Campbell’s Chapter 29

Neoplasms of the Testis

Brent Zamzow D.O.

Introduction• Most common malignancy in males 15-35

• Survival– <50% prior to 1970– >95% in 1997

• Improved survival:– Accurate tumor markers– Effective chemo– Modifications of surgical technique– Mostly radiosensitive– Backup treatments if primary treatments fail

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 more than one histologic type (mixed forms)-specify types and estimate percentage

• Sex Cord/Gonadal Stromal Tumors• Pure forms 

– Leydig's cell tumor  – Sertoli's cell tumor    

• Large-cell calcifying Sertoli's cell tumor    • Lipid-rich Sertoli's cell tumor

• Granulosa cell tumor – Adult-type granulosa cell tumor  – Juvenile-type granulosa cell tumor

• Tumors of thecoma/fibroma group• Incompletely differentiated sex cord/gonadal stromal tumors• Mixed forms• Unclassified Forms• Tumors Containing Both Germ Cell and Sex Cord/Gonadal Stromal

Elements• Gonadoblastoma• Mixed germ cell-sex cord/gonadal stromal tumors, unclassified• Miscellaneous Tumors• Carcinoid tumor• Tumors of ovarian epithelial types• Lymphoid and Hematopoietic Tumors• Lymphoma• Plasmacytoma• Leukemia

• 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• Granulomatous orchitis• Malakoplakia• Adrenal cortical rest• Fibromatous peritonitis• FuniculitisResidue of meconium peritonitis• Sperm granuloma• Vasitis nodosa• Sclerosing lipogranuloma• Gonadal splenic fusion• Mesonephric remnants• Endometriosis• Epidermal cyst• Cystic dysplasia• Mesolithial cyst• Others

Classification• Germ Cell Tumors (GCT)

– Seminoma• Classic or Typical• Anaplastic• Spermatocytic

– Nonseminoma• Embryonal Cell Carcinoma• Yolk Sac Tumor• Teratoma• Choriocarcinoma

• >50% GCT are mixed

Normal testis

Classic Seminoma

• 82-85% of seminomas• Mostly men in 30’s• 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%

Classic Seminoma

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

Anaplastic Seminoma

Spermatocytic Seminoma

• 3 sizes of cells

• 9% of seminomas

• 50% older than 50

• Very low metastatic potential– Prognosis favorable– Orchiectomy only

Spermatocytic Seminoma

Seminoma

• Painless testicular mass

• Testis size normal or smaller in 15%

• Age– 35-55 classic seminoma– Peak 35-39– >60 spermatocytic seminoma

• Most common germ cell tumor in men >65

– Rare before 10

Nonseminomatous Germ Cell Tumors (NSGCTs)

• Embryonal

• Choriocarcinoma

• Teratoma

• Yolk Sac

• Mixed

Embryonal Carcinoma

• Small, hard, irregular mass • Age 25-35• Smallest germ cell tumor

– 40% <2cm

• Invades tunica vaginalis• Often close to rete testis

• Gray/white with necrosis or hemorrhage• Highly malignant

Embryonal

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

Choriocarcinoma

• Commonly present metastatic

• Usually a peripheral mass• Central hemorrhage • Must have synctiotrophoblasts &

cytotrophoblasts

• 1-2% of tumors• hCG elevated in >99%• Age 20-30• Worst prognosis

Choriocarcinoma

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

Teratoma

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

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 >90%

• In adult mixed tumors, 1/3 have yolk sac elements

Yolk Sac Tumor• Yellow, mucinous• Higher incidence of hematogenous spread

• Treatment– >80% 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

Yolk sac

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

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

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

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

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

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

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

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

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

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

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

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– Yolk sac– Combined

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

LDH

• High levels in muscle, liver, kidney, brain

• High false positive rate

• Most useful as a marker for bulky disease

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

Treatment of GCTs

• Radical orchiectomy for local control– Offer sperm banking prior to surgery

• >50% 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

Partial Orchiectomy

• Option for– Organ confined tumor <2cm

• Especially incidentally found, nonpalpable

– Solitary testis or w/ B/L tumors

• Careful frozen sections

• Can use crushed ice, gentle occlusion of spermatic cord

Stage I Seminoma• 15-25% staging error

• Radiation – treatment of choice– 20-25 Gy to para-aortic nodes– 5-year disease free survival >95%– 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 <6cm, no vascular invasion, normal hCG,

compliant, <34– 15-20% will relapse & require XRT or chemo

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

Stage IIc & III Seminoma

• Before platinum – radiation

• Cisplatin-based chemo now treatment of choice– Bleomycin, Etoposide, Cisplatin (BEP) x3–4 – Etoposide, Cisplatin (EP) x4– 90% complete response to chemo at 4yrs– 10% relapse after initial chemo response

• Postchemo residual retroperitoneal mass– Well-delineated, >3cm – resect

• Mass = GCT, then salvage chemo (vinblastine, ifosfamide, cisplatin)

– Otherwise observation

NSGCTs

• Low Stage– Surveillance– Chemo– RPLND

• High Stage– Chemo

• Good vs. Poor risk

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

Stage I NSGCTs• Radiation - not used in North America, relapse rate 24%

• Surveillance– Option for low risk:

• No vascular/lymphatic invasion (<T2)• <40% 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)• >40% embryonal

• Modified template RPLND– If negative, then observe

• 70% of RPLNDs find no disease– If <2cm nodes (N1), observe or adjuvant chemo – BEP x2 or EP x2– If >2cm nodes (N2), adjuvant chemo – BEP x2 or EP x2– 5-10% relapse outside field of RPLND

Stage IIa & IIb NSGCTs

• Bilateral RPLND– N1 (nodes <2cm) – 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 >3cm

Stage IIc & III NSGCTs

• Low Risk– No nonpulmonary visceral mets– AFP <1000, hCG <5000, and LDH <1.5x normal

• Intermediate Risk– No nonpulmonary visceral mets– Markers between low & high risk

• High Risk– Nonpulmonary visceral mets– AFP >10,000, hCG >50,000, or LDH >10x normal

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

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

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

Other Testicular Tumors

• Extragonadal Germ Cell Tumors– Mediastinum, retroperitoneum, sacroccygeal

region, pineal gland

• Leydig Cell Tumor

• Sertoli Cell Tumor

• Gonadoblastoma

• Lymphoma

Leydig Cell Tumors

• 1-3% of testicular tumors• 10% malignant

– Average survival – 3 years if malignant• Reinke’s 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

Leydig Cell Tumor

Sertoli’s Cell Tumors

• <1% testicular tumors

• Most common testicular tumor in dogs

• 10% malignant

• Any age

• Radical orchiectomy – RPLND if metastatic

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– Most common secondary tumor– Most common testicular tumor in age >50– ½ are B/L

• THE END