Campbell

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Campbells Chapter 29Neoplasms of the
TestisBrent Zamzow D.O.
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Introduction

• Most common malignancy in males 15-35
• Survival
• lt50 prior to 1970
• gt95 in 1997
• Improved survival
• Accurate tumor markers
• Effective chemo
• Modifications of surgical technique
• Mostly radiosensitive
• Backup treatments if primary treatments fail

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WHO Classification of Testicular Tumors

• Germ Cell Tumors
• Precursor lesions-intratubular malignant germ
  cells (carcinoma in situ)
• Tumors of one histologic type (pure forms)  
• Seminoma    
• Variant-seminoma with syncytiotrophoblastic
  cells  
• Spermatocytic seminoma    
• Variant-spermatocytic seminoma with sarcoma 
• Embryonal carcinoma  
• Yolk sac tumor  
• Polyembryoma  
• Trophoblastic tumors    
• Choriocarcinoma    
• Choriocarcinoma with other cell types   
• Placental site trophoblastic tumor  
• Teratoma    
• Mature teratoma    
• Dermoid cyst    
• Immature teratoma    
• Teratoma with malignant areas

• Tumors of Collecting Ducts and Rete
• Adenoma
• Carcinoma
• Tumors of the Tunica, Epididymis, Spermatic Cord,
  Supporting Structures, and Appendices
• Adenomatoid tumor
• Mesothelioma  
• Benign  
• Malignant
• Adenoma
• Carcinoma
• Melanotic neuroectodermal
• Desmoplastic small round cell tumor
• Soft Tissue TumorsUnclassified TumorsSecondary
  TumorsTumor-like Lesions
• Nodules of immature tubules
• Testicular lesions of adrenogenital syndrome
• Testicular lesions of androgen-insensitivity
  syndrome
• Nodular precocious maturation
• Specific orchitis
• Nonspecific orchitis

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Classification

• Germ Cell Tumors (GCT)
• Seminoma
• Classic or Typical
• Anaplastic
• Spermatocytic
• Nonseminoma
• Embryonal Cell Carcinoma
• Yolk Sac Tumor
• Teratoma
• Choriocarcinoma
• gt50 GCT are mixed

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Normal testis
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Classic Seminoma

• 82-85 of seminomas
• Mostly men in 30s
• Rarely occurs in adolescents or infants
• Clear cytoplasm, dense nucleus
• Synctiotrophoblasts in 10-15
• Elevated B-HCG in 10
• hCG up to 500 ng/mL
• Lymphocytes in 20

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Classic Seminoma
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Anaplastic Seminoma

• 5-10 of seminomas
• Greater mitotic activity
• Higher rate of local invasion
• Increased rate of metastasis
• Higher rate of B-HCG production
• Stage for stage treatment outcomes same as
  classic seminoma
• Classification no longer used

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Anaplastic Seminoma
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Spermatocytic Seminoma

• 3 sizes of cells
• 9 of seminomas
• 50 older than 50
• Very low metastatic potential
• Prognosis favorable
• Orchiectomy only

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Spermatocytic Seminoma
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Seminoma

• Painless testicular mass
• Testis size normal or smaller in 15
• Age
• 35-55 classic seminoma
• Peak 35-39
• gt60 spermatocytic seminoma
• Most common germ cell tumor in men gt65
• Rare before 10

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Nonseminomatous Germ Cell Tumors (NSGCTs)

• Embryonal
• Choriocarcinoma
• Teratoma
• Yolk Sac
• Mixed

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Embryonal Carcinoma

• Small, hard, irregular mass
• Age 25-35
• Smallest germ cell tumor
• 40 lt2cm
• Invades tunica vaginalis
• Often close to rete testis
• Gray/white with necrosis or hemorrhage
• Highly malignant

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Embryonal
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Embryonal Tumor Markers

• Can have elevated hCG AFP
• Synctiotrophoblasts common in stroma
• hCG not elevated in pure embryonal
• AFP usually due to yolk sac elements

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Choriocarcinoma

• Commonly present metastatic
• Usually a peripheral mass
• Central hemorrhage
• Must have synctiotrophoblasts cytotrophoblasts
• 1-2 of tumors
• hCG elevated in gt99
• Age 20-30
• Worst prognosis

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Choriocarcinoma
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Teratoma

• Derived from ectoderm, mesoderm, endoderm
• 2 or more embryonic germ cell layers in various
  stages of maturation
• Can contain bone, cartilage, intestinal,
  pancreatic, liver, muscle, neural cells
• Lined by any cell type
• Large, lobulated, nonhomogeneous
• Rarely can get malignant teratoma

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Teratoma
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Teratoma

• Classifications
• Mature
• Immature
• With malignant transformation
• Simple epidermoid cysts
• 3 of adult, 38 of children
• Elevated AFP 20-25
• Age 25-35
• Epidermoid cysts benign
• Metastatic teratoma resistant to chemo
  radiation

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Yolk Sac Tumor

• Other names
• Endodermal Sinus Tumor
• Adenocarcinoma of the infantile testis
• Juvenile Embryonal Carcinoma
• Orchioblastoma
• Most common testis tumor age 0-10
• Slow growing mass
• 25 have hydrocele
• AFP elevated in gt90
• In adult mixed tumors, 1/3 have yolk sac elements

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Yolk Sac Tumor

• Yellow, mucinous
• Higher incidence of hematogenous spread
• Treatment
• gt80 confined to testis cured by radical
  orchiectomy
• Low-volume retroperitoneal lymph node involvement
  RPLND
• Advanced disease chemo
• Residual mass unresponsive to chemo radiation
• Survival 87 for all stages

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Yolk sac
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Mixed Tumors

• 60 of tumors
• Most frequent mixed tumor
• Embryonal, seminoma, yolk sac, teratoma
  syncytiotrophoblasts
• Document of volume for each type
• AFP hCG can be elevated
• Age 10-30
• Managed as NSGCT

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Intratubular Germ Cell Neoplasia CIS of Testis

• Precursor to all GCTs except spermatocytic
  seminoma
• Risk Factors
• Contralateral testis w/ unilateral ca (2-38)
• Cryptorchidism (5-6)
• Infertility (1)
• Extragonadal GCT (35-50)
• Intersex (25-100)
• Evenly distributed through testis
• Open biopsy is reliable
• US unreliable
• Treatment Options
• Observation treatment of choice
• Orchiectomy
• Radiation (European treatment)
• Chemo ineffective

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Epidemiology of GCTs

• Incidence
• Lifetime risk white male 1 in 500
• 1/3 risk for American blacks
• Highest incidence Scandinavia, Switzerland,
  Germany, New Zealand
• Lowest incidence Asia, Africa
• Laterality
• 2-3 are bilateral
• More common on R

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Etiology

• Cryptorchidism
• 7-10 of tumors had cryptorchidism
• 1940 48x higher risk
• 1980 3-14x higher risk
• 5-10 cryptorchidism make tumor in other side
• Structural abnormalities seen in cryptorchid
  testis at 3 years
• Orchiopexy does not prevent cancer, allows
  clinical surveillance

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Pathogenesis

• Tunica albuginea barrier to spread
• ½ of NSGCT present as metastatic
• Complete spontaneous regressions rare
• Consider all adult GCT malignant
• Infantile teratoma is benign
• Lymphatic mets is common in all GCTs
• Choriocarcinoma lymph vascular

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Patterns of Spread

• Predictable (except for choriocarcinoma)
• Spermatic cord has 4-8 lymph channels
• Right-sided tumors
• Interaortocaval at level of L2 body
• Can cross from R to L
• Left-sided tumors
• Para-aortic between L ureter, L renal vein,
  aorta, origin of IMA
• NSGCT doubling time 10-30 days
• 85 of those who die from GCT, die within 2yrs of
  orchiectomy

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Presentation

• Signs symptoms
• Usually painless lump
• 30-40 c/o heaviness or dull ache
• 10 acute pain
• 10 present with metastatic manifestations
• Neck mass, cough, nausea, vomiting, lumbar pain,
  bone pain
• Gynecomastia is present in 5 of GCTs
• Any hypoechoic area on US w/i tunica suspicious
  for tumor

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Staging

• Based on pathology of primary tumor imaging of
  chest retroperitoneum
• Understage 20 (Stage I undergoing RPLND)
• 10-15 have undetectable nodal mets
• 5-10 relapse at extranodal sites

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Staging Systems

• American Joint Committee on Cancer (AJCC) 1997,
  2002
• TNMS system
• Stage grouping
• Stage 0, Ia, Ib, Is, IIa, IIb, IIc, III
• Stage I
• No nodes, no mets
• Stage II
• Positive regional nodes
• Stage III
• Nonregional nodes or pulmonary mets

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Imaging

• CXR
• PA lateral CXR should be initial radiologic
  procedures
• CT
• Abdominal CT is best test to look for
  retroperitoneal mets
• Do after orchiectomy
• If CXR or abdominal CT is abnormal, get chest CT
• MRI no benefit
• PET Scan no benefit over CT
• Cannot detect microscopic disease

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Tumor Markers

• Draw tumor markers prior to orchiectomy
• Alpha-fetoprotein (AFP)
• Serum protein of early embryo
• Human Chorionic Gonadotropin (hCG)
• Secreted by placenta
• Lactic Acid Dehydrogenase (LDH)
• Placental Alkaline Phosphatase (PLAP)
  Gamma-Glutamyl-Transpeptidase (GGTP)
• Low sensitivity

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AFP

• Early levels
• In fetus produced by fetal yolk sac, liver, GI
  tract
• Highest levels at 12-14 weeks gestation
• At 1 year declines to low adult levels
• 5-7 day half life
• Can be elevated in
• Testis, liver, pancreas, stomach, lung ca
• Normal pregnancy
• Benign liver disease
• Ataxia-telangiectasia
• Tyrosinemia
• Never elevated in pure choriocarcinoma or
  seminoma
• Can be elevated in
• Pure embryonal
• Teratocarcinoma

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HCG

• Has alpha beta subunits
• Alpha subunit similar to FSH, LH, TSH
• Beta subunit is distinct
• Secreted by placenta to maintain corpus luteum
• Syncytiotrophoblastic cells produce hCG in GCTs
• 24-36 hour half life
• Elevated in all choriocarcinoma, 40-60 of
  embryonal, 5-10 of seminomas
• Can be elevated in
• Marijuana smokers
• Liver, pancreas, stomach, lung, breast, kidney,
  bladder ca
• Elevated LH - false positive HCG

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LDH

• High levels in muscle, liver, kidney, brain
• High false positive rate
• Most useful as a marker for bulky disease

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Tumor Markers

• NSGCTs
• Elevated AFP 50-70
• Elevated hCG 40-60
• Elevated either or both 90
• 10 of advanced disease will have normal tumor
  markers
• Be careful
• Elevated AFP can be from liver dysfunction
• Elevated hCG can be from hypogonadism marijuana
• Normal markers does not mean no residual disease
• 10-20 after chemo RPLND for bulky disease have
  viable tumor despite normal markers
• Degree of AFP or hCG elevation is proportional to
  tumor burden

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Treatment of GCTs

• Radical orchiectomy for local control
• Offer sperm banking prior to surgery
• gt50 have mets, so most require further treatment
• Treat retroperitoneal lymph nodes
• Large retroperitoneal mets chemo initially
• 65-85 seminomas confined to testis
• 60-70 nonseminomas present as recognizable
  metastatic disease

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Partial Orchiectomy

• Option for
• Organ confined tumor lt2cm
• Especially incidentally found, nonpalpable
• Solitary testis or w/ B/L tumors
• Careful frozen sections
• Can use crushed ice, gentle occlusion of
  spermatic cord

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Stage I Seminoma

• 15-25 staging error
• Radiation treatment of choice
• 20-25 Gy to para-aortic nodes
• 5-year disease free survival gt95
• Long-term side effects
• Infertility, GI, 2nd malignancy
• 3 relapse (outside retroperitoneum) need chemo
• Chemotherapy
• Carboplatin x1-2 experimental
• Surveillance
• Optimum surveillance protocol unknown
• Give option for lt6cm, no vascular invasion,
  normal hCG, compliant, lt34
• 15-20 will relapse require XRT or chemo

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Stage IIa IIb Seminoma

• XRT
• Ipslilateral external iliac, b/l common iliac,
  paracaval, para-aortic, cisterna chyli
• Avoid kidney
• Shield contralateral testis
• 5-yr disease free survival 80
• 3 relapse
• Chemo
• If nodes close to kidney

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Stage IIc III Seminoma

• Before platinum radiation
• Cisplatin-based chemo now treatment of choice
• Bleomycin, Etoposide, Cisplatin (BEP) x34
• Etoposide, Cisplatin (EP) x4
• 90 complete response to chemo at 4yrs
• 10 relapse after initial chemo response
• Postchemo residual retroperitoneal mass
• Well-delineated, gt3cm resect
• Mass GCT, then salvage chemo (vinblastine,
  ifosfamide, cisplatin)
• Otherwise observation

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NSGCTs

• Low Stage
• Surveillance
• Chemo
• RPLND
• High Stage
• Chemo
• Good vs. Poor risk

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RPLND

• 1948
• Retroperitoneal nodes are first sometimes only
  areas of mets
• Gold Standard of staging
• Modified template RPLND
• Most likely areas to be involved
• Minimize side effects
• Infertility, ejaculatory dysfunction

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Stage I NSGCTs

• Radiation - not used in North America, relapse
  rate 24
• Surveillance
• Option for low risk
• No vascular/lymphatic invasion (ltT2)
• lt40 embryonal
• Motivated, reliable pts
• Relapse 28, survival 99
• Protocol
• CXR, tumor markers q1mo x1yr, q2mo x1yr, q3-6mo
  up to 10 more yrs
• CT q2-3mo x2yrs, q6mo up to 10yrs
• Chemo BEP x2-3
• Option for low or high risk
• T2 or higher (vascular/lymphatic invasion)
• gt40 embryonal
• Modified template RPLND
• If negative, then observe

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Stage IIa IIb NSGCTs

• Bilateral RPLND
• N1 (nodes lt2cm) observe or adjuvant chemo BEP
  x2
• N2 (nodes 2-5cm) adjuvant chemo BEP x2
• Chemo BEP x3 or EP x4
• If post-orchiectomy tumor markers elevated
• If nodes gt3cm

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Stage IIc III NSGCTs

• Low Risk
• No nonpulmonary visceral mets
• AFP lt1000, hCG lt5000, and LDH lt1.5x normal
• Intermediate Risk
• No nonpulmonary visceral mets
• Markers between low high risk
• High Risk
• Nonpulmonary visceral mets
• AFP gt10,000, hCG gt50,000, or LDH gt10x normal

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Stage IIc III NSGCTs

• Low risk
• Chemo BEP x3 or EP x4
• 92 5-yr survival
• High risk
• Chemo BEP x4 or B/isosfamide/P
• 48 5-yr survival

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Stage IIc III NSGCTs

• After Chemo
• Complete response (normal tumor markers, no
  residual mass)
• Observe
• 10 relapse need salvage chemo
• Partial response (normal tumor markers, residual
  mass)
• Full B/L RPLND resect residual mass
• 10-20 GCT salvage chemo
• 40-50 teratoma observe or resect
• 40 necrosis observe
• Poor response (elevated tumor markers or no
  shrinkage of mass)
• Salvage chemo, high dose chemo autologous bone
  marrow transplant
• 25 long term survival

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Chemo XRT Toxicity

• 2nd Malignancy
• Up to 18 25yrs after XRT
• Chemo
• Higher long-term incidence of leukemia, melanoma,
  lymphoma, colon, stomach, kidney, prostate,
  bladder, thyroid, rectum, pancreas, connective
  tissue cancers
• Bleomycin
• Pulmonary Toxicity
• Etoposide
• Myelosuppression
• Cisplatin
• Nephrotoxicity also Carboplatin
• Low Magnesium
• Neurotoxicity Ototoxicity

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Other Testicular Tumors

• Extragonadal Germ Cell Tumors
• Mediastinum, retroperitoneum, sacroccygeal
  region, pineal gland
• Leydig Cell Tumor
• Sertoli Cell Tumor
• Gonadoblastoma
• Lymphoma

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Leydig Cell Tumors

• 1-3 of testicular tumors
• 10 malignant
• Average survival 3 years if malignant
• Reinkes crystals red extracellular lobular
  crystals
• Presentation
• Precocious puberty in kids
• Elevated testosterone, urinary 17-ketosteroids
• Mass
• Impotence, gynecomastia
• Treatment
• Radical orchiectomy surveillance
• Endocrine w/u

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Leydig Cell Tumor
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Sertolis Cell Tumors

• lt1 testicular tumors
• Most common testicular tumor in dogs
• 10 malignant
• Any age
• Radical orchiectomy
• RPLND if metastatic

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Others

• Gonadoblastoma
• 0.5 testicular tumors
• 80 are in phenotypically female pts
• Good prognosis
• Epidermoid Cyst
• 1 testicular tumors
• ? Monolayer teratoma
• Benign
• Rete Testis Adenocarcinoma
• Age 20-80
• Very malignant
• Adrenal Rest Tumor
• B/L tumor, CAH remission w/ corticoid treatment
• Lymphoma
• 5 testicular tumors

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• THE END