Testicular Cancer

See also extracranial germ cell tumour

  • Germ cell tumors (demonstrating one or more of the following components)
    • Seminoma
    • Nonseminoma
      • Embryonal carcinoma
      • Teratoma
        • Mature
        • Immature
        • With malignant differentiation
      • Choriocarcinoma
      • Yolk sac tumor (endodermal sinus tumor: embryonal adenocarcinoma of the prepubertal testis)
      • Mixed (most common)

Epidemiology

  • Rare but important Ca in young men.
    • 1-2% of all cancers
    • Most common malignancy in men ( 15- 35 )
  • Age distribution
    • Small peak —> ~2yr
    • Second peak —> 25-40
    • Small peak —> >65
  • Nonseminomatous tumors are more common in childhood and in young men between 15 and 30 years of age, whereas seminomas present on average 1 decade later (at 25 to 40 years of age)
  • Geographic distribution:
    • Denmark and Switzerland
    • Lower in non-Europeans
    • White > Black x5-6
    • Low in Chinese and Japanese

Seminoma

  • Most common germ cell ( in adults )
  • never produce AFP
  • Occurs a decade later than non-seminoma cell
  • Types:(all pure tumours)
      • Seminoma
      • Teratoma
      • Yolk sac tumor
      • Choriocarcinoma
      • Embryonal carcinoma

Risk factors:

  • Family history of cancer
    • brothers and Father —> x4-6
    • Just to compare:
      • Breast, Colon and Melanoma —> only x2
  • Prior history testicular ca
    • the cumulative risk (at 15yrs) —> ~2%
  • Presence of an undescended testis(cryptorchidism)
    • Mechanism:
      • Trauma
      • High temperature
      • Prenatal etiologic process
    • x6 folds
    • Mostly ipsilateral
      • 5-20% contralateral
  • Gonadal dysgenesis
  • Subfertility
  • Testicular microlithiasis
  • Other genitourinary abnormalities associated with testicular cancers:
    • Hydrocele
    • Hypospadias
  • Genetics
    • Rare gr/gr deletions of the Y chromosome
    • Isochromosome 12p
      • Chromosome 12p22 mutation (Relative Risk —> x4)
        • KITLG gene
          • Encoding the ligand for the receptor tyrosine kinase KIT
    • Chromosome 5q31.3 (Relative Risk —> x1.4)
      • SPRY4 gene
        • Encoding sprouty 4, an inhibitor of the MAP kinase pathway
    • Chromosome 6
    • Activating mutations of the KIT gene
    • Deletions of the KIT gene
  • Environmental Factors
    • Increased body mass index
    • Immunosuppression
    • HIV
    • Prenatal factors (association):
      • Threatened miscarriage
      • Excessive maternal nausea
      • Birth by caesarean delivery
      • Mechanism:
        • Exposure of the germinal epithelium in utero to an elevated level of free unbound maternal estrogen (unproven)
          • ==> Cryptorchidism and an elevated risk of developing a testicular tumor

Prevention and Early Detection

  • Testicular self-examination
  • Important in high risk population
  • Patients with unilateral testicular GCTs and those with cryptorchidism
    • risk: 2%-5% of developing a future testicular cancer
  • Yearly US(?)
  • Microscopically
    • Poorly circumscribed & infiltrates in between tubules at the periphery
    • The histologic features:
      • Large, round, coarse nuclei
        • One to two prominent central nucleoli
      • Monomorphic cells
      • Network of delicate cell membranes
      • Associated inflammation, especially lymphocytes, granulomas, and fibrosis
      • Delicate branching fibrovascular septa
      • Surrounding intratubular germ cell neoplasia

Pathology

Intratubular Germ Cell Neoplasia

Think of intratubular germ cell neoplasia (IGCN) as the carcinoma in situ of the testis.

  • Seen with ~100% of GCT
  • Scattered dark, or large, or fried egg–type cells
  • Few big cells in the tubule, spreading in pagetoid fashion, or as obvious as a lumen packed with malignant cells
  • Resemble seminoma cells and in most cases are found within the seminiferous tubules.
  • Cytologically, there is no difference between the CIS cells that develop into seminomas and those that develop into NSGCTs.
  • Higher in men with impaired fertility (0.5%) and in those with cryptorchid testes (2% to 4%).[18]

Seminomas

  • Necrosis and hemorrhage is rare
  • Large cells with abundant cytoplasm divided by connective tissue septae into sheets or cords
  • Round, hyperchromatic or vesicular nuclei with prominent nucleoli
  • Lymphocytic infiltrate, and macrophages, plasma cells, and multinucleated giant cells are often present
  • Syncytiotrophoblasts —> 15%-20%

IHC:

  • All —> Placental leukocyte alkaline phosphatase (PLAP) +
  • Do not express low-molecular-weight keratins, blood group Aantigens, or vimentin

Histologic variants:

  • Anaplastic seminoma
    • >3 mitoses seen per high-power field
  • Spermatocytic seminoma
    • Rare
    • Older men
    • rarely metastasize
    • Not associated with bilateral disease and CIS
    • PLAP negative
    • Less lymphocyte infirltration and less cytoplasm

Work-up:

  • CXR
  • CT Abdo Pelvis
  • blood work
    • Beta HCG
    • LDH
  • AFP can be rised after Alcohol consumption.
    • Half-life of AFP : 5-7 days
  • Cannabis ==> increase in beta-HCG
    • Serum half-life of HCG-β is 18-36 hours.

Nonseminomatous

  • Cosiderable ammount of necrosis and hemorrhage

IHC:

  • + low-molecular-weight keratins
  • Vimentin expression in mature teratomas.
  • Teratomas
    • Derived from two or more of the germ cell layers (ectoderm, mesoderm, or endoderm)
    • Teratoma with malignant transformation:
      • When one of the component tissues in any of the types of teratoma exhibits the histologic appearance of another malignant tumor, such as sarcoma or carcinoma
  • Choriocarcinomas
    • Multinucleated syncytiotrophoblasts and mononuclear cytotrophoblast cells
    • Widespread metastases
    • Very high levels of β-HCG
    • Poor prognosis
    • Elements of choriocarcinoma are found in up to 10% of NSGCTs and do not appear to affect the prognosis.
  • Yolk sac tumor=Endodermal sinus tumor
    • Usually produce AFP
    • Resemble those seen in the yolk sac in an embryo
    • MPure yolk sac tumour —> most common variant of childhood GCT

Pathways of Spread

  • Direct extension
    • Into the epididymis, through the tunica vaginalis(T2), into the spermatic cord (T3), and rarely into the scrotum (T4)
      • Locally extensive tumors —> Rare
  • Lymphatic spread
    • Most common route of metastatic spread
    • Directly to the para-aortic lymph nodes
    • Left
      • Left renal vein
      • Para-aortic area, directly below the left renal hilum
    • Right
      • Directly to the IVC below the level of the renal vein
      • Paracaval and interaortocaval nodes are the first ones to be involved in right-sided tumors
      • Contralateral LN+ —> 15%
        • only contralateral is rare
    • Thoracic duct —> Supradiaphragmatic
    • Left supraclavicular nodal
    • Pelvic and inguinal —> RARE(<3%)
    • Factors predisposing to inguinal LN+
      • Prior scrotal or inguinal surgery
      • Scrotal orchiectomy with incision of the tunica albuginea
      • Tumor invasion of the tunica vaginalis(T2)
      • Lower third of the epididymis(T3)
      • Cryptorchid testis
      • Disruption of lymphatic vessels in the spermatic cord during inguinal surgery ==> anastomoses between the testicular LN & regional LN ==> inguinal & pelvic LN
  • Hematogenous
    • NSGCTs —> common
      • 40% at presentation
    • Lung (commonest)
    • Liver, bone, brain, kidney, GI

Clinical Manifestations

  • Painless testicular mass
  • some may have pain with symptoms of acute epididymitis(25%)
  • beta-HCG ==> Gynecomastia
  • Hyperthyroidism <== alpha subunit of HCG is identical to that of TSH
  • Differential diagnosis of a testicular mass:
    • Torsion
    • Hydrocele
    • Varicocele
    • Spermatocele
    • Epididymitis
    • A small percentage of tumors are associated with a hydrocele, so the presence of transillumination on examination does not rule out a diagnosis of malignancy.

Investigation

  • Diagnostic and therapeutic radical orchiectomy
  • Serum tumor markers
    • α-fetoprotein (AFP)
    • β-human chorionic gonadotropin (β-HCG)
    • Lactate dehydrogenase (LDH)
      • Should be measure pre-op —> monitoring of decay
    • Baseline pulmunary function
      • for chemo/ lung mets
    • CBC, KFT, Liver function test
      • For chemo
  • Staging investigations
    • CXR
    • CT Abdomen-Pelvis
    • CT Thorax
      • Not in seminoma if no retro peritoneal LN
    • tumor markers
    • Bone Scan
      • Stage II and III
      • Bulky retroperitoneal dis
    • Brain CT/MRI
      • Extensive metastatic disease
      • Nonpulmonary visceral metastases
      • Very high tumor marker

All about Tumor Markers

beta-HCG

  • Glycoprotein with a molecular weight of 45,000 daltons
  • Two subunits
    • α-subunit is identical to that of
      • LH
      • FSH
      • TSH
    • Distinct β-subunit
  • Normally produced by the placenta
  • High in 15% of patients with seminoma
  • Other causes of high beta-HCG:
    • Low levels of β-HCG may be found in other neoplasms:
      • Prostate Ca
      • Bladder Ca
      • Renal Ca
    • Use of marijuana derivatives
  • Half-life —> 22 hours

AFP

  • A major serum protein of fetal life
  • Glycoprotein of molecular weight 70,000 daltons
  • Other causes of high AFP:
    • Hepatocellular carcinoma
    • Cirrhosis
    • Hepatitis
    • Pregnancy
  • Half-life —> 5 days
  • NOT found in pure seminoma

One or both of these markers are elevated in 85% of patients with nonseminomatous GCTs

LDH

  • Elevated in up to 60% of patients with NSGCT
  • Also in a high proportion of patients with advanced seminomas

PLAP

  • Placental Alkaline Phosphatase
  • Normally expressed by placental syncytiotrophoblasts
  • Also expressed by testicular tissue
  • Elevated in seminoma too

Staging

  • Stage II
    • Extent of retroperitoneal adenopathy
      • <5cm (N1/N2)
        • Regional therapy
          • RPLND (NSGCT)
          • RT (SGCT)
    • Serum tumor marker level determines treatment and outcome
    • >5cm
      • High risk of DM
      • Systemic chemotherapy
        • cisplatin-based chemo

Prognostic Factors:

  • Histologic type (nonseminoma vs. seminoma)
  • Site of the primary tumor (testis, retroperitoneal site, or other)
  • Presence or absence of non pulmunary mets(brain, bone, or liver)
  • Degree of marker elevation (AFP, β-HCG, and LDH)
Seminoma 5yr OS
Without Nonpulmunary Mets 86%
With Nonpulmunary Mets 72%
Nonseminoma 5yr OS
Good Prognosis 90%
Intermediate Prognosis 80%
Poor Prognosis 50%

Management of Seminoma