Guidelines

Testicular Cancer

5. DIAGNOSTIC EVALUATION

5.1. Physical examination

Testicular cancer usually presents as a unilateral scrotal testicular mass detected by the patient, or as an incidental finding on US. Scrotal pain may be present in 27% of patients [33,34] and a potential reason for delayed diagnosis in 10% of cases [33]. Around 1% of patients presenting with gynaecomastia have a germ cell or sex cord/gonadal tumour of the testes [35] and 11% present with back and flank pain [34]. As such, when there is suspicion of TC, physical examination must include abdominal, chest and supraclavicular exploration.

5.2. Imaging

5.2.1. Ultrasonography of the testes

High-frequency (>10 MHz) testicular US should be used to confirm a testicular tumour even in the presence of a clinically evident testicular lesion [34,36].

The use of testicular US can:

  1. determine whether a mass is intra- or extra-testicular;
  2. determine the volume and anatomical location of the testicular lesion;
  3. be used to characterise the contralateral testicle – to exclude other lesions and identify risk factors for GCNIS (see section 5.4.4).

Testicular US is also recommended for all men with retroperitoneal or visceral masses and/or without elevated serum human chorionic gonadotropin (hCG) or alpha-fetoprotein (AFP) in the absence of a palpable testicular mass; and for fertility work-up evaluation [34,36-38].

A range of modalities of US have been investigated (B-mode, dynamic contrast enhanced, real-time elastography, and shear wave elastography) in small cohorts to determine if these can distinguish between benign and malignant testicular lesions [39-42]. So far, the results are not reliable enough to replace the mandatory histopathological tissue diagnosis.

5.2.2. Computerised tomography

Contrast enhanced computerised tomography (CECT) is the most sensitive means to evaluate the thorax, abdomen, and pelvis for TC staging [43]. Contrast enhanced computerised tomography is recommended in all patients for staging before orchidectomy but may be postponed until histopathological confirmation of malignancy.

The size of metastases should be described in three dimensions, or at least by the greatest axial diameter. For abdominal staging, a recent systematic review reports a median sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy with CECT of 67% (range 37-100%), 92% (range 58-100%), 87% (60-100%), 73% (67-100%) and 83% (range 71-100%), respectively [43].

Sensitivity decreases and specificity increases with increasing lymph node cut-off size. With nodes > 4 mm pooled sensitivity and specificity are 93% and 58% respectively, whereas for nodes > 10 mm sensitivity is 37% and specificity increases to 100% [43]. Using a 10 mm short-axis lymph node diameter as a cut-off yielded a high specificity (97%), a moderate sensitivity (59%) and false-negative rate of 20% in the retroperitoneum [44]. The expected patterns of nodal spread in TC should be considered when evaluating small and borderline nodes.

Chest CT was evaluated in three studies in a systematic review by Pierorazio et al., [43]. This presents a median sensitivity, specificity, PPV, NPV and accuracy of 100% (range 95-100%), 93% (range 89-97%), 68% (range 25-84%), 100% (range 99-100%) and 93% (range 91-97%), respectively. Computerised tomography of the chest is more sensitive but less specific than chest X-ray (CXR) in thoracic staging. Nevertheless, potential harms of chest CT imaging in low-stage seminoma should be taken into consideration [43].

In patients with masses (< 2 cm) in the retroperitoneum or chest and negative tumour markers, restaging after six to eight weeks rather than treatment initiation is advisable (See sections 7.2.2.1 and 7.2.2.2).

Cerebral imaging by CECT is recommended in patients with NSGCT, multiple lung metastases and poor-prognosis IGCCCG risk group (for patients with hCG values > 5,000 UI/L), or if clinical symptoms are present [45].

5.2.3. Magnetic resonance imaging

Magnetic resonance imaging (MRI) of the scrotum provides higher sensitivity and specificity than scrotal US in the diagnosis of TC, but its high cost does not justify its routine use for this purpose [46-48], It should only be considered when US is inconclusive, as local staging for testis-sparing surgery (TSS) planning, to differentiate between paratesticular and intratesticular lesions and/or to characterise intratesticular masses (e.g., distinctive features of Leydig tumours) [46,47,49].

Magnetic resonance imaging of the abdomen may be used for staging in case of allergy to iodine-based contrast media with similar accuracy to CECT in the detection of retroperitoneal nodal enlargement [43].

There is no literature regarding the comparative accuracy of CECT and MRI for the detection and evaluation of cerebral metastases in CGTs. Data from cerebral metastasis detection in other malignancies suggest that MRI is far more sensitive than CECT but requires specific expertise [42,50,51]. Therefore, when available, MRI should be preferentially used in the evaluation of cerebral metastases in GCTs [51]. Magnetic resonance imaging of the spine is also advisable in patients with symptoms suggesting metastatic disease or if there is equivocal staging on CECT [50].

5.2.4. Fluorodeoxyglucose-positron emission tomography

There is no evidence to support the use of Fluorodeoxyglucose-positron emission tomography (FDG-PET) for initial staging and follow-up of TC [43,50,52,53]. Fluorodeoxyglucose-positron emission tomography is only recommended for seminoma patients with post-chemotherapy residual masses > 3 cm (largest diameter) to assess FDG activity [54]. Fluorodeoxyglucose-positron emission tomography should not be performed until at least two months after completion of the last cycle of chemotherapy, as inflammation and the desmoplastic reaction induced by chemotherapy may result in FDG avidity and a false positive result [53]. Whilst the NPV for active disease is > 90% [55,56], the PPV ranges from 23% to 69% [55-57]. False positives are common and may occur in up to 80% of lesions [55,57], indicating that necrosis, fibrosis, and the consequent inflammation are also associated with FDG activity. Caution is advised on initiating active therapy driven only by positive findings on FDG-PET-CT [57].

5.2.5. Bone scan

There is no evidence to support the use of bone scan for staging of TC.

5.3. Serum tumour markers

5.3.1. Pre-operative serum tumour markers

Alphafetoprotein beta subunit of human Chorionic Gonadotropin (β-hCG) and LDH should be determined before and after orchidectomy as they support the diagnosis of TC, may be indicative of GCT histology and are used for disease staging and risk stratification (Table 4.3), as well as to monitor treatment response and detect disease relapse [58,59].

In a recently reported cohort, the three markers (AFP, β-hCG and LDH) are simultaneously elevated in 7.1% of patients. The elevation of any of these three markers is seen in up to 60% of patients at diagnosis [50.2% (44-56%) in CS I and 93% in CS III (75.8-98.8%)] [59].

Both alphafetoprotein and β-hCG increase is detected in 39% of patients with NSGCT [59], and up to 90% of NSGCTs present with a rise in either AFP or β-hCG at diagnosis [33,59,60]. Pure seminomas may also have modestly elevated β-hCG level at diagnosis in up to 30% (9-32%) of cases [58,59].

Tumour markers have limitations due to their low sensitivity as normal levels do not exclude the presence of disease [60].

5.3.2. Serum tumour markers after orchidectomy

Serum levels of AFP, β-hCG and LDH following orchidectomy provide staging and prognostic information [61]. As the serum half-life of AFP and β-hCG are five to seven days and one to three days respectively, it may take several weeks until normalisation occurs [58,60]. The persistence of, or increase in, serum tumour marker elevation following orchidectomy indicates the likely presence of metastatic disease [59]. Whilst normalisation of marker levels after orchidectomy is a favourable indicator, it does not exclude the possibility of metastatic disease. With metastatic TC, risk stratification is based on serum tumour marker levels immediately before initiation of systemic treatment [61]. Before chemotherapy AFP and LDH levels may act as prognostic factors for OS in non-seminoma intermediate risk group [62].

At relapse, only 25% of patients have elevated AFP and β-hCG, and LDH may remain persistently elevated in 30% of patients despite cure [59]. Tumour markers should be routinely used for follow-up as indicators of recurrence, although the precise frequency of testing is not well defined [63].

5.3.3. Other tumour markers

Micro RNAs (miRNAs) are emerging as potential new biomarkers for TC. A number of studies suggest higher discriminatory accuracy for miRNAs (particularly miR-371a-3p) compared to conventional GCT markers in diagnosis, treatment monitoring, and predicting of residual or recurrent viable disease [64-71]. Furthermore, they may differentiate between GCT and other (stromal/non-germ cell originated) tumours [71]. However, before miRNAs can be considered for use in routine clinical practice, several issues including laboratory standardisation, availability of the test and, importantly, prognostic validation [70] need to be resolved.

5.4. Inguinal exploration and initial management

5.4.1. Orchidectomy

Orchidectomy including division of the spermatic cord at the internal inguinal ring represents the standard of care in patients with TC. Scrotal approach should be avoided when TC is suspected as it results in a higher local recurrence rate [72].

5.4.2. Testis-sparing surgery

Testis-sparing surgery is a valid treatment option in men with interstitial cell or benign testicular tumours and may prevent hypogonadism, lifelong testosterone supplementation and infertility in young men.

In men with TGCTs orchiectomy represents the standard of care as pathological studies describe multifocal and/or adjacent GCNIS in 20-30% of patients [73,74]. However, TSS when feasible, is indicated in synchronous bilateral tumours or in tumours in solitary testis [75]. Importantly, when indicated in this setting, besides enucleation of the testicular lesion, at least two additional testicular biopsies should be taken to exclude GCNIS [76].

Testis-sparing surgery can also be offered in cases of small or indeterminate testicular masses with negative tumour markers in the presence of a normal contralateral testis in order to avoid the over-treatment of potentially benign lesions and to preserve testicular function [75,77].

Patients should be informed that cancer can be present even in small (i.e., < 1 cm) masses [75,78,79], thus obtaining histology is mandatory.

In both settings, TSS should only be offered together with frozen section examination (FSE). Frozen section examination has shown to be reliable and highly concordant with final histopathology, with a 99% and 96% of sensitivity and specificity respectively and 98% and 97% of PPV and NPV, respectively [77,80,81]. In cases of discordance between FSE and final pathology delayed orchiectomy might be needed.

Whether history of GCT or indeterminate small testicular lesion, patients should be made aware on the following issues regarding TSS practice: that limited data exists regarding oncological safety of TSS; that local recurrence rates have been reported (overall 0-26.9%), when TC is present in the specimen [75,79,82] and that TSS has implications for ongoing surveillance of the testis. Similarly, patients should be informed about the role and impact of adjuvant radiotherapy when GCNIS is present, on the potential infertility, the need for hormonal supplementation despite parenchyma preservation [75,79,83], and that possible discordance between FSE and final pathology may drive the need for a delayed orchidectomy.

5.4.3. Insertion of testicular prosthesis

Testicular prosthesis should be offered to all patients receiving unilateral or bilateral orchidectomy [83]. The prosthesis can be inserted at orchidectomy or subsequently without adverse consequences, including infection [84].

5.4.4. Contralateral biopsy

Contralateral biopsy has been advocated to exclude the presence of GCNIS [85]. Whilst routine policy in some countries [86], the low incidence of GCNIS and metachronous contralateral testicular tumours (up to 9% and approximately 2.5%, respectively) [87,88], the morbidity of GCNIS treatment (see section 7.1.1), and the fact that most metachronous tumours are low stage at presentation, makes it controversial to recommend routine contralateral biopsy in all patients [89,90]. Nevertheless, the risks and benefits of biopsy of the contralateral testis should be discussed with TC patients at high risk for contralateral GCNIS, i.e., testicular volume < 12 mL, and/or a history of cryptorchidism. Contralateral biopsy is not necessary in patients older than 40 years without risk factors [76,91,92]. Patients should be informed that a subsequent TGCT may arise despite a negative biopsy [93]. When indicated, a two-site surgical testicular biopsy is the technical procedure recommended [76].

5.5. Pathological examination of the testis

The recommendations for reporting and handling the pathological examination of a testis neoplasm are based on the recommendations of the International Society of Urological Pathology (ISUP) [94-97].

Mandatory pathological requirements:

  • Macroscopic features: It must indicate radical or partial orchidectomy, side, testis size, number of tumours, and macroscopic features of the epididymis, cord length, and tunica vaginalis.
  • Sampling: At least a 1 cm2 section for every centimetre of maximum tumour diameter including normal macroscopic parenchyma (if present), tunica albuginea and epididymis, with selection of suspicious areas. If the tumour is < 20 mm it should be completely sampled.
  • At least one proximal (base of the cord) and one distal section of spermatic cord plus any suspicious area. Cord blocks should preferably be taken prior to tumour sections to avoid contamination.
  • Microscopic features and diagnosis: histological types (specify individual components and estimate amount as percentage) according to WHO 2016 [94]:
    • Presence or absence of peri-tumoural lymph vessels and/or blood vessels invasion. In case of doubt, the use of endothelial markers, such as CD31, are recommended.
    • Presence or absence of GCNIS in non-tumour parenchyma.
    • In case of rete testis invasion attention should be paid to distinguishing between pagetoid involvement and stromal invasion [95].
  • If microscopic findings are not concordant with serum markers further block samples should be taken.
  • pT category according to TNM 2016 [27]. In a multifocal seminoma the largest nodule should be used to determinate pT category.

Immune-histochemical markers in cases of doubt are:

  • Seminoma: CD-117 (c-KIT), OCT 3/4, Sall4, PLAP
  • GCNIS: CD-117 (c-KIT), OCT 3 / 4, Sall4, PLAP
  • Syncytiotrophoblast: β-hCG
  • Embryonal carcinoma: CD30
  • Yolk sac tumour: Glypican 3
  • Sex cord gonadal tumours: Inhibin, calretinin

The search for i12p (FISH or PCR) or gain in Ch9 (spermatocytic tumour) are additional immuno-chemistry techniques, utility confirmation of other molecular markers such as P53, MDM2, KRAS AND HRAS is awaited [98].

In order to facilitate consistent and accurate data collection, promote research, and improve patient care, the International Collaboration on Cancer Reporting has constructed a dataset for the reporting of urological neoplasms. The dataset for testicular tumours encompasses the updated 2016 WHO classification of urological tumours, the ISUP consultation and staging with the 8th edition of the American Joint Cancer Committee (AJCC) [97].

The dataset includes those elements unanimously agreed by the expert panel as “required” (mandatory) and those “recommended” (non-mandatory) that would ideally be included but are either non-validated or not regularly used in patient management [97]. The dataset for handling pathological assessment of TC is shown in Table 5.5.

Table 5.5: Recommended dataset for reporting of neoplasia of the testis (modified from the International Collaboration on Cancer Reporting) [97].

Elements

Required

Recommended*

Content

Remarks

Clinical information


- Not provided

- Previous history of testicular cancer

- Previous therapy

- Other

Specify each

Serum tumour markers


- Not provided

- If provided within normal limits

or

- Specify serum tumour markers used

- Specify levels

- Specify date markers were drawn

Select all that apply:

Serum tumour markers: LDH (IU/L), AFP (ug/L), β-hCG (IU/L)

Operative procedure


- Not specified

- Orchidectomy partial

- Orchidectomy radical

- Other

Specify side for partial or radical orchidectomy.

Specify other

Tumour focality


- Cannot be assessed

- Indeterminate

- Unifocal

- Multifocal

If multifocal specify number of tumours in specimen.

Maximum tumour dimension


- Cannot be assessed

- Dimensions largest tumour (mm)

- Dimensions additional tumour nodules#

Specify at least maximum diameter
of largest tumour.

Preferably specified
3 dimensions/axes.#

Macroscopic extent of invasion


- Cannot be assessed

- Confined to testis

- Invades epididymis

- Invades tunica vaginalis

- Invades hilar structures

- Invades spermatic cord

- Invades scrotum

- Other

Select all that apply.

If other specify.

Block identification key


N/A

List overleaf or separately with indication of nature and origin of all tissue blocks.

Histological tumour type


- Germ cell tumour: type and percentage

- Other

Use WHO classification (2016).

If other specify.

Microscopic extent of invasion


- Rete testis of stromal/interstitial type

- Epididymis

- Hilar fat

- Tunica albuginea#

- Tunica vaginalis

- Spermatic cord

- Scrotal wall

For all:

- not submitted

- not involved

- involved

Lymphovascular extension


- Not identified

- Present

If present specify type.#

Intratubular lesions (GCNIS)


- Not identified

- Present

- Other intratubular lesions#

If other intratubular lesions present identify type.#

Margin status


- Partial orchidectomy:

. cannot be assessed

. involved

. not involved

- Radical orchidectomy:

. cannot be assessed

. spermatic cord margin involved

. spermatic cord margin not involved

- Other margin involved

In partial orchidectomy if margin not involved, distance of tumour from closest margin (mm).#

If other margin involved specify.

Coexisting pathology


- None identified

- Hemosiderin-laden macrophages

- Atrophy

- Other

If other specify

Ancillary studies


- Not performed

- Performed

If performed specify

Response to neoadjuvant therapy


- Present

- Absent,

- No prior treatment,

- Cannot be assessed

Explain reasons if cannot be assessed.

Pathologic staging*


T classification according to TNM 8th edition (UICC)**

m-multiple primary tumours

r-recurrent

y-post-therapy

* Not mandatory. Ideally to be included but either non-validated or no regularly used in patient management.

** TNM 8th edition (AJCC) used in the original publication.

# Recommended, i.p. intratubular seminoma and embryonal carcinoma.

5.6. Screening

There are no high-level evidence studies supporting screening programs. It has not been shown that screening asymptomatic patients has benefit in terms of detecting TC at a more curable stage, despite the fact that stage and prognosis have been shown to be directly related to early diagnosis [99,100].

Until clinical data supporting or refuting self-examination in the general population becomes available, TC patients and their family members should be informed about the importance of physical self-examination, particularly in the presence of clinical risk factors including family history of TC [101].

5.7. Impact on fertility and fertility-associated issues

Sperm abnormalities and Leydig cell dysfunction are frequently found in patients with TCs prior to orchidectomy [102,103]. Up to 24% of TC patients are azoospermic and almost 50% have abnormal sperm counts (oligozo-ospemic) before treatment [103].

Treatment for TC, including orchidectomy, may have a negative impact on reproductive function [104]. Chemotherapy and radiation treatment (RT) can both impair fertility; although, long-term infertility is rare after radiation therapy and is dose-cumulative-dependent after chemotherapy [105-107]. Spermatogenesis usually recovers one to four years after chemotherapy [108]. In CS I, adjuvant treatment (BEP [cisplatin, etoposide, bleomycin] x1; Carbo x1) does not appear to significantly affect testicular function compared to surveillance, with full recovery after one year [109].

All patients should be offered semen preservation as the most cost-effective strategy for fertility preservation, and pre-treatment fertility assessment (testosterone, luteinising hormone [LH] and follicle stimulating hormone [FSH] levels) is advised [110].

If cryopreservation is desired, sperm banking should be offered before orchidectomy, maximizing the chances of fertilisation, and avoiding the risk of a non-functioning remaining testicle after surgery. If not arranged before orchidectomy, it should be undertaken prior to chemotherapy or RT [105-107,110,111].

Long-term testosterone supplementation is necessary in patients who have had bilateral orchidectomy or have low testosterone levels after treatment of GCNIS [112].

Chemotherapy and RT are both teratogenic. Therefore, contraception must be used during treatment and for at least six months after its completion [113].

For more detailed information, the reader is referred to the EAU Guidelines on Sexual Reproductive Health [114].

5.8. Guidelines for the diagnosis and staging of Testicular Cancer

Summary of evidence

LE

Poor sperm quality is frequently found in TC patients, before and after treatment. Semen preservation is the most cost-effective strategy for fertility preservation.

2b

Serum tumour markers (AFP, β-hCG and LDH) should be determined before and after orchidectomy and throughout follow-up. They are used for accurate staging, risk stratification, to monitor treatment and to detect relapse.

2b

For abdominal staging, CECT has a median sensitivity, specificity, PPV, NPV and accuracy of 67%, 95%, 87%, 73% and 83%, respectively. Sensitivity decreases and specificity increases with increasing lymph node size.

2a

For chest staging, CECT has a median sensitivity, specificity, PPV, NPV and accuracy of 100%, 93%, 68%, 100% and 93%, respectively

2a

Contrast enhanced computerised tomography and MRI are key image modalities for the detection of brain metastasis. Magnetic resonance imaging is far more sensitive than CECT, though it does require expertise.

2b

Fluorodeoxyglucose-positron emission tomography has a limited diagnostic accuracy for staging before chemotherapy.

2b

There are no high-level evidence studies supporting screening programs.

2b

In testicular sparing surgery, FSE has shown to be reliable and highly concordant with final histopathology.

1b

There is no evidence supporting any size criteria for a testicular lesion to be safely followed-up.

2b

In patients without risk factors, there is low incidence of contralateral GCNIS and of metachronous GCTC.

2b

Recommendations

Strength rating

Discuss sperm banking with all men prior to starting treatment for testicular cancer (TC).

Strong

Perform bilateral testicular ultrasound (US) in all patients with suspicion of TC.

Strong

Perform physical examination including supraclavicular, cervical, axillary, and inguinal lymph nodes, breast, and testicles.

Strong

Measure serum tumour markers both before and after orchidectomy taking into account half-life kinetics.

Strong

Perform orchidectomy and pathological examination of the testis to confirm the diagnosis and to define the local extension (pT category). In a life-threatening situation due to extensive metastasis, commence chemotherapy prior to orchidectomy.

Strong

Perform contrast enhanced computerised tomography (CECT) scan (chest, abdomen, and pelvis) in patients with a diagnosis of TC. In case of iodine allergy or other limiting factors perform abdominal and pelvic magnetic resonance imaging (MRI).

Strong

Perform MRI of the brain (or brain CECT if not available) in patients with multiple lung metastases, or high beta subunit of human Chorionic Gonadotropin (β-hCG) values, or those in the poor-prognosis International Germ Cell Cancer Collaborative Group (IGCCCG) risk group.

Strong

Do not use positron emission tomography–computed tomography or bone scan for staging.

Strong

Encourage patients with TC to perform self-examination and to inform first-degree male relatives of the need for self-examination.

Weak

Discuss testis-sparing surgery with frozen section examination in patients with a high likelihood of having a benign testicular tumour which are suitable for enucleation.

Strong

Discuss biopsy of the contralateral testis to patients with TC and who are at high-risk for contralateral germ cell neoplasia “in situ”.

Strong