC-III
• Primary chemotherapy
– In IIC disease with partial response, may
proceed to RPLND
• Salvage chemotherapy or high dose
chemotherapy with autologous bone
marrow transplant
– No response to first line chemotherapy
– Incomplete resection after RPLND
 Prognosis
• Seminoma (at 5 years)
– I: 98%
– IIA: 92-94%
– IIB-III: 33-75%
• NSGT (at 5 years)
– I: 96-100%
– IIA: >90%
– IIB-III: 55-80%
 Leydig Cell
• 1-3% of all testis tumors
• Bimodal age distribution: ages 5-9 and 25-35
• Bilateral in 5-10%
• No association with cryptorchidism
• Prepubital children may present with virilization
and elevated urinary 17-ketosteroid levels;
adults are usually asymptomatic (25%
gynecomastia)
• Treatment: radical orchiectomy and RPLND for
malignant tumors (10% malignant)
• Solid sheets of cells with oval nuclei
• Reinke crystals (fusiform shaped cytoplasmic
inclusion) are pathognomic although rare
 Sertoli Cell
• Less than 1% of all testicular tumors
• Bimodal age of distribution: < 1 year and
20-45 years old
• 10% lesions are malignant
• Virilization seen in children and
gynecomastia in adults
• Radical orchiectomy with RPLND in
malignant disease
 Gonadoblastoma
• 0.5% of testicular tumors
• Seen in patients with gonadal dysgenesis
• 4/5 patients are phenotypic females with
streak gonads
• Radical orchiectomy with gonadectomy of
the contralateral gonad (bilateral in 50%)
 Questions
1. A young adult man presents with a 7 cm left testis
tumor; the serum AFP value is elevated (220 ng/ml);
the clinical stage of disease it T2N1M0S1. He
undergoes radical inguinal orchiectomy. Pathologic
study reveals an anaplastic seminoma with vascular
invasion. The serum AFP value normalizes after
orchiectomy. Further management of the patient
should include the following?

A. Low-dose external beam radiotherapy to

abdominal and pelvic lymph nodes
B. Low-dose external beam radiotherapy to
abdominal, pelvic and mediastinal lymph nodes
C. Bilateral RPLND with adjuvant radiotherapy
D. Bilateral RPLND
E. Two cycles of chemotherapy (BEP)
Answer: D (Bilateral RPLND)
The potential advantages of RPLND in the treatment of
testis cancer stem from the fact that retropertioneal
deposits are usually the first and frequently the sole
evidence of extragonadal spread. Such therapy is
capable of eradicating resectable disease in the majority
of patients with N1-N2 disease. Thorough excision of
the retroperitoneal lymph nodes therefore remains the
epitome or gold standard of staging. Although
noninvasive staging techniques are somewhat accurate,
20-25% of patients with clinical stage T1-3N0M0 disease
are understaged by all available modalities of
nonsurgical staging. The cure rate for patients with
pathologically confirmed stage I disease is roughly 95%
with surgery alone. The 5-10% of patients who may
relapse with a negative RPLND for low stage disease
have a high cure rate with chemotherapy.
2. 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.
3. 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.
4. 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.
5. A patient presents with a 6 cm right sided testis tumor
and abdominal discomfort. He undergoes right radical
inguinal orchiectomy; pathologic study reveals mixed
germ cell tumor. Serum tumor markers are elevated
(AFP, 800 ng/ml; β-HCG, 2500 mlU/ml). An abdominal
CT reveals a 10 cm retroperitoneal mass. The patient
undergoes cisplatin based chemotherapy with resultant
75% reduction of the retroperitoneal mass and
normalization of the serum tumor markers. What is the
best management at this stage?

A. Observation with a PE every 4 months, serum tumor

markers, CXR, and abdominal CT scan.
B. FNA of the residual retroperitoneal mass followed by
salvage radiotherapy for persistent germ cell tumor
C. Abdominal exploration, tumorectomy and bilateral
RPLND
D. Abdominal exploration and tumorectomy
E. Ifosfamide-based salvage chemotherapy
Answer: C
RPLND after chemotherapy involves both
resection of the residual disease and full
bilateral node dissection. In the best of
hands, this procedure is associated with
an 18% complication rate, which is
contributed to by both the technically
demanding nature of the surgery and other
factors such as reduced pulmonary
reserve due to bleomycin.