Editing Germ Cell Tumours (section)

== Diagnosis and Evaluation ==

* '''<span style="color:#ff0000">Mandatory investigations in a patient with unilateral or bilateral scrotal mass suspicious for testicular neoplasm:</span>'''
*# '''<span style="color:#ff0000">History and Physical exam</span>'''
*# '''<span style="color:#ff0000">Labs (1):</span>'''
*## '''<span style="color:#ff0000">Serum tumour markers (AFP, hCG, LDH)</span>'''
*# '''<span style="color:#ff0000">Imaging</span>'''
*#* '''<span style="color:#ff0000">Primary: scrotal US with doppler</span>'''
*#* '''<span style="color:#ff0000">Metastasis:</span>'''
*#** '''<span style="color:#ff0000">Regional: CT abdomen/pelvis</span>'''
*#** '''<span style="color:#ff0000">Distant: CT chest</span>''' (CXR can be used instead of CT if CS I seminoma)

=== History and Physical Exam ===

==== History ====
* '''<span style="color:#ff0000">Signs and Symptoms</span>'''
**'''<span style="color:#ff0000">Most common presentation of testicular cancer: painless scrotal mass</span>'''
**'''Symptoms related to metastatic disease (e.g. shortness of breath)''' are the presenting complaint in 10-20% of patients

==== Physical exam ====
* '''Genitourinary'''
** Palpate for any testicular or extra-testicular masses. Note relative size and consistency of affected and normal contralateral testicle. 
***'''A firm intratesticular mass should be managed as a malignant neoplasm until proven otherwise and should be evaluated further with a scrotal ultrasound scan.'''
** '''<span style="color:#ff0000">Differential diagnosis of a scrotal mass (8):</span>'''
**# '''<span style="color:#ff0000">Painless</span>'''
**##'''<span style="color:#ff0000">Testicular neoplasm</span>'''
**##'''<span style="color:#ff0000">Paratesticular neoplasm (benign or malignant)</span>'''
**## '''<span style="color:#ff0000">Hernia</span>'''
**## '''<span style="color:#ff0000">Varicocele</span>'''
**## '''<span style="color:#ff0000">Spermatocele</span>'''
**#'''<span style="color:#ff0000">Painful</span>'''
**##'''<span style="color:#ff0000">Torsion</span>'''
**## '''<span style="color:#ff0000">Hematoma</span>'''
**## '''<span style="color:#ff0000">Epididymoorchitis</span>'''
* '''Sites of metastases'''
** '''Supraclavicular lymph nodes'''
** Inguinal lymph nodes, if prior inguinal or scrotal surgery
* '''Gynecomastia'''
** '''Occurs in 2% of males with GCT'''
** Results from elevated serum hCG levels, decreased androgen production, and/or increased estrogen levels

=== Labs ===

==== <span style="color:#ff0000">Tumour markers </span><span style="color:#0000ff">(A YET, B SEC)</span> ====

===== <span style="color:#0000ff">A</span><span style="color:#ff0000">FP</span> =====
* At diagnosis, elevated in 50-70% of low-stage (CS I, IIA, and IIB) NSGCT and 60-80% of advanced (CS IIC and III) NSGCT
* '''<span style="color:#ff0000">Produced by (3):</span>'''
*# '''<span style="color:#0000ff">Y</span><span style="color:#ff0000">olk sac</span>'''
*# '''<span style="color:#0000ff">E</span><span style="color:#ff0000">C</span>'''
*# '''<span style="color:#0000ff">T</span><span style="color:#ff0000">eratoma</span>'''
** '''<span style="color:#ff0000">Choriocarcinomas and seminomas do not produce AFP</span>'''
*** '''<span style="color:#ff0000">Clinical implication: pure seminoma in the primary tumor with an elevated serum AFP should be treated as NSGCT</span>'''
* '''Upper limit < 11 ng/mL'''
** Despite most laboratories considering AFP > 8ng/mL to be abnormally elevated, a proportion of the population may have levels up to 15-25 ng/mL in the absence of any pathology; '''treatment decisions based solely on “elevated” AFP levels that are stable and <25 ng/mL is discouraged'''
* '''<span style="color:#ff0000">Serum half-life: 5-7 days</span>'''
* '''Other causes of elevated AFP:'''
*# '''Non-malignant liver disease (infectious, drug-induced, alcohol-induced, autoimmune)'''
*# '''Hepatocellular carcinoma'''
*# Cancers of the stomach, pancreas, biliary tract, and lung
*# Ataxic telangiectasia
*# Hereditary tyrosinemia
*# Hereditary persistence of AFP (a congenital alteration in the hepatic nuclear factor binding site of the AFP gene)

===== <span style="color:#0000ff">β</span>-hCG =====
* At diagnosis, elevated in 20-40% of low-stage NSGCT and 40-60% of advanced NSGCT
* '''<span style="color:#ff0000">Produced by (3):</span>'''
*# '''<span style="color:#0000ff">S</span><span style="color:#ff0000">eminoma (15% of cases)</span>'''
*# '''<span style="color:#0000ff">E</span><span style="color:#ff0000">C</span>'''
*# '''<span style="color:#0000ff">C</span><span style="color:#ff0000">horiocarcinoma</span>'''
* '''Upper limit: <5 mU/mL'''
**'''<span style="color:#ff0000">Levels > 10,000 IU/L are usually associated with choriocarcinoma.</span>'''
* '''<span style="color:#ff0000">Serum half-life: 24 to 36 hours</span>''' (2019 AUA Update Peds Testis Tumours says 24-48 hours)
* '''<span style="color:#ff0000">Other causes of elevated hCG:</span>'''
*# '''<span style="color:#ff0000">Hypogonadism</span>'''
*#* '''<span style="color:#ff0000">LH will be elevated and can be a cause false-positive elevated hCC due to cross-reactivity of the hCG assay with LH</span>'''
*#** '''<span style="color:#ff0000">Supplemental testosterone decreases LH levels, allowing accurate assessment of hCG levels thereafter[https://pubmed.ncbi.nlm.nih.gov/88528/]</span>'''
*# '''Cancers of the liver, biliary tract, pancreas, stomach, lung, breast, kidney, and bladder.'''
*#* The α subunit of hCG is common to several pituitary tumors, and so immunoassays for hCG are directed at the β subunit.
*# '''Cannabis use'''

===== <span style="color:#ff0000">LDH</span> =====
* At diagnosis, elevated in ≈20% of low-stage GCT and 20-60% of advanced GCT
* '''Least relevant and clinically applicable of the tumour markers'''
** Non-specific marker
** '''Main use in GCT is in the''' '''prognostic (S stage classification) assessment at diagnosis.'''
** '''Treatment decisions based solely on LDH elevation in the setting of normal AFP and hCG should be discouraged.'''
* '''Normal value 48-115 IU/liter'''
**Magnitude of LDH elevation correlates with bulk of disease.
* '''<span style="color:#ff0000">Serum half-life: varies[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3818947/]</span>'''
* LDH is expressed in smooth, cardiac, and skeletal muscles and can be elevated from cancerous (kidney, lymphoma, GI, breast) or non-cancerous conditions (heart failure, anemia, HIV)

===== <span style="color:#ff0000">Pre-orchiectomy tumour markers</span> =====
* '''<span style="color:#ff0000">Uses (2):</span>'''
*# '''<span style="color:#ff0000">Support initial diagnosis</span>'''
*#* '''<span style="color:#ff0000">Should not be used to guide decision making about whether or not to perform a radical orchiectomy''' because AFP or hCG levels in the normal range do not rule out GCT.
*# '''<span style="color:#ff0000">Interpret tumor marker levels after orchiectomy.</span>'''
*#* '''Essential to know whether persistently elevated post-orchiectomy tumour markers are declining compared to pre-orchiectomy levels by their respective half-lives or not, or whether they are rising, as this impacts subsequent treatment decisions.'''
* '''Should not be used for clinical staging and risk stratification'''
** Can lead to over- or under-treatment with resulting excess rates of toxicity or relapse, respectively.

===== <span style="color:#ff0000">Post-orchiectomy tumour markers</span> =====
* '''<span style="color:#ff0000">Uses (2):</span>'''
*# '''<span style="color:#ff0000">Evaluate for metastases in the case of persistently elevated/rising post-orchiectomy tumour markers</span>'''
*#* Tumour marker levels should normalize after 4 half-lives[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3818947]
*#**Serum AFP levels should return to normal levels 20–28 days after effective therapy.
*#*If borderline elevated (within 3x upper limit of normal) post-orchiectomy markers (AFP and hCG), confirm a rising trend before management decisions are made as false-positive elevations may occur.
*# '''<span style="color:#ff0000">Evaluate for recurrence during surveillance and after completion of therapy (chemotherapy, radiation, surgery).</span>'''

=== Imaging ===

=== Local ===

==== Modality ====

===== Scrotal ultrasound with doppler =====

* '''<span style="color:#ff0000">Important to evaluate both testicles given</span>''' '''<span style="color:#ff0000">2% incidence of bilateral GCT</span>'''
**'''In cases of bilateral GCT, a metachronous lesion is the most common presentation.'''
* '''High-frequency transducers (5 to 10 MHz)''' can readily identify and distinguish intratesticular lesions a few millimeters in size from extra-testicular pathology
* '''<span style="color:#ff0000">Indications in the context of suspected GCT (3)</span>'''
*# '''<span style="color:#ff0000">Scrotal mass</span>'''
*# '''<span style="color:#ff0000">Suspected metastatic GCT with a normal testicular examination</span>'''
*#* '''A small, impalpable scar or calcification indicates a <span style="color:#ff0000">“burned-out” primary testis tumor.</span>'''
*#** '''<span style="color:#ff0000">If sonographic evidence of intratesticular lesions (discrete nodule, stellate scar, coarse calcification), perform radical orchiectomy because GCNIS and residual teratoma are frequently encountered.</span>'''
*# '''<span style="color:#ff0000">Suspected primary extra-gonadal GCT</span>'''
*#* '''<span style="color:#ff0000">Males with advanced GCT with normal testes on physical examination and ultrasound scan are considered to have primary extragonadal GCT.</span>'''
** '''Patients with normal serum tumor markers (hCG and AFP) and indeterminate findings on physical exam or testicular ultrasound for testicular neoplasm should undergo repeat imaging in 6-8 weeks.'''
* '''Imaging findings'''
** '''Typical GCT is hypoechoic'''
** 2 or more discrete lesions may be identified
** INSERT IMAGE
** '''<span style="color:#ff0000">Testicular microlithiasis</span>'''
*** '''Unclear significance''' '''in the general population'''
**** If no history of GCT, risk of GCT is only increased if an additional established risk factor (see above) is present
**** If history of GCT, microlithiasis on ultrasound of the contralateral testis is associated with an increased risk of ITGCN.
*** '''<span style="color:#ff0000">Management</span>'''
**** '''<span style="color:#ff0000">No further evaluation or screening in incidentally detected microlithiasis</span>'''
**** '''<span style="color:#ff0000">If established risk factor and testicular microlithiasis, counsel patient about the potential increased risk of GCT, need for periodic self-examination and follow-up with a medical professional</span>'''
*** insert image

===== MRI =====
* '''<span style="color:#ff0000">Can be considered an adjunct to scrotal ultrasound in patients with lesions suspicious for benign etiology</span>'''
* '''Should not delay orchiectomy in patients in whom malignancy is suspected'''

=== Metastasis ===

==== Regional ====
* Regional lymph nodes comprises (7):
*# Inter-aortocaval
*# Para-aortic
*# Para-caval
*# Pre-aortic
*# Pre-caval
*# Retro-aortic
*# Retro-caval
* '''<span style="color:#ff0000">Modality</span>'''
** '''<span style="color:#ff0000">CT abdomen/pelvis with oral and IV contrast</span>'''
*** '''<span style="color:#ff0000">Most effective imaging modality for regional staging</span>'''
** MRI
*** Alternative to CT
* '''<span style="color:#ff0000">Imaging findings</span>'''
** '''<span style="color:#ff0000">Retroperitoneal lymph nodes</span>'''
*** '''<span style="color:#ff0000">Pattern of lymph drainage in the retroperitoneum is from right to left.</span>'''
**** '''<span style="color:#ff0000">For right testis tumors, the primary drainage site is the inter-aortocaval lymph nodes inferior to the renal vessels, followed by the paracaval and para-aortic nodes.</span>'''
**** '''<span style="color:#ff0000">For left testis tumors, the primary drainage site is the para-aortic lymph nodes, followed by the inter-aortocaval nodes.</span>'''
*** [[File:Retroperitoneal lymph flow.jpg|thumb|Direction of lymphatic flow in the retroperitoneum]]
** '''<span style="color:#ff0000">"Borderline" retroperitoneal lymph nodes</span>'''
*** '''<span style="color:#ff0000">Lymph nodes 5-9 mm in the primary landing zone should be viewed with suspicion for regional lymph node metastasis,</span> particularly if they are anterior to the great vessels'''
** '''Limitations'''
*** '''Understaging'''
**** 25-35% of patients with CSI NSGCT and a “normal” CT scan will be found to have pathologically involved retroperitoneal lymph nodes at RPLND
*** '''Overstaging'''
**** 12-40% of patients with CS IIA and IIB disease will be found to have pathologically negative lymph nodes at RPLND

==== Distant ====
* '''<span style="color:#ff0000">Chest</span>'''
** '''<span style="color:#ff0000">Timing</span>'''
*** '''<span style="color:#ff0000">Necessary to complete staging in patients with confirmed GCTs</span>'''
*** '''<span style="color:#ff0000">Should not delay orchiectomy</span>'''
** '''<span style="color:#ff0000">Modality: plain-film chest x-ray vs. CT</span>'''
*** '''<span style="color:#ff0000">Chest x-ray</span>'''
**** '''<span style="color:#ff0000">Indications</span>[https://pubmed.ncbi.nlm.nih.gov/31059667/ ★]'''
***** '''<span style="color:#ff0000">Suspected clinical stage I seminoma</span>'''; preferred over CT
****** '''When tumor markers are normal, the rate of skip metastasis to the thorax in seminoma is close to 0%,''' and the addition of CT chest to chest x-ray is very unlikely to alter treatment decisions.
*** '''<span style="color:#ff0000">CT scan</span>'''
**** '''<span style="color:#ff0000">Indications (3)</span>[https://pubmed.ncbi.nlm.nih.gov/31059667/ ★]'''
****# '''<span style="color:#ff0000">NSGCT</span>'''
****#* '''Skip metastases are more common in non-seminoma than seminoma.'''
****# '''<span style="color:#ff0000">Elevated and rising post-orchiectomy markers (hCG and AFP)</span>'''
****# '''<span style="color:#ff0000">Any evidence of metastases on abdominal/pelvic imaging, chest x-ray or physical exam.</span>'''
* '''Other'''
** '''Bone scan and CT brain'''
***'''No role for routine bone scintigraphy or brain CT imaging at the time of diagnosis.[https://pubmed.ncbi.nlm.nih.gov/31059667/ ★]'''
**** In the absence of symptoms or other clinical indicators of disease, visceral metastasis to bone and brain is uncommon in GCT
**** '''Indications for bone scan and CT brain (3):'''
****#'''Symptoms suggestive of central nervous system or bone involvement'''
****# '''Poor prognosis disease.'''
****#'''Highly elevated hCG (>10,000 mU/mL)'''
****#*'''<span style="color:#ff0000">Highly elevated hCG are often associated with metastatic choriocarcinoma, which has a propensity for brain metastases.</span>'''
** '''<span style="color:#ff0000">FDG-PET</span>'''
*** '''<span style="color:#ff0000">Currently, no role in the routine evaluation of NSGCT and seminoma at the time of diagnosis.</span>'''

=== Other ===

* '''<span style="color:#ff0000">Testicular biopsy: contraindicated</span>'''
** '''Scrotal violation increases risk of (2):'''
**# '''Pelvic or inguinal lymph node metastasis due to altered lymphatic drainage of the testicle'''
**# '''Local recurrence'''
*** '''<span style="color:#ff00ff">Systematic review of outcomes of scrotal violation in testicular cancer</span>'''
**** Scrotal violation defined at non-standard surgical approaches including trans-scrotal orchiectomy, open testicular biopsy, and fine needle aspiration
**** '''Results'''
***** '''Median follow-up: 24 to 126 months'''
***** '''Rate of local recurrence: 2.5% of patients undergoing scrotal violation vs. none of the patients who underwent radical inguinal orchiectomy''' (P<0.001)
***** Among patients undergoing excision of the scrotal scar, 9% had residual, viable GCT.
***** '''No difference in rates of metastatic disease or all-cause mortality based on scrotal violation'''
**** Capelouto, Carl C., et al."[https://pubmed.ncbi.nlm.nih.gov/7853587/ Testis cancer: a review of scrotal violation in testicular cancer: is adjuvant local therapy necessary?.]" ''The Journal of urology'' 153.3 (1995): 981-985.