2 - CA Testis Flashcards
Common presentation of testicular cancer
1) Usually painless unilateral testicular mass
2) Scrotal pain in ~20%
3) 2-7% Gynaecomastia, usually in non-seminomatous tumour, esp stromal tumour
4) Back pain or abdominal mass from bulky retroperitoneal metastasis
Testicular mass Ddx incidence based on age
1) 16-18m: pure yolk sac tumour (commonest)
2) <4yo: pure teratoma (2nd common)
3) 20-35yo: NSGCT
4) 30-40yo: Seminoma
5) >60yo: Lymphoma, TB, spermatocytic seminoma
Bimodal for both yolk sac tumour (16-18m and 25-35yo) and teratoma (<4yo and 20-40yo)
⭐️ How would you assess a patient presenting with testicular mass?
I would see him in the clinic setting in a comfortable environment
I would obtain a thorough clinical history, including:
- Onset and duration of testicular swelling
- Whether it is enlarging
- Painful or painless
- Any trauma
- Sexual Hx, UTI or STD Sx
- Any constitutional Sx
Ask for risk factors for CA testis, e.g.:
1) Personal History:
- Hx of cryptorchidism / UDT
- Hx of contralateral tumour or TIN
- Hx of sub fertility
- HIV
(X Maternal estrogen exposure)
(X Klinefelter syndrome)
(X Race)
2) Family History
- Testicular tumour in 1st degree relatives
Social history:
- marital status
- number of children, fertility wish
Physical examination
1) Scrotal exam:
- exam contralat. testis first
- then the enlarged testis for size, location of mass, attachment to skin or spermatic cord
2) Abdominal exam for enlarged LN or organomegaly
3) Any inguinal scars from childhood orchidopexy
4) Chest exam
- Gynaecomastia suggestive of elevated B-HCG
- Auscultation for lung masses
5) Supraclavicular LN
Arrange urgent ultrasound scrotum with transducer at least 7.5 MHz (Mega Hertz)
Bloods x tumour markers
- AFP
- Beta HCG
- LDH
Contrast CT T+A+P for M staging
Genetic changes of CA testis
1) iso-chromosome of short arm of chromosome 12 (i12p)
- 80% GCT has at least one i12P
2) Alteration of p53 locus
- seen in 66% of testicular TIN
Risk factors for CA testis
Personal History:
1) Hx of cryptorchidism / undescended testis
2) Hx of contralateral tumour or GCNIS
3) Hx of subfertility
4) HIV
5) Klinefelter syndrome
6) Maternal estrogen exposure
7) Scandinavian
Family History
1) Testicular tumour in 1st grade relatives
CA testis pathological classification
WHO pathological classification:
0) Germ cell neoplasia in-situ (GCNIS)
1) Germ cell tumours
a) Seminoma
b) Non-seminoma
- embryonal carcinoma
- teratoma
- yolk sac tumour
- choriocarcinoma
- mixed
2) Sex cord-stromal tumour
- Leydig cell
- Sertoli cell tumour
- Granulosa cell tumour
What is the imaging of choice for diagnosing CA testis?
Please give specific technical request
Ultrasound of testes
With transducer of at least 7.5 MHz (mega Hertz)
What to look for on USG scrotum for scrotal mass?
1) Diagnosis of testicular cancer
- almost 100% sensitivity
- can differentiate intra-testicular vs. extra-testicular lesion
2) Assess contralateral testis
3) See any testicular atrophy (<12mL) which is an indication for contralat testis Bx
Serum markers for CA testis, what are their:
- Roles
- Half Life
- Normal value
- Source and Implication
Role: Diagnosis, staging, and prognosis
1) Alpha Fetoprotein (AFP) ➔ 5, 7, 10
- T1/2 = 5-7 days
- Normal <10
- from yolk sac cells (cytotrophoblastic element)
- i.e. Suggestive of Embryonal, Yolk Sac, Teratoma with yolk sac component (never in pure chorio or pure seminoma)
2) Beta hCG (B-hCG) ➔ 36, 5
- T1/2 = 36 hours
- Normal <5
- from syncytiotrophoblasts
- i.e. Suggestive of Embryonal (40-60%), ChorioCA (100%), Seminoma (10-30%)
3) Lactate Dehydrogenase
- T1/2 = cannot be calculated due to isoforms (usually around 4 days)
- Proportional to tumour volume and cell necrosis
±4) Placenta Like Alkaline Phosphatase (PLAP)
- T1/2 = 24 hours
- For monitoring in pure seminoma
Do all patients have raised tumour markers at presentation? (Viva book Q)
(Viva book Answer)
No, only ~51% of testicular tumour would have elevated tumour markers
For Seminoma, ~10-30% has elevated B-hCG (never high AFP if pure seminoma)
For NSGCT (non-seminomatous germ cell tumour), ~90% has elevated tumour markers (50-70% with high AFP from yolk sac component, 40% with high B-hCG).
Elevated βhCG is found in 100% of choriocarcinoma and 40%–60% of embryonal carcinoma cases
What is the significance of LDH in testicular cancer? (Viva book Q)
This is useful in determining tumour burden and is a surrogate marker for tumour volume and cell necrosis.
This is usually helpful for seminomas and to the oncologist as a measure of tumour response. It is raised in approximately 10% of seminomas.
Are there any other condition in which testicular cancer tumour markers may be raised? (i.e. false positive)
Other conditions and malignancies can elevate the markers:
1) AFP
- liver HCC / pancreatic / stomach / lung
- smoking, alcoholism
- liver conditions e.g. cirrhosis, hepatitis, Wilson’s disease
- IBD
- Ataxia telangiectasia
2) B-HCG
- liver / pancreatic / stomach / lung
- Cannabis use
- Cirrhosis
- IBD
- Heterophilic antibodies
- Cross-reactivity of assay with elevated LH (e.g. in primary hypogonadism i.e. hypergonadotrophic), so need to check exogenous testosterone
3) LDH is non-specific
- liver disease
- heart disease
- kidney disease
- cancers, lymphoma
- skeletal muscle injury
- etc.
After initial assessment and USG, how would you manage a young man with suspected testicular cancer?
1) I would arrange for an urgent radical inguinal orchidectomy within ~1 week
I would offer further counselling and assessments in regards to:
2) Need of contralateral testicular biopsy
3) Sperm banking
4) Testicular prosthesis insertion
How would you perform a radical inguinal orchidectomy? (Viva book Q)
Obtain informed consent, performed within 1 week’s time
GA or SA procedure, supine position
Inguinal incision
Early clamping of the cord / pedicle control with non-crushing vascular clamp, prior to manipulation of testis
- to control the draining lymphatics
- minimise tumour spill and metastatic release to the LNs
Cord is transfixed and ligated in bundles, with a prolene suture left long to act as a marker for future nodal dissection
Testis is removed with epididymis and spermatic coverings and cord, transected at the deep inguinal ring
What surgical approach can be used if patient wishes for diagnosis before orchidectomy for testicular mass?
(Henry’s notes)
Consider intra-op frozen section with:
1) Testicular bivalve
2) Chevassu maneuvre
- occlusion of the testicular vessels before biopsy
Why inguinal orchidectomy, but not scrotal approach for CA testis?
Testicular CA usually metastasise by lymphatic spread. Drainage is predictable and stepwise to retroperitoneal nodes. Inguinal approach can preserve the normal lymphatic drainage.
If scrotal violation:
1) Lymphatic drainage will be altered, with risk of inguinal LN metastasis
2) Higher local recurrence rate with scrotal approach (EAU 2023) i.e. 2.5% vs. 0% (blue book)
(but does not increase systemic relapse or overall survival)
Why do we need to consider sperm banking before inguinal orchidectomy?
(Henry’s notes)
Risk of subfertility or infertility during course of CA testis treatment:
1) Baseline abnormality (EAU 2024):
- 24% are azoospermic
- 50% have abnormal sperm parameters even before treatment
2) After inguinal orchidectomy:
- 4% will become azoospermic
3) After RPLND:
- 80% anejaculation if full template
- 7% anejaculation if modified template
4) After chemotherapy:
- all patients become azoospermic around 3 months after chemo
- 50% recover after 2 years
- 80% recover after 5 years
5) After radiotherapy:
- dose dependent, with permanent sterility if dose >6 Gy
- recovery may take up to 2-3 years
6) Also chemo & RT are teratogenic (EAU 2024): contraception must be used during treatment and for at least 6 months after its completion
How does a patient sperm bank? Any special issues to inform the patient
1) Assessment in fertility clinic / sperm bank
- FSH / LH / AM testosterone
- 3 semen samples for analysis with 2-3 days of abstinence
2) Also need to check HIV / HBV / HCV
- if positive, then need separate storage vessel / facility
3) Sample is then frozen in liquid nitrogen at -196’C
- banking can still be done within first few weeks of chemotherapy
4) Special issue (Viva book Ans):
- Only ~10% of patient would use the sperm
- Maximal storage year = 10 years
- quality of sperm is not guaranteed when thawed
- illness prior to or at the time of banking would affect sperm quality
- some research showed that quality of sperm is poor in germ cell cancer
What do you know about insertion of testicular prosthesis? How is it inserted?
EAU (2024): Testicular prosthesis should be offered to all patients receiving unilateral or bilateral orchidectomy
Only FDA approved testicular implant is saline-filled implant called Torosa. Different sizes available.
Not associated with increased length of stay / re-admission / return to theatre rate (BJUI 2016 Audit)
Insertion technique:
- same session after inguinal orchidectomy
- anchor star or button at inferior pole, sutured to Dartos to prevent migration
Complications of testicular prosthesis
1) Erosion, or even Extrusion from scrotum 3-8%
2) Scrotal contraction and migration 3-5%
3) Chronic pain or discomfort 1-3%
4) Scrotal oedema
5) Haematoma
6) Infection 0.6-2%
➔ may delay chemo therefore some oncologist does not prefer if likely need chemo e.g. mets or very high tumour markers
➔ however in BJUI 2016 audit of 900 patients, showed no adverse infective consequences
7) Deflation or rupture
8) Pulmonary embolism
Would you recommend contralateral testis biopsy during CA testis treatment? Explain the indication and arguments
Rationale: to identify GCNIS (germ cell neoplasia in-situ) and metachronous CA testis:
- 9% risk of contralateral GCNIS
- 2.5% risk of metachronous CA testis
- Maase BMJ 1986 classical paper: if untreated GCNIS then 50% progression to germ cell tumour in 5 years (70% in 7 years)
1) Overall low incidence (9% and 2.5%)
2) Morbidity of overtreating GCNIS
3) Most metachronous tumours are at low stage
Therefore I would choose a risk-stratified approach for patients with high risk for contralateral GCNIS
EAU 2023 suggested:
1) Contralateral testicular volume <12cc
2) History of crypto-orchidism
+) Not necessary in patients > 40 years without risk factors
Additional risk factors to be considered including:
- poor spermatogenesis with Johnson score 1-3
- Age <40yo
- extra-gonadal GCT
What is the risk of contralateral GCNIS in CA testis?
Up to 9% (EAU 2023), but depends on risk factors
According to landmark papers:
1) Harland, JU 1998
- overall risk = 5%
- Hx of UDT = 4%
- Age ≤30 and volume <12mL = 34%
2) Dieckmann, EU 2007
- Age ≤40 and volume <12mL = 18%
- Age ≤40 and poor spermatogenesis score = 54%
How would you perform contralateral testis biopsy?
Open inguinal approach
Two-pole technique:
- small incisions of tunica albuginea at upper and lower pole (5mm), then extruded seminiferous tubules sampled
- can identify 99% of GCNIS
Placed in Bouin Solution (not formalin)
Name some occasions where an immediate orchidectomy is not performed for a testicular tumour
1) In high volume metastatic disease (esp if life threatening), urgent upfront chemotherapy is needed. For example:
- respiratory compromise from extensive lung mets
- severe back pain from retroperitoneal disease
- extensive brain mets
2) Poor local tumour condition e.g. T4 disease with difficulty of orchidectomy
Is orchidectomy still needed if a CA testis patient received upfront chemo (e.g. high metastatic load)
Yes, a later orchidectomy after chemo due to:
- poor penetration of chemotherapy through the blood-testis barrier
- would still be ~30% microscopic tumour in testis
Patient had inguinal orchidectomy and this is the specimen. What is the likely histological diagnosis?
Seminoma
Large cells with:
- clear cytoplasm
- densely staining nuclei “fried egg appearance” with nucleoli of varying sizes
- lymphocytic infiltrates also characteristic
What information would you look for in the pathology report of a radical orchidectomy specimen? (Viva book Q)
Based on the EAU guideline 2023 5.5:
➔ pathological examination and reporting should follow ISUP
Viva Book Answer:
1) Histological type of tumour
- germ cell (seminoma or non-seminomatous) or non-germ cell
2) T staging
- T1: limited to testis / epididymis, with no vascular or lymphatic invasion, may involve TA
- T2: vascular or lymphatic invasion, extends to involve TV
- T3: invades spermatic cord (with or without vascular or lymphatic involvement)
- T4: Invades scrotum (with or without vascular or lymphatic invasion)
3) Any GCNIS
4) Seminoma (stage 1) prognostic risk factors for relapse:
- tumour size > 4cm
- invasion of rete testis
5) NSGCT (stage 1) prognostic factors for relapse (Freedman in Lancet):
- vascular or lymphatic invasion
- absence of yolk sac elements
- presence of undifferentiated tumour
6) NSGCT prognostic factors for metastatic disease:
- vasular or lymphatic invasion
- % embryonal carcinoma >50% (predicts vascular invasion)
- Proliferation rate by MIB-1 immunostaining >70%
What staging for testicular cancer do you know? Briefly explain
➔ The AJCC staging system is most commonly used. Other staging systems include the Royal Marsden system, or the Boden-Gibbs classification
1) American Joint Committee on Cancer (AJCC) TNM + S staging
- T1 = testis/epididymis, without vascular / lymphatic, may involve TA
- T2 = testis/epididymis, with vascular / lymphatic; or involves TV
- T3 = spermatic cord
- T4 = scrotum
- N1 = LNs ≤2cm
- N2 = >2-5cm
- N3 = >5cm
- M1a = non-regional LN or lung met
- M1b = other sites
- S0 = normal serum markers
- S1 = (AFP BhCG LDH = <1000 / <5000 / <1.5 xULN)
- S2 = 1000-10000 / 5000-50000 / 1.5-10 xULN
- S3 = >10000 / >50000 / >10x ULN
Stage IA = pT1 only (N0M0S0)
Stage IB = pT2-4 only (N0M0S0)
Stage IS = N0M0 but S1-3
Stage II = N+ with S0-1 only
- IIA = N1
- IIB = N2
- IIC = N3
Stage III = M+, or N+ with S2-3
2) Royal Marsden System
- Stage I = confined to testis
- Stage II = retroperitoneal LNs (A<2cm, B=2-5, C=5-10, D>10)
- Stage III = supra or infra-diaphragmatic LNs
- Stage IV = disseminated disease (liver / lung / bone)
3) Boden-Gibbs
- A = confined to testis
- B = Regional LN mets
- C = Supra-diaphragmatic or extra-lymphatic mets
What are some seminoma prognosis factors?
For seminoma
A. IGCCCG risk group for survival prognosis
1) Good prognosis = 5y OS 95%, PFS 89%
- no non-pulmonary visceral mets
- AND any primary site
- AND normal AFP, any B-hCG, any LDH
2) Intermediate prognosis = 5y OS 88%, PFS 79%
- Presence of non-pulmonary visceral met
3) No poor prognosis for seminoma
B. Prognostic risk factors for relapse in stage I seminoma:
(Aparicio Spanish GCCG)
- tumour size > 4cm
- invasion of rete testis
What are some NSGCT prognosis factors?
For NSGCT:
A. IGCCCG risk group for survival prognosis
1) Good prognosis = 5y OS 96%, PFS 90%
- Testis or retroperitoneal primary
- AND no non-pulmonary met
- AND S0 or S1 (i.e. AFP BhCG LDH = <1000 / <5000 / <1.5 xULN)
2) Intermediate = 5y OS 89%, PFS 78%
- Testis or retroperitoneal primary
- AND no non-pulmonary met
- AND S2
3) Poor = 5y OS 67%, PFS 54%
- Mediastinal primary
- or Presence of non-pulmonary visceral met
- or S3 (i.e. >10000, >50000, >10xULN)
B. NSGCT prognostic factors for metastatic disease:
- vasular or lymphatic invasion
- % embryonal carcinoma >50% (predicts vascular invasion)
- Proliferation rate by MIB-1 immunostaining >70%
C. Prognostic factors for relapse in stage 1 NSGCT
(Freedman in Lancet):
- vascular or lymphatic invasion
- absence of yolk sac elements
- presence of undifferentiated tumour
=> EAU 2023: Lympho-vascular invasion is the strongest and most reproducible predictive factor
Tell me about IGCCCG risk groups
International Germ Cell Cancer Collaboration Group
For Seminoma:
1) Good prognosis = 5y OS 95%, PFS 89%
- no non-pulmonary visceral mets
- AND any primary site
- AND normal AFP, any B-hCG, any LDH
2) Intermediate prognosis = 5y OS 88%, PFS 79%
- Presence of non-pulmonary visceral met
3) No poor prognosis for seminoma
For NSGCT:
1) Good prognosis = 5y OS 96%, PFS 90%
- Testis or retroperitoneal primary
- AND no non-pulmonary met
- AND S0 or S1 (i.e. AFP BhCG LDH = <1000 / <5000 / <1.5 xULN)
2) Intermediate = 5y OS 89%, PFS 78%
- Testis or retroperitoneal primary
- AND no non-pulmonary met
- AND S2
3) Poor = 5y OS 67%, PFS 54%
- Mediastinal primary
- or Presence of non-pulmonary visceral met
- or S3 (i.e. >10000, >50000, >10xULN)
What are the indications for partial orchidectomy for CA testis?
Any contraindication?
AKA “Testis-sparing surgery”, may be able to prevent hypogonadism and infertility in young men
Based on EAU 2023 guideline, indication includes:
1) synchronous bilateral tumours
2) tumours in solitary testis
+) May be offered if small or indeterminate testicular masses, negative tumour markers and a normal contralateral testis to prevent over-treatment
Contraindication:
(Based on Henry’s notes): Tumour volume > 30% testicular volume
How would you perform a partial orchidectomy for suspected CA testis?
- Inguinal incision
- Spermatic cord and testis retracted to inguinal wound
- Spermatic cord occluded with a non-crushing vascular clamp and the testis is cooled with ice for 10min
- Tumour localised by palpation or intra-op USG
- Excision with 2 to 5mm margin by blunt dissection or bipolar
➔ ** Send For frozen section *** - EAU 2024: at least two additional testicular biopsies should be taken to exclude GCNIS (e.g. random biopsy of adjacent testicular parenchyma)
- Closure of TA with 4-O Vicryl
Management of scrotal violation for CA testis
May occur if T4 disease, trans-scrotal orchidectomy or biopsy
Increases local recurrence risk (2.5%)
Optimal treatment is unclear. AUA 2019 guideline suggested “adjunctive therapy may rarely be considered for local control due to 2.5% local recurrence risk”, including:
1) Hemiscrotectomy or excision of trans-scrotal scar
2) If seminoma ➔ Radiotherapy with modified field to include ipsilateral iliac and inguinal LNs, and ipsilateral scrotum
3) Chemotherapy
Give a brief overview of treatment of different stages of Seminoma after inguinal orchidectomy
1) IA and IB
i) Surveillance is preferred
ii) Alternative: Adjuvant chemo i.e. Carboplatin x 1-2
iii) If not suitable for surveillance and chemo: Can consider adjuvant RT to retroperitoneum
2) IS
i) monitor serum tumour markers and CT T+A+P to determine location of recurrence
3) IIA and IIB
i) Chemo is preferred: BEP x 3 (or EP x 4 if cannot B)
ii) Alternative: RT as follows:
- IIA: 2Gy x 15 dog-leg field
- IIB: Above + boost to enlarged LN 2 Gy x 3
4) IIC or III
i) Chemo depending on IGCCCG risk:
- Good: BEP x 3 (or EP x 4 if cannot B)
- Intermediate: BEP x 4 (or PEI x 4 if cannot B)
Give a brief overview of treatment of different stages of NSGCT after inguinal orchidectomy
1) Stage I ➔ Surveillance for all patients
OR
1) Stage I ➔ Risk adapted Treatment:
1A) Low risk (i.e. Stage IA, without LVI)
i) Standard = surveillance
ii) If refuse surveillance = chemo BEP x 1
iii) RPLND is less preferred due to lower 2-year RFS than chemo, only if refuses AS and chemo
1B) High risk (i.e. Stage IB, or with LVI)
i) Chemo: BEP x 1 preferred over BEP x 2
ii) Surveillance or RPLND is less preferred, only if refuses chemo
3) Stage IIA IIB with S0
➔ need to clarify stage by either surveillance or RPLND
i) Surveillance: repeat CT and tumour markers at 6/52:
- if S0, regression ➔ observe
- if S0, no change or PD ➔ NS-RPLND
- if S+, treat as stage III with chemo based on prognosis group, +/- resection of residual tumour
ii) or primary NS-RPLND
- if pathological stage I: follow-up
- if pathological stage IIA/B: follow-up or BEP x 2
4) Stage IIA IIB with S1 / IIC / III
i) Chemo depending on IGCCCG risk:
- Good prognosis: BEP x 3 (or EP x 4)
- Intermediate prog: BEP x 4
- poor prognosis: BEP x 4 (or PEI x 4) by 1 cycle first followed by tumour markers in 3 weeks to see if dose intensification is needed
Management of stage I Seminoma
What is the rationale?
i) Surveillance is preferred
ii) Alternative: Adjuvant chemo i.e. Carboplatin x 1-2
iii) If not suitable for surveillance and chemo: Can consider adjuvant RT to retroperitoneum
Rationale for Surveillance:
1) Relapse risk is not high
- based on Princess Margaret Hospital in Toronto series: 15%
2) CSS >97% with surveillance in PMH series
3) Even if relapse, salvage chemo or RT is effective
What is the risk of relapse in stage I seminoma? What are the risk factors?
Overall risk of relapse = 15% based on Princess Margaret Hospital in Toronto series
Aparicio Spanish SGCCG showed recurrence depends on risk factors:
1) Tumour size >4cm
2) Rete testis invasion
- 6% if no risk factor
- 16% if 1 risk factor
- 32% if 2 risk factors
Should stage 1 seminoma use a risk adapted approach?
No, surveillance is preferred due to:
Rationale for Surveillance:
1) Relapse risk is not high
- based on Princess Margaret Hospital in Toronto series: 15%
2) CSS >97% with surveillance in PMH series
3) Even if relapse, salvage chemo or RT is effective
Risk adapted approach is not suggested because despite systematic reviews showing risk factors (>4cm, rete testis) predict relapse, the quality and level of evidence is low, therefore should not be used to guide treatment choice (EAU)
