TESTICULAR TUMORS

1
TESTICULAR TUMORS

• Epidemiology, Pathogenesis, Prognosis
• Western Reserve Care System Dept. of Surgery

2
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

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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

4

• Gonadal Dysgenesis
• 20-30 develop cancer (gonadoblastoma)
• Trauma
• prompts evaluation
• Hormones
• DES/OCP probably do not increase risk
• Atrophy (nonspecific vs. mumps orchitis)
• Speculative

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Testicular Atrophy
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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

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Differential Diagnosis

• Torsion
• Epididymitis
• Epididimoorchitis
• Hydrocele
• Hernia

• Hematoma
• Spermatocele
• Syphilitic gumma

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Work-up

• Exam
• U/S
• CXR /- Chest CT
• Abdominal CT
• Can identify small nodal deposits lt2 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

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The Exam v.1
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The Exam v.2
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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

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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

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• 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

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Primary Testicular Cancer

• GERM CELL
• Seminoma 30-60
• Embryonal 3-4
• Yolk sac
• Teratoma 5-10
• Choriocarcinoma 1
• Mixed 40

• NONGERM CELL
• Leydig 1-3
• Sertoli lt1
• Gonadoblastoma 0.5

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Radical Orchiectomy

• Inguinal approach
• Avoid seeding the scrotum and disrupting
  lymphatics
• Wait 5 half lives before rechecking markers

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Staging
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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

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• Classic 82-85
• Age 30s
• Islands/sheets of cells with syncytiotrophoblasts
  (5-10)

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• Anaplastic 5-10
• Stage for stage no different than classic
• Spermatocytic 2-12
• Low metastatic potential
• Older population (gt50)
• 6 bilateral (as opposed to 2 of classic
  seminomas)

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Treatment Seminoma
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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

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• Surveillance
• Indicated only for compliant patients
• Favorable tumors
• Tumors lt6cm
• 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

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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)

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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 gt3cm and well circumscribed

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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

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• 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)

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• 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

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• 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

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Treatment NSGCT
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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)

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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

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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

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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

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• 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

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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 gt3cm
• 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)

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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

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Prognosis

• Seminoma (at 5 years)
• I 98
• IIA 92-94
• IIB-III 33-75
• NSGT (at 5 years)
• I 96-100
• IIA gt90
• IIB-III 55-80

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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)

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• Solid sheets of cells with oval nuclei
• Reinke crystals (fusiform shaped cytoplasmic
  inclusion) are pathognomic although rare

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Sertoli Cell

• Less than 1 of all testicular tumors
• Bimodal age of distribution lt 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

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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)

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Remember
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Questions

• 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)

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• 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.

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• 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.

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

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• 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 (gt40)
• C. Teratoma (gt50)
• D. Vascular invasion
• E. Absence of yolk sac elements

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• Answer C
• Six factors have been analyzed in many of these
  studies and include stage of the primary tumor
  (pT lt/ 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.

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• 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.

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• 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.

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• 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
  ß-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

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• 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.